Lack of systemic oxidative stress during PAF challenge in mild asthma

SummaryTo further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant–antioxidant balance in 12 asthmatic patients (age, 25±3[sem] yr; FEV1, 95±10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design.Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant–antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45min after PAF and L-PAF (18μg each) bronchoprovocation. Urinary leukotriene E4 (uLTE4) elimination was measured 120min after challenge.Compared with baseline, as expected, PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible.We conclude that there is no systemic oxidant–antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma

A first approach for an evidence-based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis

[EN] Background Patients with cystic fibrosis have to take enzymatic supplements to allow for food digestion. However, an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy (PERT) is inexistent, and lipid content of meals is used as a rough criterion. Objective In this study, an in vitro digestion model was set up to determine the theoretical optimal dose (TOD) of enzymatic supplement for a selection of foods, which is the dose that allows for maximum lipolysis extent. Methods A static in vitro digestion model was applied to simulate digestion of eight foods covering a wide range of lipid contents. First, the dose of the enzymatic supplement was fixed at 2000 lipase units per gram of fat (LU/g fat) using intestinal pH and bile salt concentration as variables. Second, intestinal pH and bile salt concentrations were fixed and the variable was the dose of the enzymatic supplement. Lipolysis extent was determined by measuring the free fatty acids released from initial triglycerides content of foods after digestion. Results in terms of percentage of lipolysis extent were fitted into a linear-mixed segmented model and the deducted equations were used to predict the TOD to reach 90% of lipolysis in every food. In addition, the effect of intestinal pH and bile salt concentration were investigated. Results The predictive equations obtained for the assessed foods showed that lipolysis was not only dependent on the dose of the enzyme supplement or the lipid content. Moreover, intestinal pH and bile salt concentration had significant effects on lipolysis. Therefore an evidence-based model can be developed taking into account these variables. Conclusions Depending on food characteristics, a specific TOD should be assigned to achieve an optimal digestion extent. This work represents a first step towards an evidence-based method for PERT dosing, which will be applied in an in vivo setting to validate its efficacy.This work was fully funded by the European Union and the Horizon 2020 Research and Innovation Framework Programme (PHC-26-2014 call Self management of health and disease: citizen engagement and mHealth) under grant number 643806.Calvo-Lerma, J.; Fornes-Ferrer, V.; Peinado Pardo, I.; Heredia Gutiérrez, AB.; Ribes-Koninckx C.; Andrés Grau, AM. (2019). A first approach for an evidence-based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis. PLoS ONE. 14(2):1-14. https://doi.org/10.1371/journal.pone.0212459S114142Lesmes, U., & McClements, D. J. (2012). Controlling lipid digestibility: Response of lipid droplets coated by β-lactoglobulin-dextran Maillard conjugates to simulated gastrointestinal conditions. Food Hydrocolloids, 26(1), 221-230. doi:10.1016/j.foodhyd.2011.05.011Humbert, L., Rainteau, D., Tuvignon, N., Wolf, C., Seksik, P., Laugier, R., & Carrière, F. (2018). Postprandial bile acid levels in intestine and plasma reveal altered biliary circulation in chronic pancreatitis patients. Journal of Lipid Research, 59(11), 2202-2213. doi:10.1194/jlr.m084830Lamothe, S., Azimy, N., Bazinet, L., Couillard, C., & Britten, M. (2014). Interaction of green tea polyphenols with dairy matrices in a simulated gastrointestinal environment. Food Funct., 5(10), 2621-2631. doi:10.1039/c4fo00203bMuggeo, V. & Muggeo, V. M. R. Segmented mixed models with random changepoints in R Working paper (2016)

Determinación de la transmisibilidad hidráulica en un acuífero costero mediante estimación óptima de la relación Qe-T usando el filtro de Kalman

Background: The knowledge on the management of water as a vital resource to develop agriculture allows having greater effectiveness in its use. Goals: The agricultural activity in the lower part of the Sinaloa Riverdepends on the fresh water of the regional dams and the aquifer. Methods: The use of groundwater represents approximately 15% of the total water used. In the presence of prolonged periods of drought, new wells are drilled without the use of an appropriate guide for farmers on the location of aquifer areas with a greater hydraulic transmissivity with the purpose of exploiting them more rationally. The National Water Commission has registered more than 680 wells on both banks of the Sinaloa River. Results: The information of 205 of these pumping wells for agricultural or domestic use and the specific capacity information was analyzed. Then, 79 out of 205 wells have pumping tests. It is then determined that the objective of this research work was to find the relationship between the specific capacity (Qe) and hydraulic transmissivity (T) data of the study area using the Thiem formula, considering a fixed value of the radius of influence. This hypothetical consideration and the heterogeneities of the aquifer environment add to the T-Qe relationship an additional component, it is determined that it has a normal behavior. Using the Kalman filter it is possible to eliminate or reduce such a component, thus improving the determination of the T-Qe relation of an R-value of 0.95 (without filter) to 0.97 (with filter), for a linear and exponential relationship. Conclusions: The application of a T-Qe estimate allows characterizing the aquifer area, with this procedure a map was obtained on the distribution of T, which will serve as a guide for future exploitations of groundwater in the study area.Antecedentes: El conocimiento sobre el manejo del agua como recurso indispensable para desarrollar la agricultura permite tener mayor efectividad en su uso. Objetivos: La actividad agrícola en la parte baja del río Sinaloa depende del agua dulce de las presas regionales y del acuífero. Métodos: El uso del agua subterránea, representa aproximadamente el 15% del agua total usada. Ante la aparición de periodos de sequía prolongados, se perforan nuevos pozos sin el uso de una guía apropiada que oriente a los agricultores sobre la ubicación de las zonas acuíferas que tienen una mayor transmisividad hidráulica con el propósito de explotarlos de manera más racional. Resultados: La Comisión Nacional del agua tiene registrados más de 680 pozos en ambas márgenes del Río Sinaloa. Se analizó la información de 205 de estos pozos de bombeo para uso agrícola o doméstico y la información de capacidad específica. De este número, 79 pozos tienen pruebas de bombeo. Se determina entonces que el objetivo de este trabajo de investigación fue encontrar la relación entre los datos de capacidad especifica (Qe) y transmisividad hidráulica (T) de la zona de estudio usando la fórmula de Thiem, considerando un valor fijo del radio de influencia. Conclusiones: Esta consideración hipotética y las heterogeneidades del medio acuífero suman a la relación T Qe una componente adicional, se determina que tiene un comportamiento normal. Mediante el filtro de Kalman es posible eliminar o reducir tal componente, mejorando así la determinación de la relación T-Qe de un valor r de 0.95 (sin filtro) a 0.97 (con filtro), para una relación lineal y exponencial. La aplicación de una estimación T-Qe permite caracterizar la zona acuífera, con este procedimiento se obtuvo un mapa sobre ladistribución de T, que servirá de guía para futuras explotaciones del agua subterránea en la zona de estudio

Survivin inhibition with YM155 ameliorates experimental pulmonary arterial hypertension

Background: Imbalance between cell proliferation and apoptosis underlies the development of pulmonary arterial hypertension (PAH). Current vasodilator treatment of PAH does not target the uncontrolled proliferative process in pulmonary arteries. Proteins involved in the apoptosis pathway may play a role in PAH and their inhibition might represent a potential therapeutic target. Survivin is a member of the apoptosis inhibitor protein family involved in cell proliferation.Objectives: This study aimed to explore the potential role of survivin in the pathogenesis of PAH and the effects of its inhibition.Methods: In SU5416/hypoxia-induced PAH mice we assessed the expression of survivin by immunohistochemistry, western-blot analysis, and RT-PCR; the expression of proliferation-related genes (Bcl2 and Mki67); and the effects of the survivin inhibitor YM155. In explanted lungs from patients with PAH we assessed the expression of survivin, BCL2 and MKI67.Results: SU5416/hypoxia mice showed increased expression of survivin in pulmonary arteries and lung tissue extract, and upregulation of survivin, Bcl2 and Mki67 genes. Treatment with YM155 reduced right ventricle (RV) systolic pressure, RV thickness, pulmonary vascular remodeling, and the expression of survivin, Bcl2, and Mki67 to values similar to those in control animals. Lungs of patients with PAH also showed increased expression of survivin in pulmonary arteries and lung extract, and also that of BCL2 and MKI67 genes, compared with control lungs.Conclusion: We conclude that survivin might be involved in the pathogenesis of PAH and that its inhibition with YM155 might represent a novel therapeutic approach that warrants further evaluation

Cigarette smoking induced decrease in fibronectin and COL1A1 in locomotor muscle in a guinea pig COPD model

Background: Sarcopenia is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD) caused by decreased physical activity capacity, cigarette smoke (CS) and chronic hypoxia (CH). These risk factors affect muscle anabolic and catabolic biomarkers responsible for sarcopenia. However, whether CS and CH affect muscle extracellular matrix (ECM) biomarkers is still unknown. Intramuscular ECM plays an important role in muscle growth and repair processes, but their role in sarcopenia is under investigated. The aim of this study was to investigate alterations in the expression of intramuscular ECMs biomarkers in response to CH and CS. We hypothesize that altered expression of the ECM molecules promoted by CH and CS contribute to development of sarcopenia. Methods: Skeletal muscle from a guinea pig animal model exposed (a) to 12 weeks CS (CS group), (b) to 10-week normal atmospheric air followed by 2-week of inspiratory oxygen fraction (FI,O2) of 0.12 in a hypoxic chamber (CH group), (c) to 12-week CS followed by 2-week CH (CS-CH group), (d) to 12-week sham CS followed by 2-week normal atmospheric air (Control group) were analysed by Real-time PCR for the change in expression of intramuscular ECM biomarkers. Results: Only CS treatment induced significant decreased in fibronectin and COLA1 transcriptomes by 43 (p=0.05) and by 84.1 (p=0.026) respectively, compared to controls. CH and CS-CH treatment downregulated fibronectin and COLA1, but not significantly compared to controls. No significant differences in ECM gene expression were observed when comparing CH with CS treatment.Conclusion: CS affects ECM composition altering the expression of fibronectin and COL1A1. The role of ECM biomarkers to muscle sarcopenia is being investigated

New Biochemical Insights into the Mechanisms of Pulmonary Arterial Hypertension in Humans

Diagnosis of pulmonary arterial hypertension (PAH) is difficult due to the lack of specific clinical symptoms and biomarkers, especially at early stages. We compared plasma metabolic fingerprints of PAH patients (n = 20) with matched healthy volunteers (n = 20) using, for the first time, untargeted multiplatform metabolomics approach consisting of high-performance liquid and gas chromatography coupled with mass spectrometry. Multivariate statistical analyses were performed to select metabolites that contribute most to groups' classification (21 from liquid in both ionization modes and 9 from gas chromatography-mass spectrometry). We found metabolites related to energy imbalance, such as glycolysis-derived metabolites, as well as metabolites involved in fatty acid, lipid and amino acid metabolism. We observed statistically significant changes in threitol and aminomalonic acid in PAH patients, which could provide new biochemical insights into the pathogenesis of the disease. The results were externally validated on independent case and control cohorts, confirming up to 16 metabolites as statistically significant in the validation study. Multiplatform metabolomics, followed by multivariate chemometric data analysis has a huge potential for explaining pathogenesis of PAH and for searching potential and new more specific and less invasive markers of the disease.This research was supported by the Polish National Science Center (2014/13/N/NZ7/04231), the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-58920R), by the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) (PI14-01427), and by the quality-promoting subsidy from the Ministry of Science and Higher Education of Poland, Leading National Research Centre (KNOW programme 2012-2017). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm.

The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation, 'nephron-like' features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1-a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases.This work was supported by Wellcome Trust grants awarded to H.S. (072441 and 079221, H.W., B.D., H.S.); Deutsche Forschungsgemeinschaft (SFB 590) awarded to Elisabeth Knust (F.G.), ARC 1242 (H.W., B.D., H.S., F.G.); MEC grant awarded to M.R-G. (BFU2007-62201, S.P-S., M.R-G.); Fundación Ramón Areces grant to the CBMSO (M.R-G.); EC grant LSHG-CT-2004-511978 to MYORES (M.R-G.); an FPU fellowship from the MEC awarded to A.G-L.Peer reviewe

Proyectos de emprendimiento para la empleabilidad de titulados en periodismo

Objetivo principal: poner a disposición de los alumnos de segundo ciclo del Grado de Periodismo un espacio de coworking en condiciones adecuadas así como docentes que les tutelen para que puedan afrontar sus ideas y proyectarlas hacia el mercado de la Comunicación, en el que puedan desarrollar sus proyectos periodísticos y lograr la creación de una micro-pyme informativa y/o de comunicación. Objetivos específicos: a) Diseñar un marco integral de conocimientos a partir de las competencias periodísticas aprendidos en la titulación de periodismo: la empresa informativa, la estructura, la tecnología, la dirección y gestión periodística y de medios, para acercar a los estudiantes al mundo empresarial. b) Facilitar la salida al mercado laboral, empresarial y en Comunicación a cuantas ideas de negocio se valoren como posibles y se puedan gestionar desde estos espacios de trabajo colaborativo, mediante la tutorización y la mentoría. En cuanto a la metodología aplicada, se trata de evaluar y proyectar ideas creativas previas a su lanzamiento al mercado, a partir de una personalidad jurídica concreta y presumible (viabilidad societaria), durante el cuatrimestre de trabajo (fase de recuperación de datos) a partir de dos grupos (muestra total de unos 132 alumnos) divididos en 18 equipos (17 presenciales y uno virtual) organizados a partir de un proyecto de innovación docente. Se les explica el contenido del proyecto y las razones de llevarlo a cabo, tras lo cual sólo 16 alumnos han decidido no participar, por lo que el total de alumnos participantes ha sido de 116. Los espacios de desarrollo metodológico se sitúan en el marco de las clases de 4º curso del Grado de Periodismo, asignatura de “Dirección y Gestión de Empresas Periodísticas”, grupos A y C, durante el 2ª Cuatrimestre del curso 2017-2018 (enero-mayo) y termina con una presentación de cada proyecto a la finalización del periodo lectivo. Destacar como resultados más notables que de los 18 equipos que todos son proyectos nativos digitales y que internet es la red por excelencia que les acoge y les permite distribuir sus productos a partir de contenidos periodísticos de información, bien generalista o de diferentes temáticas que a su vez se van especializando. Seis de estos proyectos se basan en la información general y otros cuatro establecen la información cultural como el valor fundamental sobre el que descansa su idea emprendedora. Ocho proyectos se distinguen por ser considerados temáticos con especializaciones muy diversas: el fútbol sala y la hípica (en el marco deportivo); la arquitectura; la información universitaria; videojuegos y tecnología; los productos lácteos (alimentación); sobre la tercera edad, y sobre el negocio de las “bodas… y divorcios”. Se observa una clara tendencia para su oportunidad de negocio y encuentran razones de mercado para un lanzamiento a corto – medio plazo. Uno de estos proyectos está residente en Tetuán Valley

CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation

Purpose: Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q10 (CoQ10) as a pleiotropic factor that crosses the blood-brain barrier and accumulates in cell membranes acting as an antioxidant, and in mitochondrial membranes as a regulator of cell bioenergetics and gene expression. Methods: Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro. Results: CoQ10 treatment decreased tumor volume in xenografts and orthotopic models, although its effect on tumor cell proliferation was not direct. Tumors from mice treated with CoQ10 were less hypoxic and vascularized, having less infiltration from inflammatory cells. Treatment-induced downregulation of HIF-1α and NF-kB led to a complete remodeling of the tumor cells proteome and secretome, impacting angiogenesis, monocyte infiltration, and their differentiation into macrophages. Besides, tumor cell migration and invasion were drastically restricted by mechanisms involving modulation of the actin cytoskeleton and downregulation of matrix metalloproteases (MMPs). Conclusions: CoQ10 has a pleiotropic effect on GBM growth, targeting several hallmarks simultaneously. Thus, its integration into current treatments of this fatal disease should be considered. Keywords: Angiogenesis; Coenzyme Q10; Glioblastoma; Inflammation; Invasion.Propósito: La mayoría de las monoterapias disponibles contra el glioblastoma multiforme (GBM) se dirigen a las características individuales de este tumor cerebral agresivo con un éxito mínimo. En este artículo proponemos una estrategia terapéutica utilizando la coenzima Q 10 (CoQ 10 ) como factor pleiotrópico que atraviesa la barrera hematoencefálica y se acumula en las membranas celulares actuando como antioxidante, y en las membranas mitocondriales como regulador de la bioenergética celular y gen expresión. Métodos: Se utilizaron xenoinjertos de células U251 en ratones nu/nu para analizar el crecimiento tumoral, la hipoxia, la angiogénesis y la inflamación. Se utilizó un modelo ortotópico para explorar la infiltración microglial, el crecimiento tumoral y la invasión del parénquima cerebral. Se ensayaron in vitro la proliferación celular, la migración, la invasión, la remodelación del proteoma y el secretoma. Se usaron medios acondicionados para analizar la angiogénesis, la quimioatracción de monocitos y la diferenciación en macrófagos in vitro. Resultados: el tratamiento con CoQ 10 disminuyó el volumen tumoral en xenoinjertos y modelos ortotópicos, aunque su efecto sobre la proliferación de células tumorales no fue directo. Los tumores de ratones tratados con CoQ 10 eran menos hipóxicos y vascularizados, con menos infiltración de células inflamatorias. La regulación a la baja inducida por el tratamiento de HIF-1α y NF-kB condujo a una remodelación completa del proteoma y el secretoma de las células tumorales, lo que impactó en la angiogénesis, la infiltración de monocitos y su diferenciación en macrófagos. Además, la migración e invasión de células tumorales se vieron drásticamente restringidas por mecanismos que involucran la modulación del citoesqueleto de actina y la regulación a la baja de las metaloproteasas de matriz (MMP). Conclusiones: CoQ 10 tiene un efecto pleiotrópico en el crecimiento de GBM, apuntando a varios sellos simultáneamente. Por lo tanto, se debe considerar su integración en los tratamientos actuales de esta enfermedad mortal