Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity

Recurrent infection-inflammation cycles in cystic fibrosis (CF) patients generate a highly oxidative environment, leading to progressive destruction of the airway epithelia. The identification of novel modifier genes involved in oxidative stress susceptibility in the CF airways might contribute to devise new therapeutic approaches. We performed an unbiased genome-wide RNAi screen using a randomized siRNA library to identify oxidative stress modulators in CF airway epithelial cells. We monitored changes in cell viability after a lethal dose of hydrogen peroxide. Local similarity and protein-protein interaction network analyses uncovered siRNA target genes/pathways involved in oxidative stress. Further mining against public drug databases allowed identifying and validating commercially available drugs conferring oxidative stress resistance. Accordingly, a catalog of 167 siRNAs able to confer oxidative stress resistance in CF submucosal gland cells targeted 444 host genes and multiple circuitries involved in oxidative stress. The most significant processes were related to alternative splicing and cell communication, motility, and remodeling (impacting cilia structure/function, and cell guidance complexes). Other relevant pathways included DNA repair and PI3K/AKT/mTOR signaling. The mTOR inhibitor everolimus, the α1-adrenergic receptor antagonist doxazosin, and the Syk inhibitor fostamatinib significantly increased the viability of CF submucosal gland cells under strong oxidative stress pressure. Thus, novel therapeutic strategies to preserve airway cell integrity from the harsh oxidative milieu of CF airways could stem from a deep understanding of the complex consequences of oxidative stress at the molecular level, followed by a rational repurposing of existing "protective" drugs. This approach could also prove useful to other respiratory pathologies

Rail corrugation growth accounting for the flexibility and rotation of the wheel set and the non-Hertzian and non-steady-state effects at contact patch

[EN] In this work, a simulation tool is developed to analyse the growth of rail corrugation consisting of several models connected in a feedback loop in order to account for both the short-term dynamic vehicle track interaction and the long-term damage. The time-domain vehicle track interaction model comprises a flexible rotating wheel set model, a cyclic track model based on a substructuring technique and a non-Hertzian and non-steady-state three-dimensional wheel rail contact model, based on the variational theory by Kalker. Wear calculation is performed with Archard s wear model by using the contact parameters obtained with the non-Hertzian and non-steady-state three-dimensional contact model. The aim of this paper is to analyse the influence of the excitation of two coinciding resonances of the flexible rotating wheel set on the rail corrugation growth in the frequency range from 20 to 1500 Hz, when contact conditions similar to those that can arise while a wheel set is negotiating a gentle curve are simulated. Numerical results show that rail corrugation grows only on the low rail for two cases in which two different modes of the rotating wheel set coincide in frequency. In the first case, identified by using the Campbell diagram, the excitation of both the backward wheel mode and the forward third bending mode of the wheel set model (B-F modes) promotes the growth of rail corrugation with a wavelength of 110mm for a vehicle velocity of 142 km/h. In the second case, the excitation of both the backward wheel mode and the backward third bending mode (B-B modes) gives rise to rail corrugation growth at a wavelength of 156 mm when the vehicle velocity is 198 km/h.The authors acknowledge the financial contribution by the Spanish Ministry of Economy and Competitiveness through the project TRA2010-15669.Vila Tortosa, MP.; Baeza González, LM.; Martínez Casas, J.; Carballeira, J. (2014). Rail corrugation growth accounting for the flexibility and rotation of the wheel set and the non-Hertzian and non-steady-state effects at contact patch. Vehicle System Dynamics. 52:92-108. https://doi.org/10.1080/00423114.2014.881513S9210852Grassie, S. L., & Kalousek, J. (1993). Rail Corrugation: Characteristics, Causes and Treatments. Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit, 207(1), 57-68. doi:10.1243/pime_proc_1993_207_227_02Hempelmann, K., Hiss, F., Knothe, K., & Ripke, B. (1991). The formation of wear patterns on rail tread. Wear, 144(1-2), 179-195. doi:10.1016/0043-1648(91)90014-lHempelmann, K., & Knothe, K. (1996). An extended linear model for the prediction of short pitch corrugation. Wear, 191(1-2), 161-169. doi:10.1016/0043-1648(95)06747-7GRASSIE, S. L., & ELKINS, J. A. (1998). RAIL CORRUGATION ON NORTH AMERICAN TRANSIT SYSTEMS. Vehicle System Dynamics, 29(sup1), 5-17. doi:10.1080/00423119808969548Egana, J. I., Vinolas, J., & Seco, M. (2006). Investigation of the influence of rail pad stiffness on rail corrugation on a transit system. Wear, 261(2), 216-224. doi:10.1016/j.wear.2005.10.004Igeland, A. (1996). Railhead Corrugation Growth Explained by Dynamic Interaction between Track and Bogie Wheelsets. Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit, 210(1), 11-20. doi:10.1243/pime_proc_1996_210_322_02Gómez, I., & Vadillo, E. G. (2003). A linear model to explain short pitch corrugation on rails. Wear, 255(7-12), 1127-1142. doi:10.1016/s0043-1648(03)00282-5Collette, C., Vanhonacker, P., Bastaits, R., & Levy, D. (2008). Comparison between time and frequency studies of a corrugated curve of RER Paris network. Wear, 265(9-10), 1249-1258. doi:10.1016/j.wear.2008.01.030Daniel, W. J. T., Horwood, R. J., Meehan, P. A., & Wheatley, N. (2008). Analysis of rail corrugation in cornering. Wear, 265(9-10), 1183-1192. doi:10.1016/j.wear.2008.02.030Fayos, J., Baeza, L., Denia, F. D., & Tarancón, J. E. (2007). An Eulerian coordinate-based method for analysing the structural vibrations of a solid of revolution rotating about its main axis. Journal of Sound and Vibration, 306(3-5), 618-635. doi:10.1016/j.jsv.2007.05.051Baeza, L., & Ouyang, H. (2011). A railway track dynamics model based on modal substructuring and a cyclic boundary condition. Journal of Sound and Vibration, 330(1), 75-86. doi:10.1016/j.jsv.2010.07.023Kalker, J. J. (1990). Three-Dimensional Elastic Bodies in Rolling Contact. Solid Mechanics and Its Applications. doi:10.1007/978-94-015-7889-9Xie, G., & Iwnicki, S. D. (2008). Simulation of wear on a rough rail using a time-domain wheel–track interaction model. Wear, 265(11-12), 1572-1583. doi:10.1016/j.wear.2008.03.016Igeland, A., & Ilias, H. (1997). Rail head corrugation growth predictions based on non-linear high frequency vehicle/track interaction. Wear, 213(1-2), 90-97. doi:10.1016/s0043-1648(97)00172-5Vila, P., Fayos, J., & Baeza, L. (2011). Simulation of the evolution of rail corrugation using a rotating flexible wheelset model. Vehicle System Dynamics, 49(11), 1749-1769. doi:10.1080/00423114.2011.552619Popp, K., Kruse, H., & Kaiser, I. (1999). Vehicle-Track Dynamics in the Mid-Frequency Range. Vehicle System Dynamics, 31(5-6), 423-464. doi:10.1076/vesd.31.5.423.8363Johnson, K. L. (1985). Contact Mechanics. doi:10.1017/cbo9781139171731Hiensch, M., Nielsen, J. C. O., & Verheijen, E. (2002). Rail corrugation in The Netherlands—measurements and simulations. Wear, 253(1-2), 140-149. doi:10.1016/s0043-1648(02)00093-5Jin, X., Xiao, X., Wen, Z., Guo, J., & Zhu, M. (2009). An investigation into the effect of train curving on wear and contact stresses of wheel and rail. Tribology International, 42(3), 475-490. doi:10.1016/j.triboint.2008.08.004Ilias, H., & Müller, S. (1994). A discrete-continuous track-model for wheelsets rolling over short wavelength sinusoidal rail irregularities. Vehicle System Dynamics, 23(sup1), 221-233. doi:10.1080/0042311930896951

Eficàcia dels porters en els Jocs ODESUR i Campionat Panamericà d’Handbol al 2014

Objectius. Descriure les característiques de l’eficàcia presentada pels porters al 2014 en els Jocs Sud-americans ­(ODESUR) i en el Campionat Panamericà, en la categoria adults masculina; relacionar aquesta eficàcia amb el resultat dels partits i la classificació final dels seus equips; i analitzar la influència de l’eficàcia dels porters en la probabilitat de guanyar un partit en aquests campionats. Metodologia. Metodologia observacional. Mostra. 3008 llançaments en 32 partits. Principals resultats. Coeficient d’eficàcia del porter (CEP 0.33 i 0.31) i coeficient d’eficàcia ampliat (CEAP 0.40 i 0.38) en tots dos campionats. Diferències significatives entre guanyadors i perdedors en defensa posicional (p<0.01). Conclusions. Els millors resultats van aparèixer davant llançaments de contraatac, mentre que els valors enfront de 7 m van ser baixos. L’eficàcia dels porters es va relacionar amb el resultat dels partits i la classificació final dels seus equips. Els equips guanyadors van presentar millors valors durant les fases de defensa posicional. La probabilitat de guanyar un partit es veu influenciada per l’eficàcia dels porters, però també pel nombre de llançaments rebuts

Dipolos impresos multifrecuencia cargados con partículas metamateriales

Multi-frequency printed dipoles based on antipodal printed dipoles loaded with metamaterial particles are presented. Split Ring Resonators (SRRs) are used as metamaterial particles in order to obtain fully printed and planar antennas. First, a simplified model of these antennas is developed. This model is based on a printed dipole loaded with the equivalent circuit of the SRRs. This model shows that the working frequencies are very close to the self-resonant frequencies of the dipole and the SRRs. Moreover, a dualfrequency printed dipole is designed, manufactured and measured. This dipole works simultaneously at 1.32 GHz and 2.82 GHz. Finally, the previous idea is extended to increase the bandwidth of the dual-band dipoles and develop multifrequency printed dipoles (printed dipoles which work simultaneously at three or more frequencies). This is made by using SRRs with different dimensions

MIRACLE’s hybrid approach to bilingual and monolingual Information Retrieval

The main goal of the bilingual and monolingual participation of the MIRACLE team at CLEF 2004 was testing the effect of combination approaches to information retrieval. The starting point is a set of basic components: stemming, transformation, filtering, generation of n-grams, weighting and relevance feedback. Some of these basic components are used in different combinations and order of application for document indexing and for query processing. Besides this, a second order combination is done, mainly by averaging or by selective combination of the documents retrieved by different approaches for a particular query

Explainable artificial intelligence to predict and identify prostate cancer tissue by gene expression

This work was supported by the ERDF and the Ministry of Economy, Innovation and Science of the Regional Government of Andalusia (grant number P18-RT-2248)Background and Objective: Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Traditional screening strategies such as serum PSA levels, which are not necessarily cancer-specific, or digital rectal exams, which are often inconclusive, are still the screening methods used for the disease. Some studies have focused on identifying biomarkers of the disease but none have been reported for diagnosis in routine clinical practice and few studies have provided tools to assist the pathologist in the decision-making process when analyzing prostate tissue. Therefore, a classifier is proposed to predict the occurrence of PCa that provides physicians with accurate predictions and understandable explanations. Methods: A selection of 47 genes was made based on differential expression between PCa and normal tissue, GO gene ontology as well as the literature to be used as input predictors for different machine learning methods based on eXplainable Artificial Intelligence. These methods were trained using different class-balancing strategies to build accurate classifiers using gene expression data from 550 samples from ’The Cancer Genome Atlas’. Our model was validated in four external cohorts with different ancestries, totaling 463 samples. In addition, a set of SHapley Additive exPlanations was provided to help clinicians understand the underlying reasons for each decision. Results: An in-depth analysis showed that the Random Forest algorithm combined with majority class downsampling was the best performing approach with robust statistical significance. Our method achieved an average sensitivity and specificity of 0.90 and 0.8 with an AUC of 0.84 across all databases. The relevance of DLX1, MYL9 and FGFR genes for PCa screening was demonstrated in addition to the important role of novel genes such as CAV2 and MYLK. Conclusions: This model has shown good performance in 4 independent external cohorts of different ancestries and the explanations provided are consistent with each other and with the literature, opening a horizon for its application in clinical practice. In the near future, these genes, in combination with our model, could be applied to liquid biopsy to improve PCa screening.European Union (EU)Ministry of Econ-omy, Innovation and Science of the Regional Government of Andalusia P18-RT-224

Design method for actively matched antennas with non-foster elements

The design of electrically small antennas (ESAs) loaded with active non-Foster elements is a topic whose interest has grown in the last years. In this communication, a new strategy for the design of actively matched antennas loaded with non-Foster elements is presented. The analysis of different parameters, such as the sensitivity to non-Foster circuit placement, the overall antenna system stability, and current distributions, has to be considered in order to enhance the antenna performance. A design example using an ESA and its realization is presented to validate the proposed strategy.This work was supported in part by MINECO under the project TEC2013-47753-C3-2-R and RTC 2014-2380-4.Publicad

Application of digital image correlation at the microscale in fiber-reinforced composites

Digital image correlation (DIC) is applied to analyzing the deformation mechanisms under transverse compression in a fiber-reinforced composite. To this end, compression tests in a direction perpendicular to the fibers were carried out inside a scanning electron microscope and secondary electron images obtained at different magnifications during the test. Optimum DIC parameters to resolve the displacement and strain field were computed from numerical simulations of a model composite and they were applied to micrographs obtained at different magnifications (250_, 2000_, and 6000_). It is shown that DIC of low-magnification micrographs was able to capture the long range fluctuations in strain due to the presence of matrix-rich and fiber-rich zones, responsible for the onset of damage. At higher magnification, the strain fields obtained with DIC qualitatively reproduce the non-homogeneous deformation pattern due to the presence of stiff fibers dispersed in a compliant matrix and provide accurate results of the average composite strain. However, comparison with finite element simulations revealed that DIC was not able to accurately capture the average strain in each phase

Influence of oxidative stress-related genes on susceptibility to Fibromyalgia.

Background: Fibromyalgia (FM) is a complex syndrome to diagnose and treat because of its unknown etiology. However, previous studies reported that patients with FM experience oxidative stress. Objectives: In this study, we investigated single-nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in oxidative stress (superoxide dismutase 1 [SOD1], catalase, and NADPH oxidase [CYBA]) in patients with FM and in healthy subjects, as well as the possible relation with demographic and clinical manifestations of FM. Methods: A total of 141 patients with FM and 73 healthy subjects participated in this case–control study. For DNA extraction, buccal swabs were collected from patients with FM, and a peripheral blood sample was extracted from controls. We analyzed SNPs in genes related to oxidative stress (rs10432782 in SOD1, rs1001179 in catalase, and rs4673 in CYBA) using TaqMan probes. In patients with FM, severity of FM, fatigue, and pain were assessed by Fibromyalgia Impact Questionnaire, Multidimensional Fatigue Inventory, and Visual Analogue Scale (VAS), respectively. Physical (PCS-12) and mental (MCS-12) health statuses were evaluated by the 12-Item Short-Form Health Survey. Results: The selected SNPs did not show significant differences between patients with FM and controls. The rs10432782 (SOD1) was associated with Fibromyalgia Impact Questionnaire scores in patients with FM, whereas the rs4673 (CYBA) was associated with the Multidimensional Fatigue Inventory score, MCS-12 score, and duration of the disease. Discussion: We have identified significant correlations between SOD1 and CYBA variants with clinical manifestations of FM. These results provide new insights into the pathogenesis of FM that could be useful for guiding future studies along the way to find the cause(s) of this syndrome

Mecanismos de Deformación en laminados de matriz polimérica correlación digital de imágenes y micromecánica computacional

Se ha realizado un estudio micromecánico experimental del comportamiento de laminados unidireccionales sometidos a compresión en la dirección perpendicular a las fibras. Se ha empleado la técnica de correlación digital de imágenes para observar la evolución de los campos de desplazamientos y deformaciones en la microestructura del material compuesto. En los contornos de deformación obtenidos experimentalmente se ha comprobado como las fibras tienen una deformación muy pequeña, mientras que las mayores deformaciones se concentran en las zonas de matriz de menor fracción volumétrica de fibras. Simulando por elementos finitos la microestructura estudiada se han reproducido los resultados experimentales, obteniendo distribuciones de campos de desplazamientos y deformaciones muy similares a las observadas experimentalmente