Mathematics preservice teachers’ argumentation

ABSTARCT: This research deals with the preservice teachers’ dialogic argumentationswhen presenting geometry tasks to their colleagues, during discussion sessions previous to teaching to children. An argumentation analysis tool is used that complement Toulmin’s analysis proposal and that includes features related to mathematicallogic, rhetoric and dialectic features.We propose both a representation for the dialogic argumentation and a way to identify its structural qualitie

In silico assessment of drug safety in human heart applied to late sodium current blockers

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.This work was supported by (1) Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, (2) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (3) Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universidad Politecnica de Valencia, (4) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana and (5) Gilead Sciences, Ltd.Trenor Gomis, BA.; Gomis-Tena Dolz, J.; Cardona Urrego, KE.; Romero Pérez, L.; Rajamani, S.; Belardinelli, L.; Giles, WR.... (2013). In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels. 7(4):1-14. doi:10.4161/chan.24905S11474Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Zaza, A., Belardinelli, L., & Shryock, J. C. (2008). Pathophysiology and pharmacology of the cardiac «late sodium current». Pharmacology & Therapeutics, 119(3), 326-339. doi:10.1016/j.pharmthera.2008.06.001Song, Y., Shryock, J. C., Wagner, S., Maier, L. S., & Belardinelli, L. (2006). Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction. Journal of Pharmacology and Experimental Therapeutics, 318(1), 214-222. doi:10.1124/jpet.106.101832Milberg, P., Pott, C., Fink, M., Frommeyer, G., Matsuda, T., Baba, A., … Eckardt, L. (2008). Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm, 5(10), 1444-1452. doi:10.1016/j.hrthm.2008.06.017Jia, S., Lian, J., Guo, D., Xue, X., Patel, C., Yang, L., … Yan, G.-X. (2011). Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKrblockade. British Journal of Pharmacology, 164(2), 308-316. doi:10.1111/j.1476-5381.2010.01181.xUNDROVINAS, A. I., BELARDINELLI, L., UNDROVINAS, N. A., & SABBAH, H. N. (2006). Ranolazine Improves Abnormal Repolarization and Contraction in Left Ventricular Myocytes of Dogs with Heart Failure by Inhibiting Late Sodium Current. Journal of Cardiovascular Electrophysiology, 17(s1), S169-S177. doi:10.1111/j.1540-8167.2006.00401.xWu, L., Shryock, J. C., Song, Y., Li, Y., Antzelevitch, C., & Belardinelli, L. (2004). Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome. Journal of Pharmacology and Experimental Therapeutics, 310(2), 599-605. doi:10.1124/jpet.104.066100MOSS, A. J., ZAREBA, W., SCHWARZ, K. Q., ROSERO, S., MCNITT, S., & ROBINSON, J. L. (2008). Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due to Type-3 Long-QT Syndrome. Journal of Cardiovascular Electrophysiology, 19(12), 1289-1293. doi:10.1111/j.1540-8167.2008.01246.xSong, Y., Shryock, J. C., Wu, L., & Belardinelli, L. (2004). Antagonism by Ranolazine of the Pro-Arrhythmic Effects of Increasing Late INa in Guinea Pig Ventricular Myocytes. Journal of Cardiovascular Pharmacology, 44(2), 192-199. doi:10.1097/00005344-200408000-00008Belardinelli, L., Liu, G., Smith-Maxwell, C., Wang, W.-Q., El-Bizri, N., Hirakawa, R., … Shryock, J. C. (2012). A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias. Journal of Pharmacology and Experimental Therapeutics, 344(1), 23-32. doi:10.1124/jpet.112.198887Banyasz, T., Koncz, R., Fulop, L., Szentandrassy, N., Magyar, J., & Nanasi, P. (2004). Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade. Current Medicinal Chemistry, 11(1), 45-60. doi:10.2174/0929867043456304Hopenfeld, B. (2006). A mathematical analysis of the action potential plateau duration of a human ventricular myocyte. Journal of Theoretical Biology, 240(2), 311-322. doi:10.1016/j.jtbi.2005.09.021Maleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). Electrotonic Coupling between Human Atrial Myocytes and Fibroblasts Alters Myocyte Excitability and Repolarization. Biophysical Journal, 97(8), 2179-2190. doi:10.1016/j.bpj.2009.07.054Nygren, A., Fiset, C., Firek, L., Clark, J. W., Lindblad, D. S., Clark, R. B., & Giles, W. R. (1998). Mathematical Model of an Adult Human Atrial Cell. Circulation Research, 82(1), 63-81. doi:10.1161/01.res.82.1.63Viswanathan, P. (1999). Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovascular Research, 42(2), 530-542. doi:10.1016/s0008-6363(99)00035-8Wu, R., & Patwardhan, A. (2007). Effects of rapid and slow potassium repolarization currents and calcium dynamics on hysteresis in restitution of action potential duration. Journal of Electrocardiology, 40(2), 188-199. doi:10.1016/j.jelectrocard.2006.01.001Zaniboni, M. (2011). 3D current–voltage–time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study. Mathematical Biosciences, 233(2), 98-110. doi:10.1016/j.mbs.2011.06.008Zaniboni, M. (2012). Late Phase of Repolarization is Autoregenerative and Scales Linearly with Action Potential Duration in Mammals Ventricular Myocytes: A Model Study. IEEE Transactions on Biomedical Engineering, 59(1), 226-233. doi:10.1109/tbme.2011.2170987Zaniboni, M., Riva, I., Cacciani, F., & Groppi, M. (2010). How different two almost identical action potentials can be: A model study on cardiac repolarization. Mathematical Biosciences, 228(1), 56-70. doi:10.1016/j.mbs.2010.08.007Belardinelli, L., Antzelevitch, C., & Vos, M. A. (2003). Assessing predictors of drug-induced torsade de pointes. Trends in Pharmacological Sciences, 24(12), 619-625. doi:10.1016/j.tips.2003.10.002Shah, R. R., & Hondeghem, L. M. (2005). Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm, 2(7), 758-772. doi:10.1016/j.hrthm.2005.03.023Hondeghem, L. M., Carlsson, L., & Duker, G. (2001). Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic. Circulation, 103(15), 2004-2013. doi:10.1161/01.cir.103.15.2004Mirams, G. R., Cui, Y., Sher, A., Fink, M., Cooper, J., Heath, B. M., … Noble, D. (2011). Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovascular Research, 91(1), 53-61. doi:10.1093/cvr/cvr044Obiol-Pardo, C., Gomis-Tena, J., Sanz, F., Saiz, J., & Pastor, M. (2011). A Multiscale Simulation System for the Prediction of Drug-Induced Cardiotoxicity. Journal of Chemical Information and Modeling, 51(2), 483-492. doi:10.1021/ci100423zSuzuki, S., Murakami, S., Tsujimae, K., Findlay, I., & Kurachi, Y. (2008). In silico risk assessment for drug-induction of cardiac arrhythmia. Progress in Biophysics and Molecular Biology, 98(1), 52-60. doi:10.1016/j.pbiomolbio.2008.05.003Mirams, G. R., Davies, M. R., Cui, Y., Kohl, P., & Noble, D. (2012). Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing. British Journal of Pharmacology, 167(5), 932-945. doi:10.1111/j.1476-5381.2012.02020.xSarkar, A. X., & Sobie, E. A. (2011). Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis. Heart Rhythm, 8(11), 1749-1755. doi:10.1016/j.hrthm.2011.05.023CHANG, C., ACHARFI, S., WU, M., CHIANG, F., WANG, J., SUNG, T., & CHAHINE, M. (2004). A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. Cardiovascular Research, 64(2), 268-278. doi:10.1016/j.cardiores.2004.07.007Weirich, J., & Antoni, H. (1998). Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs. Basic Research in Cardiology, 93(0), s125-s132. doi:10.1007/s003950050236O’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Wu, L., Ma, J., Li, H., Wang, C., Grandi, E., Zhang, P., … Belardinelli, L. (2011). Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of I Kr Inhibition on Ventricular Repolarization. Circulation, 123(16), 1713-1720. doi:10.1161/circulationaha.110.000661Banyasz, T., Barandi, L., Harmati, G., Virag, L., Szentandrassy, N., Marton, I., … P. Nanasi, P. (2011). Mechanism of Reverse Rate-Dependent Action of Cardioactive Agents. Current Medicinal Chemistry, 18(24), 3597-3606. doi:10.2174/092986711796642355Noble D, Tsien RW. The repolarization process of heart cells. In: DeMello WC, ed. Electrical Phenomena in the Heart. New York: Academic Press, 1972:133-161.Fink, M., Noble, D., Virag, L., Varro, A., & Giles, W. R. (2008). Contributions of HERG K+ current to repolarization of the human ventricular action potential. Progress in Biophysics and Molecular Biology, 96(1-3), 357-376. doi:10.1016/j.pbiomolbio.2007.07.011Goineau, S., Castagné, V., Guillaume, P., & Froget, G. (2012). The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine-induced cardiac effects. Journal of Pharmacological and Toxicological Methods, 66(1), 52-58. doi:10.1016/j.vascn.2012.06.001Wu, L., Guo, D., Li, H., Hackett, J., Yan, G.-X., Jiao, Z., … Belardinelli, L. (2008). Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm, 5(12), 1726-1734. doi:10.1016/j.hrthm.2008.09.008Diness, J. G., Hansen, R. S., Nissen, J. D., Jespersen, T., & Grunnet, M. (2009). Antiarrhythmic effect of IKr activation in a cellular model of LQT3. Heart Rhythm, 6(1), 100-106. doi:10.1016/j.hrthm.2008.10.020Laursen, M., Olesen, S.-P., Grunnet, M., Mow, T., & Jespersen, T. (2011). Characterization of cardiac repolarization in the Göttingen minipig. Journal of Pharmacological and Toxicological Methods, 63(2), 186-195. doi:10.1016/j.vascn.2010.10.001HONDEGHEM, L. M. (2006). Thorough QT/QTc Not So Thorough: Removes Torsadogenic Predictors from the T-Wave, Incriminates Safe Drugs, and Misses Profibrillatory Drugs. Journal of Cardiovascular Electrophysiology, 17(3), 337-340. doi:10.1111/j.1540-8167.2006.00347.xHondeghem, L. M., & Snyders, D. J. (1990). Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation, 81(2), 686-690. doi:10.1161/01.cir.81.2.686Bril, A. (1998). Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide. Cardiovascular Research, 37(1), 130-140. doi:10.1016/s0008-6363(97)00216-2Jurkiewicz, N. K., & Sanguinetti, M. C. (1993). Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circulation Research, 72(1), 75-83. doi:10.1161/01.res.72.1.75O’Hara, T., & Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology, 302(5), H1023-H1030. doi:10.1152/ajpheart.00785.2011Stengl, M., Volders, P. G. A., Thomsen, M. B., Spatjens, R. L. H. M. G., Sipido, K. R., & Vos, M. A. (2003). Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. The Journal of Physiology, 551(3), 777-786. doi:10.1113/jphysiol.2003.044040Shah, R. R. (2002). The significance of QT interval in drug development. British Journal of Clinical Pharmacology, 54(2), 188-202. doi:10.1046/j.1365-2125.2002.01627.xNuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., … Carmeliet, P. (2001). Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nature Medicine, 7(9), 1021-1027. doi:10.1038/nm0901-1021Gautier, M., Zhang, H., & Fearon, I. M. (2008). Peroxynitrite formation mediates LPC-induced augmentation of cardiac late sodium currents. Journal of Molecular and Cellular Cardiology, 44(2), 241-251. doi:10.1016/j.yjmcc.2007.09.007Fearon, I. M., & Brown, S. T. (2004). Acute and chronic hypoxic regulation of recombinant hNav1.5 α subunits. Biochemical and Biophysical Research Communications, 324(4), 1289-1295. doi:10.1016/j.bbrc.2004.09.188Ward, C. A., & Giles, W. R. (1997). Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. The Journal of Physiology, 500(3), 631-642. doi:10.1113/jphysiol.1997.sp022048Saint, D. A. (2009). The cardiac persistent sodium current: an appealing therapeutic target? British Journal of Pharmacology, 153(6), 1133-1142. doi:10.1038/sj.bjp.0707492Zygmunt, A. C., Eddlestone, G. T., Thomas, G. P., Nesterenko, V. V., & Antzelevitch, C. (2001). Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. American Journal of Physiology-Heart and Circulatory Physiology, 281(2), H689-H697. doi:10.1152/ajpheart.2001.281.2.h689Trenor, B., Cardona, K., Gomez, J. F., Rajamani, S., Ferrero, J. M., Belardinelli, L., & Saiz, J. (2012). Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure. PLoS ONE, 7(3), e32659. doi:10.1371/journal.pone.0032659Martin, R. L., McDermott, J. S., Salmen, H. J., Palmatier, J., Cox, B. F., & Gintant, G. A. (2004). The Utility of hERG and Repolarization Assays in Evaluating Delayed Cardiac Repolarization: Influence of Multi-Channel Block. Journal of Cardiovascular Pharmacology, 43(3), 369-379. doi:10.1097/00005344-200403000-00007Antzelevitch, C., Belardinelli, L., Zygmunt, A. C., Burashnikov, A., Di Diego, J. M., Fish, J. M., … Thomas, G. (2004). Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties. Circulation, 110(8), 904-910. doi:10.1161/01.cir.0000139333.83620.5dNoble, D. (2006). Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart, 92(suppl_4), iv1-iv5. doi:10.1136/hrt.2005.078782Scirica, B. M., Morrow, D. A., Hod, H., Murphy, S. A., Belardinelli, L., Hedgepeth, C. M., … Braunwald, E. (2007). Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non–ST-Segment–Elevation Acute Coronary Syndrome. Circulation, 116(15), 1647-1652. doi:10.1161/circulationaha.107.724880Hoefen, R., Reumann, M., Goldenberg, I., Moss, A. J., O-Uchi, J., Gu, Y., … Lopes, C. M. (2012). In Silico Cardiac Risk Assessment in Patients With Long QT Syndrome. Journal of the American College of Cardiology, 60(21), 2182-2191. doi:10.1016/j.jacc.2012.07.053Silva, J. R., Pan, H., Wu, D., Nekouzadeh, A., Decker, K. F., Cui, J., … Rudy, Y. (2009). A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. Proceedings of the National Academy of Sciences, 106(27), 11102-11106. doi:10.1073/pnas.0904505106STARMER, C. (1991). Lidocaine blockade of continuously and transiently accessible sites in cardiac sodium channels*1. Journal of Molecular and Cellular Cardiology, 23, 73-83. doi:10.1016/0022-2828(91)90026-iRudy, Y., & Silva, J. R. (2006). Computational biology in the study of cardiac ion channels and cell electrophysiology. Quarterly Reviews of Biophysics, 39(1), 57-116. doi:10.1017/s0033583506004227Clancy, C. E., Zhu, Z. I., & Rudy, Y. (2007). Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation. American Journal of Physiology-Heart and Circulatory Physiology, 292(1), H66-H75. doi:10.1152/ajpheart.00312.2006Zygmunt, A. C., Nesterenko, V. V., Rajamani, S., Hu, D., Barajas-Martinez, H., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1606-H1614. doi:10.1152/ajpheart.00242.2011Nesterenko, V. V., Zygmunt, A. C., Rajamani, S., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1615-H1624. doi:10.1152/ajpheart.00243.2011Zemzemi, N., Bernabeu, M. O., Saiz, J., Cooper, J., Pathmanathan, P., Mirams, G. R., … Rodriguez, B. (2013). Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. British Journal of Pharmacology, 168(3), 718-733. doi:10.1111/j.1476-5381.2012.02200.xHille B. Ionic Channels of Excitable Membranes. 2nd ed. Sunderland, MA: Sinauer Associates, 1992.Rajamani, S., Shryock, J. C., & Belardinelli, L. (2008). Rapid Kinetic Interactions of Ranolazine With HERG K+ Current. Journal of Cardiovascular Pharmacology, 51(6), 581-589. doi:10.1097/fjc.0b013e3181799690Rajamani, S., El-Bizri, N., Shryock, J. C., Makielski, J. C., & Belardinelli, L. (2009). Use-dependent block of cardiac late Na+ current by ranolazine. Heart Rhythm, 6(11), 1625-1631. doi:10.1016/j.hrthm.2009.07.042Bassingthwaighte, J., Hunter, P., & Noble, D. (2009). The Cardiac Physiome: perspectives for the future. Experimental Physiology, 94(5), 597-605. doi:10.1113/expphysiol.2008.044099Quinn, T. A., Granite, S., Allessie, M. A., Antzelevitch, C., Bollensdorff, C., Bub, G., … Delmar, M. (2011). Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing. Progress in Biophysics and Molecular Biology, 107(1), 4-10. doi:10.1016/j.pbiomolbio.2011.07.001Glukhov, A. V., Fedorov, V. V., Lou, Q., Ravikumar, V. K., Kalish, P. W., Schuessler, R. B., … Efimov, I. R. (2010). Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle. Circulation Research, 106(5), 981-991. doi:10.1161/circresaha.109.204891MALTSEV, V., & UNDROVINAS, A. (2006). A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovascular Research, 69(1), 116-127. doi:10.1016/j.cardiores.2005.08.015Drouin, E., Charpentier, F., Gauthier, C., Laurent, K., & Le Marec, H. (1995). Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. Journal of the American College of Cardiology, 26(1), 185-192. doi:10.1016/0735-1097(95)00167-xBerecki, G., Zegers, J. G., Bhuiyan, Z. A., Verkerk, A. O., Wilders, R., & Van Ginneken, A. C. G. (2006). Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique. The Journal of Physiology, 570(2), 237-250. doi:10.1113/jphysiol.2005.096578Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Valdivia, C. R., Chu, W. W., Pu, J., Foell, J. D., Haworth, R. A., Wolff, M. R., … Makielski, J. C. (2005). Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. Journal of Molecular and Cellular Cardiology, 38(3), 475-483. doi:10.1016/j.yjmcc.2004.12.012Belardinelli, L. (2006). Inhibition of the late sodium current as a potential cardioprotective principle:

Effect of Biodiversity Changes in Disease Risk: Exploring Disease Emergence in a Plant-Virus System

The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk) is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect), and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect). Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin) under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or “late” component of the Na+ current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.In Valencia, this work was supported by: (i) VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-0O3-01) and the European Commission (European Regional Development Funds-ERDF-FEDER)., (ii) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (iii) Programa deApoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universitat Politecnica de Valencia, (iv) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana, and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.; Giles, WR. (2013). Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations. Frontiers in Physiology. 4:1-11. https://doi.org/10.3389/fphys.2013.00282S111

Turbidity and Secchi disc depth with Sentinel-2 in different trophic status reservoirs at the Comunidad Valenciana

[ES] En los estudios de calidad de aguas por teledetección, uno de los principales indicadores es la transparencia o turbidez del agua. La transparencia puede ser medida in situ mediante la profundidad del disco de Secchi (SD), y la turbidez con un turbidímetro. En las últimas décadas se han utilizado diferentes relaciones entre bandas de diferentes sensores obtenidas por teledetección para la estimación de estos parámetros. En este trabajo, a partir de datos de campo obtenidos a lo largo de 2017 y 2018 en embalses de la cuenca del Júcar con gran variedad de estados tróficos, se han calibrado diferentes índices y bandas para poder estimar la transparencia a partir de imágenes Sentinel-2 (S2). A las imágenes S2 nivel L1C tomadas en el mismo día que los datos de campo, se les han aplicado tres métodos de corrección atmosférica desarrollados para aguas: Polymer, C2RCC y C2X. A partir de los espectros de S2 obtenidos y de los datos de campo de SD se ha observado que el menor error se obtiene con las imágenes corregidas con Polymer y un ajuste potencial del cociente de reflectividades en las bandas azul y verde (R490/R560), que permiten la estimación de SD con un error relativo del 13%. También el método C2X presenta buen ajuste con el mismo cociente de bandas, aunque un error mayor, presentando la corrección C2RCC la peor correlación. Se ha obtenido también la relación entre SD (en m) y turbidez (en NTU), lo que proporciona un método operativo para la estimación de la turbidez con S2. Se muestra, además, la relación para los diferentes embalses entre el SD y la concentración de clorofila-a, sólidos en suspensión y materia orgánica disuelta.[EN] Transparency or turbidity is one of the main indicators in studies of water quality using remote sensing. Transparency can be measured in situ through the Secchi disc depth (SD), and turbidity using a turbidimeter. In recent decades, different relationships between bands from different remote sensing sensors have been used for the estimation of these variables. In this paper, several indices and spectral bands have been calibrated in order to estimate transparency from Sentinel-2 (S2) images from field data, obtained throughout 2017 and 2018 in Júcar basin reservoirs with a great variety of trophic states. Three atmospheric correction methods developed for waters have been applied to the S2 level L1C images taken at the same day as the field data: Polymer, C2RCC and C2X. From the spectra obtained from S2 and the SD field data, it has been found that the smallest error is obtained with the images atmospherically corrected with Polymer and a potential adjustment of the reflectivities’ ratio of the blue and green bands (R490/R560), which allow the estimation of SD with a relative error of 13%. Also the C2X method presents good adjustment with the same bands ratio, although with a greater error, while the correction C2RCC shows the worst correlation. The relationship between SD (in m) and turbidity (in NTU) has also been obtained, which provides an operational method for estimating turbidity with S2. The relationship for the different reservoirs between SD and chlorophyll-a concentration, suspended solids and dissolved organic matter, is also shownEste trabajo ha sido posible gracias al Proyecto ESAQS del Programa Prometeo para grupos de investigación de excelencia de la Conselleria d’Educació, Investigació, Cultura i Esport (GVPROMETEO2016-132) de la Generalitat Valenciana.Delegido, J.; Urrego, P.; Vicente, E.; Sòria-Perpinyà, X.; Soria, J.; Pereira-Sandoval, M.; Ruiz-Verdú, A.... (2019). Turbidez y profundidad de disco de Secchi con Sentinel-2 en embalses con diferente estado trófico en la Comunidad Valenciana. Revista de Teledetección. 0(54):15-24. https://doi.org/10.4995/raet.2019.12603OJS1524054Alikas, K., Kratzer, S. 2017. Improved retrieval of Secchi depth for optically-complex waters using remote sensing data. Ecological indicators, 77, 218- 227. https://doi.org/10.1016/j.ecolind.2017.02.007Ansper, A., Alikas, K. 2019. Retrieval of Chlorophyll-a from Sentinel-2 MSI Data for the European Union Water Framework Directive Reporting Purposes. Remote Sensing, 11, 64. https://doi.org/10.3390/rs11010064APHA, 1992. Standard methods for the examination of water and wastewater. 18th edition. American Public Health Association. Washington D.C., USA. 1105 pp.Baughman, C.A., Jones, B.M., Bartz, K.K., Young, D.B., Zimmerman, C.E. 2015. Reconstructing Turbidity in a Glacially Influenced Lake Using the Landsat TM and ETM+ Surface Reflectance Climate Data Record Archive, Lake Clark, Alaska. Remote Sensing, 7, 13692-13710. https://doi.org/10.3390/rs71013692Brockmann, C., Doerffer, R., Peters, M., Kerstin, S., Embacher, S., Ruescas, A. 2016. Evolution of the C2RCC neural network for Sentinel 2 and 3 for the retrieval of ocean colour products in normal and extreme optically complex waters. In Proceedings of the "ESA Living Planet Symposium 2016", Prague, Czech Republic, 9-13 May 2016.Delegido, J., Urrego, P., Ruiz-Verdú, A., PereiraSandoval, M., Vicente, E., Sòria-Perpinyà, X., Soria, J.M., Moreno, J. 2019. Transparencia de diferentes embalses de la cuenca del Júcar con imágenes Sentinel-2. XVIII Congreso de la Asociación Española de Teledetección. Valladolid, 24-27 septiembre 2019.Doron, M., Babin, M., Mangin, A., Hembise, O. 2007. Estimation of light penetration, and horizontal and vertical visibility in oceanic and coastal waters from surface reflectance. J. Geophys. Res., 112, C06003. https://doi.org/10.1029/2006JC004007Gholizadeh, M.H., Melesse, A.M., Reddi, L. 2016. A Comprehensive Review on Water Quality Parameters Estimation Using Remote Sensing Techniques. Sensors, 16(8), E1298. https://doi.org/10.3390/s16081298Jeffrey, S.T., Humphrey, G.F. 1975. New spectrophotometric equations for determining chlorophylls a, b, c1 and c2 in higher plants, algae and natural phytoplankton. Biochem. Physiol. Pflanz., 167, 191-194. https://doi.org/10.1016/S0015-3796(17)30778-3Khorram, S., Cheshire, H., Geraci, A.L., Rosa, G.L., 1991. Water quality mapping of Augusta Bay, Italy from Landsat-TM data. Int. J. Remote Sens., 12(4), 803- 808. https://doi.org/10.1080/01431169108929696Koponen, S., Pulliainen, J., Kallio, K., Hallikainen, M. 2002, Lake water quality classification with airborne hyperspectral spectrometer and simulated MERIS data. Remote Sensing of Environment, 79, 51-59. https://doi.org/10.1016/S0034-4257(01)00238-3Korshin, G.V., Li, C.W., Benjamin, M.M. 1997. Monitoring the properties of natural organic matter through UV spectroscopy: A consistent theory. Water Research, 31, 1787-1795. https://doi.org/10.1016/S0043-1354(97)00006-7Kratzer, S., Brockmann, C., Moore, G. 2008. Using MERIS full resolution data to monitor coastal waters - A case study from Himmerfjärden, a fjordlike bay in the northwestern Baltic Sea. Remote Sensing of Environment, 112(5), 2284-2300. https://doi.org/10.1016/j.rse.2007.10.006Lee, Z., Shang, S., Hu, C., Du, K., Weidemann, A., Hou, W., Lin, J., Lin, G. 2016. Secchi disk depth: a new theory and mechanistic model for underwater visibility. Remote Sens. Environ., 169, 139-149. https://doi.org/10.1016/j.rse.2015.08.002Matthews, M.W. 2011. A current review of empirical procedures of remote sensing in inland and near-coastal transitional waters. International Journal of Remote Sensing, 32(21), 6855-6899. https://doi.org/10.1080/01431161.2010.512947Mosquera, A., Torres, J.M., González-Vilas, L., Martínez-Iglesias, G., Pazos, Y. 2006. Estudio de una floración tóxica de Pseudonitzschias sp. en las costas de Galicia usando una imagen MERIS y datos in situ. Revista de Teledetección, 25, 75-79. Disponible en: http://www.aet.org.es/revistas/revista25/AET25- 15.pdf. Último acceso: Diciembre de 2019.Mueller, J. L. 2000. SeaWiFS algorithm for the diffuse attenuation coefficient, K (490), using water-leaving radiances at 490 and 555 nm. SeaWiFS Postlaunch Calibration and Validation Analyses, part 3, edited by S. B. Hooker, pp. 24-27, NASA Goddard Space Flight Center.Page, B., Kumar, A., Mishra, D. 2018. A novel crosssatellite based assessment of the spatio-temporal development of a cyanobacterial harmful algal bloom. Int. J. Appl. Earth Obs. Geoinf., 66, 68-81. https://doi.org/10.1016/j.jag.2017.11.003Page, B., Olmanson, L., Mishra, D. 2019. A harmonized image processing workflow using Sentinel-2/MSI and Landsat-8/OLI for mapping water clarity in optically variable lake systems. Remote Sens. Environ., 231, 111284. https://doi.org/10.1016/j.rse.2019.111284Pahlevan, N., Chittimalli, S., Balasubramanian, S., Vellucci, V. 2019. Sentinel2/Landsat8 product consistency and implications for monitoring aquatic systems. Remote Sens. Environ., 220, 19-29. https://doi.org/10.1016/j.rse.2018.10.027Pereira-Sandoval, M., Ruescas, A.B., Urrego, P., Delegido, J., Ruiz-Verdú, A, Tenjo, C., SoriaPerpinyà, X., Vicente, E, Soria, J., Peña, R., Moreno, J. 2018. Evaluación de métodos de corrección atmosférica sobre imágenes Sentinel2-MSI en aguas continentales. XVIII Simposio Internacional SELPER y Sistemas de Información Espacial, Noviembre de 2018, La Habana, Cuba.Pereira-Sandoval, M., Urrego, P., Ruiz-Verdú, A., Tenjo, C., Delegido, J., Soria-Perpinyà, X., Vicente, E., Soria, J., Moreno, J. 2019a. Calibration and validation of algorithms for the estimation of chlorophyll-a concentration and Secchi depth in inland waters with Sentinel-2. Limnetica, 38(1), 471- 487. https://doi.org/10.1109/IGARSS.2018.8517371Pereira-Sandoval, M., Ruescas, A., Urrego, P., RuizVerdú, A., Delegido, J., Tenjo, C, Soria-Perpinyà, X., Vicente, E., Soria, J., Moreno, J. 2019b. Evaluation of Atmospheric Correction Algorithms over Spanish Inland Waters for Sentinel-2 Multi Spectral Imagery Data. Remote Sensing, 11, 1469. https://doi.org/10.3390/rs11121469Shoaf, W.T., Lium, B.W. 1976. Improved extraction of chlorophyll a and b from algae using dimethyl sulphoxide. Limnol. Oceanogr., 21, 926-928. https://doi.org/10.4319/lo.1976.21.6.0926Soria, X., Vicente, E., Durán, C., Soria, J.M., Peña, R. 2017. Uso de imágenes Landsat-8 para la estimación de la profundidad del disco de Secchi en aguas continentales. XVII Congreso de la Asociación Española de Teledetección. pp. 293-296. Murcia 3-7 octubre 2017.Sòria-Perpinyà, X., Urrego, P., Pereira-Sandoval, M., Ruiz-Verdú, A., Peña, R., Soria, J.M., Delegido, J., Vicente, E., Moreno, J. 2019. Monitoring the ecological state of a hypertrophic lake (Albufera of València, Spain) using multitemporal Sentinel-2 images. Limnetica, 38(1), 457-469. https://doi.org/10.23818/limn.38.26Steinmetz, F., Deschamps, P.Y., Ramon, D. 2011. Atmospheric correction in presence of sun glint: Application to MERIS. Optics Express, 19(10), 9783-800. https://doi.org/10.1364/OE.19.009783Toming, K., Kutser, T., Laas, A., Sepp, M., Paavel, B., Nõges, T. 2016. First experiences in mapping lake water quality parameters with Sentinel-2 MSI imagery. Remote Sens., 8, 640. https://doi.org/10.3390/rs8080640Tyler, A.N., Hunter, P.D., Spyrakos, E., Groom, S., Constantinescu, A.M., Kitchen, J. 2016. Developments in Earth observation for the assessment and monitoring of inland, transitional, coastal and shelf-sea waters. Sci. Total Environ., 572, 1307-1321. https://doi.org/10.1016/j.scitotenv.2016.01.020Zhao, D., Cai, Y., Jiang, H., Xu, D., Zhang, W., An, S. 2011. Estimation of water clarity in Taihu Lake and surrounding rivers using Landsat imagery. Advances in Water Resources, 34(2), 165-173. https://doi.org/10.1016/j.advwatres.2010.08.01

Reconstructing Disturbances and Their Biogeochemical Consequences over Multiple Timescales

Ongoing changes in disturbance regimes are predicted to cause acute changes in ecosystem structure and function in the coming decades, but many aspects of these predictions are uncertain. A key challenge is to improve the predictability of postdisturbance biogeochemical trajectories at the ecosystem level. Ecosystem ecologists and paleoecologists have generated complementary data sets about disturbance (type, severity, frequency) and ecosystem response (net primary productivity, nutrient cycling) spanning decadal to millennial timescales. Here, we take the first steps toward a full integration of these data sets by reviewing how disturbances are reconstructed using dendrochronological and sedimentary archives and by summarizing the conceptual frameworks for carbon, nitrogen, and hydrologic responses to disturbances. Key research priorities include further development of paleoecological techniques that reconstruct both disturbances and terrestrial ecosystem dynamics. In addition, mechanistic detail from disturbance experiments, long-term observations, and chronosequences can help increase the understanding of ecosystem resilienc

Reconstructing Disturbances and Their Biogeochemical Consequences over Multiple Timescales

Ongoing changes in disturbance regimes are predicted to cause acute changes in ecosystem structure and function in the coming decades, but many aspects of these predictions are uncertain. A key challenge is to improve the predictability of postdisturbance biogeochemical trajectories at the ecosystem level. Ecosystem ecologists and paleoecologists have generated complementary data sets about disturbance (type, severity, frequency) and ecosystem response (net primary productivity, nutrient cycling) spanning decadal to millennial timescales. Here, we take the first steps toward a full integration of these data sets by reviewing how disturbances are reconstructed using dendrochronological and sedimentary archives and by summarizing the conceptual frameworks for carbon, nitrogen, and hydrologic responses to disturbances. Key research priorities include further development of paleoecological techniques that reconstruct both disturbances and terrestrial ecosystem dynamics. In addition, mechanistic detail from disturbance experiments, long-term observations, and chronosequences can help increase the understanding of ecosystem resilience

miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly

Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or infective insults. miR0449−/− mice (both alleles are deleted) showed impaired ciliated epithelial regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously in aged miR449−/− mice. We identified Aurora kinase A and its effector target HDAC6 as key mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is downregulated upon miR449 overexpression in vitro and upregulated in miR449−/− mouse lungs. Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and coverage in miR449−/− cells, consistent with its tubulin-deacetylating function. Altogether, our study establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis