Identification of Genes Influencing Skeletal Phenotypes in Congenic P/NP Rats

We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference. The aim of this study was to identify the genes segregating for skeletal phenotypes in congenic P and NP rats. Transfer of the NP chromosome 4 QTL into the P background (P.NP) significantly decreased areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) at several skeletal sites, whereas transfer of the P chromosome 4 QTL into the NP background (NP.P) significantly increased bone mineral content (BMC) and aBMD in the same skeletal sites. Microarray analysis from the femurs using Affymetrix Rat Genome arrays revealed 53 genes that were differentially expressed among the rat strains with a false discovery rate (FDR) of less than 10%. Nine candidate genes were found to be strongly correlated (r2 > 0.50) with bone mass at multiple skeletal sites. The top three candidate genes, neuropeptide Y (Npy), α synuclein (Snca), and sepiapterin reductase (Spr), were confirmed using real-time quantitative PCR (qPCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism involving β-estradiol, interferon-γ, and a voltage-gated calcium channel. We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats. © 2010 American Society for Bone and Mineral Research

Effect of metallacarborane salt H[COSANE] doping on the performance properties of polybenzimidazole membranes for high temperature PEMFCs

[EN] In this paper, a series of composite proton exchange membranes comprising a cobaltacarborane protonated H[Co(C2B9H11)(2)] named (H[COSANE]) and polybenzimidazole (PBI) for a high temperature proton exchange membrane fuel cell (PEMFC) is reported, with the aim of enhancing the proton conductivity of PBI membranes doped with phosphoric acid. The effects of the anion [Co(C2B9H11)(2)] concentration in three different polymeric matrices based on the PBI structure, poly(2,2 '-(m-phenylene)-5,5 '-bibenzimidazole) (PBI-1), poly[2,2 '-(p-oxydiphenylene)-5,5 '-bibenzimidazole] (PBI-2) and poly(2,2 '-(p-hexafluoroisopropylidene)-5,5 '-bibenzimidazole) (PBI-3), have been investigated. The conductivity, diffusivity and mobility are greater in the composite membrane poly(2,2 '-(p-hexafluoroisopropylidene)-5,5 '-bibenzimidazole) containing fluorinated groups, reaching a maximum when the amount of H[COSANE] was 15%. In general, all the prepared membranes displayed excellent and tunable properties as conducting materials, with conductivities higher than 0.03 S cm(-1)above 140 degrees C. From an analysis of electrode polarization (EP) the proton diffusion coefficients and mobility have been calculated.This work was financially supported by the Ministerio de Economia y Competitividad (MINECO) under project ENE/2015-69203-R and by Consejo Nacional de Ciencia y Tecnologia (CONACyT) for the postdoctoral grant to J. O. The technical support of Servei de Microscpia Electrnica at Universitat Politecnica de Valencia and Servei Central d'Instrumentacio Cientifica at Universitat Jaume I is gratefully acknowledged. The authors thanks Prof. Santiago V. Luis (from Universitat Jaume I) and Dr Isabel Fuentes, Prof. Francesc Teixidor and Prof. Clara Vinas (from Instituto de Materiales de Barcelona, CSIC), for supplying the H[COSANE] compound.Olvera-Mancilla, J.; Escorihuela, J.; Alexandrova, L.; Andrio, A.; Garcia-Bernabe, A.; Del Castillo, LF.; Compañ Moreno, V. (2020). Effect of metallacarborane salt H[COSANE] doping on the performance properties of polybenzimidazole membranes for high temperature PEMFCs. Soft Matter. 16(32):7624-7635. https://doi.org/10.1039/d0sm00743aS762476351632https://earthsky.org/earth/atmospheric-co2-record-high-may-2019Steele, B. C. H., & Heinzel, A. (2001). Materials for fuel-cell technologies. Nature, 414(6861), 345-352. doi:10.1038/35104620CLEGHORN, S. (1997). Pem fuel cells for transportation and stationary power generation applications. International Journal of Hydrogen Energy, 22(12), 1137-1144. doi:10.1016/s0360-3199(97)00016-5Wang, Y., Chen, K. S., Mishler, J., Cho, S. C., & Adroher, X. C. (2011). A review of polymer electrolyte membrane fuel cells: Technology, applications, and needs on fundamental research. Applied Energy, 88(4), 981-1007. doi:10.1016/j.apenergy.2010.09.030Savage, J., Tse, Y.-L. S., & Voth, G. A. (2014). Proton Transport Mechanism of Perfluorosulfonic Acid Membranes. The Journal of Physical Chemistry C, 118(31), 17436-17445. doi:10.1021/jp504714dMauritz, K. A., & Moore, R. B. (2004). State of Understanding of Nafion. Chemical Reviews, 104(10), 4535-4586. doi:10.1021/cr0207123Kraytsberg, A., & Ein-Eli, Y. (2014). Review of Advanced Materials for Proton Exchange Membrane Fuel Cells. Energy & Fuels, 28(12), 7303-7330. doi:10.1021/ef501977kHickner, M. A., Ghassemi, H., Kim, Y. S., Einsla, B. R., & McGrath, J. E. (2004). Alternative Polymer Systems for Proton Exchange Membranes (PEMs). Chemical Reviews, 104(10), 4587-4612. doi:10.1021/cr020711aKongstein, O. E., Berning, T., Børresen, B., Seland, F., & Tunold, R. (2007). Polymer electrolyte fuel cells based on phosphoric acid doped polybenzimidazole (PBI) membranes. Energy, 32(4), 418-422. doi:10.1016/j.energy.2006.07.009Pant, B., Park, M., & Park, S.-J. (2019). One-Step Synthesis of Silver Nanoparticles Embedded Polyurethane Nano-Fiber/Net Structured Membrane as an Effective Antibacterial Medium. Polymers, 11(7), 1185. doi:10.3390/polym11071185Suryani, Chang, Y.-N., Lai, J.-Y., & Liu, Y.-L. (2012). Polybenzimidazole (PBI)-functionalized silica nanoparticles modified PBI nanocomposite membranes for proton exchange membranes fuel cells. Journal of Membrane Science, 403-404, 1-7. doi:10.1016/j.memsci.2012.01.043Escorihuela, J., Sahuquillo, Ó., García-Bernabé, A., Giménez, E., & Compañ, V. (2018). Phosphoric Acid Doped Polybenzimidazole (PBI)/Zeolitic Imidazolate Framework Composite Membranes with Significantly Enhanced Proton Conductivity under Low Humidity Conditions. Nanomaterials, 8(10), 775. doi:10.3390/nano8100775Escorihuela, J., García-Bernabé, A., Montero, Á., Sahuquillo, Ó., Giménez, E., & Compañ, V. (2019). Ionic Liquid Composite Polybenzimidazol Membranes for High Temperature PEMFC Applications. Polymers, 11(4), 732. doi:10.3390/polym11040732Compañ, V., Escorihuela, J., Olvera, J., García-Bernabé, A., & Andrio, A. (2020). Influence of the anion on diffusivity and mobility of ionic liquids composite polybenzimidazol membranes. Electrochimica Acta, 354, 136666. doi:10.1016/j.electacta.2020.136666Fuentes, I., Andrio, A., García-Bernabé, A., Escorihuela, J., Viñas, C., Teixidor, F., & Compañ, V. (2018). Structural and dielectric properties of cobaltacarborane composite polybenzimidazole membranes as solid polymer electrolytes at high temperature. Physical Chemistry Chemical Physics, 20(15), 10173-10184. doi:10.1039/c8cp00372fDechnik, J., Gascon, J., Doonan, C. J., Janiak, C., & Sumby, C. J. (2017). Mixed‐Matrix Membranes. Angewandte Chemie International Edition, 56(32), 9292-9310. doi:10.1002/anie.201701109Chung, T.-S., Jiang, L. Y., Li, Y., & Kulprathipanja, S. (2007). Mixed matrix membranes (MMMs) comprising organic polymers with dispersed inorganic fillers for gas separation. Progress in Polymer Science, 32(4), 483-507. doi:10.1016/j.progpolymsci.2007.01.008Zhang, J., Xie, Z., Zhang, J., Tang, Y., Song, C., Navessin, T., … Holdcroft, S. (2006). High temperature PEM fuel cells. Journal of Power Sources, 160(2), 872-891. doi:10.1016/j.jpowsour.2006.05.034Araya, S. S., Zhou, F., Liso, V., Sahlin, S. L., Vang, J. R., Thomas, S., … Kær, S. K. (2016). A comprehensive review of PBI-based high temperature PEM fuel cells. International Journal of Hydrogen Energy, 41(46), 21310-21344. doi:10.1016/j.ijhydene.2016.09.024Asensio, J. A., Sánchez, E. M., & Gómez-Romero, P. (2010). Proton-conducting membranes based on benzimidazole polymers for high-temperature PEM fuel cells. A chemical quest. Chemical Society Reviews, 39(8), 3210. doi:10.1039/b922650hWang, Y., Shi, Z., Fang, J., Xu, H., & Yin, J. (2011). Graphene oxide/polybenzimidazole composites fabricated by a solvent-exchange method. Carbon, 49(4), 1199-1207. doi:10.1016/j.carbon.2010.11.036Li, J., Li, X., Zhao, Y., Lu, W., Shao, Z., & Yi, B. (2012). High-Temperature Proton-Exchange-Membrane Fuel Cells Using an Ether-Containing Polybenzimidazole Membrane as Electrolyte. ChemSusChem, 5(5), 896-900. doi:10.1002/cssc.201100725Qian, G., & Benicewicz, B. C. (2009). Synthesis and characterization of high molecular weight hexafluoroisopropylidene-containing polybenzimidazole for high-temperature polymer electrolyte membrane fuel cells. Journal of Polymer Science Part A: Polymer Chemistry, 47(16), 4064-4073. doi:10.1002/pola.23467Núñez, R., Tarrés, M., Ferrer-Ugalde, A., de Biani, F. F., & Teixidor, F. (2016). Electrochemistry and Photoluminescence of Icosahedral Carboranes, Boranes, Metallacarboranes, and Their Derivatives. Chemical Reviews, 116(23), 14307-14378. doi:10.1021/acs.chemrev.6b00198Pepiol, A., Teixidor, F., Sillanpää, R., Lupu, M., & Viñas, C. (2011). Stepwise Sequential Redox Potential Modulation Possible on a Single Platform. Angewandte Chemie International Edition, 50(52), 12491-12495. doi:10.1002/anie.201105668González-Cardoso, P., Stoica, A.-I., Farràs, P., Pepiol, A., Viñas, C., & Teixidor, F. (2010). Additive Tuning of Redox Potential in Metallacarboranes by Sequential Halogen Substitution. Chemistry - A European Journal, 16(22), 6660-6665. doi:10.1002/chem.200902558Tarrés, M., Viñas, C., Cioran, A. M., Hänninen, M. M., Sillanpää, R., & Teixidor, F. (2014). Towards Multifunctional Materials Incorporating Elastomers and Reversible Redox-Active Fragments. Chemistry - A European Journal, 20(48), 15808-15815. doi:10.1002/chem.201403424Tarrés, M., Arderiu, V. S., Zaulet, A., Viñas, C., Fabrizi de Biani, F., & Teixidor, F. (2015). How to get the desired reduction voltage in a single framework! Metallacarborane as an optimal probe for sequential voltage tuning. Dalton Transactions, 44(26), 11690-11695. doi:10.1039/c5dt01464fFuentes, I., Andrio, A., Teixidor, F., Viñas, C., & Compañ, V. (2017). Enhanced conductivity of sodium versus lithium salts measured by impedance spectroscopy. Sodium cobaltacarboranes as electrolytes of choice. Physical Chemistry Chemical Physics, 19(23), 15177-15186. doi:10.1039/c7cp02526bEaton, P. E., Carlson, G. R., & Lee, J. T. (1973). Phosphorus pentoxide-methanesulfonic acid. Convenient alternative to polyphosphoric acid. The Journal of Organic Chemistry, 38(23), 4071-4073. doi:10.1021/jo00987a028Musto, P., Karasz, F. E., & MacKnight, W. J. (1989). Hydrogen bonding in polybenzimidazole/polyimide systems: a Fourier-transform infra-red investigation using low-molecular-weight monofunctional probes. Polymer, 30(6), 1012-1021. doi:10.1016/0032-3861(89)90072-4Xu, H., Chen, K., Guo, X., Fang, J., & Yin, J. (2007). Synthesis of novel sulfonated polybenzimidazole and preparation of cross-linked membranes for fuel cell application. Polymer, 48(19), 5556-5564. doi:10.1016/j.polymer.2007.07.029Kumar B., S., Sana, B., Unnikrishnan, G., Jana, T., & Kumar K. S., S. (2020). Polybenzimidazole co-polymers: their synthesis, morphology and high temperature fuel cell membrane properties. Polymer Chemistry, 11(5), 1043-1054. doi:10.1039/c9py01403aChuang, S.-W., & Hsu, S. L.-C. (2006). Synthesis and properties of a new fluorine-containing polybenzimidazole for high-temperature fuel-cell applications. Journal of Polymer Science Part A: Polymer Chemistry, 44(15), 4508-4513. doi:10.1002/pola.21555Chuang, S.-W., Hsu, S. L.-C., & Hsu, C.-L. (2007). Synthesis and properties of fluorine-containing polybenzimidazole/montmorillonite nanocomposite membranes for direct methanol fuel cell applications. Journal of Power Sources, 168(1), 172-177. doi:10.1016/j.jpowsour.2007.03.021Kang, Y., Zou, J., Sun, Z., Wang, F., Zhu, H., Han, K., … Meng, Q. (2013). Polybenzimidazole containing ether units as electrolyte for high temperature proton exchange membrane fuel cells. International Journal of Hydrogen Energy, 38(15), 6494-6502. doi:10.1016/j.ijhydene.2013.03.051Mack, F., Aniol, K., Ellwein, C., Kerres, J., & Zeis, R. (2015). Novel phosphoric acid-doped PBI-blends as membranes for high-temperature PEM fuel cells. Journal of Materials Chemistry A, 3(20), 10864-10874. doi:10.1039/c5ta01337bErgun, D., Devrim, Y., Bac, N., & Eroglu, I. (2012). Phosphoric acid doped polybenzimidazole membrane for high temperature PEM fuel cell. Journal of Applied Polymer Science, 124(S1), E267-E277. doi:10.1002/app.36507Yuan, S., Yan, G., Xia, Z., Guo, X., Fang, J., & Yang, X. (2013). Preparation and properties of covalently cross-linked sulfonated poly(sulfide sulfone)/polybenzimidazole blend membranes for fuel cell applications. High Performance Polymers, 26(2), 212-222. doi:10.1177/0954008313507589Sacco, A. (2017). Electrochemical impedance spectroscopy: Fundamentals and application in dye-sensitized solar cells. Renewable and Sustainable Energy Reviews, 79, 814-829. doi:10.1016/j.rser.2017.05.159Gomadam, P. M., & Weidner, J. W. (2005). Analysis of electrochemical impedance spectroscopy in proton exchange membrane fuel cells. International Journal of Energy Research, 29(12), 1133-1151. doi:10.1002/er.1144Klein, R. J., Zhang, S., Dou, S., Jones, B. H., Colby, R. H., & Runt, J. (2006). Modeling electrode polarization in dielectric spectroscopy: Ion mobility and mobile ion concentration of single-ion polymer electrolytes. The Journal of Chemical Physics, 124(14), 144903. doi:10.1063/1.2186638Serghei, A., Tress, M., Sangoro, J. R., & Kremer, F. (2009). Electrode polarization and charge transport at solid interfaces. Physical Review B, 80(18). doi:10.1103/physrevb.80.184301Leys, J., Wübbenhorst, M., Preethy Menon, C., Rajesh, R., Thoen, J., Glorieux, C., … Longuemart, S. (2008). Temperature dependence of the electrical conductivity of imidazolium ionic liquids. The Journal of Chemical Physics, 128(6), 064509. doi:10.1063/1.2827462Coelho, R. (1983). Sur la relaxation d’une charge d’espace. Revue de Physique Appliquée, 18(3), 137-146. doi:10.1051/rphysap:01983001803013700Coelho, R. (1991). On the static permittivity of dipolar and conductive media — an educational approach. Journal of Non-Crystalline Solids, 131-133, 1136-1139. doi:10.1016/0022-3093(91)90740-wEscorihuela, J., García-Bernabé, A., & Compañ, V. (2020). A Deep Insight into Different Acidic Additives as Doping Agents for Enhancing Proton Conductivity on Polybenzimidazole Membranes. Polymers, 12(6), 1374. doi:10.3390/polym12061374Villa, D. C., Angioni, S., Barco, S. D., Mustarelli, P., & Quartarone, E. (2014). Polysulfonated Fluoro-oxyPBI Membranes for PEMFCs: An Efficient Strategy to Achieve Good Fuel Cell Performances with Low H3PO4Doping Levels. Advanced Energy Materials, 4(11), 1301949. doi:10.1002/aenm.201301949Ma, Y.-L., Wainright, J. S., Litt, M. H., & Savinell, R. F. (2004). Conductivity of PBI Membranes for High-Temperature Polymer Electrolyte Fuel Cells. Journal of The Electrochemical Society, 151(1), A8. doi:10.1149/1.1630037Li, Q., Jensen, J. O., Savinell, R. F., & Bjerrum, N. J. (2009). High temperature proton exchange membranes based on polybenzimidazoles for fuel cells. Progress in Polymer Science, 34(5), 449-477. doi:10.1016/j.progpolymsci.2008.12.003Kumar, S. R., Wang, J.-J., Wu, Y.-S., Yang, C.-C., & Lue, S. J. (2020). Synergistic role of graphene oxide-magnetite nanofillers contribution on ionic conductivity and permeability for polybenzimidazole membrane electrolytes. Journal of Power Sources, 445, 227293. doi:10.1016/j.jpowsour.2019.227293Guerrero Moreno, N., Gervasio, D., Godínez García, A., & Pérez Robles, J. F. (2015). Polybenzimidazole-multiwall carbon nanotubes composite membranes for polymer electrolyte membrane fuel cells. Journal of Power Sources, 300, 229-237. doi:10.1016/j.jpowsour.2015.09.070Üregen, N., Pehlivanoğlu, K., Özdemir, Y., & Devrim, Y. (2017). Development of polybenzimidazole/graphene oxide composite membranes for high temperature PEM fuel cells. International Journal of Hydrogen Energy, 42(4), 2636-2647. doi:10.1016/j.ijhydene.2016.07.009Yang, J., Gao, L., Wang, J., Xu, Y., Liu, C., & He, R. (2017). Strengthening Phosphoric Acid Doped Polybenzimidazole Membranes with Siloxane Networks for Using as High Temperature Proton Exchange Membranes. Macromolecular Chemistry and Physics, 218(10), 1700009. doi:10.1002/macp.201700009Satheesh Kumar, B., Sana, B., Mathew, D., Unnikrishnan, G., Jana, T., & Santhosh Kumar, K. S. (2018). Polybenzimidazole-nanocomposite membranes: Enhanced proton conductivity with low content of amine-functionalized nanoparticles. Polymer, 145, 434-446. doi:10.1016/j.polymer.2018.04.081Singha, S., & Jana, T. (2014). Structure and Properties of Polybenzimidazole/Silica Nanocomposite Electrolyte Membrane: Influence of Organic/Inorganic Interface. ACS Applied Materials & Interfaces, 6(23), 21286-21296. doi:10.1021/am506260jKannan, R., Kagalwala, H. N., Chaudhari, H. D., Kharul, U. K., Kurungot, S., & Pillai, V. K. (2011). Improved performance of phosphonated carbon nanotube–polybenzimidazole composite membranes in proton exchange membrane fuel cells. Journal of Materials Chemistry, 21(20), 7223. doi:10.1039/c0jm04265jXu, C., Cao, Y., Kumar, R., Wu, X., Wang, X., & Scott, K. (2011). A polybenzimidazole/sulfonated graphite oxide composite membrane for high temperature polymer electrolyte membrane fuel cells. Journal of Materials Chemistry, 21(30), 11359. doi:10.1039/c1jm11159kMamlouk, M., Ocon, P., & Scott, K. (2014). Preparation and characterization of polybenzimidzaole/diethylamine hydrogen sulphate for medium temperature proton exchange membrane fuel cells. Journal of Power Sources, 245, 915-926. doi:10.1016/j.jpowsour.2013.07.050Fuentes, I., Mostazo‐López, M. J., Kelemen, Z., Compañ, V., Andrio, A., Morallón, E., … Teixidor, F. (2019). Are the Accompanying Cations of Doping Anions Influential in Conducting Organic Polymers? The Case of the Popular PEDOT. Chemistry – A European Journal, 25(63), 14308-14319. doi:10.1002/chem.201902708Springer, T. E., Zawodzinski, T. A., & Gottesfeld, S. (1991). Polymer Electrolyte Fuel Cell Model. Journal of The Electrochemical Society, 138(8), 2334-2342. doi:10.1149/1.2085971Otomo, J. (2003). Protonic conduction of CsH2PO4 and its composite with silica in dry and humid atmospheres. Solid State Ionics, 156(3-4), 357-369. doi:10.1016/s0167-2738(02)00746-4Gebbie, M. A., Smith, A. M., Dobbs, H. A., Lee, A. A., Warr, G. G., Banquy, X., … Atkin, R. (2017). Long range electrostatic forces in ionic liquids. Chemical Communications, 53(7), 1214-1224. doi:10.1039/c6cc08820aWeingärtner, H. (2008). Understanding Ionic Liquids at the Molecular Level: Facts, Problems, and Controversies. Angewandte Chemie International Edition, 47(4), 654-670. doi:10.1002/anie.200604951Rivera, A., & Rössler, E. A. (2006). Evidence of secondary relaxations in the dielectric spectra of ionic liquids. Physical Review B, 73(21). doi:10.1103/physrevb.73.212201Pu, H., Lou, L., Guan, Y., Chang, Z., & Wan, D. (2012). Proton exchange membranes based on semi-interpenetrating polymer networks of polybenzimidazole and perfluorosulfonic acid polymer with hollow silica spheres as micro-reservoir. Journal of Membrane Science, 415-416, 496-503. doi:10.1016/j.memsci.2012.05.036Sørensen, T. S., & Compañ, V. (1995). Complex permittivity of a conducting, dielectric layer containing arbitrary binary Nernst–Planck electrolytes with applications to polymer films and cellulose acetate membranes. J. Chem. Soc., Faraday Trans., 91(23), 4235-4250. doi:10.1039/ft9959104235Sørensen, T. S., Compañ, V., & Diaz-Calleja, R. (1996). Complex permittivity of a film of poly[4-(acryloxy)phenyl-(4-chlorophenyl)methanone] containing free ion impurities and the separation of the contributions from interfacial polarization, Maxwell–Wagner–Sillars effects and dielectric relaxations of the polymer chains. J. Chem. Soc., Faraday Trans., 92(11), 1947-1957. doi:10.1039/ft9969201947Wang, Y., Fan, F., Agapov, A. L., Saito, T., Yang, J., Yu, X., … Sokolov, A. P. (2014). Examination of the fundamental relation between ionic transport and segmental relaxation in polymer electrolytes. Polymer, 55(16), 4067-4076. doi:10.1016/j.polymer.2014.06.085Valverde, D., Garcia-Bernabé, A., Andrio, A., García-Verdugo, E., Luis, S. V., & Compañ, V. (2019). Free ion diffusivity and charge concentration on cross-linked polymeric ionic liquid iongel films based on sulfonated zwitterionic salts and lithium ions. Physical Chemistry Chemical Physics, 21(32), 17923-17932. doi:10.1039/c9cp01903kLee, S. H., & Rasaiah, J. C. (2011). Proton transfer and the mobilities of the H+ and OH− ions from studies of a dissociating model for water. The Journal of Chemical Physics, 135(12), 124505. doi:10.1063/1.3632990Liang, T., Shin, Y. K., Cheng, Y.-T., Yilmaz, D. E., Vishnu, K. G., Verners, O., … van Duin, A. C. T. (2013). Reactive Potentials for Advanced Atomistic Simulations. Annual Review of Materials Research, 43(1), 109-129. doi:10.1146/annurev-matsci-071312-121610Wang, Y., Sun, C.-N., Fan, F., Sangoro, J. R., Berman, M. B., Greenbaum, S. G., … Sokolov, A. P. (2013). Examination of methods to determine free-ion diffusivity and number density from analysis of electrode polarization. Physical Review E, 87(4). doi:10.1103/physreve.87.042308Bennour, I., Cioran, A. M., Teixidor, F., & Viñas, C. (2019). 3,2,1 and stop! An innovative, straightforward and clean route for the flash synthesis of metallacarboranes. Green Chemistry, 21(8), 1925-1928. doi:10.1039/c8gc03943

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation

Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in Congolese populations of Central Africa

Background: HIV-infection, tuberculosis and malaria are the big three communicable diseases that plague sub-Saharan Africa. If these diseases occur as co-morbidities they require polypharmacy, which may lead to severe drug-drug-gene interactions and variation in adverse drug reactions, but also in treatment outcomes. Polymorphisms in genes encoding drug-metabolizing enzymes are the major cause of these variations, but such polymorphisms may support the prediction of drug efficacy and toxicity. There is little information on allele frequencies of pharmacogenetic variants of enzymes involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in the Republic of Congo (ROC). The aim of this study was therefore to investigate the occurrence and allele frequencies of 32 pharmacogenetic variants localized in absorption distribution, metabolism and excretion (ADME) and non-ADME genes and to compare the frequencies with population data of Africans and non-Africans derived from the 1000 Genomes Project. Results: We found significant differences in the allele frequencies of many of the variants when comparing the findings from ROC with those of non-African populations. On the other hand, only a few variants showed significant differences in their allele frequencies when comparing ROC with other African populations. In addition, considerable differences in the allele frequencies of the pharmacogenetic variants among the African populations were observed. Conclusions: The findings contribute to the understanding of pharmacogenetic variants involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in ROC and their diversity in different populations. Such knowledge helps to predict drug efficacy, toxicity and ADRs and to inform individual and population-based decisions

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362