Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis : a genome-wide association study

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early-and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.Peer reviewe

Modulating charge carrier density and mobility in doped graphene by covalent functionalization

[EN] Covalent B-functionalization of B-doped graphene has been performed for the first time. The electronic properties and Hall effect of functionalized N- and B-doped graphene can be tuned by tailoring the electron-donating/-withdrawing properties of the organic addend.The authors appreciate support from the Ministerio de Economia y Competitividad (MINECO) of Spain (projects CTQ2015-69153-CO2-1, CTQ2016-79189-R and MAT2015-69669-P) and the Junta de Comunidades de Castilla-La Mancha (project SBPLY/17/180501/000254). L. M. A. thanks MINECO (CTQ2016-79189-R) for a doctoral FPI grant.Arellano, LM.; Yue, S.; Atienzar Corvillo, PE.; Gómez-Escalonilla, MJ.; Ortega Higueruelo, FJ.; Fierro, JLG.; García Gómez, H.... (2019). Modulating charge carrier density and mobility in doped graphene by covalent functionalization. Chemical Communications. 55(67):9999-10002. https://doi.org/10.1039/c9cc04571fS9999100025567Wang, X., Sun, G., Routh, P., Kim, D.-H., Huang, W., & Chen, P. (2014). Heteroatom-doped graphene materials: syntheses, properties and applications. Chem. Soc. Rev., 43(20), 7067-7098. doi:10.1039/c4cs00141aLavorato, C., Primo, A., Molinari, R., & Garcia, H. (2013). N-Doped Graphene Derived from Biomass as a Visible-Light Photocatalyst for Hydrogen Generation from Water/Methanol Mixtures. Chemistry - A European Journal, 20(1), 187-194. doi:10.1002/chem.201303689Latorre-Sánchez, M., Primo, A., & García, H. (2013). P-Doped Graphene Obtained by Pyrolysis of Modified Alginate as a Photocatalyst for Hydrogen Generation from Water-Methanol Mixtures. Angewandte Chemie International Edition, 52(45), 11813-11816. doi:10.1002/anie.201304505Duan, J., Chen, S., Jaroniec, M., & Qiao, S. Z. (2015). Heteroatom-Doped Graphene-Based Materials for Energy-Relevant Electrocatalytic Processes. ACS Catalysis, 5(9), 5207-5234. doi:10.1021/acscatal.5b00991Putri, L. K., Ong, W.-J., Chang, W. S., & Chai, S.-P. (2015). Heteroatom doped graphene in photocatalysis: A review. Applied Surface Science, 358, 2-14. doi:10.1016/j.apsusc.2015.08.177Niu, L., Li, Z., Hong, W., Sun, J., Wang, Z., Ma, L., … Yang, S. (2013). Pyrolytic synthesis of boron-doped graphene and its application as electrode material for supercapacitors. Electrochimica Acta, 108, 666-673. doi:10.1016/j.electacta.2013.07.025Sahoo, M., Sreena, K. P., Vinayan, B. P., & Ramaprabhu, S. (2015). Green synthesis of boron doped graphene and its application as high performance anode material in Li ion battery. Materials Research Bulletin, 61, 383-390. doi:10.1016/j.materresbull.2014.10.049Khai, T. V., Na, H. G., Kwak, D. S., Kwon, Y. J., Ham, H., Shim, K. B., & Kim, H. W. (2012). Comparison study of structural and optical properties of boron-doped and undoped graphene oxide films. Chemical Engineering Journal, 211-212, 369-377. doi:10.1016/j.cej.2012.09.081Osumi, S., Saito, S., Dou, C., Matsuo, K., Kume, K., Yoshikawa, H., … Yamaguchi, S. (2016). Boron-doped nanographene: Lewis acidity, redox properties, and battery electrode performance. Chemical Science, 7(1), 219-227. doi:10.1039/c5sc02246kXu, Q., Jiang, X., Zhu, W., Chen, C., Hu, G., & Li, Q. (2016). Synthesis, preliminary biological evaluation and 3D-QSAR study of novel 1,5-disubstituted-2(1H)-pyridone derivatives as potential anti-lung cancer agents. Arabian Journal of Chemistry, 9(5), 721-735. doi:10.1016/j.arabjc.2015.08.001Pimenta, M. A., Dresselhaus, G., Dresselhaus, M. S., Cançado, L. G., Jorio, A., & Saito, R. (2007). Studying disorder in graphite-based systems by Raman spectroscopy. Phys. Chem. Chem. Phys., 9(11), 1276-1290. doi:10.1039/b613962kVoggu, R., Rout, C. S., Franklin, A. D., Fisher, T. S., & Rao, C. N. R. (2008). Extraordinary Sensitivity of the Electronic Structure and Properties of Single-Walled Carbon Nanotubes to Molecular Charge-Transfer. The Journal of Physical Chemistry C, 112(34), 13053-13056. doi:10.1021/jp805136eBiswal, M., Zhang, X., Schilter, D., Lee, T. K., Hwang, D. Y., Saxena, M., … Ruoff, R. S. (2017). Sodide and Organic Halides Effect Covalent Functionalization of Single-Layer and Bilayer Graphene. Journal of the American Chemical Society, 139(11), 4202-4210. doi:10.1021/jacs.7b00932Vizuete, M., Gómez-Escalonilla, M. J., Fierro, J. L. G., Ohkubo, K., Fukuzumi, S., Yudasaka, M., … Langa, F. (2014). Photoinduced electron transfer in a carbon nanohorn–C60 conjugate. Chemical Science, 5(5), 2072. doi:10.1039/c3sc53342eAllongue, P., Delamar, M., Desbat, B., Fagebaume, O., Hitmi, R., Pinson, J., & Savéant, J.-M. (1997). Covalent Modification of Carbon Surfaces by Aryl Radicals Generated from the Electrochemical Reduction of Diazonium Salts. Journal of the American Chemical Society, 119(1), 201-207. doi:10.1021/ja963354sBarrejón, M., Gómez-Escalonilla, M. J., Fierro, J. L. G., Prieto, P., Carrillo, J. R., Rodríguez, A. M., … Langa, F. (2016). Modulation of the exfoliated graphene work function through cycloaddition of nitrile imines. Physical Chemistry Chemical Physics, 18(42), 29582-29590. doi:10.1039/c6cp05285aBarrejón, M., Primo, A., Gómez-Escalonilla, M. J., Fierro, J. L. G., García, H., & Langa, F. (2015). Covalent functionalization of N-doped graphene by N-alkylation. Chemical Communications, 51(95), 16916-16919. doi:10.1039/c5cc06285cSu, C.-Y., Xu, Y., Zhang, W., Zhao, J., Tang, X., Tsai, C.-H., & Li, L.-J. (2009). Electrical and Spectroscopic Characterizations of Ultra-Large Reduced Graphene Oxide Monolayers. Chemistry of Materials, 21(23), 5674-5680. doi:10.1021/cm902182

A photoresponsive graphene oxide-C60 conjugate

[EN] An all-carbon donor–acceptor hybrid combining graphene oxide (GO) and C60 has been prepared. Laser flash photolysis measurements revealed the occurrence of photoinduced electron transfer from the GO electron donor to the C60 electron acceptor in the conjugate.This research was financially supported by the Spanish Ministry of Economy and Competitiveness of Spain (CTQ2010-17498, MAT2010-20843-C02-01 and PLE-2009-0038) and a Severo Ochoa operating grant from the Spanish Ministry of Economy and Competitiveness. We also acknowledge financial support from the Spanish Ministry of Economy and Competitiveness, Comunidad de Madrid (CAM 09-S2009_MAT-1467), Generalitat Valenciana (PROMETEO program), and VLC/Campus Microcluster "Nanomateriales Funcionales y Nanodispositivos".Barrejón, M.; Vizuete, M.; Gómez Escalonilla, M.; Fierro, J.; Berlanga, I.; Zamora, F.; Abellán, G.... (2014). A photoresponsive graphene oxide-C60 conjugate. Chemical Communications. 50(65):9053-9055. doi:10.1039/C3CC49589BS90539055506

ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Understandingthepathogenicmechanismsof diseasemutations is critical toadvancingtreatments.ALS-associated mutations in the gene encoding the microtubulemotor KIF5A result in skipping of exon 27 (KIF5ADExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore,mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis

A sex-chromosome mutation in Silene latifolia

Silene latifolia is dioecious, yet rare hermaphrodites have been found, and such natural mutants can provide valuable insight into genetic mechanisms. Here, we describe a hermaphrodite-inducing mutation that is almost certainly localized to the gynoecium-suppression region of the Y chromosome in S. latifolia. The mutant Y chromosome was passed through the megaspore, and the presence of two X chromosomes was not necessary for seed development in the parent. This result supports a lack of degeneration of the Y chromosome in S. latifolia, consistent with the relatively recent formation of the sex chromosomes in this species. When crossed to wild-type plants, hermaphrodites performed poorly as females, producing low seed numbers. When hermaphrodites were pollen donors, the sex ratio of offspring they produced through crosses was biased towards females. This suggests that hermaphroditic S. latifolia would fail to thrive and potentially explains the rarity of hermaphrodites in natural populations of S. latifolia. These results indicate that the Y chromosome in Silene latifolia remains very similar to the X, perhaps mostly differing in the primary sex determination regions

Different DNA methylation patterns detected by the Amplified Methylation Polymorphism Polymerase Chain Reaction (AMP PCR) technique among various cell types of bulls

Background: The purpose of this study was to apply an arbitrarily primed methylation sensitive polymerase chain reaction (PCR) assay called Amplified Methylation Polymorphism Polymerase Chain Reaction (AMP PCR) to investigate the methylation profiles of somatic and germ cells obtained from Holstein bulls

A high-resolution melt curve toolkit to identify lineage-defining SARS-CoV-2 mutations.

The emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) variants of concern (VOCs), with mutations linked to increased transmissibility, vaccine escape and virulence, has necessitated the widespread genomic surveillance of SARS-CoV-2. This has placed a strain on global sequencing capacity, especially in areas lacking the resources for large scale sequencing activities. Here we have developed three separate multiplex high-resolution melting assays to enable the identification of Alpha, Beta, Delta and Omicron VOCs. The assays were evaluated against whole genome sequencing on upper-respiratory swab samples collected during the Alpha, Delta and Omicron [BA.1] waves of the UK pandemic. The sensitivities of the eight individual primer sets were all 100%, and specificity ranged from 94.6 to 100%. The multiplex HRM assays have potential as a tool for high throughput surveillance of SARS-CoV-2 VOCs, particularly in areas with limited genomics facilities

Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins

In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fresh primary human hepatocytes) at the gene expression level and analyze their metabolic cytochrome P450 capabilities. The cellular models were exposed to three different CYP450 inducers; beta-naphthoflavone (BNF), phenobarbital (PB), and rifampicin (RIF). HepG2 cells responded very weakly to the different inducers at the gene expression level, and this translated generally into low CYP450 activities in the induced cells compared with the control cells. On the contrary, HepaRG cells and the three human donors were inducible after exposure to BNF, PB, and RIF according to gene expression responses and CYP450 activities. Consequently, HepaRG cells could be used in screening as a substitute and/or in complement to primary hepatocytes for CYP induction studies. The second objective was to investigate the predictivity of the different cellular models to detect hepatotoxins (16 hepatotoxic and 5 nonhepatotoxic compounds). Specificity was 100% with the different cellular models tested. Cryopreserved human hepatocytes gave the highest sensitivity, ranging from 31% to 44% (depending on the donor), followed by lower sensitivity (13%) for HepaRG and HepG2 cells (6.3%). Overall, none of the models under study gave desirable sensitivities (80–100%). Consequently, a high metabolic capacity and CYP inducibility in cell lines does not necessarily correlate with a high sensitivity for the detection of hepatotoxic drugs. Further investigations are necessary to compare different cellular models and determine those that are best suited for the detection of hepatotoxic compounds