6,736 results on '"Hardy, John"'
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52. Potential for Chemistry in Multidisciplinary, Interdisciplinary, and Transdisciplinary Teaching Activities in Higher Education
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Hardy, John G., Sdepanian, Stephanie, Stowell, Alison F., Aljohani, Amal D., Allen, Michael J., Anwar, Ayaz, Barton, Dik, Baum, John V., Bird, David, Blaney, Adam, Brewster, Liz, Cheneler, David, Efremova, Olga, Entwistle, Michael, Esfahani, Reza N., Firlak, Melike, Foito, Alex, Forciniti, Leandro, Geissler, Sydney A., Guo, Feng, Hathout, Rania M., Jiang, Richard, Kevin, Punarja, Leese, David, Low, Wan Li, Mayes, Sarah, Mozafari, Masoud, Murphy, Samuel T., Nguyen, Hieu, Ntola, Chifundo N. M., Okafo, George, Partington, Adam, Prescott, Thomas A. K., Price, Stephen P., Soliman, Sherif, Sutar, Papri, Townsend, David, Trotter, Patrick, and Wright, Karen L.
- Abstract
For some professionally, vocationally, or technically oriented careers, curricula delivered in higher education establishments may focus on teaching material related to a single discipline. By contrast, multidisciplinary, interdisciplinary, and transdisciplinary teaching(MITT) results in improved affective and cognitive learning and critical thinking, offering learners/students the opportunity to obtain a broad general knowledge base. Chemistry is a discipline that sits at the interface of science, technology, engineering, mathematics, and medicine(STEMM) subjects (and those aligned with or informed by STEMM subjects). This article discusses the significant potential of inclusion of chemistry in MITT activities in higher education and the real-world importance in personal, organizational, national, and global contexts. It outlines the development and implementation challenges attributed to legacy higher education infrastructures (that call for creative visionary leadership with strong and supportive management and administrative functions), and curriculum design that ensures inclusivity and collaboration and is pitched and balanced appropriately. It concludes with future possibilities, notably highlighting that chemistry, as a discipline, underpins industries that have multibillion dollar turnovers and employ millions of people across the world.
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- 2021
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53. Two forgotten Anglo-Catholic pioneer priests
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Hardy, John, primary
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- 2024
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54. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study
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Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Seeley, William W, additional, Lee, Edward B, additional, Frosch, Matthew P, additional, Molina-Porcel, Laura, additional, Gefen, Tamar, additional, Redding-Ochoa, Javier, additional, Ghetti, Bernardino, additional, Robinson, Andrew C, additional, Kobylecki, Christopher, additional, Rowe, James B, additional, Beach, Thomas G, additional, Teich, Andrew F, additional, Keith, Julia L, additional, Bodi, Istvan, additional, Halliday, Glenda M, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Morris, Christopher M, additional, White, Charles L, additional, Mechawar, Naguib, additional, Boluda, Susana, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nagra, Rashed M, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Carvalho, Agostinho, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, Ross, Owen A, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Petersen, Ronald C, additional, Whitwell, Jennifer L, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Schneider, Julie A, additional, Peng, Lihua, additional, Zhu, Xiongwei, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Jones, Matthew, additional, Richardson, Anna, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Singh, Poonam, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Black, Sandra E, additional, Masellis, Mario, additional, King, Andrew, additional, Al-Sarraj, Safa, additional, Troakes, Claire, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Thomas, Alan J, additional, Evers, Bret M., additional, Bieniek, Kevin F, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, Bird, Thomas, additional, Castellani, Rudolph J, additional, Chaffee, Ann, additional, Franklin, Erin, additional, Haroutunian, Vahram, additional, Jacobsen, Max, additional, Keene, Dirk, additional, Latimer, Caitlin S, additional, Metcalf, Jeff, additional, Perrin, Richard J, additional, Purohit, Dushyant P, additional, Rissman, Robert A, additional, Schantz, Aimee, additional, Walker, Jamie, additional, De Deyn, Peter P, additional, Duyckaerts, Charles, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Turbant-Leclere, Sabrina, additional, Ervin, John F, additional, Nennesmo, Inger, additional, Riehl, James, additional, Nacmias, Benedetta, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, and Wszolek, Zbigniew K, additional
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- 2024
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55. New insights into the genetic etiology of Alzheimer’s disease and related dementias
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Bellenguez, Céline, Küçükali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, de Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antúnez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Pastor, Alfonso Arias, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belén, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Mercè, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Brusco, Luis Ignacio, Buiza-Rueda, Dolores, Bûrger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Geneviève, Chung, Jaeyoon, Cuccaro, Michael L., Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gómez, Anaïs, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-François, de Deyn, Peter Paul, de Paiva Lopes, Katia, de Witte, Lot D., Debette, Stéphanie, Deckert, Jürgen, del Ser, Teodoro, Denning, Nicola, DeStefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Mónica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Düzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernández-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fließbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macías, Emlio, Bullido, María J., Frank-García, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, García-Alberca, Jose Maria, García-González, Pablo, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, González-Pérez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grünblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Vilas, Raquel Huerto, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Ståhlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleó, Alberto, Longstreth, Jr, William, Lopez, Oscar, de Munain, Adolfo Lopez, Love, Seth, Löwemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macías, Juan, MacLeod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquié, Marta, Marshall, Rachel, Martin, Eden R., Montes, Angel Martín, Rodríguez, Carmen Martínez, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menéndez-González, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nöthen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Børge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Pérez-Cordón, Alba, Pérez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Piñol-Ripoll, Gerard, Pisanu, Claudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Inés, Thomassen, Jesper Qvist, Rábano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Allende, Irene Rosas, Rosende-Roca, Maitée, Royo, Jose Luis, Rubino, Elisa, Rujescu, Dan, Sáez, María Eugenia, Sakka, Paraskevi, Saltvedt, Ingvild, Sanabria, Ángela, Sánchez-Arjona, María Bernal, Sanchez-Garcia, Florentino, Juan, Pascual Sánchez, Sánchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloé, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbæk, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Tartan, Juan Pablo, Tárraga, Lluís, Tesí, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjærg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Broeckhoven, Christine Van, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Dongen, Jasper Van, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sébastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonça, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-François, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustín, Ramirez, Alfredo, and Lambert, Jean-Charles
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- 2022
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56. Light-responsive nanomaterials with pro-oxidant and anti-oxidant activity
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Podder, Soumik, Ghosh, Chandan Kumar, Das, Avijit, and Hardy, John George
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- 2022
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57. Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer's disease pathogenesis
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Bracher-Smith, Matthew, Leonenko, Ganna, Baker, Emily, Crawford, Karen, Graham, Andrew C., Salih, Dervis A., Howell, Brian W., Hardy, John, and Escott-Price, Valentina
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- 2022
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58. Instructive electroactive electrospun silk fibroin-based biomaterials for peripheral nerve tissue engineering
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Phamornnak, Chinnawich, Han, Bing, Spencer, Ben F., Ashton, Mark D., Blanford, Christopher F., Hardy, John G., Blaker, Jonny J., and Cartmell, Sarah H.
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- 2022
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59. 10 Drone Warfare
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Lushenko, Paul, primary and Hardy, John, additional
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- 2022
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60. Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia.
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Bonham, Luke W, Steele, Natasha ZR, Karch, Celeste M, Broce, Iris, Geier, Ethan G, Wen, Natalie L, Momeni, Parastoo, Hardy, John, Miller, Zachary A, Gorno-Tempini, Maria Luisa, Hess, Christopher P, Lewis, Patrick, Miller, Bruce L, Seeley, William W, Manzoni, Claudia, Desikan, Rahul S, Baranzini, Sergio E, Ferrari, Raffaele, Yokoyama, Jennifer S, and International FTD-Genomics Consortium (IFGC)
- Subjects
International FTD-Genomics Consortium ,Humans ,DNA-Binding Proteins ,RNA ,Risk Factors ,Cohort Studies ,Apoptosis ,Transcription ,Genetic ,Gene Expression Regulation ,Polymorphism ,Single Nucleotide ,Databases ,Genetic ,Gene Regulatory Networks ,Genome-Wide Association Study ,Primary Progressive Nonfluent Aphasia ,Protein Interaction Maps ,Frontotemporal Dementia (FTD) ,Human Genome ,Dementia ,Aphasia ,Rare Diseases ,Neurodegenerative ,Neurosciences ,Genetics ,Brain Disorders ,Biotechnology ,Aging ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Neurological - Abstract
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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- 2019
61. Non-coding variability at the APOE locus contributes to the Alzheimer's risk.
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Zhou, Xiaopu, Chen, Yu, Mok, Kin Y, Kwok, Timothy CY, Mok, Vincent CT, Guo, Qihao, Ip, Fanny C, Chen, Yuewen, Mullapudi, Nandita, Alzheimer’s Disease Neuroimaging Initiative, Giusti-Rodríguez, Paola, Sullivan, Patrick F, Hardy, John, Fu, Amy KY, Li, Yun, and Ip, Nancy Y
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Alzheimer’s Disease Neuroimaging Initiative ,Brain ,Humans ,Alzheimer Disease ,Genetic Predisposition to Disease ,Apolipoproteins C ,Apolipoproteins E ,Case-Control Studies ,Cognition ,Gene Expression ,Haplotypes ,Polymorphism ,Single Nucleotide ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Genetic Variation ,Nectins ,Polymorphism ,Single Nucleotide ,and over - Abstract
Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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- 2019
62. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease
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Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto
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Parkinson's Disease ,Human Genome ,Genetics ,Neurosciences ,Brain Disorders ,Prevention ,Neurodegenerative ,Genetic Testing ,2.3 Psychological ,social and economic factors ,2.1 Biological and endogenous factors ,Aetiology ,Decent Work and Economic Growth ,Endocytosis ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Mendelian Randomization Analysis ,Parkinson Disease ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Risk Factors ,International Parkinson's Disease Genomics Consortium ,Parkinson's disease ,endocytosis ,genetic risk ,heritability ,polygenic risk score ,Clinical Sciences ,Human Movement and Sports Sciences ,Neurology & Neurosurgery - Abstract
BackgroundPD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.ResultsThe heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.ConclusionsWe provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.
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- 2019
63. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
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Reynolds, Regina H, Botía, Juan, Nalls, Mike A, Hardy, John, Gagliano Taliun, Sarah A, and Ryten, Mina
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Genetics ,Brain Disorders ,Human Genome ,Parkinson's Disease ,Neurodegenerative ,Neurosciences ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,International Parkinson’s Disease Genomics Consortium ,System Genomics of Parkinson’s Disease ,Neuroscience ,Parkinson's disease - Abstract
Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.
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- 2019
64. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.
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Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, van Swieten, John C, van Rooij, Jeroen, Pijnenburg, Yolande, van der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, and International FTD-Genomics Consortium (IFGC)
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International FTD-Genomics Consortium ,Humans ,Amyotrophic Lateral Sclerosis ,Age of Onset ,DNA Methylation ,Gene Expression Regulation ,CpG Islands ,Genotype ,Heterozygote ,Polymorphism ,Single Nucleotide ,Aged ,Middle Aged ,Female ,Male ,Frontotemporal Dementia ,C9orf72 Protein ,C9orf72 ,genetic association ,age of onset ,amyotrophic lateral sclerosis ,frontotemporal dementia ,Polymorphism ,Single Nucleotide ,Neurology & Neurosurgery ,Medical and Health Sciences ,Psychology and Cognitive Sciences - Abstract
The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
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- 2018
65. Protein network analysis reveals selectively vulnerable regions and biological processes in FTD
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Bonham, Luke W, Steele, Natasha ZR, Karch, Celeste M, Manzoni, Claudia, Geier, Ethan G, Wen, Natalie, Ofori-Kuragu, Aaron, Momeni, Parastoo, Hardy, John, Miller, Zachary A, Hess, Christopher P, Lewis, Patrick, Miller, Bruce L, Seeley, William W, Baranzini, Sergio E, Desikan, Rahul S, Ferrari, Raffaele, Yokoyama, Jennifer S, Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, M Landqvist, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, G-YR, Mann, D, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, van der Zee, J, Van Broeckhoven, C, Cappa, SF, Leber, I, Hannequin, D, and Golfier, V
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,Acquired Cognitive Impairment ,Dementia ,Biotechnology ,Neurodegenerative ,Rare Diseases ,Neurosciences ,Brain Disorders ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,International FTD-Genomics Consortium ,Clinical sciences - Abstract
ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.
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- 2018
66. Impact of an intensive multi-disciplinary STEM enrichment program on underrepresented minority student success
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Ghazzawi, Dina, Pattison, Donna Lynn, Horn, Catherine, Hardy, John, and Brown, Beverly
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- 2022
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67. Elevation of gangliosides in four brain regions from Parkinson’s disease patients with a GBA mutation
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Blumenreich, Shani, Nehushtan, Tamar, Barav, Or B., Saville, Jennifer T., Dingjan, Tamir, Hardy, John, Fuller, Maria, and Futerman, Anthony H.
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- 2022
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68. APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease
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Okubadejo, Njideka U., Okunoye, Olaitan, Ojo, Oluwadamilola O., Arabambi, Babawale, Akinyemi, Rufus O., Osaigbovo, Godwin O., Abubakar, Sani A., Iwuozo, Emmanuel U., Wahab, Kolawole W., Agabi, Osigwe P., Agulanna, Uchechi, Imarhiagbe, Frank A., Abiodun, Oladunni V., Achoru, Charles O., Adebowale, Akintunde A., Adeniji, Olaleye, Akpekpe, John E., Ali, Mohammed W., Ani-Osheku, Ifeyinwa, Arigbodi, Ohwotemu, Balarabe, Salisu A., Bello, Abiodun H., Ekenze, Oluchi S., Erameh, Cyril O., Farombi, Temitope H., Fawale, Michael B., Komolafe, Morenikeji A., Nwani, Paul O., Nwazor, Ernest O., Nyandaiti, Yakub, Obehighe, Emmanuel E., Obiabo, Yahaya O., Odeniyi, Olanike A., Odiase, Francis E., Ojini, Francis I., Onwuegbuzie, Gerald A., Osemwegie, Nosakhare, Oshinaike, Olajumoke O., Otubogun, Folajimi M., Oyakhire, Shyngle I., Taiwo, Funlola T., Williams, Uduak E., Ozomma, Simon, Zubair, Yusuf, Hernandez, Dena, Bandres-Ciga, Sara, Blauwendraat, Cornelis, Singleton, Andrew, Houlden, Henry, Hardy, John, and Rizig, Mie
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- 2022
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69. Multi-modality machine learning predicting Parkinson’s disease
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Makarious, Mary B., Leonard, Hampton L., Vitale, Dan, Iwaki, Hirotaka, Sargent, Lana, Dadu, Anant, Violich, Ivo, Hutchins, Elizabeth, Saffo, David, Bandres-Ciga, Sara, Kim, Jonggeol Jeff, Song, Yeajin, Maleknia, Melina, Bookman, Matt, Nojopranoto, Willy, Campbell, Roy H., Hashemi, Sayed Hadi, Botia, Juan A., Carter, John F., Craig, David W., Van Keuren-Jensen, Kendall, Morris, Huw R., Hardy, John A., Blauwendraat, Cornelis, Singleton, Andrew B., Faghri, Faraz, and Nalls, Mike A.
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- 2022
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70. PhenoExam: gene set analyses through integration of different phenotype databases
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Cisterna, Alejandro, González-Vidal, Aurora, Ruiz, Daniel, Ortiz, Jordi, Gómez-Pascual, Alicia, Chen, Zhongbo, Nalls, Mike, Faghri, Faraz, Hardy, John, Díez, Irene, Maietta, Paolo, Álvarez, Sara, Ryten, Mina, and Botía, Juan A.
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- 2022
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71. Controlled Sr(ii) ion release from
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Fırlak Demirkan, Melike, Öztürk, Dilek, Çifçibaşı, Zeynep Sude, Ertan, Fatma, Hardy, John George, Nurşeval Oyunlu, Aslı, Darıcı, Hakan, Fırlak Demirkan, Melike, Öztürk, Dilek, Çifçibaşı, Zeynep Sude, Ertan, Fatma, Hardy, John George, Nurşeval Oyunlu, Aslı, and Darıcı, Hakan
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The development of electrochemical stimuli-responsive drug delivery systems is of both academic and industrial interest due to the ease with which it is possible to trigger payload release, providing drug delivery in a controllable manner. Herein, the preparation of forming hydrogels including electroactive polypyrrole nanoparticles (PPy-NPs) where Sr ions are electrochemically loaded for electrically triggered release of Sr ions is reported. The hydrogels were characterized by a variety of techniques including Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), X-ray diffraction (XRD), cyclic voltammetry (CV), The cytocompatibility towards human mesenchymal stem cells (MSCs) and fibroblasts were also studied. The Sr ion loaded PEC-ALD/CS/PPy-NPs hydrogel showed no significant cytotoxicity towards human mesenchymal stem cells (MSCs) and fibroblasts. Sr ions were electrochemically loaded and released from the electroactive hydrogels, and the application of an electrical stimulus enhanced the release of Sr ions from gels by 2-4 fold relative to the passive release control experiment. The antibacterial activity of Sr ions against and was demonstrated . Although these prototypical examples of Sr loaded electroactive gels don't release sufficient Sr ions to show antibacterial activity against and , we believe future iterations with optimised physical properties of the gels will be capable of doing so. [Abstract copyright: This journal is © The Royal Society of Chemistry.]
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- 2024
72. Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4
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Chen, Zhongbo, Gustavsson, Emil K., Macpherson, Hannah, Anderson, Claire, Clarkson, Chris, Rocca, Clarissa, Self, Eleanor, Alvarez Jerez, Pilar, Scardamaglia, Annarita, Pellerin, David, Montgomery, Kylie, Lee, Jasmaine, Gagliardi, Delia, Luo, Huihui, Hardy, John, Polke, James, Singleton, Andrew B., Blauwendraat, Cornelis, Mathews, Katherine D., Tucci, Arianna, Fu, Ying-Hui, Houlden, Henry, Ryten, Mina, Ptáček, Louis J., Chen, Zhongbo, Gustavsson, Emil K., Macpherson, Hannah, Anderson, Claire, Clarkson, Chris, Rocca, Clarissa, Self, Eleanor, Alvarez Jerez, Pilar, Scardamaglia, Annarita, Pellerin, David, Montgomery, Kylie, Lee, Jasmaine, Gagliardi, Delia, Luo, Huihui, Hardy, John, Polke, James, Singleton, Andrew B., Blauwendraat, Cornelis, Mathews, Katherine D., Tucci, Arianna, Fu, Ying-Hui, Houlden, Henry, Ryten, Mina, and Ptáček, Louis J.
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Background: Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. Objectives: Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region. Methods: We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features. Results: Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare. Conclusions: These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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- 2024
73. A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups
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Jiang, Yuanbing, Uhm, Hyebin, Ip, Fanny C., Ouyang, Li, Lo, Ronnie M. N., Cheng, Elaine Y. L., Cao, Xiaoyun, Tan, Clara M. C., Law, Brian C. H., Ortiz-Romero, Paula, Puig-Pijoan, Albert, Fernández-Lebrero, Aida, Contador, José, Mok, Kin Ying Boniface, Hardy, John, Kwok, Timothy C. Y., Mok, Vincent C. T., Suárez-Calvet, Marc, Zetterberg, Henrik, Fu, Amy K. Y., Ip, Nancy Yuk-yu, Jiang, Yuanbing, Uhm, Hyebin, Ip, Fanny C., Ouyang, Li, Lo, Ronnie M. N., Cheng, Elaine Y. L., Cao, Xiaoyun, Tan, Clara M. C., Law, Brian C. H., Ortiz-Romero, Paula, Puig-Pijoan, Albert, Fernández-Lebrero, Aida, Contador, José, Mok, Kin Ying Boniface, Hardy, John, Kwok, Timothy C. Y., Mok, Vincent C. T., Suárez-Calvet, Marc, Zetterberg, Henrik, Fu, Amy K. Y., and Ip, Nancy Yuk-yu
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INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed. © 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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- 2024
74. Stimuli-responsive biomaterials for drug delivery
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Abdelmohsen, Hend, Hardy, John, Copeland, Nikki, Abdelmohsen, Hend, Hardy, John, and Copeland, Nikki
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Corneal neovascularization is one of the most severe ocular diseases. Current therapy is limited to repeated intraocular injections of antiangiogenic drugs, associated with significant side effects including infection, bleeding and retinal detachment. The work presented herein attempts to address these issues through the development of degradable and cytocompatible light responsive drug delivery systems. These biomaterials facilitate the delivery of therapeutic drugs and nucleic acids, with tuneable, on demand qualities, which highlights their potential for treating a variety of conditions. The translucency of eyes and advances in laser technology in ophthalmology make light-responsive delivery of drugs feasible. Importantly, light can be applied in a non-invasive fashion; therefore, light-triggered drug delivery systems have great potential for clinical application. Novel methacrylate-based photo-responsive polymers are reported here, demonstrating the ability to process them into spherical nanogels. The nanogels comprising an immobilized metformin photocage were shown to release a consistent amount of drug with temporal control when stimulated with light. These nanogels were optimized to release metformin with tailored profiles based on their chemical characteristics. In order to explore the potential for co-delivery of different drugs independently, synthesis of photocleavable drug cage with bathochromic shift was successfully accomplished and incorporated into nanogels. The resulted particles were shown to exhibit sequential wavelength dependent release profiles of ciprofloxacin and metformin in line with their irradiation with infrared light. Methacrylate nanogels suffer from compromised degradability due to the reduced labile groups in their polymer backbone. Therefore, our approach was to modify them via co-polymerization with cyclic ketene acetals via ring opening mechanism. The formulated nanogels displayed improved degradation potential with enzymatic trea
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- 2024
75. Editorial for the Special Issue Entitled “Recent Advances in Crosslinked Gels”
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Demirkan, Melike Firlak, Hardy, John G., Demirkan, Melike Firlak, and Hardy, John G.
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A gel can be defined as a semi-solid structure that has mechanical properties ranging from tough to soft, depending on their constituents [...]
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- 2024
76. Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification
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Zhong, Huan, Zhou, Xiaopu, Uhm, Hyebin, Jiang, Yuanbing, Cao, Han, Chen, Yu, Mak, Tiffany T. W., Lo, Ronnie Ming Nok, Wong, Bonnie Wing Yan, Cheng, Elaine Yee Ling, Mok, Kin Ying Boniface, Chan, Andrew Lung Tat, Kwok, Timothy C. Y., Mok, Vincent C. T., Ip, Fanny Chui Fun, Hardy, John, Fu, Amy Kit Yu, Ip, Nancy Yuk-yu, Zhong, Huan, Zhou, Xiaopu, Uhm, Hyebin, Jiang, Yuanbing, Cao, Han, Chen, Yu, Mak, Tiffany T. W., Lo, Ronnie Ming Nok, Wong, Bonnie Wing Yan, Cheng, Elaine Yee Ling, Mok, Kin Ying Boniface, Chan, Andrew Lung Tat, Kwok, Timothy C. Y., Mok, Vincent C. T., Ip, Fanny Chui Fun, Hardy, John, Fu, Amy Kit Yu, and Ip, Nancy Yuk-yu
- Abstract
INTRODUCTION Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.
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- 2024
77. The Rise of the Modern Intelligence State
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Hardy, John, Masys, Anthony J., Series Editor, Bichler, Gisela, Advisory Editor, Bourlai, Thirimachos, Advisory Editor, Johnson, Chris, Advisory Editor, Karampelas, Panagiotis, Advisory Editor, Leuprecht, Christian, Advisory Editor, Morse, Edward C., Advisory Editor, Skillicorn, David, Advisory Editor, Yamagata, Yoshiki, Advisory Editor, Henschke, Adam, editor, Reed, Alastair, editor, Robbins, Scott, editor, and Miller, Seumas, editor
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- 2021
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78. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study
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McDonagh, Ellen M, Rueda, Antonio, Polychronopoulos, Dimitris, Chan, Georgia, Angus-Leppan, Heather, Bhatia, Kailash P, Davison, James E, Festenstein, Richard, Fratta, Pietro, Giunti, Paola, Howard, Robin, Venkata, Laxmi, Laurá, Matilde, McEntagart, Meriel, Menzies, Lara, Morris, Huw, Reilly, Mary M, Robinson, Robert, Rosser, Elisabeth, Faravelli, Francesca, Schrag, Anette, Schott, Jonathan M, Warner, Thomas T, Wood, Nicholas W, Bourn, David, Eggleton, Kelly, Labrum, Robyn, Twiss, Philip, Abbs, Stephen, Santos, Liana, Almheiri, Ghareesa, Sheikh, Isabella, Vandrovcova, Jana, Patch, Christine, Taylor Tavares, Ana Lisa, Hyder, Zerin, Need, Anna, Brittain, Helen, Baple, Emma, Moutsianas, Loukas, Deshpande, Viraj, Perry, Denise L, Ajay, Subramanian S., Chawla, Aditi, Rajan, Vani, Oprych, Kathryn, Chinnery, Patrick F, Douglas, Angela, Wilson, Gill, Ellard, Sian, Temple, I Karen, Mumford, Andrew, McMullan, Dom, Naresh, Kikkeri, Flinter, Frances A, Taylor, Jenny C, Greenhalgh, Lynn, Newman, William, Brennan, Paul, Sayer, John A, Raymond, F Lucy, Chitty, Lyn S, Ambrose, John C., Arumugam, Prabhu, Bleda, Marta, Boardman-Pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Craig, Clare E.H., de Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Furió-Tarí, Pedro, Hackett, Joanne, Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James, Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kayikci, Melis, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, Mason, Joanne, Mueller, Michael, Murugaesu, Nirupa, Odhams, Chris A., Perez-Gil, Daniel, Pullinger, John, Rahim, Tahrima, Riesgo-Ferreiro, Pablo, Rogers, Tim, Ryten, Mina, Savage, Kevin, Sawant, Kushmita, Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Thompson, Simon R., Tregidgo, Carolyn, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena, Ibañez, Kristina, Polke, James, Hagelstrom, R Tanner, Dolzhenko, Egor, Pasko, Dorota, Thomas, Ellen Rachel Amy, Daugherty, Louise C, Kasperaviciute, Dalia, Smith, Katherine R, Deans, Zandra C, Hill, Sue, Fowler, Tom, Scott, Richard H, Hardy, John, Houlden, Henry, Rendon, Augusto, Caulfield, Mark J, Eberle, Michael A, Taft, Ryan J, and Tucci, Arianna
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- 2022
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79. In Silico Toxicity Screening as a Tool for the Development of Sustainable Electronics, Exemplified with Organic Light‐Emitting Electrochemical Cells.
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Sutar, Papri, McGrath, Thomas P., Lulla, Kunal, Somerton, Christopher, Ashton, Mark D., Harper, Garry R., Halcovitch, Nathan R., Mort, Richard L., Wright, Karen L., Stowell, Alison F., Bird, David, Young, Robert J., and Hardy, John G.
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Electrical and electronic equipment (EEE) have revolutionized our lives, however, their associated waste (WEEE) presents a global challenge because at this time EEE relies heavily on metals that are not commonly found in the living environment (Biosphere), which find their way into the environment during both production/disposal of EEE/WEEE. The use of organic components in EEE is increasingly common, particularly with the growing interest in flexible electronics. Here we describe an approach to device design employing in silico toxicity screening to assess the toxicity of the components chosen for use in EEE that is exemplified using inorganic and organic components known in the literature for the production of prototype organic light‐emitting electrochemical cells. This approach could easily be employed to screen a variety of components for which datasets to produce safety data sheets (SDSs) don't yet exist because they have not been produced in large scale or in a regulatory environment which necessitates this. The approach has significant potential to improve high throughput screening of components for EEE that are "safe‐by‐design", potentially in combination with AI and ML approaches. [ABSTRACT FROM AUTHOR]
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- 2024
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80. Poly(2-Hydroxyethyl Methacrylate) Hydrogel-Based Microneedles for Bioactive Release.
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Sharma, Manoj B., Abdelmohsen, Hend A. M., Kap, Özlem, Kilic, Volkan, Horzum, Nesrin, Cheneler, David, and Hardy, John G.
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METHACRYLATES ,MEROPENEM ,MELATONIN ,HYDROGELS ,MOLECULES - Abstract
Microneedle arrays are minimally invasive devices that have been extensively investigated for the transdermal/intradermal delivery of drugs/bioactives. Here, we demonstrate the release of bioactive molecules (estradiol, melatonin and meropenem) from poly(2-hydroxyethyl methacrylate), pHEMA, hydrogel-based microneedle patches in vitro. The pHEMA hydrogel microneedles had mechanical properties that were sufficiently robust to penetrate soft tissues (exemplified here by phantom tissues). The bioactive release from the pHEMA hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application in the transdermal delivery of bioactives (exemplified here by estradiol, melatonin and meropenem) for the treatment of various conditions. [ABSTRACT FROM AUTHOR]
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- 2024
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81. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies
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Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Bandres-Ciga, Sara, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blauwendraat, Cornelis, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Bras, Jose, Brice, Alexis, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Corvol, Jean-Christophe, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Faghri, Faraz, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Finkbeiner, Steven, Foltynie, Thomas, Gan-Or, Ziv, Garcia, Ciara, García-Ruiz, Pedro, Gasser, Thomas, Gibbs, J Raphael, Gomez Heredia, Maria Jose, Gómez-Garre, Pilar, González, Manuel Menéndez, Gonzalez-Aramburu, Isabel, Guelfi, Sebastian, Guerreiro, Rita, Hardy, John, Hassin-Baer, Sharon, Hernandez, Dena G, Heutink, Peter, Hoenicka, Janet, Holmans, Peter, Houlden, Henry, Infante, Jon, Iwaki, Hirotaka, Jesús, Silvia, Jimenez-Escrig, Adriano, Kaishybayeva, Gulnaz, Kaiyrzhanov, Rauan, Karimova, Altynay, Kia, Demis A, Kinghorn, Kerri J, Koks, Sulev, Krohn, Lynne, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Leonard, Hampton L, Lesage, Suzanne, Lewis, Patrick, Lopez-Sendon, Jose Luis, Lovering, Ruth, Lubbe, Steven, Lungu, Codrin, Macias, Daniel, Majamaa, Kari, Manzoni, Claudia, Marín, Juan, Marinus, Johan, Marti, Maria Jose, Martinez, Maria, Martínez Torres, Irene, Martínez-Castrillo, Juan Carlos, Mata, Marina, Mencacci, Niccolo E, Méndez-del-Barrio, Carlota, Middlehurst, Ben, Mínguez, Adolfo, Mir, Pablo, Mok, Kin Y, Morris, Huw R, Muñoz, Esteban, Nalls, Mike A, Narendra, Derek, Noyce, Alastair J, Ojo, Oluwadamilola O, Okubadejo, Njideka U, Pagola, Ana Gorostidi, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Pihlstrom, Lasse, Plun-Favreau, Helene, Quinn, John, R'Bibo, Lea, Reed, Xylena, Rezola, Elisabet Mondragon, Rizig, Mie, Rizzu, Patrizia, Robak, Laurie, Rodriguez, Antonio Sanchez, Rouleau, Guy A, Ruiz-Martínez, Javier, Ruz, Clara, Ryten, Mina, Sadykova, Dinara, Scholz, Sonja W, Schreglmann, Sebastian, Schulte, Claudia, Sharma, Manu, Shashkin, Chingiz, Shulman, Joshua M, Sierra, María, Siitonen, Ari, Simón-Sánchez, Javier, Singleton, Andrew B, Suarez-Sanmartin, Esther, Taba, Pille, Tabernero, Cesar, Tan, Manuela X, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Toft, Mathias, Tolosa, Eduard, Trabzuni, Daniah, Valldeoriola, Francesc, van Hilten, Jacobus J, Van Keuren-Jensen, Kendall, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Williams, Nigel, Wood, Nicholas W, Zharkinbekova, Nazira, Zharmukhanov, Zharkyn, Zholdybayeva, Elena, Zimprich, Alexander, Ylikotila, Pauli, Shulman, Lisa M., von Coelln, Rainer, Reich, Stephen, Savitt, Joseph, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Huber, Karen E., Hicks, Barry, Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce, Vacic, Vladimir, Wang, Xin, Wilson, Catherine H., Anderson, Tim, Bentley, Steven, Dalrymple-Alford, John, Fowdar, Javed, Gratten, Jacob, Halliday, Glenda, Henders, Anjali K., Hickie, Ian, Kassam, Irfahan, Kennedy, Martin, Kwok, John, Lewis, Simon, Mellick, George, Montgomery, Grant, Pearson, John, Pitcher, Toni, Sidorenko, Julia, Silburn, Peter A., Vallerga, Costanza L., Visscher, Peter M., Wallace, Leanne, Wray, Naomi R., Xue, Angli, Yang, Jian, Zhang, Futao, Vallerga, Costanza L, Heilbron, Karl, Chang, Diana, Tan, Manuela, Young, Emily, Pihlstrøm, Lasse, Leonard, Hampton, Botia, Juan A, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Andreassen, Ole A, Bangale, Tushar, Hinds, David A, Hardy, John A, Visscher, Peter M, and Graham, Robert R
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- 2019
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82. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
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Alić, Ivan, Goh, Pollyanna A., Murray, Aoife, Portelius, Erik, Gkanatsiou, Eleni, Gough, Gillian, Mok, Kin Y., Koschut, David, Brunmeir, Reinhard, Yeap, Yee Jie, O’Brien, Niamh L., Groet, Jürgen, Shao, Xiaowei, Havlicek, Steven, Dunn, N. Ray, Kvartsberg, Hlin, Brinkmalm, Gunnar, Hithersay, Rosalyn, Startin, Carla, Hamburg, Sarah, Phillips, Margaret, Pervushin, Konstantin, Turmaine, Mark, Wallon, David, Rovelet-Lecrux, Anne, Soininen, Hilkka, Volpi, Emanuela, Martin, Joanne E., Foo, Jia Nee, Becker, David L., Rostagno, Agueda, Ghiso, Jorge, Krsnik, Željka, Šimić, Goran, Kostović, Ivica, Mitrečić, Dinko, Francis, Paul T., Blennow, Kaj, Strydom, Andre, Hardy, John, Zetterberg, Henrik, and Nižetić, Dean
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- 2021
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83. The Amyloid-β Pathway in Alzheimer’s Disease
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Hampel, Harald, Hardy, John, Blennow, Kaj, Chen, Christopher, Perry, George, Kim, Seung Hyun, Villemagne, Victor L., Aisen, Paul, Vendruscolo, Michele, Iwatsubo, Takeshi, Masters, Colin L., Cho, Min, Lannfelt, Lars, Cummings, Jeffrey L., and Vergallo, Andrea
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- 2021
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84. Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum.
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Karch, Celeste M, Wen, Natalie, Fan, Chun C, Yokoyama, Jennifer S, Kouri, Naomi, Ross, Owen A, Höglinger, Gunter, Müller, Ulrich, Ferrari, Raffaele, Hardy, John, Schellenberg, Gerard D, Sleiman, Patrick M, Momeni, Parastoo, Hess, Christopher P, Miller, Bruce L, Sharma, Manu, Van Deerlin, Vivianna, Smeland, Olav B, Andreassen, Ole A, Dale, Anders M, Desikan, Rahul S, and International Frontotemporal Dementia (FTD)–Genomics Consortium, International Collaboration for Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, and International Parkinson’s Disease Genomics Consortium
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International Frontotemporal Dementia (FTD)–Genomics Consortium ,International Collaboration for Frontotemporal Dementia ,Progressive Supranuclear Palsy (PSP) Genetics Consortium ,and International Parkinson’s Disease Genomics Consortium ,Humans ,Basal Ganglia Diseases ,Parkinson Disease ,Supranuclear Palsy ,Progressive ,Alzheimer Disease ,Amyotrophic Lateral Sclerosis ,Genetic Predisposition to Disease ,tau Proteins ,Vesicular Transport Proteins ,Proto-Oncogene Proteins c-bcl-2 ,Nerve Tissue Proteins ,Genome-Wide Association Study ,TDP-43 Proteinopathies ,Frontotemporal Dementia ,Superoxide Dismutase-1 ,C9orf72 Protein ,International Frontotemporal Dementia (FTD)–Genomics Consortium ,International Collaboration for Frontotemporal Dementia ,Progressive Supranuclear Palsy (PSP) Genetics Consortium ,and International Parkinson’s Disease Genomics Consortium ,Supranuclear Palsy ,Progressive - Abstract
Importance:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives:To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants:In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures:The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results:Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P
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- 2018
85. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
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Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, de Munain, Adolfo López, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Sabbagh, Marwan Noel, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, and Pickering-Brown, Stuart
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Dementia ,Genetics ,Aging ,Prevention ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Human Genome ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Age of Onset ,Aged ,Case-Control Studies ,Cerebellum ,Female ,Frontotemporal Lobar Degeneration ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,Humans ,Male ,Middle Aged ,Mutation ,Progranulins ,RNA ,Messenger ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p
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- 2018
86. CXCR4 involvement in neurodegenerative diseases.
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Bonham, Luke W, Karch, Celeste M, Fan, Chun C, Tan, Chin, Geier, Ethan G, Wang, Yunpeng, Wen, Natalie, Broce, Iris J, Li, Yi, Barkovich, Matthew J, Ferrari, Raffaele, Hardy, John, Momeni, Parastoo, Höglinger, Günter, Müller, Ulrich, Hess, Christopher P, Sugrue, Leo P, Dillon, William P, Schellenberg, Gerard D, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Barkovich, A James, Yokoyama, Jennifer S, Desikan, Rahul S, International FTD-Genomics Consortium (IFGC), International Parkinson’s Disease Genetics Consortium (IPDGC), and International Genomics of Alzheimer’s Project (IGAP)
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International FTD-Genomics Consortium ,International Parkinson’s Disease Genetics Consortium ,International Genomics of Alzheimer’s Project ,Brain ,Microglia ,Animals ,Mice ,Transgenic ,Humans ,Neurodegenerative Diseases ,Genetic Predisposition to Disease ,Receptors ,CXCR4 ,Risk Factors ,Gene Expression ,Polymorphism ,Single Nucleotide ,Gene Regulatory Networks ,Genome-Wide Association Study ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Alzheimer's Disease Related Dementias (ADRD) ,Aging ,Genetics ,Rare Diseases ,Parkinson's Disease ,Neurosciences ,Frontotemporal Dementia (FTD) ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Neurodegenerative ,Dementia ,2.1 Biological and endogenous factors ,Neurological ,Clinical Sciences ,Public Health and Health Services ,Psychology - Abstract
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
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- 2018
87. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis
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Zhou, Xiaopu, Chen, Yu, Mok, Kin Y, Zhao, Qianhua, Chen, Keliang, Chen, Yuewen, Hardy, John, Li, Yun, Fu, Amy KY, Guo, Qihao, Ip, Nancy Y, Saykin, Andrew J, Toga, Arthur W, Borowski, Bret, Ward, Chad, DeCarli, Charles, Mathis, Chet, Jack, Clifford R, Harvey, Danielle, Holtzman, David, Jones, David, Gessert, Devon, Lilly, Eli, Reiman, Eric M, Franklin, Erin, Hefti, Franz, Sorensen, Greg, Jimenez, Gustavo, Fillit, Howard, Gunter, Jeff, Salazar, Jennifer, Hsiao, John, Morris, John, Trojanowki, John Q, Neu, Karen Crawford Scott, Kantarci, Kejal, Faber, Kelley, Harless, Kelly, Chen, Kewei, Nho, Kwangsik, Beckett, Laurel, Thal, Lean, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Shen, Li, Hergesheimer, Lindsey, Taylor-Reinwald, Lisa, Mesulam, M Marcel, Korecka, Magdalena, Raichle, Marc, Carrillo, Maria, Albert, Marilyn, Senjem, Matt, Bernstein, Matthew, Donohue, Michael, Weiner, Michael, Figurski, Michal, Buckholtz, Neil, Fox, Nick, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Aisen, Paul, Thompson, Paul, Davies, Peter, Snyder, Peter J, Snyder, Peter, Vemuri, Prashanthi, Frank, Richard, Koeppe, Robert A, Green, Robert C, Petersen, Ronald, Walter, Sarah, Paul, Steven, Potkin, Steven, Kim, Sungeun, Foroud, Tatiana M, Montine, Tom, Lee, Virginia, Jagust, William, Potter, William, Cabrera, Yuliana, Khachaturian, Zaven, Fleisher, Adam, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Norbash, Alexander, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Ulysse, Anaztasia, Budson, Andrew E, Kertesz, Andrew, Oliver, Angela, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, and Porsteinsson, Anton P
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Biological Sciences ,Genetics ,Dementia ,Acquired Cognitive Impairment ,Prevention ,Brain Disorders ,Aging ,Human Genome ,Neurosciences ,Alzheimer's Disease ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Aetiology ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Good Health and Well Being ,Age of Onset ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Apolipoproteins E ,Asian People ,China ,Cohort Studies ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Immune System ,Male ,Middle Aged ,Potassium Channels ,Inwardly Rectifying ,Risk Factors ,Alzheimer’s Disease Neuroimaging Initiative ,Alzheimer’s disease ,GWAS ,immune ,risk variant ,whole-genome sequencing - Abstract
Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
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- 2018
88. An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers.
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Rusbridge, Clare, Salguero, Francisco J, David, Monique Antoinette, Faller, Kiterie ME, Bras, Jose T, Guerreiro, Rita J, Richard-Londt, Angela C, Grainger, Duncan, Head, Elizabeth, Brandner, Sebastian GP, Summers, Brian, Hardy, John, and Tayebi, Mourad
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Alzheimer ,Aβ oligomers ,aggregation ,canine ,canine cognitive dysfunction ,neuropathology ,neurotoxicity ,Biochemistry and Cell Biology ,Neurosciences ,Cognitive Sciences - Abstract
Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides. We report that soluble oligomers were specifically detected in the dog's blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-Aβ specific binders. Importantly, our results reveal the potent neurotoxic effects of the dog's CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human Aβ. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed.
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- 2018
89. Correction: Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.
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Broce, Iris, Karch, Celeste M, Wen, Natalie, Fan, Chun C, Wang, Yunpeng, Tan, Chin Hong, Kouri, Naomi, Ross, Owen A, Höglinger, Günter U, Muller, Ulrich, Hardy, John, International FTD-Genomics Consortium, Momeni, Parastoo, Hess, Christopher P, Dillon, William P, Miller, Zachary A, Bonham, Luke W, Rabinovici, Gil D, Rosen, Howard J, Schellenberg, Gerard D, Franke, Andre, Karlsen, Tom H, Veldink, Jan H, Ferrari, Raffaele, Yokoyama, Jennifer S, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Desikan, Rahul S, and Sugrue, Leo P
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International FTD-Genomics Consortium ,General & Internal Medicine ,Medical and Health Sciences - Abstract
[This corrects the article DOI: 10.1371/journal.pmed.1002487.].
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- 2018
90. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
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Broce, Iris, Karch, Celeste M, Wen, Natalie, Fan, Chun C, Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A, Höglinger, Günter U, Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P, Dillon, William P, Miller, Zachary A, Bonham, Luke W, Rabinovici, Gil D, Rosen, Howard J, Schellenberg, Gerard D, Franke, Andre, Karlsen, Tom H, Veldink, Jan H, Ferrari, Raffaele, Yokoyama, Jennifer S, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Desikan, Rahul S, Sugrue, Leo P, Brayne, Carol, and International FTD-Genomics Consortium
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- 2018
91. Large-scale visualisation of α-synuclein oligomers in Parkinson's disease brain tissue
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Andrews, Rebecca, primary, Fu, Bin, additional, Toomey, Christina E., additional, Breiter, Jonathan C., additional, Lachica, Joanne, additional, Tian, Ru, additional, Beckwith, Joseph S., additional, Needham, Lisa-Maria, additional, Chant, Gregory J., additional, Loiseau, Camille, additional, Deconfin, Angèle, additional, Baspin, Kenza, additional, Magill, Peter J., additional, Jaunmuktane, Zane, additional, Freeman, Oliver J., additional, Taylor, Benjamin J.M., additional, Hardy, John, additional, Lashley, Tammaryn, additional, Ryten, Mina, additional, Vendruscolo, Michele, additional, Wood, Nicholas W., additional, Weiss, Lucien E., additional, Gandhi, Sonia, additional, and Lee, Steven F., additional
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- 2024
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92. Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification
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Zhong, Huan, primary, Zhou, Xiaopu, additional, Uhm, Hyebin, additional, Jiang, Yuanbing, additional, Cao, Han, additional, Chen, Yu, additional, Mak, Tiffany T. W., additional, Lo, Ronnie Ming Nok, additional, Wong, Bonnie Wing Yan, additional, Cheng, Elaine Yee Ling, additional, Mok, Kin Y., additional, Chan, Andrew Lung Tat, additional, Kwok, Timothy C. Y., additional, Mok, Vincent C. T., additional, Ip, Fanny C. F., additional, Hardy, John, additional, Fu, Amy K. Y., additional, and Ip, Nancy Y., additional
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- 2024
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93. A blood‐based multi‐pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups
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Jiang, Yuanbing, primary, Uhm, Hyebin, additional, Ip, Fanny C., additional, Ouyang, Li, additional, Lo, Ronnie M. N., additional, Cheng, Elaine Y. L., additional, Cao, Xiaoyun, additional, Tan, Clara M. C., additional, Law, Brian C. H., additional, Ortiz‐Romero, Paula, additional, Puig‐Pijoan, Albert, additional, Fernández‐Lebrero, Aida, additional, Contador, José, additional, Mok, Kin Y., additional, Hardy, John, additional, Kwok, Timothy C. Y., additional, Mok, Vincent C. T., additional, Suárez‐Calvet, Marc, additional, Zetterberg, Henrik, additional, Fu, Amy K. Y., additional, and Ip, Nancy Y., additional
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- 2024
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94. Controlled Sr(ii) ion release from in situ crosslinking electroactive hydrogels with potential for the treatment of infections
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Fırlak Demirkan, Melike, primary, Öztürk, Dilek, additional, Çifçibaşı, Zeynep Sude, additional, Ertan, Fatma, additional, Hardy, John George, additional, Nurşeval Oyunlu, Aslı, additional, and Darıcı, Hakan, additional
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- 2024
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95. Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases
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Feleke, Rahel, Reynolds, Regina H., Smith, Amy M., Tilley, Bension, Taliun, Sarah A. Gagliano, Hardy, John, Matthews, Paul M., Gentleman, Steve, Owen, David R., Johnson, Michael R., Srivastava, Prashant K., and Ryten, Mina
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- 2021
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96. Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias
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Vavouraki, Nikoleta, Tomkins, James E., Kara, Eleanna, Houlden, Henry, Hardy, John, Tindall, Marcus J., Lewis, Patrick A., and Manzoni, Claudia
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- 2021
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97. Aluminization Coatings and Glass Seals for High Temperature Systems - CRADA 536 (Final Report)
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Hardy, John, primary, Chou, Yeung Shyung, additional, Choi, Jung-Pyung, additional, and Li, Jesse, additional
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- 2022
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98. Realism, drone warfare, and the future of the international system
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Hardy, John, primary
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- 2021
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99. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study
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Mok, Kin Y., Murphy, David P., Al-Sarraj, Safa, Troakes, Claire, Gentleman, Steve M., Allinson, Kieren S.J., Jaunmuktane, Zane, Holton, Janice L., Lees, Andrew J., Morris, Christopher M., Compta, Yaroslau, Gelpi, Ellen, van Swieten, John C., Rajput, Alex, Ferguson, Leslie, Cookson, Mark R., Gibbs, J. Raphael, Blauwendraat, Cornelis, Ding, Jinhui, Chia, Ruth, Traynor, Bryan J., Pantelyat, Alexander, Viollet, Coralie, Pletnikova, Olga, Troncoso, Juan C., Rosenthal, Liana S., Boxer, Adam L., Respondek, Gesine, Arzberger, Thomas, Roeber, Sigrun, Giese, Armin, Burn, David J., Pavese, Nicola, Gerhard, Alexander, Kobylecki, Christopher, Leigh, P. Nigel, Church, Alistair, T.M. Hu, Michele, Jabbari, Edwin, Koga, Shunsuke, Valentino, Rebecca R, Reynolds, Regina H, Ferrari, Raffaele, Tan, Manuela M X, Rowe, James B, Dalgard, Clifton L, Scholz, Sonja W, Dickson, Dennis W, Warner, Thomas T, Revesz, Tamas, Höglinger, Günter U, Ross, Owen A, Ryten, Mina, Hardy, John, Shoai, Maryam, and Morris, Huw R
- Published
- 2021
- Full Text
- View/download PDF
100. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.
- Author
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Witoelar, Aree, Jansen, Iris E, Wang, Yunpeng, Desikan, Rahul S, Gibbs, J Raphael, Blauwendraat, Cornelis, Thompson, Wesley K, Hernandez, Dena G, Djurovic, Srdjan, Schork, Andrew J, Bettella, Francesco, Ellinghaus, David, Franke, Andre, Lie, Benedicte A, McEvoy, Linda K, Karlsen, Tom H, Lesage, Suzanne, Morris, Huw R, Brice, Alexis, Wood, Nicholas W, Heutink, Peter, Hardy, John, Singleton, Andrew B, Dale, Anders M, Gasser, Thomas, Andreassen, Ole A, Sharma, Manu, and International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators
- Subjects
International Parkinson’s Disease Genomics Consortium (IPDGC) ,North American Brain Expression Consortium (NABEC) ,and United Kingdom Brain Expression Consortium (UKBEC) Investigators ,Humans ,Arthritis ,Rheumatoid ,Colitis ,Ulcerative ,Crohn Disease ,Celiac Disease ,Multiple Sclerosis ,Parkinson Disease ,Psoriasis ,Diabetes Mellitus ,Type 1 ,Autoimmune Diseases ,Genetic Predisposition to Disease ,Risk Factors ,Genome-Wide Association Study ,Genetic Loci ,Genetic Pleiotropy ,Prevention ,Neurosciences ,Brain Disorders ,Digestive Diseases ,Autoimmune Disease ,Aging ,Arthritis ,Biotechnology ,Neurodegenerative ,Parkinson's Disease ,Genetics ,Human Genome ,Inflammatory Bowel Disease ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Neurological ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ImportanceRecent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.ObjectivesTo test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.Design, setting, and participantsUsing the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.Main outcomes and measuresThe primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.ResultsGenome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.Conclusions and relevanceThe study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.
- Published
- 2017
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