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153. Gene deletions in spinal muscular atrophy

Author

Rodrigues, Nanda R., Owen, Nicholas, Talbot, Kevin, Patel, Shobhna, Muntoni, Francesco, Ignatius, Jaakko, Dubowitz, Victor, and Davies, Kay E.

Published
1996

165. Verifying nomenclature of DNA variants in submitted manuscripts: Guidance for journals.

Author

Higgins, Jan, Dalgleish, Raymond, Dunnen, Johan T., Barsh, Greg, Freeman, Peter J., Cooper, David N., Cullinan, Sara, Davies, Kay E., Dorkins, Huw, Gong, Li, Imoto, Issei, Klein, Teri E., Korf, Bruce, Misra, Adya, Paalman, Mark H., Ratzel, Sarah, Reichardt, Juergen K. V., Rehm, Heidi L., Tokunaga, Katsushi, and Weck, Karen E.

Abstract

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation. [ABSTRACT FROM AUTHOR]

Published
2021
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169. ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins

Author

Ponting, Chris P., Blake, Derek J., Davies, Kay E., Kendrick-Jones, John, and Winder, Steven J.

Subjects
Duchenne muscular dystrophy -- Research, Dystrophin -- Analysis, Biological sciences, Chemistry
Abstract

Duchenne muscular dystrophy (DMD) is a severe, muscle-wasting disease linked to the X-chromosome affecting about one in 3500 male births. It is caused by deficiency in the protein dystrophin. ZZ and TAZ are the two new classes of putative zinc fingers that have been identified. They are most likely associated with the mediation of protein-protein interactions between dystrophin, utrophin, 87K and their proteins and between transcriptional adaptors and activators.

Published
1996

170. Coiled-coil regions in the carboxy-terminal domains of dystrophin and related proteins: potentials for protein-protein interactions

Author

Blake, Derek J., Tinsley, Jonathon M., and Davies, Kay E.

Subjects
Dystrophin -- Research, Muscle proteins -- Analysis, Biological sciences, Chemistry
Abstract

The protein dystrophin contains a coiled region of amino acids which is treminated by a carboxyl group. This terminal domain may be responsible for dystrophin's function as a binder of neuromuscular and extracellular proteins such as actin, merosin, syntrophin and troglycan. Minor differences exist between proteins that are similar to dystrophin, and all contain the coiled-coil structure that is characterized by a alpha helixes that form six closely bound heptads.

Published
1995

179. Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid

Author

Chatzopoulou, Maria, Claridge, Tim D. W., Davies, Kay E., Davies, Stephen G., Elsey, David J., Emer, Enrico, Fletcher, Ai M., Harriman, Shawn, Robinson, Neil, Rowley, Jessica A., Russell, Angela J., Tinsley, Jonathon M., Weaver, Richard, Wilkinson, Isabel V. L., Willis, Nicky J., Wilson, Francis X., and Wynne, Graham M.

Abstract

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

Published
2020
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181. A YAC contig in Xp21 containing the adrenal hypoplasia congenita and glycerol kinase deficiency genes

Author

Walker, Ann P., Chelly, Jamel, Love, Donald R., Brush, Yumiko Ishikawa, Récan, Dominique, Chaussain, Jean-Louis, Oley, Christine A., Connor, J.Michael, Yates, John, Price, David A., Super, Maurice, Bottani, Armand, Steinman, Beat, Kaplan, Jean-Claude, Davies, Kay E., Monaco, Anthony P., Walker, Ann P., Chelly, Jamel, Love, Donald R., Brush, Yumiko Ishikawa, Récan, Dominique, Chaussain, Jean-Louis, Oley, Christine A., Connor, J.Michael, Yates, John, Price, David A., Super, Maurice, Bottani, Armand, Steinman, Beat, Kaplan, Jean-Claude, Davies, Kay E., and Monaco, Anthony P.

Abstract

The gene loci for adrenal hypoplasia congenita (AHC) and glycerol kinase deficiency (GK) map in Xp21 distal to Duchenne muscular dystrophy (DMD), and proximal to DXS28 (C7), by analysis of patient deletions. We have constructed a yeast artificial chromosome (YAC) contig encompassing a 1.2 Mb region extending distally from DMD, and containing DXS708 (JC-1), the distal junction clone of a patient with GK and DMD. A pulsed-field gel electrophoresis map of the YAC contig identified 3 potential CpG islands. Whole YAC hybridization identified cosmids both for construction of cosmid contigs, and isolation of single copy probes. Thirteen new single copy probes and DXS28 and DXS708 were hybridized on a panel of patients; the deletion mapping indicates that the YAC contig contains both GK and at least part of AHC, and together with the physical map defines a GK critical region of 50-250 kb. In one AHC patient with a cytogenetically detectable deletion we used the new probes to characterize a complex double deletion. Non-overlapping deletions observed in other unrelated AHC patients indicate that the AHC gene is large, extending over at least 200-500 kb. This mapping provides the basis for the identification of the AHC and GK genes

Published
2017

182. Laf4/Aff3, a Gene Involved in Intellectual Disability, Is Required for Cellular Migration in the Mouse Cerebral Cortex

Author

Moore, Justin M., Oliver, Peter L., Lee, Sheena, Lickiss, Tom, and Davies, Kay E.

Subjects
Multidisciplinary
Abstract

Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets. For example, deletion of human lymphoid nuclear protein related to AF4/AFF member 3 (LAF4/AFF3) is known to cause severe neurodevelopmental defects, and silencing of the gene is also associated with ID at the folate-sensitive fragile site (FSFS) FRA2A; yet the normal function of this gene in the nervous system is unclear. The aim of this study was to further investigate the function of Laf4 in the brain by focusing on its role in the cortex. By manipulating expression levels in organotypic slices, we demonstrate here that Laf4 is required for normal cellular migration in the developing cortex and have subsequently identified Mdga2, an important structural protein in neurodevelopment, as a target of Laf4 transcriptional activity. Furthermore, we show that the migration deficit caused by loss of Laf4 can be partially rescued by Mdga2 over-expression, revealing an important functional relationship between these genes. Our study demonstrates the key transcriptional role of Laf4 during early brain development and reveals a novel function for the gene in the process of cortical cell migration relevant to the haploinsufficiency and silencing observed in human neurodevelopmental disorders.

Published
2014

183. Translating the Genomics Revolution: The Need for an International Gene Therapy Consortium for Monogenic Diseases

Author

Tremblay, Jacques P, Xiao, Xiao, Aartsma-Rus, Annemieke, Barbas, Carlos, Blau, Helen M, Bogdanove, Adam J, Boycott, Kym, Braun, Serge, Breakefield, Xandra O, Bueren, Juan A, Buschmann, Michael, Byrne, Barry J, Calos, Michele, Cathomen, Toni, Chamberlain, Jeffrey, Chuah, Marinee, Cornetta, Kenneth, Davies, Kay E, Dickson, J George, Duchateau, Philippe, Flotte, Terence R, Gaudet, Daniel, Gersbach, Charles A, Gilbert, Renald, Glorioso, Joseph, Herzog, Roland W, High, Katherine A, Huang, Wenlin, Huard, Johnny, Joung, J Keith, Liu, Depei, Liu, Dexi, Lochmüller, Hanns, Lustig, Lawrence, Martens, Jeffrey, Massie, Bernard, Mavilio, Fulvio, Mendell, Jerry R, Nathwani, Amit, Ponder, Katherine, Porteus, Matthew, Puymirat, Jack, Samulski, Jude, Takeda, Shin'ichi, Thrasher, Adrian, VandenDriessche, Thierry, Wei, Yuquan, Wilson, James M, Wilton, Steve D, Wolfe, John H, and Gao, Guangping

Published
2013
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191. Disrupted Circadian Rhythms in a Mouse Model of Schizophrenia

Author

Oliver, Peter L., Sobczyk, Melanie V., Maywood, Elizabeth S., Edwards, Benjamin, Lee, Sheena, Livieratos, Achilleas, Oster, Henrik, Butler, Rachel, Godinho, Sofia I.H., Wulff, Katharina, Peirson, Stuart N., Fisher, Simon P., Chesham, Johanna E., Smith, Janice W., Hastings, Michael H., Davies, Kay E., and Foster, Russell G.

Published
2012
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192. Discovery of 2-Arylbenzoxazoles as Upregulators of Utrophin Production for the Treatment of Duchenne Muscular Dystrophy

Author

Chancellor, Daniel R., Davies, Kay E., De Moor, Olivier, Dorgan, Colin R., Johnson, Peter D., Lambert, Adam G., Lawrence, Daniel, Lecci, Cristina, Maillol, Carole, Middleton, Penny J., Nugent, Gary, Poignant, Séverine D., Potter, Allyson C., Price, Paul D., Pye, Richard J., Storer, Richard, Tinsley, Jonathon M., van Well, Renate, Vickers, Richard, Vile, Julia, Wilkes, Fraser J., Wilson, Francis X., Wren, Stephen P., and Wynne, Graham M.

Abstract

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure–activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

Published
2024
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193. Oxr1 Is Essential for Protection against Oxidative Stress-Induced Neurodegeneration

Author

Oliver, Peter L., Edwards, Benjamin, Bitoun, Emmanuelle, Butts, Darcy L., Becker, Esther B. E., Cheeseman, Michael T., Davies, Ben, and Davies, Kay E.

Subjects
Cancer Research, Genetics, Genetics(clinical), Molecular Biology, Ecology, Evolution, Behavior and Systematics
Abstract

Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified the role of oxidation resistance 1 (Oxr1) as a vital protein that controls the sensitivity of neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible to exogenous stress when the gene is over-expressed. A conserved short isoform of Oxr1 is also sufficient to confer this neuroprotective property both in vitro and in vivo. In addition, biochemical assays indicate that Oxr1 itself is susceptible to cysteine-mediated oxidation. Finally we show up-regulation of Oxr1 in both human and pre-symptomatic mouse models of amyotrophic lateral sclerosis, indicating that Oxr1 is potentially a novel neuroprotective factor in neurodegenerative disease.

Published
2011

194. Preconditioning of Cardiosphere-Derived Cells with Hypoxia or Prolyl-4-Hydroxylase Inhibitors Increases Stemness and Decreases Reliance on Oxidative Metabolism

Author

Tan, Suat Cheng, primary, Gomes, Renata S. M., additional, Yeoh, Kar Kheng, additional, Perbellini, Filippo, additional, Malandraki-Miller, Sophia, additional, Ambrose, Lucy, additional, Heather, Lisa C., additional, Faggian, Giuseppe, additional, Schofield, Christopher J., additional, Davies, Kay E., additional, Clarke, Kieran, additional, and Carr, Carolyn A., additional

Published
2016
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195. A new way to regulate the NMJ

Author

Davies, Kay E and Khurana, Tejvir S

Abstract

Author(s): Kay E Davies [1]; Tejvir S Khurana [2] This year marks the twentieth anniversary of the discovery of the dystrophin gene, which is mutated in the devastating X-linked recessive [...]

Published
2007
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200. Pharmacological advances for treatment in Duchenne muscular dystrophy.

Author

Guiraud, Simon and Davies, Kay E

Subjects
*TREATMENT of Duchenne muscular dystrophy, *DRUG development, *DRUG approval, *DISEASE progression, *CLINICAL drug trials
Abstract

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of dystrophin, essential for muscle fibre integrity. Despite extensive pre-clinical studies, development of an effective treatment has proved challenging. More recently, significant progress has been made with the first drug approval using a genetic approach and the application of pharmacological agents which slow the progression of the disease. Drug development for DMD has mainly used two strategies: (1) the restoration of dystrophin expression or the expression of the compensatory utrophin protein as an efficient surrogate, and (2) the mitigation of secondary downstream pathological mechanisms. This review details current most promising pharmacological approaches and clinical trials aiming to tackle the pathogenesis of this multifaceted disorder. [ABSTRACT FROM AUTHOR]

Published
2017
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