Institution
Newcastle University
Education•Newcastle upon Tyne, United Kingdom•
About: Newcastle University is a education organization based out in Newcastle upon Tyne, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 31772 authors who have published 71187 publications receiving 2539147 citations. The organization is also known as: University of Newcastle upon Tyne.
Papers published on a yearly basis
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Harvard University1, Massachusetts Institute of Technology2, National Institutes of Health3, University of Sydney4, Children's Hospital at Westmead5, Boston Children's Hospital6, University of Florida7, University College London8, Katholieke Universiteit Leuven9, Harry Perkins Institute of Medical Research10, Newcastle University11, Royal Children's Hospital12
TL;DR: This study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.
Abstract: Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.
549 citations
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TL;DR: Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid.
549 citations
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University of Michigan1, Newcastle University2, University of Cologne3, Simon Fraser University4, Harvard University5, University of Hyogo6, Max Planck Society7, Peking University8, University of California, San Diego9, University of Zurich10, University of Washington11, Hannover Medical School12, University of Freiburg13
TL;DR: These findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
Abstract: The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
549 citations
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TL;DR: None of the metrics as evaluated systematically outperformed all other metrics across a wide range of standardised kinematic conditions, however, choice of metric explains different degrees of variance in daily human physical activity.
Abstract: Introduction: Human body acceleration is often used as an indicator of daily physical activity in epidemiological research. Raw acceleration signals contain three basic components: movement, gravit ...
547 citations
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TL;DR: A considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta of PD patients is illustrated and the important need for further research in this area is highlighted.
Abstract: Parkinson's disease (PD) is a progressive, neurodegenerative condition that has increasingly been linked with mitochondrial dysfunction and inhibition of the electron transport chain. This inhibition leads to the generation of reactive oxygen species and depletion of cellular energy levels, which can consequently cause cellular damage and death mediated by oxidative stress and excitotoxicity. A number of genes that have been shown to have links with inherited forms of PD encode mitochondrial proteins or proteins implicated in mitochondrial dysfunction, supporting the central involvement of mitochondria in PD. This involvement is corroborated by reports that environmental toxins that inhibit the mitochondrial respiratory chain have been shown to be associated with PD. This paper aims to illustrate the considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta (SNpc) of PD patients and to highlight the important need for further research in this area.
546 citations
Authors
Showing all 32219 results
Name | H-index | Papers | Citations |
---|---|---|---|
Martin White | 196 | 2038 | 232387 |
Barry Halliwell | 173 | 662 | 159518 |
Adrian L. Harris | 170 | 1084 | 120365 |
Jorge E. Cortes | 163 | 2784 | 124154 |
Frank J. Gonzalez | 160 | 1144 | 96971 |
David W. Bates | 159 | 1239 | 116698 |
Nicholas J. Talley | 158 | 1571 | 90197 |
Hans Lassmann | 155 | 724 | 79933 |
Stephen J. O'Brien | 153 | 1062 | 93025 |
Edmund T. Rolls | 153 | 612 | 77928 |
David J. Brooks | 152 | 1056 | 94335 |
Andrew J. Lees | 140 | 877 | 91605 |
Daniel Thomas | 134 | 846 | 84224 |
Peter Hall | 132 | 1640 | 85019 |
Paul Brennan | 132 | 1221 | 72748 |