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2. Explainable Deep Learning to Profile Mitochondrial Disease Using High Dimensional Protein Expression Data

Author

Khan, Atif, Lawless, Conor, Vincent, Amy E, Pilla, Satish, Ramesh, Sushanth, and McGough, A. Stephen

Subjects
Computer Science - Machine Learning
Abstract

Mitochondrial diseases are currently untreatable due to our limited understanding of their pathology. We study the expression of various mitochondrial proteins in skeletal myofibres (SM) in order to discover processes involved in mitochondrial pathology using Imaging Mass Cytometry (IMC). IMC produces high dimensional multichannel pseudo-images representing spatial variation in the expression of a panel of proteins within a tissue, including subcellular variation. Statistical analysis of these images requires semi-automated annotation of thousands of SMs in IMC images of patient muscle biopsies. In this paper we investigate the use of deep learning (DL) on raw IMC data to analyse it without any manual pre-processing steps, statistical summaries or statistical models. For this we first train state-of-art computer vision DL models on all available image channels, both combined and individually. We observed better than expected accuracy for many of these models. We then apply state-of-the-art explainable techniques relevant to computer vision DL to find the basis of the predictions of these models. Some of the resulting visual explainable maps highlight features in the images that appear consistent with the latest hypotheses about mitochondrial disease progression within myofibres., Comment: 10 pages, 11 figures

Published
2022

8. Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy

Author

Abouhajar, Alaa, Alcock, Lisa, Bigirumurame, Theophile, Bradley, Penny, Brown, Laura, Campbell, Ian, Del Din, Silvia, Faitg, Julie, Falkous, Gavin, Gorman, Gráinne S., Lakey, Rachel, McFarland, Robert, Newman, Jane, Rochester, Lynn, Ryan, Vicky, Smith, Hesther, Steel, Alison, Stefanetti, Renae J., Su, Huizhong, Taylor, Robert W., Thomas, Naomi J.P., Tuppen, Helen, Vincent, Amy E., Warren, Charlotte, and Watson, Gillian

Published
2022
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9. Correction: Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy

Author

Abouhajar, Alaa, Alcock, Lisa, Bigirumurame, Theophile, Bradley, Penny, Brown, Laura, Campbell, Ian, Del Din, Silvia, Faitg, Julie, Falkous, Gavin, Gorman, Grainne S., Lakey, Rachel, McFarland, Robert, Newman, Jane, Rochester, Lynn, Ryan, Vicky, Smith, Hesther, Steel, Alison, Stefanetti, Renae J., Su, Huizhong, Taylor, Robert W., Thomas, Naomi J. P., Tuppen, Helen, Vincent, Amy E., Warren, Charlotte, and Watson, Gillian

Published
2022
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12. Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.

Author

Gomes, Tiago M. Bernardino, Vincent, Amy E., Menger, Katja E., Stewart, James B., and Nicholls, Thomas J.

Subjects
*MITOCHONDRIAL DNA, *HUMAN DNA, *DELETION mutation, *DNA replication, *MITOCHONDRIAL pathology, *RECESSIVE genes, *ENERGY metabolism
Abstract

Human mitochondria possess a multi-copy circular genome, mitochondrial DNA (mtDNA), that is essential for cellular energy metabolism. The number of copies of mtDNA per cell, and their integrity, are maintained by nuclear-encoded mtDNA replication and repair machineries. Aberrant mtDNA replication and mtDNA breakage are believed to cause deletions within mtDNA. The genomic location and breakpoint sequences of these deletions show similar patterns across various inherited and acquired diseases, and are also observed during normal ageing, suggesting a common mechanism of deletion formation. However, an ongoing debate over the mechanism by which mtDNA replicates has made it difficult to develop clear and testable models for how mtDNA rearrangements arise and propagate at a molecular and cellular level. These deletions may impair energy metabolism if present in a high proportion of the mtDNA copies within the cell, and can be seen in primary mitochondrial diseases, either in sporadic cases or caused by autosomal variants in nuclear-encoded mtDNA maintenance genes. These mitochondrial diseases have diverse genetic causes and multiple modes of inheritance, and show notoriously broad clinical heterogeneity with complex tissue specificities, which further makes establishing genotype-phenotype relationships challenging. In this review, we aim to cover our current understanding of how the human mitochondrial genome is replicated, the mechanisms by which mtDNA replication and repair can lead to mtDNA instability in the form of large-scale rearrangements, how rearranged mtDNAs subsequently accumulate within cells, and the pathological consequences when this occurs. [ABSTRACT FROM AUTHOR]

Published
2024
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24. De novoserine biosynthesis is protective in mitochondrial disease

Author

Jackson, Christopher B, primary, Marmyleva, Anastasiia, additional, Awadhpersad, Ryan, additional, Monteuuis, Geoffray, additional, Mito, Takayuki, additional, Zamboni, Nicola, additional, Tatsuta, Takashi, additional, Vincent, Amy E., additional, Wang, Liya, additional, Langer, Thomas, additional, Carroll, Christopher J, additional, and Suomalainen, Anu, additional

Published
2023
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30. Additional file 2 of Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy

Author

Abouhajar, Alaa, Alcock, Lisa, Bigirumurame, Theophile, Bradley, Penny, Brown, Laura, Campbell, Ian, Del Din, Silvia, Faitg, Julie, Falkous, Gavin, Gorman, Gráinne S., Lakey, Rachel, McFarland, Robert, Newman, Jane, Rochester, Lynn, Ryan, Vicky, Smith, Hesther, Steel, Alison, Stefanetti, Renae J., Su, Huizhong, Taylor, Robert W., Thomas, Naomi J.P., Tuppen, Helen, Vincent, Amy E., Warren, Charlotte, and Watson, Gillian

Abstract

Additional file 2. Participant information sheet.

Published
2022
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31. Additional file 1 of Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy

Author

Abouhajar, Alaa, Alcock, Lisa, Bigirumurame, Theophile, Bradley, Penny, Brown, Laura, Campbell, Ian, Del Din, Silvia, Faitg, Julie, Falkous, Gavin, Gorman, Gráinne S., Lakey, Rachel, McFarland, Robert, Newman, Jane, Rochester, Lynn, Ryan, Vicky, Smith, Hesther, Steel, Alison, Stefanetti, Renae J., Su, Huizhong, Taylor, Robert W., Thomas, Naomi J.P., Tuppen, Helen, Vincent, Amy E., Warren, Charlotte, and Watson, Gillian

Abstract

Additional file 1. Informed consent form.

Published
2022
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32. Additional file 3 of Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy

Author

Abouhajar, Alaa, Alcock, Lisa, Bigirumurame, Theophile, Bradley, Penny, Brown, Laura, Campbell, Ian, Del Din, Silvia, Faitg, Julie, Falkous, Gavin, Gorman, Gráinne S., Lakey, Rachel, McFarland, Robert, Newman, Jane, Rochester, Lynn, Ryan, Vicky, Smith, Hesther, Steel, Alison, Stefanetti, Renae J., Su, Huizhong, Taylor, Robert W., Thomas, Naomi J.P., Tuppen, Helen, Vincent, Amy E., Warren, Charlotte, and Watson, Gillian

Abstract

Additional file 3. PIS Summary.

Published
2022
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36. Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant

Author

Bacalhau, Mafalda, Simões, Marta, Rocha, Mariana C., Hardy, Steven A., Vincent, Amy E., Durães, João, Macário, Maria C., Santos, Maria João, Rebelo, Olinda, Lopes, Carla, Pratas, João, Mendes, Cândida, Zuzarte, Mónica, Rego, A. Cristina, Girão, Henrique, Wong, Lee-Jun C., Taylor, Robert W., and Grazina, Manuela

Subjects
Bioenergetic dysfunction, Muscle Fibers, Skeletal, mtDNA common deletion, Middle Aged, DNA, Mitochondrial, Article, Mitochondria, Succinate Dehydrogenase, CPEO, Translation defect, Mutation, Humans, Female, Muscle, Skeletal, A%29%22">mt-tRNA variant (m.7486G>A), Sequence Deletion
Abstract

Highlights • Novel mt-tRNASer(UCN) (m.7486G>A) variant found in CPEO patient with 4,977 bp deletion. • The variant located in the anticodon loop meets the pathogenicity criteria. • Both genetic defects segregate with the biochemical phenotype in muscle. • Assembly impairment of MRC complexes was detected. • Mitochondrial translation defect and bioenergetic dysfunction were revealed., Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the “common deletion” in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The “common mtDNA deletion” is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded.

Published
2018

38. Distinctive Features of Orbital Adipose Tissue (OAT) in Graves’ Orbitopathy

Author

Zhang, Lei, primary, Evans, Anna, additional, von Ruhland, Chris, additional, Draman, Mohd Shazli, additional, Edkins, Sarah, additional, Vincent, Amy E., additional, Berlinguer-Palmini, Rolando, additional, Rees, D. Aled, additional, Haridas, Anjana S, additional, Morris, Dan, additional, Tee, Andrew R., additional, Ludgate, Marian, additional, Turnbull, Doug M., additional, Karpe, Fredrik, additional, and Dayan, Colin M., additional

Published
2020
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44. Astrocytic Changes in Mitochondrial Oxidative Phosphorylation Protein Levels in Parkinson's Disease.

Author

Chen, Chun, Mossman, Emily, Malko, Philippa, McDonald, David, Blain, Alasdair P., Bone, Laura, Erskine, Daniel, Filby, Andrew, Vincent, Amy E., Hudson, Gavin, and Reeve, Amy K.

Abstract

Background: Mitochondrial dysfunction within neurons, particularly those of the substantia nigra, has been well characterized in Parkinson's disease and is considered to be related to the pathogenesis of this disorder. Dysfunction within this important organelle has been suggested to impair neuronal communication and survival; however, the reliance of astrocytes on mitochondria and the impact of their dysfunction on this essential cell type are less well characterized. Objective: This study aimed to uncover whether astrocytes harbor oxidative phosphorylation (OXPHOS) deficiencies in Parkinson's disease and whether these deficiencies are more likely to occur in astrocytes closely associated with neurons or those more distant from them. Methods: Postmortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key OXPHOS proteins across all five complexes. Results: We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age. Conclusion: Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could have an impact on their reactivity and ability to support neurons in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Published
2022
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46. Sub-cellular origin of mtDNA deletions in human skeletal muscle

Author

Vincent, Amy E., Rosa, Hannah S., Pabis, Kamil, Lawless, Conor, Chen, Chun, Grunewald, Anne, Rygiel, Karolina A., Rocha, Mariana C., Reeve, Amy K., Falkous, Gavin, Perissi, Vanessa, White, Kathryn, Davey, Tracey, Petrof, Basil J., Sayer, Avan Aihie, Cooper, Cyrus, Deehan, David, Taylor, Robert W., Turnbull, Douglass M., and Picard, Martin

Published
2018

47. Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

Author

Vincent, Amy E., Rosa, Hannah S., Pabis, Kamil, Lawless, Conor, Chen, Chun, Anne Grünewald, Rygiel, Karolina A., Rocha, Mariana C., Reeve, Amy K., Falkous, Gavin, Perissi, Valentina, White, Kathryn, Davy, Tracey, Petrof, Basil J., Sayer, Avan A., Cooper, Cyrus, Deehan, David, Taylor, Robert W., Turnbull, Doug M., and Picard, Martin

Subjects
Aging, muscle, Muscle Fibers, Skeletal, mitochondrial DNA, respiratory chain deficiency, Biochemistry, biophysics & molecular biology [F05] [Life sciences], DNA, Mitochondrial, mitochondria, Humans, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], Muscle, Skeletal, Gene Deletion, Research Articles, Subcellular Fractions, Research Article
Abstract

Objective In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub‐cellular origin and potential mechanisms underlying this process. Methods Serial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. Results We report respiratory chain–deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three‐dimensional organization of the human skeletal muscle mitochondrial network. Interpretation We propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy. Ann Neurol 2018;84:289–301

Published
2018

48. Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level

Author

Lehmann, Diana, primary, Tuppen, Helen A L, additional, Campbell, Georgia E, additional, Alston, Charlotte L, additional, Lawless, Conor, additional, Rosa, Hannah S, additional, Rocha, Mariana C, additional, Reeve, Amy K, additional, Nicholls, Thomas J, additional, Deschauer, Marcus, additional, Zierz, Stephan, additional, Taylor, Robert W, additional, Turnbull, Doug M, additional, and Vincent, Amy E, additional

Published
2019
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49. Quantitative 3D Mapping of the Human Skeletal Muscle Mitochondrial Network

Author

Vincent, Amy E., primary, White, Kathryn, additional, Davey, Tracey, additional, Philips, Jonathan, additional, Ogden, R. Todd, additional, Lawless, Conor, additional, Warren, Charlotte, additional, Hall, Matt G., additional, Ng, Yi Shiau, additional, Falkous, Gavin, additional, Holden, Thomas, additional, Deehan, David, additional, Taylor, Robert W., additional, Turnbull, Doug M., additional, and Picard, Martin, additional

Published
2019
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50. Subcellular origin of mitochondrial DNA deletions in human skeletal muscle.

Author

Vincent, Amy E, Rosa, Hannah S, Pabis, Kamil, Lawless, Conor, Chen, Chun, Grünewald, Anne, Rygiel, Karolina A., Rocha, Mariana C., Reeve, Amy K., Falkous, Gavin, Perissi, Valentina, White, Kathryn, Davy, Tracey, Petrof, Basil J., Sayer, Avan A., Cooper, Cyrus, Deehan, David, Taylor, Robert W., Turnbull, Doug M., Picard, Martin, Vincent, Amy E, Rosa, Hannah S, Pabis, Kamil, Lawless, Conor, Chen, Chun, Grünewald, Anne, Rygiel, Karolina A., Rocha, Mariana C., Reeve, Amy K., Falkous, Gavin, Perissi, Valentina, White, Kathryn, Davy, Tracey, Petrof, Basil J., Sayer, Avan A., Cooper, Cyrus, Deehan, David, Taylor, Robert W., Turnbull, Doug M., and Picard, Martin

Abstract

OBJECTIVE: In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub-cellular origin and potential mechanisms underlying this process. METHODS: Serial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. RESULTS: We report respiratory chain-deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three-dimensional organization of the human skeletal muscle mitochondrial network. INTERPRETATION: We propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy.

Published
2018

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