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8. Letters

Author

Clarke, Michael

Published
2013

9. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model

Author

Reinitz, Felicia, Chen, Elizabeth Y, di Robilant, Benedetta Nicolis, Chuluun, Bayarsaikhan, Antony, Jane, Jones, Robert C, Gubbi, Neha, Lee, Karen, Ho, William Hai Dang, Kolluru, Sai Saroja, Qian, Dalong, Adorno, Maddalena, Piltti, Katja, Anderson, Aileen, Monje, Michelle, Heller, H Craig, Quake, Stephen R, and Clarke, Michael F

Subjects
Biochemistry and Cell Biology, Biological Sciences, Regenerative Medicine, Genetics, Stem Cell Research, Alzheimer's Disease, Neurosciences, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Cellular Senescence, Disease Models, Animal, Inflammation, Mice, Mice, Transgenic, Neurodegenerative Diseases, Plaque, Amyloid, Ubiquitin Thiolesterase, neural stem cells, Alzheimer's, neurodegeneration, Mouse, mouse, regenerative medicine, stem cells, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

Published
2022

13. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse

Author

Almanzar, Nicole, Antony, Jane, Baghel, Ankit S, Bakerman, Isaac, Bansal, Ishita, Barres, Ben A, Beachy, Philip A, Berdnik, Daniela, Bilen, Biter, Brownfield, Douglas, Cain, Corey, Chan, Charles KF, Chen, Michelle B, Clarke, Michael F, Conley, Stephanie D, Darmanis, Spyros, Demers, Aaron, Demir, Kubilay, De Morree, Antoine, du Bois, Tessa Divita Haley, Ebadi, Hamid, Espinoza, F Hernan, Fish, Matt, Gan, Qiang, George, Benson M, Gillich, Astrid, Gomez-Sjoberg, Rafael, Green, Foad, Genetiano, Geraldine, Gu, Xueying, Gulati, Gunsagar S, Hahn, Oliver, Haney, Michael Seamus, Hang, Yan, Harris, Lincoln, He, Mu, Hosseinzadeh, Shayan, Huang, Albin, Huang, Kerwyn Casey, Iram, Tal, Isobe, Taichi, Ives, Feather, Jones, Robert C, Kao, Kevin S, Karkanias, Jim, Karnam, Guruswamy, Keller, Andreas, Kershner, Aaron M, Khoury, Nathalie, Kim, Seung K, Kiss, Bernhard M, Kong, William, Krasnow, Mark A, Kumar, Maya E, Kuo, Christin S, Lam, Jonathan, Lee, Davis P, Lee, Song E, Lehallier, Benoit, Leventhal, Olivia, Li, Guang, Li, Qingyun, Liu, Ling, Lo, Annie, Lu, Wan-Jin, Lugo-Fagundo, Maria F, Manjunath, Anoop, May, Andrew P, Maynard, Ashley, McGeever, Aaron, Mckay, Marina, McNerney, M Windy, Merrill, Bryan, Metzger, Ross J, Mignardi, Marco, Min, Dullei, Nabhan, Ahmad N, Neff, Norma F, Ng, Katharine M, Nguyen, Patricia K, Noh, Joseph, Nusse, Roel, Palovics, Robert, Patkar, Rasika, Peng, Weng Chuan, Penland, Lolita, Pisco, Angela Oliveira, Pollard, Katherine, Puccinelli, Robert, Qi, Zhen, Quake, Stephen R, Rando, Thomas A, Rulifson, Eric J, Schaum, Nicholas, Segal, Joe M, Sikandar, Shaheen S, Sinha, Rahul, Sit, Rene V, Sonnenburg, Justin, and Staehli, Daniel

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Aging, Animals, Cellular Senescence, DNA Mutational Analysis, Female, Gene Expression Regulation, Developmental, Genomic Instability, Immunity, Liver, Male, Mice, Models, Animal, Organ Specificity, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Tabula Muris Consortium, General Science & Technology
Abstract

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.

Published
2020

15. Oral dosing for antenatal corticosteroids in the Rhesus macaque.

Author

Schmidt, Augusto F, Kemp, Matthew W, Milad, Mark, Miller, Lisa A, Bridges, James P, Clarke, Michael W, Kannan, Paranthaman S, and Jobe, Alan H

Subjects
Liver, Lung, Hippocampus, Animals, Macaca mulatta, Humans, Premature Birth, Betamethasone, Dexamethasone, Adrenal Cortex Hormones, Prenatal Care, Administration, Oral, Injections, Intramuscular, Gene Expression Profiling, Models, Animal, Gene Expression Regulation, Developmental, Fetal Organ Maturity, Pregnancy, Female, Administration, Oral, Gene Expression Regulation, Developmental, Injections, Intramuscular, Models, Animal, General Science & Technology
Abstract

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

Published
2019

18. 'No Cracks, no Blind Spots, no Gaps': Technologically-Enabled 'Preventative' Counterterrorism and Mass Repression in Xinjiang, China

Author

Clarke, Michael, 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

Published
2021
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20. Interlaboratory comparison of 25-hydroxyvitamin D assays: Vitamin D Standardization Program (VDSP) Intercomparison Study 2 — Part 1 liquid chromatography – tandem mass spectrometry (LC-MS/MS) assays — impact of 3-epi-25-hydroxyvitamin D3 on assay performance

Author

Wise, Stephen A., Camara, Johanna E., Burdette, Carolyn Q., Hahm, Grace, Nalin, Federica, Kuszak, Adam J., Merkel, Joyce, Durazo-Arvizu, Ramón A., Williams, Emma L., Hoofnagle, Andrew N., Ivison, Fiona, Fischer, Ralf, van den Ouweland, Jody M. W., Ho, Chung S., Law, Emmett W. K., Simard, Jean-Nicolas, Gonthier, Renaud, Holmquist, Brett, Meadows, Sarah, Cox, Lorna, Robyak, Kimberly, Creer, Michael H., Fitzgerald, Robert, Clarke, Michael W., Breen, Norma, Lukas, Pierre, Cavalier, Étienne, and Sempos, Christopher T.

Published
2022
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21. Assessment of serum total 25-hydroxyvitamin D assays for Vitamin D External Quality Assessment Scheme (DEQAS) materials distributed at ambient and frozen conditions

Author

Sempos, Christopher T., Williams, Emma L., Carter, Graham D., Jones, Julia, Camara, Johanna E., Burdette, Carolyn Q., Hahm, Grace, Nalin, Federica, Duewer, David L., Kuszak, Adam J., Merkel, Joyce, Hoofnagle, Andrew N., Lukas, Pierre, Cavalier, Étienne, Durazo-Arvizu, Ramón A., Crump, Peter M., Popp, Christian, Beckert, Christian, Schultess, Jan, Van Slooten, Glen, Tourneur, Carole, Pease, Camille, Kaul, Ravi, Villarreal, Alfredo, Ivison, Fiona, Fischer, Ralf, van den Ouweland, Jody M. W., Ho, Chung S., Law, Emmett W. K., Simard, Jean-Nicolas, Gonthier, Renaud, Holmquist, Brett, Batista, Marcelo Cidade, Meadows, Sarah, Cox, Lorna, Jansen, Eugene, Khan, Dilshad Ahmed, Robyak, Kimberly, Creer, Michael H., Kilbane, Mark, Twomey, Patrick J., Freeman, James, Parker, Neil, Yuan, Jinyun, Fitzgerald, Robert, Mushtaq, Sohail, Clarke, Michael W., Breen, Norma, Simpson, Christine, and Wise, Stephen A.

Published
2022
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24. Classical Antiquity and Medieval Ireland

Author

Clarke, Michael, Poppe, Erich, and Torrance, Isabelle

Subjects
Middle Irish, Gaelic, Celtic, Troy, Trojan War, Aeneid, Statius, Lucan, epic, Annals of Tigernach, Togail Troí, Cóemáin, Mainistrech, Jason, Imtheachta Aeniasa, In Cath Catharda, Dindshenchas, thema EDItEUR::D Biography, Literature and Literary studies::DS Literature: history and criticism::DSB Literary studies: general::DSBB Literary studies: ancient, classical and medieval
Abstract

Through an extensive series of extracts and accompanying interpretative and contextual essays, this volume showcases the expertise in classical learning that flourished in medieval Gaelic Ireland. Providing translations of all excerpts, it situates better known ‘antiquity sagas’ in the Middle Irish language, such as Togail Troí (The Siege of Troy, based on Dares Phrygius), Imtheachta Aeniasa (The Wanderings of Aeneas, based on Virgil’s Aeneid), In Cath Catharda (The Civil War, based on Lucan) and Togail na Tebe (The Siege of Thebes, based on Statius), within the broader constellation of medieval Irish literature that references and engages with classical antiquity. Included are synchronistic poetry and world chronologies; lesser-known Irish poetry and prose recounting episodes from Graeco-Roman mythography and featuring, for instance, Jason and the Argonauts, Ulysses and Penelope, Agamemnon and Clytemnestra, Daedalus and the Minotaur; linguistic and metaphysical tracts; place-name lore; and medieval historiographies of Alexander the Great, Hercules, and warriors of Irish legend recast as classical heroes. Creating access to this body of texts and revealing the marked influences of classical concepts on the imaginative resources of medieval Ireland fills a conspicuous lacuna in our knowledge of classical reception in European literatures. The ebook editions of this book are available open access under a CC BY-NC-ND 4.0 licence on www.bloomsburycollections.com. Open access was funded by the European Research Council, grant no. 818366.

Published
2024
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26. A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland

Author

Cai, Shang, Kalisky, Tomer, Sahoo, Debashis, Dalerba, Piero, Feng, Weiguo, Lin, Yuan, Qian, Dalong, Kong, Angela, Yu, Jeffrey, Wang, Flora, Chen, Elizabeth Y, Scheeren, Ferenc A, Kuo, Angera H, Sikandar, Shaheen S, Hisamori, Shigeo, van Weele, Linda J, Heiser, Diane, Sim, Sopheak, Lam, Jessica, Quake, Stephen, and Clarke, Michael F

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Stem Cell Research, Cancer, Breast Cancer, Animals, Antigens, CD, Cell Cycle, Cell Lineage, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Epithelial Cells, Female, Gene Deletion, Homeostasis, Mammary Glands, Animal, Mice, Inbred C57BL, Mice, Knockout, Regeneration, Repressor Proteins, Stem Cells, Tumor Suppressor Proteins, quiescence, stem cell exhaustion, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11bhigh cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland.

Published
2017

27. Assessment of serum total 25-hydroxyvitamin D assay commutability of Standard Reference Materials and College of American Pathologists Accuracy-Based Vitamin D (ABVD) Scheme and Vitamin D External Quality Assessment Scheme (DEQAS) materials: Vitamin D Standardization Program (VDSP) Commutability Study 2

Author

Camara, Johanna E., Wise, Stephen A., Hoofnagle, Andrew N., Williams, Emma L., Carter, Graham D., Jones, Julia, Burdette, Carolyn Q., Hahm, Grace, Nalin, Federica, Kuszak, Adam J., Merkel, Joyce, Durazo-Arvizu, Ramón A., Lukas, Pierre, Cavalier, Étienne, Popp, Christian, Beckert, Christian, Schultess, Jan, Van Slooten, Glen, Tourneur, Carole, Pease, Camille, Kaul, Ravi, Villarreal, Alfredo, Ivison, Fiona, Fischer, Ralf, van den Ouweland, Jody M. W., Ho, Chung S., Law, Emmett W.K., Simard, Jean-Nicolas, Gonthier, Renaud, Holmquist, Brett, Batista, Marcelo Cidade, Pham, Heather, Bennett, Alex, Meadows, Sarah, Cox, Lorna, Jansen, Eugene, Khan, Dilshad Ahmed, Robyak, Kimberly, Creer, Michael H., Kilbane, Mark, Twomey, Patrick J., Freeman, James, Parker, Neil, Yuan, Jinyun, Fitzgerald, Robert, Mushtaq, Sohail, Clarke, Michael W., Breen, Norma, Simpson, Christine, and Sempos, Christopher T.

Published
2021
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28. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

Author

Dalerba, Piero, Sahoo, Debashis, Paik, Soonmyung, Guo, Xiangqian, Yothers, Greg, Song, Nan, Wilcox-Fogel, Nate, Forgó, Erna, Rajendran, Pradeep S, Miranda, Stephen P, Hisamori, Shigeo, Hutchison, Jacqueline, Kalisky, Tomer, Qian, Dalong, Wolmark, Norman, Fisher, George A, van de Rijn, Matt, and Clarke, Michael F

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Digestive Diseases, Prevention, Genetics, Colo-Rectal Cancer, Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Analysis of Variance, Antineoplastic Agents, Biomarkers, Tumor, CDX2 Transcription Factor, Chemotherapy, Adjuvant, Colonic Neoplasms, Computational Biology, Databases, Genetic, Disease-Free Survival, Female, Gene Expression, Homeodomain Proteins, Humans, Male, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Prognosis, RNA, Messenger, Retrospective Studies, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).

Published
2016

33. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA–protein interaction

Author

Williamson, Kathleen A., Hall, H. Nikki, Owen, Liusaidh J., Livesey, Benjamin J., Hanson, Isabel M., Adams, G. G. W., Bodek, Simon, Calvas, Patrick, Castle, Bruce, Clarke, Michael, Deng, Alexander T., Edery, Patrick, Fisher, Richard, Gillessen-Kaesbach, Gabriele, Heon, Elise, Hurst, Jane, Josifova, Dragana, Lorenz, Birgit, McKee, Shane, Meire, Francoise, Moore, Anthony T., Parker, Michael, Reiff, Charlotte M., Self, Jay, Tobias, Edward S., Verheij, Joke B. G. M., Willems, Marjolaine, Williams, Denise, van Heyningen, Veronica, Marsh, Joseph A., and FitzPatrick, David R.

Published
2020
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37. Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter

Author

Fee, Erin L., primary, Takahashi, Tsukasa, additional, Takahashi, Yuki, additional, Carter, Sean W. D., additional, Clarke, Michael W., additional, Milad, Mark A., additional, Usuda, Haruo, additional, Ikeda, Hideyuki, additional, Kumagai, Yusaku, additional, Saito, Yuya, additional, Ireland, Demelza J., additional, Newnham, John P., additional, Saito, Masatoshi, additional, Jobe, Alan H., additional, and Kemp, Matthew W., additional

Published
2023
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38. Clinical features, management and outcomes of intermittent exotropia in the United Kingdom

Author

Clarke, Michael Patrick

Subjects
618.920977
Abstract

Intermittent Exotropia [X(T)], is a common form of childhood strabismus. Clinical decision making for this condition is hampered by lack of evidence from well designed prospective studies. This thesis consists of five papers authored by myself and my collaborators, and a linking statement placing these papers in a scientific context. The first two papers describe the development and clinical utility of a novel scoring system for the control of X(T), which can be used to assess the progress of the condition and the effect of treatment on this parameter. This scoring system, the Newcastle Control Score for Intermittent Exotropia, consists of a parent/carer reported 'Home' component and an objective, 'Clinic', assessment of the ease of realignment of the exotropia in response to disruption of fusion by a cover test. The second two papers describe the establishment of relevant age related normal ranges of a new test of distance stereoacuity, the Frisby Davis Distance Stereotest (FDiffi ), and the application of this test to a cohort of children with X(T). In contrast to previous studies, we found an 'all or none' pattern of distance stereoacuity in X(T), rather than a gradual decline in distance stereoacuity. The final paper describes the initial results of a prospective study of a cohort of 460 children with X(T), recruited in 26 centres, which examined their clinical phenotype and management in the first year following recruitment. The striking finding of this study was that over half the children in the cohort received no treatment in the first year after diagnosis, suggesting that decision making by professionals in this condition was hampered by a lack of evidence about natural history and treatment outcomes. The linking statement concludes with a brief description of related and ongoing research by our group and others.

Published
2013

39. Usp16 contributes to somatic stem-cell defects in Down’s syndrome

Author

Adorno, Maddalena, Sikandar, Shaheen, Mitra, Siddhartha S, Kuo, Angera, Nicolis di Robilant, Benedetta, Haro-Acosta, Veronica, Ouadah, Youcef, Quarta, Marco, Rodriguez, Jacqueline, Qian, Dalong, Reddy, Vadiyala M, Cheshier, Samuel, Garner, Craig C, and Clarke, Michael F

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Stem Cell Research, Intellectual and Developmental Disabilities (IDD), Down Syndrome, Stem Cell Research - Nonembryonic - Non-Human, Brain Disorders, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Adult Stem Cells, Animals, Cell Proliferation, Cellular Senescence, Chromosomes, Human, Pair 21, Cyclin-Dependent Kinase Inhibitor p16, Disease Models, Animal, Epithelium, Female, Fibroblasts, Gene Dosage, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Mammary Glands, Animal, Mice, Molecular Targeted Therapy, Neural Stem Cells, Trisomy, Ubiquitin Thiolesterase, Ubiquitination, General Science & Technology
Abstract

Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.

Published
2013

42. Special education needs co-ordinators perceptions of local education support services with particular reference to pupils with social, emotional and behavioural difficulties : A case study of Luton local authority

Author

Clarke, Michael J.

Subjects
371.9
Abstract

This Thesis is a case study of Luton Local Authority (LA) and its approach to delivering special educational needs (SEN) support services to Luton schools. The study concentrates on the delivery of behaviour support to schools and pupils and explores how pupils with social emotional and behavioural difficulties may be included or excluded from school as a result of this support. The case study incorporates a multi-method research strategy, which sought to gain an LA perspective of service delivery by involving all Luton's special educational needs co-ordinators (SENCOs) in a questionnaire about behaviour support service delivery to their schools. The case study approach also involved using semi-structured interviews with thirteen Luton SENCOs. In Luton the delivery mechanism for SEN support services is through termly meetings with schools. These school consultation meetings (SCMs) are the strategy used by the LA to deliver support services. The study involved observing eight SCMs so that first hand knowledge of the delivery process could be investigated. The data collected is presented in three layers. Layer one Presents the questionnaire data, layer two presents the inter-view data and layer three presents the observation data. All three data sets are presented under the key research questions. The three key research questions are: 1) How do schools use School Consultation Meetings to access Behaviour Support? 2) Who from the LA carries out the Behaviour Support work with the Schools? 3) Why have SEN support services, which focus on pupil deficits instead of pupil strengths? The case study found that the concept of SEN is a contentious and complex issue, which is subject to redefinition over time. The English education system is viewed as being segregationist and the concept of inclusion is found to apply to different pupils along class, ethnic and gender dimensions.

Published
2008

50. Conversational interaction between children using communication aids and their peers

Author

Clarke, Michael Timothy

Subjects
418.0083
Abstract

This thesis uses the principles and practices of Conversation Analysis in an examination of conversational interaction between non-speaking children with Cerebral Palsy using voice output communication aids (VOCAs) and their speaking peers. In order to capture the unique and subtle ways in which these interactions are organised this thesis presents a detailed examination of three dyads. Many children with Cerebral Palsy experience profound difficulty producing intelligible speech. Such children may be provided with communication aids, including VOCAs, as an alternative communication modality. Despite recognition of the value of children's peer relationships, few studies have focused on interaction between children using communication aids and their peers. The central aim of this thesis is to examine how such interactions are organised. In particular, this work is concerned with examining the role of the speaking partners in conversational organisation, how VOCAs contribute to interaction and how conversations are organised when non-speaking children participate through unintelligible vocalisations and non-verbal actions. A significant feature of each dyad is the work that speaking partners do in organising particular types of structural integrity for the conversation. This includes speaking partners locating the production of VOCA mediated turns and non-verbal actions within specific sequential contexts. Such practices provide frameworks within which VOCA mediated contributions and non-verbal actions may be understood. VOCA use initiated outside such predefined sequential locations may be realised problematically. Speaking children may also seek to organise the interaction through the treatment of their partners' unintelligible vocalisations and non-verbal actions with rich meaning. In so doing, speaking partners portray children with Cerebral Palsy with particular types of competence. By revealing the ways in which these children organise conversational interaction, this thesis highlights implications for intervention by Speech and Language Therapists who support children using communication aids in schools.

Published
2005

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