22 results on '"Ian Smyth"'
Search Results
2. Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice
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Fenny Wiradjaja, Denny L. Cottle, Lynelle Jones, and Ian Smyth
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Medicine ,Pathology ,RB1-214 - Abstract
SUMMARY Fras1-related extracellular matrix protein 1 (FREM1) is required for epidermal adhesion during embryogenesis, and mice lacking the gene develop fetal skin blisters and a range of other developmental defects. Mutations in members of the FRAS/FREM gene family cause diseases of the Fraser syndrome spectrum. Embryonic epidermal blistering is also observed in mice lacking PdgfC and its receptor, PDGFRα. In this article, we show that FREM1 binds to PDGFC and that this interaction regulates signalling downstream of PDGFRα. Fibroblasts from Frem1-mutant mice respond to PDGFC stimulation, but with a shorter duration and amplitude than do wild-type cells. Significantly, PDGFC-stimulated expression of the metalloproteinase inhibitor Timp1 is reduced in cells with Frem1 mutations, leading to reduced basement membrane collagen I deposition. These results show that the physical interaction of FREM1 with PDGFC can regulate remodelling of the extracellular matrix downstream of PDGFRα. We propose that loss of FREM1 function promotes epidermal blistering in Fraser syndrome as a consequence of reduced PDGFC activity, in addition to its stabilising role in the basement membrane.
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- 2013
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3. Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.
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Lisenka E L M Vissers, Timothy C Cox, A Murat Maga, Kieran M Short, Fenny Wiradjaja, Irene M Janssen, Fernanda Jehee, Debora Bertola, Jia Liu, Garima Yagnik, Kiyotoshi Sekiguchi, Daiji Kiyozumi, Hans van Bokhoven, Carlo Marcelis, Michael L Cunningham, Peter J Anderson, Simeon A Boyadjiev, Maria Rita Passos-Bueno, Joris A Veltman, Ian Smyth, Michael F Buckley, and Tony Roscioli
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Genetics ,QH426-470 - Abstract
The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.
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- 2011
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4. Correction: Dual Functions of ASCIZ in the DNA Base Damage Response and Pulmonary Organogenesis.
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Sabine Jurado, Ian Smyth, Bryce van Denderen, Nora Tenis, Andrew Hammet, Kimberly Hewitt, Jane-Lee Ng, Carolyn J. McNees, Sergei V. Kozlov, Hayato Oka, Masahiko Kobayashi, Lindus A. Conlan, Timothy J. Cole, Ken-ichi Yamamoto, Yoshihito Taniguchi, Shunichi Takeda, Martin F. Lavin, and Jörg Heierhorst
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Genetics ,QH426-470 - Published
- 2010
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5. Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis.
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Sabine Jurado, Ian Smyth, Bryce van Denderen, Nora Tenis, Andrew Hammet, Kimberly Hewitt, Jane-Lee Ng, Carolyn J McNees, Sergei V Kozlov, Hayato Oka, Masahiko Kobayashi, Lindus A Conlan, Timothy J Cole, Ken-Ichi Yamamoto, Yoshihito Taniguchi, Shunichi Takeda, Martin F Lavin, and Jörg Heierhorst
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Genetics ,QH426-470 - Abstract
Zn²(+)-finger proteins comprise one of the largest protein superfamilies with diverse biological functions. The ATM substrate Chk2-interacting Zn²(+)-finger protein (ASCIZ; also known as ATMIN and ZNF822) was originally linked to functions in the DNA base damage response and has also been proposed to be an essential cofactor of the ATM kinase. Here we show that absence of ASCIZ leads to p53-independent late-embryonic lethality in mice. Asciz-deficient primary fibroblasts exhibit increased sensitivity to DNA base damaging agents MMS and H2O2, but Asciz deletion knock-down does not affect ATM levels and activation in mouse, chicken, or human cells. Unexpectedly, Asciz-deficient embryos also exhibit severe respiratory tract defects with complete pulmonary agenesis and severe tracheal atresia. Nkx2.1-expressing respiratory precursors are still specified in the absence of ASCIZ, but fail to segregate properly within the ventral foregut, and as a consequence lung buds never form and separation of the trachea from the oesophagus stalls early. Comparison of phenotypes suggests that ASCIZ functions between Wnt2-2b/ß-catenin and FGF10/FGF-receptor 2b signaling pathways in the mesodermal/endodermal crosstalk regulating early respiratory development. We also find that ASCIZ can activate expression of reporter genes via its SQ/TQ-cluster domain in vitro, suggesting that it may exert its developmental functions as a transcription factor. Altogether, the data indicate that, in addition to its role in the DNA base damage response, ASCIZ has separate developmental functions as an essential regulator of respiratory organogenesis.
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- 2010
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6. Palmitoylation regulates epidermal homeostasis and hair follicle differentiation.
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Pleasantine Mill, Angela W S Lee, Yuko Fukata, Ryouhei Tsutsumi, Masaki Fukata, Margaret Keighren, Rebecca M Porter, Lisa McKie, Ian Smyth, and Ian J Jackson
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Genetics ,QH426-470 - Abstract
Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear beta-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis.
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- 2009
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7. Correction: A Mouse Model of Harlequin Ichthyosis Delineates a Key Role for Abca12 in Lipid Homeostasis.
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Ian Smyth, Douglas F. Hacking, Adrienne A. Hilton, Nigora Mukhamedova, Peter J. Meikle, Sarah Ellis, Keith Slatterley, Janelle E. Collinge, Carolyn A. de Graaf, Melanie Bahlo, Dmitri Sviridov, Benjamin T. Kile, and Douglas J. Hilton
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Genetics ,QH426-470 - Published
- 2008
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8. A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis.
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Ian Smyth, Douglas F Hacking, Adrienne A Hilton, Nigora Mukhamedova, Peter J Meikle, Sarah Ellis, Keith Satterley, Janelle E Collinge, Carolyn A de Graaf, Melanie Bahlo, Dmitri Sviridov, Benjamin T Kile, and Douglas J Hilton
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Genetics ,QH426-470 - Abstract
Harlequin Ichthyosis (HI) is a severe and often lethal hyperkeratotic skin disease caused by mutations in the ABCA12 transport protein. In keratinocytes, ABCA12 is thought to regulate the transfer of lipids into small intracellular trafficking vesicles known as lamellar bodies. However, the nature and scope of this regulation remains unclear. As part of an original recessive mouse ENU mutagenesis screen, we have identified and characterised an animal model of HI and showed that it displays many of the hallmarks of the disease including hyperkeratosis, loss of barrier function, and defects in lipid homeostasis. We have used this model to follow disease progression in utero and present evidence that loss of Abca12 function leads to premature differentiation of basal keratinocytes. A comprehensive analysis of lipid levels in mutant epidermis demonstrated profound defects in lipid homeostasis, illustrating for the first time the extent to which Abca12 plays a pivotal role in maintaining lipid balance in the skin. To further investigate the scope of Abca12's activity, we have utilised cells from the mutant mouse to ascribe direct transport functions to the protein and, in doing so, we demonstrate activities independent of its role in lamellar body function. These cells have severely impaired lipid efflux leading to intracellular accumulation of neutral lipids. Furthermore, we identify Abca12 as a mediator of Abca1-regulated cellular cholesterol efflux, a finding that may have significant implications for other diseases of lipid metabolism and homeostasis, including atherosclerosis.
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- 2008
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9. Interferons limit autoantigen-specific CD8
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Gaurang, Jhala, Balasubramanian, Krishnamurthy, Thomas C, Brodnicki, Tingting, Ge, Satoru, Akazawa, Claudia, Selck, Prerak M, Trivedi, Evan G, Pappas, Leanne, Mackin, Nicola, Principe, Erwan, Brémaud, David J, De George, Louis, Boon, Ian, Smyth, Jonathan, Chee, Thomas W H, Kay, and Helen E, Thomas
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Interferon-gamma ,Mice ,Suppressor of Cytokine Signaling 1 Protein ,Mice, Inbred NOD ,Diabetes Mellitus ,Animals ,Cytokines ,Interleukin-2 ,Suppressor of Cytokine Signaling Proteins ,Interferons ,CD8-Positive T-Lymphocytes ,Autoantigens - Abstract
Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNγ is ineffective in reducing disease. We characterize islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes is minimally affected, but at 125 days of age, antigen-specific CD8
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- 2021
10. An investigation into apprenticeship completion and retention in Northern Ireland: a social exchange perspective
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Chilemwa Zimba and Ian Smyth
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Organizational Behavior and Human Resource Management ,Medical education ,Cost–benefit analysis ,05 social sciences ,Perspective (graphical) ,050301 education ,Focus group ,Education ,Work (electrical) ,Turnover ,Social exchange theory ,0502 economics and business ,Apprenticeship ,Psychology ,Set (psychology) ,0503 education ,050203 business & management - Abstract
This paper investigates effective strategies for enhancing completion rates of apprentices and their retention after completing their training. The study was cross sectional and qualitative, involving semi‐structured interviews with managers and four focus groups involving current and completed apprentices from within the engineering sector. The findings revealed that the factors that can enhance intentions of completing an apprenticeship were perceived organisation support (POS) factors such as apprentice pay, recognition and employer support. Leader Member Exchange (LMX) factors such as support from trainers and supervisors, would increase their intentions to complete an apprenticeship and stay on with an organisation after training. The key Percieved Organisational Support factors that would enhance intentions to stay with the organisation after completion were post apprenticeship pay, career progression and challenging and interesting work. Participants with high Perceived Organisational Support and Leader‐Member Exchange, had higher intentions of completing an apprenticeship and staying with the employer after completion and vice versa. This research added to the literature on apprenticeships as it analysed the factors influencing current and completed apprentices’ intentions to discontinue or complete an apprenticeship and stay with or leave their employer after completion through the lens of social exchange theory (SET) (Blau, 1964). This is unlike previous studies that emphasised motivation theory. Social Exchange Theory was supported as both employers and apprentices weighed the costs and benefits of their relationship which impacted on their completion and retention choices. The implication of this study is that employers should develop effective strategies for enhancing completion and retention rates to reap the full benefits from apprenticeships.
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- 2019
11. Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse
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Gaurang Jhala, Balasubramanian Krishnamurthy, Thomas C. Brodnicki, Tingting Ge, Satoru Akazawa, Claudia Selck, Prerak M. Trivedi, Evan G. Pappas, Leanne Mackin, Nicola Principe, Erwan Brémaud, David J. De George, Louis Boon, Ian Smyth, Jonathan Chee, Thomas W.H. Kay, and Helen E. Thomas
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General Biochemistry, Genetics and Molecular Biology - Published
- 2022
12. Cross-Talk Between Interferon-Gamma and IL-2 Signaling Regulates Antigen-Specific CD8 + T-Cell Number
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Gaurang Jhala, Balasubramanian Krishnamurthy, Thomas C. Brodnicki, TingTing Ge, Satoru Akazawa, Claudia Selck, Prerak M. Trivedi, Evan Pappas, Leanne Mackin, Nicola Principe, Erwan Brémaud, David de George, Louis Boon, Ian Smyth, Jonathan Chee, Thomas William Kay, and Helen E. Thomas
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2021
13. A 53BP1 Inhibitory Compound Enhances CRISPR Efficiency for Generating Knock-In Mice
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Jeanette Rientjes, Jieqiong Lou, Menachem Gunzburg, Bradley Doak, Jacqueline Norris, Caroline Foley, Sarah N. Dishman, Stephanie Cholensky, Dirk Truman, Emily Kelly, Susan Thomas, Michelle Meilak, Alyce Lynas, Bec Hurley, Fleur Rodda, Casey Grist, Emma Rooney, Tanya Lennane, Leanne Hawkey, Ian Smyth, Kenneth Pearce, Elizabeth Hinde, Lindsey Ingerman James, and Stephen Headey
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- 2020
14. Maintaining Adherence Programme: evaluation of an innovative service model
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Judi Mallalieu, Llewellyn Lewis, Ian Smyth, Christine O'Keeffe, Sam Oliver, and Laura Baldock
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Service (business) ,medicine.medical_specialty ,business.industry ,Alternative medicine ,Schizoaffective disorder ,Disease ,computer.software_genre ,medicine.disease ,Service model ,Original Papers ,030227 psychiatry ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Rating scale ,Schizophrenia ,Family medicine ,Health care ,Medicine ,Data mining ,business ,computer ,030217 neurology & neurosurgery - Abstract
Aims and methodThe Maintaining Adherence Programme (MAP) is a new model of care for patients with schizophrenia, schizoaffective disorder and bipolar affective disorder which aims to encourage adherence and prevent relapse. This evaluation, conducted by retrospective and prospective data collection (including patient questionnaires and staff interviews), aimed to describe MAP's impact on healthcare resource use, clinical measures and patient and staff satisfaction, following its implementation in a university National Health Service (NHS) foundation trust in England. We included 143 consenting patients who entered MAP before 31 March 2012.ResultsIn-patient bed days and non-MAP NHS costs reduced significantly in the 18 months post-MAP entry. At 15–18 months post-MAP, Medication Adherence Rating Scale scores had improved significantly from baseline and there was a shift towards less severe clinician-rated disease categories. Based on patient surveys, 96% would recommend MAP to friends, and staff were also overwhelmingly positive about the service.Clinical implicationsMAP was associated with reduced cost of treatment, improvements in clinical outcomes and very high patient and staff satisfaction.
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- 2016
15. Further steps to define and deliver high quality care for care clusters: the mental health care clusters and pathways website
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Miranda Stead, Ian Smyth, Carole Green, Michael Clark, Wendy Shiels, Karen Batty, Joseph Flahive, Christina Walters, and Clare Hilton
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Knowledge management ,Relation (database) ,business.industry ,media_common.quotation_subject ,Evidence-based medicine ,Sensemaking ,Public relations ,Mental health ,Psychiatry and Mental health ,Work (electrical) ,Payment by Results ,Medicine ,Quality (business) ,Set (psychology) ,business ,media_common - Abstract
PurposeWith care clusters an established framework for mental health services it is timely to consider how to use them to deliver high quality, evidence based care that is socially inclusive and recovery oriented. This paper aims to describe conceptual thinking about these issues, specifically in relation to the challenges and balances inherent in the care packages approach. It seeks to describe work to develop an internet based, high‐level description of such packages for each care cluster.Design/methodology/approachThe background to the project is described, along with a discussion of the conceptual and practice issues behind the work.FindingsWith mental health care now trying to make sense of local services in terms of care clusters the authors offer a high‐level framework to help people in this sensemaking. Coherent, socially inclusive and recovery oriented packages are set out on the website.Research limitations/implicationsThe work discussed in the article is highly innovative, being the first systematic attempt to provide evidence‐based, high‐level care packages for the care clusters model. Hence, a limitation is the challenge remaining to operationalise the work to real world care contexts.Practical implicationsThe website sets out a framework to help local services and commissioners plan and organise their services, drawing on the best guidance and evidence and developing care packages on the basis of the right ethos of care.Social implicationsIn moving to services fully commissioned and organised around the care clusters model, there remain major conceptual and practice challenges to address including operationalising evidence‐based care packages and means of flexibly delivering individual care.Originality/valueThis is the first view of socially inclusive packages for each of the care clusters that also draw together the best of guidance and standards of care.
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- 2013
16. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes
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Jacqueline K. White, Anna-Karin Gerdin, Natasha A. Karp, Ed Ryder, Marija Buljan, James N. Bussell, Jennifer Salisbury, Simon Clare, Neil J. Ingham, Christine Podrini, Richard Houghton, Jeanne Estabel, Joanna R. Bottomley, David G. Melvin, David Sunter, Niels C. Adams, David Tannahill, Darren W. Logan, Daniel G. MacArthur, Jonathan Flint, Vinit B. Mahajan, Stephen H. Tsang, Ian Smyth, Fiona M. Watt, William C. Skarnes, Gordon Dougan, David J. Adams, Ramiro Ramirez-Solis, Allan Bradley, Karen P. Steel, Lauren Baker, Caroline Barnes, Ryan Beveridge, Emma Cambridge, Damian Carragher, Prabhjoat Chana, Kay Clarke, Yvette Hooks, Natalia Igosheva, Ozama Ismail, Hannah Jackson, Leanne Kane, Rosalind Lacey, David Tino Lafont, Mark Lucas, Simon Maguire, Katherine McGill, Rebecca E. McIntyre, Sophie Messager, Lynda Mottram, Lee Mulderrig, Selina Pearson, Hayley J. Protheroe, Laura-Anne Roberson, Grace Salsbury, Mark Sanderson, Daniel Sanger, Carl Shannon, Paul C. Thompson, Elizabeth Tuck, Valerie E. Vancollie, Lisa Brackenbury, Wendy Bushell, Ross Cook, Priya Dalvi, Diane Gleeson, Bishoy Habib, Matt Hardy, Kifayathullah Liakath-Ali, Evelina Miklejewska, Stacey Price, Debarati Sethi, Elizabeth Trenchard, Dominique von Schiller, Sapna Vyas, Anthony P. West, John Woodward, Elizabeth Wynn, Arthur Evans, David Gannon, Mark Griffiths, Simon Holroyd, Vivek Iyer, Christian Kipp, Morag Lewis, Wei Li, Darren Oakley, David Richardson, Damian Smedley, Chukwuma Agu, Jackie Bryant, Liz Delaney, Nadia I. Gueorguieva, Helen Tharagonnet, Anne J. Townsend, Daniel Biggs, Ellen Brown, Adam Collinson, Charles-Etienne Dumeau, Evelyn Grau, Sarah Harrison, James Harrison, Catherine E. Ingle, Helen Kundi, Alla Madich, Danielle Mayhew, Tom Metcalf, Stuart Newman, Johanna Pass, Laila Pearson, Helen Reynolds, Caroline Sinclair, Hannah Wardle-Jones, Michael Woods, Liam Alexander, Terry Brown, Francesca Flack, Carole Frost, Nicola Griggs, Silvia Hrnciarova, Andrea Kirton, Jordan McDermott, Claire Rogerson, Gemma White, Pawel Zielezinski, Tia DiTommaso, Andrew Edwards, Emma Heath, Mary Ann Mahajan, Binnaz Yalcin, The Wellcome Trust Sanger Institute [Cambridge], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, University of Iowa [Iowa City], Monash University [Melbourne], Wellcome Trust - MRC Cambridge, Columbia University [New York], University of Cambridge [UK] (CAM), Wolfson Centre for Age-Related Diseases [Londres, Royaume-Uni], Guy's Campus [Londres, Royaume-Uni], King‘s College London-King‘s College London, Sanger Institute Mouse Genetics Project: Lauren Baker, Caroline Barnes, Ryan Beveridge, Emma Cambridge, Damian Carragher, Prabhjoat Chana, Kay Clarke, Yvette Hooks, Natalia Igosheva, Ozama Ismail, Hannah Jackson, Leanne Kane, Rosalind Lacey, David Tino Lafont, Mark Lucas, Simon Maguire, Katherine McGill, Rebecca E McIntyre, Sophie Messager, Lynda Mottram, Lee Mulderrig, Selina Pearson, Hayley J Protheroe, Laura-Anne Roberson, Grace Salsbury, Mark Sanderson, Daniel Sanger, Carl Shannon, Paul C Thompson, Elizabeth Tuck, Valerie E Vancollie, Lisa Brackenbury, Wendy Bushell, Ross Cook, Priya Dalvi, Diane Gleeson, Bishoy Habib, Matt Hardy, Kifayathullah Liakath-Ali, Evelina Miklejewska, Stacey Price, Debarati Sethi, Elizabeth Trenchard, Dominique von Schiller, Sapna Vyas, Anthony P West, John Woodward, Elizabeth Wynn, Arthur Evans, David Gannon, Mark Griffiths, Simon Holroyd, Vivek Iyer, Christian Kipp, Morag Lewis, Wei Li, Darren Oakley, David Richardson, Damian Smedley, Chukwuma Agu, Jackie Bryant, Liz Delaney, Nadia I Gueorguieva, Helen Tharagonnet, Anne J Townsend, Daniel Biggs, Ellen Brown, Adam Collinson, Charles-Etienne Dumeau, Evelyn Grau, Sarah Harrison, James Harrison, Catherine E Ingle, Helen Kundi, Alla Madich, Danielle Mayhew, Tom Metcalf, Stuart Newman, Johanna Pass, Laila Pearson, Helen Reynolds, Caroline Sinclair, Hannah Wardle-Jones, Michael Woods, Liam Alexander, Terry Brown, Francesca Flack, Carole Frost, Nicola Griggs, Silvia Hrnciarova, Andrea Kirton, Jordan McDermott, Claire Rogerson, Gemma White, Pawel Zielezinski, Tia Ditommaso, Andrew Edwards, Emma Heath, Mary Ann Mahajan, Binnaz Yalcin., Dupuis, Christine, Estabel, Jeanne [0000-0002-4472-3820], Tannahill, David [0000-0002-3811-6864], Dougan, Gordon [0000-0003-0022-965X], Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository
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Resource ,Male ,[SDV]Life Sciences [q-bio] ,Mutant ,Genome-wide association study ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Animals ,Disease ,Gene ,030304 developmental biology ,Genetics ,Mice, Knockout ,0303 health sciences ,Genes, Essential ,Biochemistry, Genetics and Molecular Biology(all) ,Robustness (evolution) ,Phenotype ,[SDV] Life Sciences [q-bio] ,Disease Models, Animal ,Genetic Techniques ,Knockout mouse ,Female ,Haploinsufficiency ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Summary Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PaperClip, Graphical Abstract, Highlights • Large openly available resource of targeted mouse mutants and phenotypic data • Screen for broad range of disease features and traits • Many novel phenotypes suggest functions for both studied and unstudied genes • Haploinsufficiency and pleiotropy are common, More than 900 new mutant mice lines and a multifaceted phenotypic screening platform reveal unanticipated pleiotropies, widespread effects of haploinsufficiency, potential disease models, and functions for unstudied genes.
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- 2013
17. The development of baseball in Northern England, 1935–39
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Ian Smyth
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History ,Political science ,Political economy ,Social Sciences (miscellaneous) - Published
- 1993
18. The spectrum of patched mutations in a collection of Australian basal cell carcinomas
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Timothy Evans, Waranya Boonchai, Susan Shanley, Ian Smyth, Susan Gillies, Kylie Georgas, Brandon Wainwright, Georgia Chenevix-Trench, and Carol Wicking
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Male ,Patched Receptors ,Polymorphism, Genetic ,Skin Neoplasms ,DNA Mutational Analysis ,Molecular Sequence Data ,Australia ,Loss of Heterozygosity ,Membrane Proteins ,Receptors, Cell Surface ,DNA, Neoplasm ,Patched-1 Receptor ,Amino Acid Substitution ,Carcinoma, Basal Cell ,Arsenic Poisoning ,Mutation ,Genetics ,Humans ,Female ,Genes, Tumor Suppressor ,Genetics (clinical) ,Alleles ,Polymorphism, Single-Stranded Conformational ,DNA Primers - Abstract
Inactivating mutations in the human patched (PTCH) gene have been identified in both familial and sporadic basal cell carcinomas (BCCs). In some tumors mutations have been detected in both alleles thereby supporting the role of PTCH as a tumor suppressor gene. We have analyzed 22/23 coding exons of PTCH for mutations in 44 sporadic BCCs, and detected 10 novel mutations in nine tumors. In two of the mutant tumors the remaining allele was inactivated by loss of heterozygosity. Five novel PTCH polymorphisms were also identified. Most of the variations found were CT substitutions at dipyrimidine sites, supporting previous studies which indicate a role for ultraviolet-B in the genesis of sporadic BCCs.
- Published
- 2000
19. Hydrocyclone Based Treatment Methods for Oily Wastewaters
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Ian Smyth, Martin Thew, Yves Aurelle, and Dimitre Hadjiev
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Hydrocyclone ,Waste management ,business.industry ,Field data ,Food processing ,Environmental science ,Treatment method ,Sewage treatment ,Oily wastewater ,business ,Effluent ,Offshore industry - Abstract
The successful introduction of oil/water separating hydrocyclones into the offshore oil industry over the last ten years has provided a basis for the further development of the technology and scope for applications in the wider field of wastewater treatment where liquid contaminants are a problem; e. g. removal of fats and oils from food processing and agricultural effluents. Central to this development process has been establishing the limits of hydrocyclonic water deoiling capabilities, especially in streams contaminated with other components, and the extension of the hydrocyclone concept to achieve multi-component separations (e.g. oil and sand from water) in a single unit. These aspects will be discussed with reference to both laboratory tests and field data.
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- 1997
20. Prospects for the Use of Hydrocyclones for Biological Separations
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J. Onions, D. Rickwood, B. Bendixen, and Ian Smyth
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Centrifugal force ,Hydrocyclone ,business.industry ,Test rig ,Environmental science ,Process engineering ,business - Abstract
The development of the hydrocyclone at Southampton University for separating oil/water emulsions for the oil industry during the last 15 years would also appear to offer a possible new dimension for biological separations since both types of separation are similar in terms of their shear sensitivity and low differential density. The peak centrifugal forces generated in small hydrocyclones can be several thousand times the force of gravity which is similar to the centrifugal force used to sediment cells in centrifuges. Therefore, there would seem to be a potential for separating different types of cells in hydrocyclones. In addition, hydrocyclones are low cost, low inventory separators that are easy to isolate and clean; this last property is important for biotechnological applications such as production of genetically-engineered proteins in microorganisms. This paper reports on the preliminary assessment of the degree of compatibility of biological samples with separation in hydrocyclone systems and describes the initial results of dense separations in a small hydrocyclone test rig originally designed for low shear liquid-liquid separations.
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- 1992
21. Patched 1 conditional null allele in mice.
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Tammy Ellis, Ian Smyth, Emily Riley, Scott Graham, Kate Elliot, Monica Narang, and Graham F. Kay
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- 2003
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22. Eficácia terapêutica do programa de remediação fonológica em escolares com dislexia do desenvolvimento Therapeutic effectiveness of phonological remediation program in students with developmental dyslexia
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Simone Aparecida Capellini, Maria Nobre Sampaio, Kelssy Hitomi dos Santos Kawata, Niura Aparecida de Moura Ribeiro Padula, Lara Cristina Antunes dos Santos, Maria Dalva Lorencetti, and Ian Smythe
- Subjects
Dislexia ,Leitura ,Estudos de Intervenção ,Dyslexia ,Reading ,Intervention Studies ,Philology. Linguistics ,P1-1091 ,Otorhinolaryngology ,RF1-547 - Abstract
OBJETIVOS: comparar os achados da avaliação em situação de pré e pós-testagem em escolares com dislexia do desenvolvimento e escolares bons leitores submetidos ao programa de remediação fonológica e verificar a eficácia terapêutica do programa de remediação fonológica em escolares com dislexia do desenvolvimento. MÉTODOS: participaram deste estudo 40 escolares de 2ª a 4ª série de ensino público do município de Marília-SP, de ambos os sexos, na faixa etária de 8 a 12 anos distribuídos em: GI: composto de 20 escolares com diagnóstico interdisciplinar de dislexia do desenvolvimento que foram submetidos a programa de remediação fonológica, GII: composto de 20 escolares sem dificuldades de aprendizagem da rede municipal de ensino público, pareados segundo sexo, faixa etária e escolaridade com os escolares do GI que não foram submetidos aos programas de remediação. Em situação de pré e pós-testagem, todos os escolares foram submetidos à aplicação do Teste de Desempenho Cognitivo-Linguístico nas versões coletiva e individual, seguido de leitura oral e compreensão de textos. RESULTADOS: foram evidenciadas diferenças estatisticamente significantes, indicando que os escolares do GI e GII submetidos ao programa de remediação fonológica apresentaram desempenho superior em situação de pós-testagem em comparação com a situação de pré-testagem para a maioria das habilidades cognitivo-linguísticas avaliadas, incluindo a leitura e compreensão de texto. CONCLUSÃO: o programa de remediação fonológica para crianças com e sem dislexia do desenvolvimento foi eficaz, sugerindo que a habilidade de relação letra-som deve ser utilizada em contexto de sala de aula favorecendo a leitura desses escolares.PURPOSES: to compare the findings of pre-test and post-test evaluation in students with developmental dyslexia and good readers submitted to phonological remediation program and to check the therapeutic effectiveness of phonological remediation program in students with developmental dyslexia. METHODS: 40 students of the 2nd to 4th grades of public schools of Marília-SP, both genders, from to 8 to 12-year old took part in this study; distributed in GI: 20 students with the interdisciplinary diagnosis of developmental dyslexia and GII: 20 good readers paired according to gender, age and school level. All students were submitted to the Cognitive-Linguistic Performance Test in the collective and individual version, oral reading and text comprehension. RESULTS: the results showed statistically significant differences indicating that the GI and GII students submitted to phonological remediation program showed higher performance in post-test when compared to pre-test in the most evaluated cognitive-linguistic skills, including reading and text comprehension. CONCLUSION: the phonological remediation program was effective for students with or without developmental dyslexia, suggesting that the sound-letter relation skill should be used in the classroom context in order to improve the reading skills for these students.
- Published
- 2010
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