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171 results on '"Andrew Dunham"'

1. Hemanext Announces Founder Martin Cannon's Retirement, Appoints Andrew Dunham as CEO, and Raises Funding for Growth

Subjects
United States. National Institutes of Health -- Officials and employees -- Government finance, Chief executive officers -- Appointments, resignations and dismissals, Executives -- Compensation and benefits, General interest
Abstract

New Delhi, Sept. 19 -- Martin Cannon, the visionary leader who founded Hemanext in 2008 with support from a National Institutes of Health (NIH) grant, leaves an enduring legacy. His [...]

Published
2023

4. Preclinical evaluation of the preservation of red blood cell concentrates by hypoxic storage technology for transfusion in sickle cell disease

Author

Laura Bencheikh, Kim-Anh Nguyen, Philippe Chadebech, Laurent Kiger, Gwellaouen Bodivit, Alicia Jouard, Sadaf Pakdaman, Sandia Adypagavane, Etienne Audureau, Khouloud Tebbakha, Thibaut Bocquet, Blandine Mignen, Nicolas Hebert, Marion Seguin, France Pirenne, Samuel Sowemimo-Coker, Andrew Dunham, and Pablo Bartolucci

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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5. Oxygen in Red Blood Cell Concentrates: Influence of Donors’ Characteristics and Blood Processing

Author

Manon Bardyn, Agathe Martin, Nora Dögnitz, Mélanie Abonnenc, Andrew Dunham, Tatsuro Yoshida, and Michel Prudent

Subjects
oxygen saturation (sO2), resonance Raman (RR) spectroscopy, red blood cell, red blood cell concentrate, donor variation, donors’ characteristics, Physiology, QP1-981
Abstract

Objective: Unexpectedly wide distribution (90%) of hemoglobin oxygen saturation (sO2) within red cell concentrates (RCCs) has recently been observed. Causes of such variability are not yet completely explained whereas the roles of oxygen and oxidative lesions during the storage of RCCs are known. The objectives of the present study are to characterize sO2 distribution in RCCs produced in a Swiss blood center and to investigate the influence of processing and donors’ characteristics.Methods: The level of sO2 was measured in 1701 leukocyte-depleted RCCs derived from whole blood donations in both top–bottom (TB; component filtered, SAGM) and top–top (TT; whole blood filtration, PAGGSM) RCCs. The sO2 value was measured non-invasively through the PVC bag prior to storage by resonance Raman spectroscopy. Gender, age, blood type, hemoglobin level, and living altitude of donors, as well as process method and time-to-process were recorded.Results: Overall, the sO2 exhibited a wide non-Gaussian distribution with a mean of 51.2 ± 18.5%. Use of top-top kits resulted in a 16% higher sO2 (P < 0.0001) than with top-bottom ones. Waiting time before processing only had a modest impact, but the blood processing itself reduced the sO2 by almost 12% (P < 0.0001). sO2 was also significantly affected by some donors’ characteristics. RCCs from men exhibited 25% higher sO2 (P < 0.0001) than those donated by women. Multivariate analysis revealed that the apparent correlation observed with hemoglobin level and age was actually due to multicollinearity with the sex variable. Finally, we noticed no significant differences across blood type but found that altitude of residence was associated with the sO2 (i.e., higher in higher living place).Conclusion: These data confirm wide sO2 distribution in RCCs reported recently. The sO2 was impacted by the processing and also by donors’ characteristics such as the gender and the living altitude, but not by the hemoglobin level, blood group and donor age. This study provides new hints on the factors influencing red blood cells storage lesions, since they are known to be related to O2 content within the bags, giving clues to better process and to better store RCCs and therefore potentially improve the efficacy of transfusion.

Published
2020
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6. NATIONAL CITY BANK ELECTS JEFFREY M. BIGGAR, EXECUTIVE VICE PRESIDENT; J. ANDREW DUNHAM AND DAVID C. FYNN, SENIOR VICE PRESIDENT

Subjects
National City Bank (Cleveland, Ohio) -- Officials and employees, Banking industry -- Officials and employees, Business, News, opinion and commentary
Abstract

CLEVELAND, April 1 /PRNewswire/ -- National City Bank's Board of Directors approved the following key management appointments, effective today: Jeffrey M. Biggar to executive vice president and regional trust executive; [...]

Published
1994

7. Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Author

Travis Nemkov, Kaiqi Sun, Julie A. Reisz, Anren Song, Tatsuro Yoshida, Andrew Dunham, Matthew J. Wither, Richard O. Francis, Robert C. Roach, Monika Dzieciatkowska, Stephen C. Rogers, Allan Doctor, Anastasios Kriebardis, Marianna Antonelou, Issidora Papassideri, Carolyn T. Young, Tiffany A. Thomas, Kirk C. Hansen, Steven L. Spitalnik, Yang Xia, James C. Zimring, Eldad A. Hod, and Angelo D’Alessandro

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from 95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1–7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and – preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo. Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates.

Published
2018
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8. Metabolism of Citrate and Other Carboxylic Acids in Erythrocytes As a Function of Oxygen Saturation and Refrigerated Storage

Author

Travis Nemkov, Kaiqi Sun, Julie A. Reisz, Tatsuro Yoshida, Andrew Dunham, Edward Y. Wen, Alexander Q. Wen, Rob C. Roach, Kirk C. Hansen, Yang Xia, and Angelo D’Alessandro

Subjects
hypoxia, metabolomics, mass spectrometry, tracing experiments, flux analysis, Medicine (General), R5-920
Abstract

State-of-the-art proteomics technologies have recently helped to elucidate the unanticipated complexity of red blood cell metabolism. One recent example is citrate metabolism, which is catalyzed by cytosolic isoforms of Krebs cycle enzymes that are present and active in mature erythrocytes and was determined using quantitative metabolic flux analysis. In previous studies, we reported significant increases in glycolytic fluxes in red blood cells exposed to hypoxia in vitro or in vivo, an observation relevant to transfusion medicine owing to the potential benefits associated with hypoxic storage of packed red blood cells. Here, using a combination of steady state and quantitative tracing metabolomics experiments with 13C1,2,3-glucose, 13C6-citrate, 13C515N2-glutamine, and 13C1-aspartate via ultra-high performance liquid chromatography coupled on line with mass spectrometry, we observed that hypoxia in vivo and in vitro promotes consumption of citrate and other carboxylates. These metabolic reactions are theoretically explained by the activity of cytosolic malate dehydrogenase 1 and isocitrate dehydrogenase 1 (abundantly represented in the red blood cell proteome), though moonlighting functions of additional enzymes cannot be ruled out. These observations enhance understanding of red blood cell metabolic responses to hypoxia, which could be relevant to understand systemic physiological and pathological responses to high altitude, ischemia, hemorrhage, sepsis, pulmonary hypertension, or hemoglobinopathies. Results from this study will also inform the design and testing of novel additive solutions that optimize red blood cell storage under oxygen-controlled conditions.

Published
2017
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9. Hypoxia and hypocapnia storage of γ-irradiated red cell concentrates

Author

Manon, Bardyn, David, Crettaz, Marie, Borlet, Emmanuel, Längst, Agathe, Martin, Mélanie, Abonnenc, Jean-Daniel, Tissot, Andrew, Dunham, Tatsuro, Yoshida, and Michel, Prudent

Subjects
Blood Components And Regenerative Medicine, Erythrocytes, Hypocapnia, Blood Preservation, Humans, Hypoxia, Hemolysis
Abstract

BACKGROUND: γ-irradiation is used to treat red blood cell (RBC) concentrates (RCCs) transfused to immunosuppressed patients. This treatment damages RBCs and increases storage lesions. Several studies have shown the beneficial effect of reducing O(2) content during RBC storage. The present research work investigated the effect of γ-irradiation on RCCs stored under normal and hypoxia/hypocapnia conditions. MATERIALS AND METHODS: O(2) concentration (measured as oxyhaemoglobin fraction, sO(2)) and ABO-matched RCCs from whole blood donations, leukoreduced and prepared in phosphate, adenine, glucose, guanosine, saline and mannitol (PAGGSM) were pooled and split in two identical RCCs within 24 h post donation. One bag (Hx) was submitted to O(2) and CO(2) adsorption for 3 h on an orbital shaker at 22±2 °C and then transferred to a storage bag impermeable to gas. The other bag (Ctrl) was left as it was. The two bags were then stored at 4 °C. γ-irradiation (25 Gy) was applied at day 2 or 14, and the RCCs were stored until day 43. Different parameters (metabolites, haemolysis, morphology) were measured. RESULTS: Starting sO(2) values were 63.7±18.4% (n=12) in Ctrl and 20.8±9.8% (n=12) in Hx bags, and reached 90.8±9.1% and 6.6±5.9% at day 43, respectively. As expected, an increase in glycolysis rate was observed after deoxygenation. Extracellular potassium concentrations were identical and reached around 70 mM at expiry with an irradiation-dependent kinetic release. No difference in haemolysis was observed after irradiation on day 2 in either group (0.9999). When irradiated at day 14, haemolysis was lower (p=0.033) in RCCs under hypoxia at the end of storage (day 28, 0.67±0.16%) compared to control (1.06±0.33%). Percentages of spherocytes were lower under hypoxia. DISCUSSION: The storage under hypoxia provided equivalent storage when RCCs were irradiated at day 2 and was advantageous when irradiated at day 14. In summary, O(2)-depletion of RCCs enable a better storage of RBCs, particularly when late irradiation is applied.

Published
2020

10. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Corneliu A. Bodea, Benjamin M. Neale, Stephan Ripke, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombel, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A. Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Jane M. Andrews, Peter A. Bampton, Timothy H. Florin, Richard Gearry, Krupa Krishnaprasad, Ian C. Lawrance, Gillian Mahy, Graham Radford-Smith, Rebecca L. Roberts, Lisa A. Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, André Van Gossum, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M. Barrie, Karen Beck, Edmond-Jean Bernard, David G. Binion, Alain Bitton, Steve R. Brant, Judy H. Cho, Albert Cohen, Kenneth Croitoru, Lisa W. Datta, Colette Deslandres, Richard H. Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R. Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G. Lahaie, Dermot P. McGovern, Linda Nelson, Sok Meng Ng, Kaida Ning, Pierre Paré, Miguel D. Regueiro, John D. Rioux, Elizabeth Ruggiero, L. Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S. Silverberg, Denise Spears, A. Hillary Steinhart, Joanne M. Stempak, Jason M. Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Jan Aerts, Tariq Ahmad, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Chris Barnes, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Niall Cardin, Chris M. Clee, Alison J. Coffey, John M.C. Connell, Donald F. Conrad, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, Gareth Evans, Steve Eyre, Anne Farmer, Nicol Ferrier, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A. Franklyn, Timothy M. Frayling, Rachel M. Freathy, Eleni Giannoulatou, Polly Gibbs, Paul Gilbert, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J. Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A. Hitman, Lynne Hocking, Chris Holmes, Eleanor Howard, Philip Howard, Joanna M.M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian R. Jones, Lisa A. Jones, George Kirov, Cordelia F. Langford, Hana Lango-Allen, G. Mark Lathrop, James Lee, Kate L. Lee, Charlie Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Jonathan L. Marchini, Paul Martin, Dunecan C.O. Massey, Wendy L. McArdle, Peter McGuffin, Kirsten E. McLay, Gil McVean, Alex Mentzer, Michael L. Mimmack, Ann E. Morgan, Andrew P. Morris, Craig Mowat, Patricia B. Munroe, Simon Myers, William Newman, Elaine R. Nimmo, Michael C. O’Donovan, Abiodun Onipinla, Nigel R. Ovington, Michael J. Owen, Kimmo Palin, Aarno Palotie, Kirstie Parnell, Richard Pearson, David Pernet, John R.B. Perry, Anne Phillips, Vincent Plagnol, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Samuel Robson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy D. Sanderson, Stephen J. Sawcer, Helen Schuilenburg, Carol E. Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Kathy Stirrups, Millicent A. Stone, David P. Strachan, Zhan Su, Deborah P.M. Symmons, John R. Thompson, Wendy Thomson, Martin D. Tobin, Mary E. Travers, Clare Turnbull, Damjan Vukcevic, Louise V. Wain, Mark Walker, Neil M. Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B. Paul Wordsworth, Chris Yau, Allan H. Young, Eleftheria Zeggini, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Stephen C.L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V.S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Matthew E. Hurles, Audrey Duncanson, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Dominic P. Kwiatkowski, Mark I. McCarthy, Nick Craddock, Panos Deloukas, Peter Donnelly, Jenefer M. Blackwell, Elvira Bramon, Juan P. Casas, Aiden Corvin, Janusz Jankowski, Hugh S. Markus, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Matti Pirinen, Amy Strange, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, Heredity, Genetics, Genetics (clinical), Computer science, Genetic Linkage, Genome-wide association study, VARIANTS, 030105 genetics & heredity, computer.software_genre, Bayes' theorem, Gene Frequency, HISTORY, IMPUTATION, False positive paradox, Genetics(clinical), Disease, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Inheritance (genetic algorithm), Genotype, DATABASE, Genetic genealogy, POWER, Population, Genomics, POPULATION STRATIFICATION, Biology, INHERITANCE, Population stratification, Machine learning, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Allele frequency, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Genetic association, business.industry, Bayes Theorem, DISEASE ASSOCIATION, Human genetics, Hierarchical clustering, Genetics, Population, 030104 developmental biology, Case-Control Studies, 3111 Biomedicine, Artificial intelligence, business, computer, Software, Imputation (genetics)
Abstract

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Published
2016
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11. Transfusion des patients drépanocytaires: évaluation préclinique de la technologie Hemanext

Author

Laura Bencheikh, Kim-Anh Nguyen, Philippe Chadebech, Laurent Kiger, Gwellaouen Bodivit, Alicia Jouard, Etienne Audureau, Sadaf Pakdaman, Sandia Adypagavane, Khouloud Tebbakha, Nicolas Hebert, France Pirenne, Samuel Sowemimo-Coker, Andrew Dunham, and Pablo Bartolucci

Subjects
Biochemistry (medical), Clinical Biochemistry, Hematology
Abstract

La drepanocytose est une maladie genetique due a une mutation de l’hemoglobine (Hb), entrainant la falciformation des globules rouges (GR), une hemolyse chronique ainsi que des crises vaso-occlusives tres douloureuses. L’echange transfusionnel est une des strategies therapeutiques utilisees pour remplacer les GR malades et diminuer les crises. La qualite des GR transfuses est primordiale, a la fois pour ameliorer le rendement transfusionnel mais aussi pour limiter les interactions pathologiques entre les GR et les cellules endotheliales, endommagees par l’hemolyse. Or, au cours de leur conservation, la qualite des GR diminue, principalement a cause de dommages oxidatifs. La technologie Hemanext permet de conserver les GR en hypoxie, ameliorant la concentration en ATP, 2-3DPG, l’hemolyse et la deformabilite des GR. Notre etude avait pour but de comparer la qualite des GR conserves de facon conventionnelle a ceux conserves avec la technologie Hemanext. Nous avons demontre une non-inferiorite d’Hemanext en termes d’adherence des GR en flux sur des cellules endotheliales. De plus, nous avons mis en evidence une reduction de la concentration en Hb libre (produite par la lyse des GR) dans les poches Hemanext, une baisse de la senescence des GR et de leur adherence sur la thrombospondine, dont la concentration est augmentee pendant la crise drepanocytaire. Ces resultats suggerent que la technologie Hemanext repond aux criteres de securite pour la transfusion des patients drepanocytaires, et pourrait meme leur apporter un benefice clinique.

Published
2019
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12. Clinical and pathological impact ofVHL, PBRM1, BAP1, SETD2, KDM6A, andJARID1cin clear cell renal cell carcinoma

Author

Nitzan Rosenfeld, Andrew Slatter, Conrad Lichtenstein, Beverley Haynes, Andrew Dunham, Andreas Claas, Anne Y. Warren, Susan J. Shanahan, Tim Forshew, Muhammed Murtaza, Andrew May, Tim Eisen, Francesco Marass, Lucy Gossage, and Ian Roberts

Subjects
Cancer Research, BAP1, Mutation, Somatic cell, Melanoma, Biology, medicine.disease, medicine.disease_cause, PBRM1, Clear cell renal cell carcinoma, SETD2, Genetics, Cancer research, medicine, Clinical significance
Abstract

VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted. © 2013 Wiley Periodicals, Inc.

Published
2013
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13. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)

Subjects
endocrine system diseases, [SDV]Life Sciences [q-bio], Genome-wide association study, Pilot Projects, CCL3L1, SUSCEPTIBILITY, Arthritis, Rheumatoid, Diabetes mellitus genetics, 0302 clinical medicine, Crohn Disease, Gene Frequency, DUPLICATIONS, SCHIZOPHRENIA, Disease, Copy-number variation, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Multidisciplinary, PSORIASIS, HERITABILITY, LARGE-SCALE, Nucleic Acid Hybridization, Science & Technology - Other Topics, Wellcome Trust Case Control Consortium, Quality Control, DNA Copy Number Variations, General Science & Technology, Single-nucleotide polymorphism, COPY-NUMBER VARIATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Genetic predisposition, Diabetes Mellitus, SNP, Humans, Genetic Predisposition to Disease, Allele frequency, POLYMORPHISMS, 030304 developmental biology, Genetic association, Science & Technology, MULTIDISCIPLINARY SCIENCES, DELETION, C431 Medical Genetics, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Published
2016
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14. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Muminatou, Jallow, Yik Ying Teo, Small, Kerrin S., Rockett, Kirk A., Panos, Deloukas, Clark, Taane G., Katja, Kivinen, Bojang, Kalifa A., Conway, David J., Margaret, Pinder, Giorgio, Sirugo, Fatou Sisay Joof, Stanley, Usen, Sarah, Auburn, Bumpstead, Suzannah J., Susana, Campino, Alison, Coffey, Andrew, Dunham, Fry, Andrew E., Angela, Green, Rhian, Gwilliam, Hunt, Sarah E., Michael, Inouye, Jeffreys, Anna E., Alieu, Mendy, Aarno, Palotie, Simon, Potter, Jiannis, Ragoussis, Jane, Rogers, Kate, Rowlands, Elilan, Somaskantharajah, Pamela, Whittaker, Claire, Widden, Peter, Donnelly, Bryan, Howie, Jonathan, Marchini, Andrew, Morris, Miguel, Sanjoaquin, Eric Akum Achidi, Tsiri, Agbenyega, Angela, Allen, Olukemi, Amodu, Patrick, Corran, Abdoulaye, Djimde, Amagana, Dolo, Doumbo, Ogobara K., Chris, Drakeley, Sarah, Dunstan, Jennifer, Evans, Jeremy, Farrar, Hien Tt, Fernando D., Horstmann, R. D., Ibrahim, M., Karunaweera, N., Kokwaro, G., Koram, K. A., Lemnge, M., Makani, J., Marsh, K., Michon, P., David, Modiano, Molyneux, M. E., Mueller, I., Parker, M., Peshu, N., Plowe, C. V., Puijalon, O., Reeder, J., Reyburn, H., Riley, E. M., Sakuntabhai, A., Singhasivanon, P., Sirima, S., Tall, A., Taylor, T. E., Thera, M., Troye Blomberg, M., Williams, T. N., Wilson, M., Wellcome Trust Case Control Consortium Kwiatkowski, D. P., Epidemiology Network: Achidi, Malaria Genomic E. A., Agbenyega, T., Ahmad, T., Alcock, D., Allen, S., Amenga Etego, L., Amodu, O., Apinjoh, T. O., Attwood, A. P., Auburn, S., Ball, S. G., Balmforth, A. J., Ban, M., Barbour, J., Barnwell, D., Barrett, J. C., Barrett, J. H., Barton, A., Bentley, D., Bishop, D. T., Bojang, K., Boorman, J. P., Bougouma, E., Bradbury, L. A., Braga Marcano, C. A., Braund, P. S., Bredin, F., Breen, G., Brown, M. A., Brown, M. J., Bruce, I. N., Bryan, C., Bull, S., Bumpstead, S. J., Burke, B., Burton, P. R., Caesar, S., Campino, S., Cant, B., Cardin, N. J., Cardon, L. R., Carucci, D., Caulfield, M., Chaney, A., Clark, T., Clayton, D. G., Collier, D. A., Compston, A., Compston, D. A., Connell, J., Conway, D., Cook, K., Corran, P., Craddock, N., Cummings, F. R., Davison, D., Deloukas, P., Devries, J., Dewasurendra, R., Diakite, M., Dixon, R. J., Djimde, A., Dobson, R., Dolo, A., Dominiczak, A., Donnelly, P., Donovan, H., Doumbo, O., Downes, K., Doyle, A., Drakeley, C., Drummond, H., Duffy, P., Duncanson, A., Dunger, D. B., Dunstan, S., Duombo, O., Easton, D., Elkin, A., Elliott, K. S., Elzein, A., Enimil, A., Evans, D., Evans, J., Everson, U., Eyre, S., Farmer, A., Farrall, M., Farrar, C., Farrar, J., Fernando, D., Ferreira, T., Ferrier, I. N., Fisher, S. A., Fitzpatrick, K., Forbes, A., Franklyn, J. A., Fraser, C., Frayling, T. M., Freathy, R. M., Ghansah, A., Ghori, J., Gilbert, P. D., Gordon Smith, K., Goris, A., Gottlieb, M., Gough, S. C., Green, A., Green, E. K., Groves, C. J., Grozeva, D., Gungadoo, J., Gwilliam, R., Hall, A. S., Hallgrimsdóttir, I. B., Hamshere, M. L., Hart, L., Hattersley, A. T., Heward, J. M., Hider, S. L., Tran Tinh Hien, Hill, A. V., Hilton, E., Hinks, A. M., Hitman, G. A., Holmans, P. A., Horstmann, Rolf D., Howie, B. N., Hubbart, C., Hughes, C., Hunt, S. E., Hussein, A., Hussey, J. M., Muntaser, Ibrahim, Iles, M. M., Inouye, M., Ishengoma, D., Jallow, M., Jeffreys, A. E., Jewell, D. P., John, Sl, Jolley, J. D., Jones, I. R., Jones, L., Jones, R. W., Nadira, Karunaweera, Keniry, A., King, E., Kirov, G., Kivinen, K., Knight, A. S., Koch, K., Gilbert, Kokwaro, Koram, Kwadwo A., Lango, H., Lathrop, G. M., Lee, K. L., Lees, C. W., Martha, Lemnge, Leung, H. T., Lewis, C. M., Lin, E., Lindgren, C. M., Ly, A., Macinnis, B., Julie, Makani, Mangano, Valentina, Mangino, M., Manjurano, A., Manning, L., Mansfield, J. C., Manske, M., Maqbool, A., Marchini, J. L., Kevin, Marsh, Maslen, G., Mathew, C. G., Mcardle, W. L., Mccarthy, M. I., Mccreight, M., Mcginnis, R., Mcguffin, P., Meech, E., Mendy, A., Pascal, Michon, Mohiuddin, M. K., Molyneux, Malcolm E., Morris, A. P., Moskvina, V., Moyes, C., Ivo, Mueller, Munroe, P. B., Mutabingwa, T., Ndila, C. M., Newhouse, S. J., Newport, M., Nikolov, I., Nimmo, E. R., Nutland, S., Nyirongo, V., O'Donovan, M. C., Oluoch, T., Onipinla, A., Onnie, C. M., Ouwehand, W. H., Owen, M. J., Michael, Parker, Parkes, M., Pembrey, M., Pereira Gale, J., Perry, J. R., Norbert, Peshu, Plowe, Christopher V., Pointon, J. J., Potter, C., Potter, S., Prescott, N. J., Prowse, C. V., Odile, Puijalon, Quyen, N. T., Ragoussis, J., Rahman, N., Ravindrarajah, R., Rayner, N. W., John, Reeder, Hugh, Reyburn, Riley, Eleanor M., Ring, S. M., Risley, P., Rockett, K. A., Rogers, J., Rowlands, K., Anavaj, Sakuntabhai, Samani, N. J., Sanderson, J., Sanjoaquin, M., Satsangi, J., Sawcer, S. J., Seal, S., Shields, B. M., Silman, A. J., Simmonds, M. J., Pratap, Singhasivanon, Sodiomon, Sirima, Sirugo, G., Small, K. S., Somaskantharajah, E., Spencer, C. C., St Clair, D., Stevens, H. E., Stevens, M., Stevens, S., Strachan, D. P., Stratton, M. R., Su, Z., Suriyaphol, P., Symmons, D. P., Adama, Tall, Taylor, N. C., Taylor, Terrie E., Teo, Y., Teo, Y. Y., Mahamadou, Thera, Thompson, J. R., Thomson, W., Timpson, N. J., Tobin, M. D., Todd, J. A., Todhunter, C. E., Toure, O., Tremelling, M., Marita Troye Blomberg, Vanderwal, A., Vukcevic, D., Walker, M., Walker, N. M., Wallace, C., Walters, G. R., Walton, R., Watkins, N. A., Watson, R., Webster, J., Weedon, M. N., Whittaker, P., Widmer, B., Williams, Thomas N., Williamson, R., Michael, Wilson, Winzer, T., Withers, D., Wordsworth, P., Worthington, J., Wrigley, R., Xue, M., Young, A. H., Yuldasheva, N., and Zeggini, E.

Subjects
Linkage disequilibrium, Hemoglobin, Sickle, Population, Genome-wide association study, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Article, Gene mapping, Reference Values, Ethnicity, Genetics, Humans, education, Genetic association, education.field_of_study, Polymorphism, Genetic, Chromosome Mapping, Genetic Variation, Malaria, Gambia, Imputation (genetics), Genome-Wide Association Study
Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Published
2009
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15. The DNA sequence of the human X chromosome

Author

Gernot Glöckner, Karen Thomas, Christine Lloyd, Huda Y. Zoghbi, Adrienne Hunt, Fiona Francis, Annemarie Poustka, George M. Weinstock, Xuehong Wei, Alan Tracey, Gabriele Nordsiek, Ines Müller, Graham Clarke, Oliver Beasley, John Sulston, Alfred Beck, Christian J. Buhay, Thomas Meitinger, Manjula Maheshwari, Yvonne Ramsey, Kirsten McLay, Shannon Dugan-Rocha, James G. R. Gilbert, Louisa Faulkner, Sidney Morris, Margaret Morgan, Huntington F. Willard, Leni S. Jacob, Hermela Loulseged, K M Porter, T. Daniel Andrews, Cordelia Langford, Paul Wray, Guan Chen, Juliane Ramser, Nigel P. Carter, Georgina Warry, Ruby Banerjee, Graeme Bethel, LaDeana W. Hillier, Anne Hodgson, Stephen M. J. Searle, K F Barlow, David R. Bentley, Paul E. Tabor, Kathryn L. Evans, Russell J. Grocock, Rebecca Woodmansey, Alex V Pearce, Christie Kovar-Smith, Angela Williamson, Dean Chavez, Roy Storey, Kevin L. Howe, Zhijian J. Chen, Lesette Perez, Richard A. Gibbs, Michele D'Urso, Karen N Bates, Jackie Bye, Shirin S. Joseph, Bernd Hinzmann, Paul Heath, Susan H. Kelly, Jennifer Hume, Paula E. Burch, David Buck, Mark T. Ross, David A. Wheeler, Matthew C. Jones, A K Babbage, Erica Sodergren, Sophie Palmer, Jie Ma, Elizabeth C. Sotheran, Margaret A. Leversha, Cerissa Hamilton, Hans Lehrach, Swaroop Aradhya, Michael L. Metzker, S. M. Clegg, Elizabeth J. Huckle, Audrey Fraser, Sarah Bray-Allen, C. D. Skuce, Petra Galgoczy, Richard K. Wilson, Patrick Minx, Richard E Connor, Tamsin Eades, Alfons Meindl, Michelle Smith, John M. Davis, André Rosenthal, Stuart McLaren, Geoffery Okwuonu, M. Vaudin, Laura Carrel, Ryan J. Lozado, Harminder Sehra, Richard Pandian, Sue Y Clark, Anna Kosiura, Wen Liu, Simon G. Gregory, A Tromans, Alexandra Emery-Cohen, Charles Shaw-Smith, Donna Villasana, Joseph Chako, Katja Heitmann, Robert G. David, Jennifer L. Ashurst, Craig Chinault, S Lawlor, Paul Havlak, Jane E. Loveland, Lucy Matthews, Jianling Zhou, S. Whitehead, Paul Hunt, E Sheridan, Richard Reinhardt, Tim Hubbard, Mary G. Schueler, Patrick Meidl, Helen Beasley, David Beare, Donna M. Muzny, Kerry A Ridler, Joanne C Chapman, Jennifer McDowall, Andrew Dunham, Anne Bridgeman, Gabrielle Williams, Amanda McMurray, Stefan Taudien, Matthew E. Hurles, Helen Williamson, Preethi H. Gunaratne, Alfredo Ciccodicola, R Ainscough, Alison J. Coffey, Charlotte G. Cole, Stephan Beck, Frances L Lovell, Alan Coulson, Qiaoyan Wang, Sally Jones, Charles A. Steward, Michael Hoffs, Kim C. Worley, Sarah Pelan, David Bonnin, David Schlessinger, Mathew N Whiteley, Graham Scott, Christopher N O'Dell, Tineace Taylor, Susan Rhodes, Anthony P. West, E. Hart, Ian P. Barrett, Andrea Thorpe, D. Pearson, Huyen Dinh, Susan M. Gribble, Andrew J Knights, Laurens G. Wilming, N Corby, Steven E. Scherer, Pawandeep Dhami, Gerald Nyakatura, J Lovell, M. Ali Ansari-Lari, Kerstin P. Clerc-Blankenburg, David Swarbreck, Sara Zorilla, Yanghong Gu, Karin Blechschmidt, Matthew Dunn, Andrew Brown, Kirsten M. Timms, Darren Grafham, Yan Ding, Elspeth A. Bruford, Leanne Williams, Melanie M. Wall, Hua Shen, Dina Patel, Joanne K Kershaw, Rachel Gill, Yuan Chen, Joy Davies, D C Burford, John Burton, Vicky Cobley, R I S Ashwell, Nicola Brady, Ellson Y. Chen, Ngoc Nguyen, Gaiping Wen, Gavin K. Laird, Julia E. Parrish, Carol Scott, C Griffiths, Ratna Shownkeen, Ralf Sudbrak, Denise R. DeShazo, Shiran Pasternak, Ireena Dutta, Brian Teague, Rachael Lyne, David Parker, Jane Rogers, Steve Dodsworth, Mary J. Brown, Gary E Barker, Steve Trevanion, Joanne Burgess, Jane E. Wilkinson, James T. Warren, Jen S. Conquer, R Mark Swann, Oliver Delgado, Heather R. Draper, Shailesh L Mistry, Chris Clee, Richard Durbin, Karen Clifford, John Frankland, Sarah E. Hunt, David Steffen, Christine Burrows, Daniel Verduzco, C Carder, Robert H. Waterston, Stephen Richards, Andrea Ballabio, Catherine M. Rice, David Willey, Helen Errington, Andrew Cree, K. James Durbin, Lora Lewis, D. M. Lloyd, Helen E. Steingruber, Adam Whittaker, K D Ambrose, Rhian Gwilliam, Adam Frankish, Robert S. Fulton, Judith Hernandez, Claire L Bagguley, Pieter J. de Jong, Jennifer Yen, Matthew Ellwood, Christine P. Bird, Rui Chen, Sarah Milne, Clay Davis, Alicia Hawes, Jing Lu, Sven Klages, David L. Nelson, Wayne Burrill, Jingkun Zhang, Judith Isherwood, Kathrin Reichwald, Lenee Waldron, Rebecca Deadman, Steffen Hennig, Ziad Khan, Sarah Ho, Matthias Platzer, Gareth R. Howell, Stephen Keenan, Petra Kioschis, Phillip J Howden, George Miner, David W. Johnson, and James C. Mullikin

Subjects
Male, Genetic Linkage, Genetics, Medical, Centromere, HUMAN GENOME SEQUENCE, Biology, Y chromosome, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, Contig Mapping, Chromosome 16, Antigens, Neoplasm, Dosage Compensation, Genetic, Sequence Homology, Nucleic Acid, Chromosome 19, Testis, Animals, Humans, Crossing Over, Genetic, X chromosome, Repetitive Sequences, Nucleic Acid, Genetics, Chromosomes, Human, X, Chromosomes, Human, Y, Multidisciplinary, INACTIVATION CENTER, LINKED MENTAL-RETARDATION, Genomics, Sequence Analysis, DNA, REPEAT HYPOTHESIS, MAMMALIAN Y-CHROMOSOME, Chromosome 4, Chromosome 3, RNA, Female, Chromosome 21, Chromosome 22
Abstract

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Published
2005
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16. A physical map of the human genome

Author

Anuradha Madan, S. Naylor, Kami Dixon, Wonhee Jang, John Douglas Mcpherson, Asao Fujiyama, Simon G. Gregory, Jacquelyn R. Idol, Takashi Sasaki, David Haussler, Hong Seok Park, Jun Kudoh, Ai Shintani, Erica Sodergren, Barbara J. Trask, Norma J. Nowak, Gerald Nyakatura, Gregory D. Schuler, Shinsei Minoshima, Raluca Yonescu, J. Harley Gorrell, Roland Heilig, Vivian G. Cheung, Steve Scherer, Kazunori Shibuya, Hsiu Chuan Chen, Olivia Velasquez, Scot Kennedy, Leroy Hood, Richard Reinhardt, Lucía Ramírez, Richard M. Myers, Atsushi Toyoda, Tetsushi Yada, Nobuyoshi Shimizu, Eric D. Green, Dawn Garcia, Owen T. McCann, Kate Montgomery, Asif T. Chinwalla, Elaine R. Mardis, Peter Seranski, Valerie Maduro, W. James Kent, Cynthia Friedman, Kazutoyo Osoegawa, Carol Scott, Juliane Ramser, Marco A. Marra, Caryn Wagner-McPherson, William B. Barbazuk, Thomas Reid, Mandeep Sekhon, Lee Rowen, Nancy E. Stone, Richard A. Gibbs, Lisa French, Trevor Hawkins, J. de Jong, Jin Shang, Tamara A. Kucaba, Robert H. Waterston, Adam Whittaker, Jeremy Schmutz, Richard K. Wilson, Kristine M. Wylie, Masahira Hattori, Atsushi Shimizu, Ilan R. Kirsch, Jean Weissenbach, Céline Hoff, Julie R. Korenberg, Markus Schilhabel, Sanja Rogic, David R. Bentley, Shuichi Asakawa, Paul E. Tabor, Terrence S. Furey, Kerstin P. Clerc-Blankenburg, Raju Kucherlapati, Joseph J. Catanese, Shizhen Qin, Annemarie Poustka, Suzanne Emerling, Reiner Siebert, Brigitte Schlegelberger, Hans Lehrach, Monica Dors, Thomas Brüls, Hillary Massa, R Evans, Steven J.M. Jones, Gernot Gloeckner, Elbert Branscomb, Andrew Dunham, Jane L. Holden, Xiao Ning Chen, Ashley Miller, Jan Fang Cheng, André Rosenthal, John W. Wallis, Eunice Lee, Gaiping Wen, Sean Humphray, Carol Soderlund, Robert S. Fulton, Yoshiyuki Sakaki, David R. Cox, Norman A. Doggett, Kazuhiko Kawasaki, Anne S. Olsen, Graeme Bethel, and LaDeana W. Hillier

Subjects
Genetics, Cancer genome sequencing, Whole genome sequencing, Chromosomes, Artificial, Bacterial, Multidisciplinary, Contig, Genome, Human, Computational biology, Genome project, Biology, ENCODE, DNA Fingerprinting, Genome, Chimpanzee genome project, Contig Mapping, Gene Duplication, Humans, Cloning, Molecular, In Situ Hybridization, Fluorescence, Repetitive Sequences, Nucleic Acid, Reference genome
Abstract

The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.

Published
2001
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17. Contigs Built with Fingerprints, Markers, and FPC V4.7

Author

Lisa French, Andrew Dunham, Sean Humphray, and Carol Soderlund

Subjects
Genetic Markers, Databases, Factual, DNA Fragmentation, Computational biology, Biology, Contig Mapping, Methods, Genetics, Humans, Computer Simulation, Genetics (clinical), Internet, Models, Statistical, Chromosomes, Human, Pair 13, Contig, Gene map, Chromosomes, Human, Pair 10, Physical Chromosome Mapping, Computational Biology, food and beverages, Numerical Analysis, Computer-Assisted, DNA Fingerprinting, Human sequence, Fingerprint database, DNA profiling, Chromosomes, Human, Pair 9, Software
Abstract

Contigs have been assembled, and over 2800 clones selected for sequencing for human chromosomes 9, 10 and 13. Using the FPC (FingerPrinted Contig) software, the contigs are assembled with markers and complete digest fingerprints, and the contigs are ordered and localised by a global framework. Publicly available resources have been used, such as, the 1998 International Gene Map for the framework and the GSC Human BAC fingerprint database for the majority of the fingerprints. Additional markers and fingerprints are generated in-house to supplement this data. To support the scale up of building maps, FPC V4.7 has been extended to use markers with the fingerprints for assembly of contigs, new clones and markers can be automatically added to existing contigs, and poorly assembled contigs are marked accordingly. To test the automatic assembly, a simulated complete digest of 110 Mb of concatenated human sequence was used to create datasets with varying coverage, length of clones, and types of error. When no error was introduced and a tolerance of 7 was used in assembly, the largest contig with no false positive overlaps has 9534 clones with 37 out-of-order clones, that is, the starting coordinates of adjacent clones are in the wrong order. This paper describes the new features in FPC, the scenario for building the maps of chromosomes 9, 10 and 13, and the results from the simulation.

Published
2000
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18. High-Resolution Landmark Framework for the Sequence-Ready Mapping of Xq23–q26.1

Author

Gareth Maslen, Elizabeth C. Sotheran, Rhian Gwilliam, Pawandeep Dhami, Margaret A. Leversha, Carol Scott, S. M. Clegg, Mark T. Ross, Alison J. Coffey, Andrew Dunham, Sarah E. Hunt, David R. Bentley, Gareth R. Howell, Elizabeth J. Huckle, Cari Soderlund, Helen E. Steingruber, and Paul Hunt

Subjects
Genetic Markers, Yeast artificial chromosome, Letter, X Chromosome, Sequence analysis, Computational biology, Biology, Contig Mapping, Genetics, medicine, Humans, Chromosomes, Artificial, Yeast, In Situ Hybridization, Fluorescence, Genetics (clinical), X chromosome, medicine.diagnostic_test, Contig, Chromosome Mapping, Sequence Analysis, DNA, Electrophoresis, Gel, Pulsed-Field, Blotting, Southern, Genetic marker, Female, Human genome, Fluorescence in situ hybridization
Abstract

We have established a landmark framework map over 20–25 Mb of the long arm of the human X chromosome using yeast artificial chromosome (YAC) clones. The map has approximately one landmark per 45 kb of DNA and stretches from DXS7531 in proximal Xq23 to DXS895 in proximal Xq26, connecting to published framework maps on its proximal and distal sides. There are three gaps in the framework map resulting from the failure to obtain clone coverage from the YAC resources available. Estimates of the maximum sizes of these gaps have been obtained. The four YAC contigs have been positioned and oriented using somatic-cell hybrids and fluorescence in situ hybridization, and the largest is estimated to cover ∼15 Mb of DNA. The framework map is being used to assemble a sequence-ready map in large-insert bacterial clones, as part of an international effort to complete the sequence of the X chromosome. PAC and BAC contigs currently cover 18 Mb of the region, and from these, 12 Mb of finished sequence is available.

Published
1999
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19. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma

Author

Lucy, Gossage, Muhammed, Murtaza, Andrew F, Slatter, Conrad P, Lichtenstein, Anne, Warren, Beverley, Haynes, Francesco, Marass, Ian, Roberts, Susan J, Shanahan, Andreas, Claas, Andrew, Dunham, Andrew P, May, Nitzan, Rosenfeld, Tim, Forshew, and Tim, Eisen

Subjects
Histone Demethylases, Male, Tumor Suppressor Proteins, Nuclear Proteins, Oxidoreductases, N-Demethylating, Histone-Lysine N-Methyltransferase, DNA Methylation, Middle Aged, Chromatin Assembly and Disassembly, Kidney Neoplasms, DNA-Binding Proteins, Cytoskeletal Proteins, Humans, Female, Carrier Proteins, Carcinoma, Renal Cell, Ubiquitin Thiolesterase, Aged, Molecular Chaperones, Retrospective Studies, Transcription Factors
Abstract

VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted.

Published
2013

20. Depositional history of the upper Calvert Bluff and lower Carrizo formations, Bastrop, Texas

Author

Kevin Durney, Andrew Dunham, and Thomas E. Yancey

Subjects
Sedimentary depositional environment, Paleontology, Bluff, Outcrop, Group (stratigraphy), Transgressive, Paleosol, Geology, Marine transgression
Abstract

This fi eld trip examines exposures of transgressive and highstand marine deposits of the Sabinetown transgression that forms the upper part of the Calvert Bluff Formation of the Wilcox Group in the outcrop belt. The horizon of maximum fl ood in the Sabinetown transgression at Bastrop contains molluscs and diverse vertebrate fossils characteristic of open marine environments. The highstand deposits coarsen upward and are capped with a well-developed paleosol. These deposits are dated as early Eocene.

Published
2013
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22. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

Author

Nigel P. Carter, Ian Dunham, A. L. Atkinson, Jaime Hughes, M. Izmajlowicz, Richard Durbin, Mark T. Ross, Soumi Joseph, Adam Butler, G. L. Harper, Louise McDonald, Rohan Taylor, W. D. Burrill, Graeme Bethel, S. R. Prathalingam, David R. Bentley, Theologia Sarafidou, Vassos Neocleous, John Sulston, F. L. Dearden, C. M. Rice, E. C. Sotheran, Carol A. Edwards, S. M. Clegg, N. Brady, T. E. Wilmer, B. L. Hopkins, G. L. Maslen, Simon G. Gregory, Owen T. McCann, Andrew J. Mungall, M.A. Leversha, Elisabeth Dawson, K. J. Phillips, R Evans, A. A. Thorpe, C M Clee, Cordelia Langford, E. J. Huckle, Helen E. Steingruber, Carol Scott, Y. H. Ramsey, John E. Collins, Gareth R. Howell, Adam Whittaker, M. E. Earthrowl, M. H. Lehvaslaiho, Pamela Whittaker, G. Laird, J. C. Brook, D. J. Scott, K. J. Ashcroft, S. H. Williams, Georgina Warry, Nicholas K. Moschonas, D. M. Pearson, K. S. Halls, C. L. Wright, R. W. Heathcott, C. Carder, Jane L. Holden, D. C. Burford, S. A. Ranby, P. J. Howard, K. Aubin, K. M. Porter, E. Holloway, R. A. Cooper, A. J. Coffey, David Beare, J. J. Catanese, C. A. Jones, J. S. Conquer, J. Ghori, E. J. Tinsley, Lisa French, Charlotte G. Cole, P. D. Dhami, K. M. Culley, Christopher J. Gillson, Sarah E. Hunt, Rhian Gwilliam, Panagiotis Deloukas, V. Cobley, Carol Soderlund, A. Taylor, G. J. Sharp, Luc J. Smink, S. Hammond, Andrew Dunham, L. J. Rogers, D. Mistry, Richard Wooster, P. J. De Jong, Jane Rogers, P. J. Hunt, L D Green, C. J. Shaw-Smith, Jennifer McDowall, C. Burrows, and Sean Humphray

Subjects
Genetics, Multidisciplinary, X Chromosome, Contig, Gene map, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 10, Genome, Human, Chromosomes, Human, Pair 20, food and beverages, Chromosome, Computational biology, Biology, Genome, Contig Mapping, Gene mapping, Chromosomes, Human, Pair 1, Humans, Chromosomes, Human, Pair 6, X chromosome, Genomic organization
Abstract

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.

Published
2001

23. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene

Author

Massimo Zollo, Anthony P. Cahn, Gareth R. Howell, Paul Wray, Alison J. Coffey, Toshitaka Oohashi, Arpad Lanyi, Jack R. Davis, Robert A. Brooksbank, Marco Seri, Margaret A. Leversha, Charles Shaw-Smith, Luo Yin, Ann Harris, Susan Rhodes, Genevieve de St Basile, Mark T. Ross, Alfons Meindl, Reinhard Fässler, Volker Schuster, Janos Sumegi, Alessandra Bolino, Giovanni Romeo, Alison Jones, Jillian Durham, Helene Achatz, Paul Heath, Jan Murken, M. Vaudin, Bakary S. Sylla, Gilbert M. Lenoir, Brunella Franco, David R. Bentley, Jacqueline M. Bye, David Webster, Elizabeth J. Huckle, Giovanni Porta, Andrew Dunham, Bernd H. Behloradsky, Jane Wilkinson, Oliver Brandau, Paola Serafini, Rebecca Pavitt, Coffey, A. J., and Zollo, Massimo

Subjects
Male, Herpesvirus 4, Human, X Chromosome, Genetic Linkage, T-Lymphocytes, Molecular Sequence Data, Immunoglobulins, Receptors, Cell Surface, medicine.disease_cause, Virus, src Homology Domains, Hypogammaglobulinemia, Immune system, Signaling Lymphocytic Activation Molecule Family Member 1, Antigen, Antigens, CD, hemic and lymphatic diseases, Genetics, medicine, Humans, Gammaherpesvirinae, Signaling Lymphocytic Activation Molecule Associated Protein, X-Linked Lymphoproliferative Syndrome, Cloning, Molecular, Glycoproteins, Sequence Deletion, B-Lymphocytes, biology, Intracellular Signaling Peptides and Proteins, X-linked lymphoproliferative disease, Herpesviridae Infections, medicine.disease, biology.organism_classification, Epstein–Barr virus, Virology, Lymphoproliferative Disorders, Pedigree, Mutation, Immunology, Female, Carrier Proteins, Sequence Alignment
Abstract

X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

Published
1998

24. Correction: Initial sequencing and analysis of the human genome

Author

Paul Predki, John Sulston, William Morris, Sarah Wenning, Jun Gu, Danielle Thierry-Mieg, Roger A. Schultz, Michael J. Morgan, Michael Doyle, Joseph Szustakowki, Lorenzo Cerutti, A. Coulson, Alex Bateman, Patrick Wincker, Michael C. Zody, Mark T. Ross, Paul G. Richardson, Keri Devon, Yasushi Totoki, Karsten Hokamp, George M. Weinstock, John Howland, Arek Kaspryzk, James G. R. Gilbert, Cher Miranda, Aristides Patrinos, William Saurin, A. Pia Abola, Kazuhiko Kawasaki, John Bouck, Marvin Frazier, Wonhee Jang, Jan Fang Cheng, Stephanie L. Chissoe, Matthew C. Jones, Glen A. Evans, Huanming Yang, Daniel G. Brown, Richard Durbin, Jennifer Baldwin, Tracie L. Miner, Asif T. Chinwalla, Arian F.A. Smit, C M Clee, Elaine R. Mardis, Henning Hermjakob, Nicole Stange-Thomann, Maynard V. Olson, Jian Wang, Cyrus L. Harmon, Shiaw Pyng Yang, André Rosenthal, Catherine Robert, Masahira Hattori, Jane Peterson, Ratna Shownkeen, Maria Athanasiou, Christopher B. Burge, Erica Sodergren, Carrie Sougnez, Lynn Doucette-Stamm, Hidemi Watanabe, Ronald W. Davis, Tarjei S. Mikkelsen, Mark Rosetti, Christopher J. Elkin, Todd M. Lowe, LaDeana W. Hillier, Jane Grimwood, Kazutoyo Osoegawa, Richard R. Copley, Simon Kasif, Joseph J. Catanese, Keith Weinstock, Lee Rowen, Roel Funke, Paul Kitts, Lukas Wagner, Guy Slater, Anne S. Olsen, Edward Uberbacher, Lucinda Fulton, Andrew Dunham, Andrew Heaford, David Kulp, Elbert Branscomb, William Fitzhugh, Eugene V. Koonin, Leroy Hood, Anup Madan, Jean Thierry-Mieg, Richard Reinhardt, Kim C. Worley, Richard M. Myers, Dudley Wyman, Jean Weissenbach, David R. Bentley, Panos Deloukas, Philippe Brottier, H. Blöcker, Stephan Beck, Marc Rubenfield, Terrence S. Furey, Ken Dewar, Michael L. Metzker, Rajinder Kaul, Guyang Huang, Hsiu Chuan Chen, Ewan Birney, Warren Gish, John Douglas Mcpherson, Asao Fujiyama, Aoife McLysaght, Shinsei Minoshima, Sandra W. Clifton, Lisa Kann, R Ainscough, K. Hornischer, Simon G. Gregory, Lauren Linton, Kim D. Delehaunty, James C. Mullikin, Neilay Dedhia, Matthias Platzer, Gerald Nyakatura, John V. Moran, Andrew J. Mungall, Chiharu Kawagoe, François Artiguenave, Deanna M. Church, Elia Stupka, Jun Yu, Peer Bork, Evan E. Eichler, L. Aravind, James H. Gorrell, Bruce A. Roe, Raymond Wheeler, Norman A. Doggett, Douglas R. Smith, Yu Juin Chen, David Haussler, Todd D. Taylor, Stefan Taudien, Susan Lucas, Rebecca Deadman, Hans Lehrach, Hiroaki Shizuya, Doron Lancet, Greg Schuler, Nigel P. Carter, John Burton, Huaqin Pan, Eric S. Lander, Andreas Rump, Nikola Stojanovic, Victor J. Pollara, Alan Williams, Melissa De La Bastide, W. James Kent, Mark S. Guyer, Nicola Mulder, Sarah Milne, Bruce W. Birren, John W. Wallis, Joann Dubois, Tom Slezak, Lisa Cook, Raju Kucherlapati, Andrew Delehaunty, Lucy Matthews, Ian Dunham, L. Steven Johnson, Robert H. Waterston, Andrew Sheridan, Jörg Schultz, Nancy A. Federspiel, Jason B. Kramer, Tim Hubbard, Ru Fang Yeh, Steven E. Scherer, Francis S. Collins, David L. Nelson, Sean Humphray, Tobias Doerks, Chad Nusbaum, Darren Grafham, Mei Lee Hong, Michael Proctor, Christopher K. Raymond, Diane Gage, Kris A. Wetterstrand, Feng Chen, Simon Mercer, Thomas A. Jones, Trevor Hawkins, Aravind Subramanian, Jeffrey A. Bailey, Amanda McMurray, Serafim Batzoglou, Jeremy Schmutz, Jill P. Mesirov, Shizen Qin, Rosie Levine, Adam Felsenfeld, Thomas Brüls, Kevin McKernan, Michele E. Clamp, Christine Lloyd, Susan L. Naylor, Gabriele Nordsiek, Jessica A. Lehoczky, Adrienne Hunt, Marco A. Marra, David R. Cox, Mark Dickson, Michael C. Wendl, Yuri I. Wolf, Jane Rogers, Ian F Korf, Eric Pelletier, Takehiko Itoh, Juliane Ramser, Robert S. Fulton, Sarah Sims, Richard A. Gibbs, Lisa French, Katrina Harris, Richa Agarwala, Christina Raymond, James Meldrim, Sangdun Choi, Richard K. Wilson, Patrick Minx, Douglas L. Johnson, Yoshiyuki Sakaki, Scot Kennedy, Pieter J. de Jong, Yoshihide Hayashizaki, W. Richard McCombie, Sean R. Eddy, Donna M. Muzny, Jerome Naylor, Paul A. McEwan, Atsushi Toyoda, Tetsushi Yada, Nobuyoshi Shimizu, Robert W. Plumb, Catherine M. Rives, Chris P. Ponting, Ralph Santos, Kenneth H. Wolfe, Kymberlie H. Pepin, Roland Heilig, and James E. Galagan

Subjects
Multidisciplinary, Correction, Human genome, Computational biology, Biology
Published
2001
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25. Effect of Practice Procedure on Skill Acquisition

Author

Trey Dunham, Timothy Andrew Dunham, and Paul Dunham

Subjects
Basketball, MEDLINE, Experimental and Cognitive Psychology, Sensory Systems, Dreyfus model of skill acquisition, Motor Skills, Practice, Psychological, Schema (psychology), Humans, Child, Psychology, Motor skill, Sports, Cognitive psychology
Abstract

49 children in Grade 1 in an isolated community were assessed on their form and skill in making a basket for a one-step basketball lay-up following practice using a pseudoshaping, specific, or schema procedure. Analysis gave a significant form effect but no difference in success of making baskets.

Published
1988
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26. Improved analysis of derivatized steroid hormone isomers using ion mobility-mass spectrometry (IM-MS).

Author

Neal, Shon P., Hodges, Walker N., Velosa, Diana C., Aderorho, Ralph, Lucas, Shadrack Wilson, and Chouinard, Christopher D.

Subjects
ION mobility spectroscopy, STEROID hormones, ISOMERS, SPECTROMETRY, COMPLEX compounds, STEREOCHEMISTRY
Abstract

Over the last decade, applications of ion mobility-mass spectrometry (IM-MS) have exploded due primarily to the widespread commercialization of robust instrumentation from several vendors. Unfortunately, the modest resolving power of many of these platforms (~40–60) has precluded routine separation of constitutional and stereochemical isomers. While instrumentation advances have pushed resolving power to >150 in some cases, chemical approaches offer an alternative for increasing resolution with existing IM-MS instrumentation. Herein we explore the utility of two reactions, derivatization by Girard's reagents and 1,1-carbonyldiimidazole (CDI), for improving IM separation of steroid hormone isomers. These reactions are fast (≤30 min), simple (requiring only basic lab equipment/expertise), and low-cost. Notably, these reactions are structurally selective in that they target carbonyl and hydroxyl groups, respectively, which are found in all naturally occurring steroids. Many steroid hormone isomers differ only in the number, location, and/or stereochemistry of these functional groups, allowing these reactions to "amplify" subtle structural differences and improve IM resolution. Our results show that resolution was significantly improved amongst CDI-derivatized isomer groups of hydroxyprogesterone (two-peak resolution of Rpp = 1.10 between 21-OHP and 11B-OHP), deoxycortisone (Rpp = 1.47 between 11-DHC and 21-DOC), and desoximetasone (Rpp = 1.98 between desoximetasone and fluocortolone). Moreover, characteristic collision cross section (DTCCSN2) measurements can be used to increase confidence in the identification of these compounds in complex biological mixtures. To demonstrate the feasibility of analyzing the derivatized steroids in complex biological matrixes, the reactions were performed following steroid extraction from urine and yielded similar results. Additionally, we applied a software-based approach (high-resolution demultiplexing) that further improved the resolving power (>150). Overall, our results suggest that targeted derivatization reactions coupled with IM-MS can significantly improve the resolution of challenging isomer groups, allowing for more accurate and efficient analysis of complex mixtures. [ABSTRACT FROM AUTHOR]

Published
2023
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27. Ending Lacewing Acres: Toward amplifying microperspectives on farm closure.

Author

Dubisar, Abby M. and Slocum, Julia A.

Subjects
AGRICULTURE, COMMUNITY-supported agriculture, LACEWINGS, FARMS, SCHOLARLY method
Abstract

Farmers are invited to tell stories about their farms, especially about their farm's origin and history. However, some farm stories go untold, are uninvited, or become obscured, including stories of farm closures. With this case study, we invite journalists and academics to provide further opportunities for farmers to tell their own closure stories. Written by the farmer and her CSA member and friend, who researches farmer communication, this case study calls on farmers to tell their farm-closure stories in the complicated and robust ways such stories deserve. We draw on academic and public scholarship about farm closures and farmers' disclosures to feature how one farmer decided to end her farm and farming career. We chronicle her decision-making process and her strategies to communicate the closure of her farm, as well as analyze themes from how audiences reacted to her news. We also offer a range of reasons for inviting such telling of complex closure stories. [ABSTRACT FROM AUTHOR]

Published
2022
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28. The oxygen saturation of red blood cell concentrates: The basis for a novel index of red cell oxidative stress.

Author

Yoshida, Tatsuro, McMahon, Emma, Croxon, Harry, Dunham, Andrew, Gaccione, Peter, Abbasi, Babak, Beckman, Neil, Omert, Laurel, Field, Stephen, and Waters, Allison

Subjects
ERYTHROCYTES, OXYGEN saturation, OXIDATIVE stress, OXYGEN in the blood
Abstract

Background: Oxidative stress is a major driving force in the development of storage lesions in red cell concentrates (RCCs). Unlike manufactured pharmaceuticals, differences in component preparation methods and genetic/physiological status of donors result in nonuniform biochemical characteristics of RCCs. Various characteristics of donated blood on oxygen saturation (SO2) distribution were investigated, and a model to estimate potential oxidative stress burden of stored RCC at transfusion is proposed. Study design and methods: The oxygen content of freshly prepared RCCs (770) was quantified noninvasively as fractional hemoglobin saturation (SO2) with visible reflectance spectrometry. Using separate RCCs and mimicking typical handling of RCCs during routine storage, evolution of SO2 was followed for construction of an empirical model. Based on this model, the oxygen exposure index (OEI) was formulated to estimate the accumulated oxygen exposure burden of RCC at the time of transfusion. Results: The SO2 of RCCs varied widely at donation (mean 43% ± 1.3%; range 20%–93%). Multivariate regression model showed that sex and processing method had small effects on SO2 (R2 = 0.12), indicating that variability was mainly attributed to other individual donor characteristics. Storage simulation model indicated that median SO2 increased gradually over 6 weeks (approx. 1.3 fold), while OEI increased at a faster rate (approx. eight‐fold). Conclusion: In addition to storage age, the OEI provides a potential new metric to assess the quality of RCCs at the time of transfusion in terms of their oxidative stress. In future studies, a single noninvasive measurement during storage could link OEI to clinical outcomes in transfusion recipients. [ABSTRACT FROM AUTHOR]

Published
2022
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29. Effects of hypoxic storage on the efficacy of gamma irradiation in abrogating lymphocyte proliferation and on the quality of gamma‐irradiated red blood cells in additive solution 3.

Author

Sowemimo‐Coker, Samuel O. and Fast, Loren D.

Subjects
ERYTHROCYTES, MONONUCLEAR leukocytes, LYMPHOCYTES, T cells, IRRADIATION
Abstract

Background: Gamma irradiation of blood products is used to prevent transfusion‐associated graft‐versus‐host disease by inhibiting the proliferation of lymphocytes that are implicated in the disease. Gamma irradiation also damages the red blood cells (RBCs). It is unknown whether hypoxia reduces the efficacy of gamma irradiation in inhibiting lymphocyte proliferation (LP). The objectives of the study were to investigate the effects of hypoxia on gamma irradiation‐induced inhibition of LP and on the in vitro properties of RBCs. Materials and methods: Forty‐four units (300–340 ml each) of less than 8‐h‐old ABO‐matched leukocyte reduced red cell concentrates (LR‐RCC) in additive solution 3 were pooled in pairs. Peripheral blood mononuclear cells were isolated from non‐leukocyte reduced RCCs and added back to the pool at a final concentration of 2 × 105/ml. The pool was divided equally into a conventional storage bag A and a hypoxic processing and storage bag B. The units were gamma‐irradiated at 25Gy on day 7 for the LP experiment and on either day 7 or 14 for the RBC quality experiments. LP was measured using a limiting dilution assay, and several in vitro metrics of RBCs were measured. Results: Gamma irradiation inhibited T‐lymphocyte proliferation by 4.7 × 104‐fold reduction in both hypoxic and conventional storage. The in vitro metrics of RBC quality were better preserved in hypoxic storage. Discussion: T lymphocytes present in hypoxic RBC are equally susceptible to gamma irradiation as conventional storage. Hypoxic storage also reduces the deleterious effects of gamma irradiation on RBCs. [ABSTRACT FROM AUTHOR]

Published
2021
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30. Old Ways New Faces.

Author

Doležal, Joshua

Subjects
FARMS, FARMERS
Abstract

The article profiles various farms and farmers in Iowa. These include Andrew Dunham of Grinnell Heritage Farm, Jill Beebout of Blue Gate Farm and Rob Faux of Genuine Faux Farm. It mentions that the first farm applies bookkeeping in maintaining its organic certification. The second sustains a rotation system for vegetable plots while the last uses sustainable methods in creating a strong community-supported agriculture (CSA) program.

Published
2012

31. Oxygen in Red Blood Cell Concentrates: Influence of Donors' Characteristics and Blood Processing.

Author

Bardyn, Manon, Martin, Agathe, Dögnitz, Nora, Abonnenc, Mélanie, Dunham, Andrew, Yoshida, Tatsuro, and Prudent, Michel

Subjects
ERYTHROCYTES, OXYGEN in the blood, BLOOD groups, RESONANCE Raman spectroscopy, BLOOD
Abstract

Objective: Unexpectedly wide distribution (<10 to >90%) of hemoglobin oxygen saturation (sO2) within red cell concentrates (RCCs) has recently been observed. Causes of such variability are not yet completely explained whereas the roles of oxygen and oxidative lesions during the storage of RCCs are known. The objectives of the present study are to characterize sO2 distribution in RCCs produced in a Swiss blood center and to investigate the influence of processing and donors' characteristics. Methods: The level of sO2 was measured in 1701 leukocyte-depleted RCCs derived from whole blood donations in both top–bottom (TB; component filtered, SAGM) and top–top (TT; whole blood filtration, PAGGSM) RCCs. The sO2 value was measured non-invasively through the PVC bag prior to storage by resonance Raman spectroscopy. Gender, age, blood type, hemoglobin level, and living altitude of donors, as well as process method and time-to-process were recorded. Results: Overall, the sO2 exhibited a wide non-Gaussian distribution with a mean of 51.2 ± 18.5%. Use of top-top kits resulted in a 16% higher sO2 (P < 0.0001) than with top-bottom ones. Waiting time before processing only had a modest impact, but the blood processing itself reduced the sO2 by almost 12% (P < 0.0001). sO2 was also significantly affected by some donors' characteristics. RCCs from men exhibited 25% higher sO2 (P < 0.0001) than those donated by women. Multivariate analysis revealed that the apparent correlation observed with hemoglobin level and age was actually due to multicollinearity with the sex variable. Finally, we noticed no significant differences across blood type but found that altitude of residence was associated with the sO2 (i.e., higher in higher living place). Conclusion: These data confirm wide sO2 distribution in RCCs reported recently. The sO2 was impacted by the processing and also by donors' characteristics such as the gender and the living altitude, but not by the hemoglobin level, blood group and donor age. This study provides new hints on the factors influencing red blood cells storage lesions, since they are known to be related to O2 content within the bags, giving clues to better process and to better store RCCs and therefore potentially improve the efficacy of transfusion. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Hypoxic storage of red blood cells improves metabolism and post-transfusion recovery.

Author

DʼAlessandro, Angelo, Yoshida, Tatsuro, Nestheide, Shawnagay, Nemkov, Travis, Stocker, Sarah, Stefanoni, Davide, Mohmoud, Fatima, Rugg, Neeta, Dunham, Andrew, and Cancelas, Jose A.

Subjects
ERYTHROCYTES, CELL metabolism, FREE fatty acids, ENERGY storage, ENERGY metabolism, ERYTHROCYTE metabolism, HUMAN research subjects, BLOOD transfusion, CROSS-sectional method, CONVALESCENCE, HEMOLYSIS & hemolysins, BLOOD collection, AUTOGRAFTS, RESEARCH funding
Abstract

Background: Blood transfusion is a lifesaving intervention for millions of recipients worldwide every year. Storing blood makes this possible but also promotes a series of alterations to the metabolism of the stored erythrocyte. It is unclear whether the metabolic storage lesion is correlated with clinically relevant outcomes and whether strategies aimed at improving the metabolic quality of stored units, such as hypoxic storage, ultimately improve performance in the transfused recipient.Study Design and Methods: Twelve healthy donor volunteers were recruited in a two-arm cross-sectional study, in which each subject donated 2 units to be stored under standard (normoxic) or hypoxic conditions (Hemanext technology). End-of-storage measurements of hemolysis and autologous posttransfusion recovery (PTR) were correlated to metabolomics measurements at Days 0, 21, and 42.Results: Hypoxic red blood cells (RBCs) showed superior PTR and comparable hemolysis to donor-paired standard units. Hypoxic storage improved energy and redox metabolism (glycolysis and 2,3-diphosphoglycerate), improved glutathione and methionine homeostasis, decreased purine oxidation and membrane lipid remodeling (free fatty acid levels, unsaturation and hydroxylation, acyl-carnitines). Intra- and extracellular metabolites in these pathways (including some dietary purines) showed significant correlations with PTR and hemolysis, though the degree of correlation was influenced by sulfur dioxide (SO2 ) levels.Conclusion: Hypoxic storage improves energy and redox metabolism of stored RBCs, which results in improved posttransfusion recoveries in healthy autologous recipients-a Food and Drug Administration gold standard of stored blood quality. In addition, we identified candidate metabolic predictors of PTR for RBCs stored under standard and hypoxic conditions. [ABSTRACT FROM AUTHOR]

Published
2020
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34. The Waning of Professional Dominance: DRGs and the Hospitals

Author

Morone, James A. and Dunham, Andrew B.

Abstract

Prologue:Government policymaking in the United States is a highly uncertain exercise that strives to solve problems through a melding of public concerns and private interests. Over the last two decades in the health sphere, this process has led to an ever-greater involvement of government in the financing of medical care and biomedical research and in the operation of the nations hospitals. Pressure for this greater involvement stems largely from one overriding concern: a belief that medical care costs have risen uncontrollably over this period. Even in an era when the administration in power advocates a retrenchment of government's role in American society, the role of government increases in health care. The majority of interests which compete in the endless competition to shape health policy gravitate toward a larger role for government for many reasons, not the least of which is a belief that its collective voice reflects public concerns. James Morone, a political scientist at Brown University, and Andrew Dunham, assistant professor of political science at Colorado College, offer here a fascinating political history of the evolution of New Jersey's early trial with hospital payment based upon diagnosis-related groups (DRGs). Medicares new DRG-based hospital payment system, though different in some respects, was modeled essentially on New Jersey's scheme. The message is that government's role never stands still, but rather reflects ceaseless evolution. In 1970, New Jersey hospitals were autonomous institutions. A decade later, the state has come to dominate hospitals in the Garden State, setting rates and regulating the pace of development and impinging on the practice of medicine. Prospective payment based on DRG measures is at the heart of this growing state role. Medicare has embarked on a similar policy course, which prompts the question: does the tight state control of hospitals in New Jersey represent the future for all American hospitals?

Published
1984
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36. Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells.

Author

Reisz, Julie A., Nemkov, Travis, Dzieciatkowska, Monika, Culp‐hill, Rachel, Stefanoni, Davide, Hill, Ryan C., Yoshida, Tatsuro, Dunham, Andrew, Kanias, Tamir, Dumont, Larry J., Busch, Michael, Eisenmesser, Elan Z., Zimring, James C., Hansen, Kirk C., D'alessandro, Angelo, and Culp-Hill, Rachel

Subjects
ASPARTATES, METHYLATION, BLOOD banks, OXIDATIVE stress, ERYTHROCYTES, ASPARTIC acid metabolism, ERYTHROCYTE metabolism, ASPARAGINE, BLOOD collection, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, PROTEINS, RESEARCH, RESEARCH funding, TIME, PROTEOMICS, EVALUATION research
Abstract

Background: Being devoid of de novo protein synthesis capacity, red blood cells (RBCs) have evolved to recycle oxidatively damaged proteins via mechanisms that involve methylation of dehydrated and deamidated aspartate and asparagine residues. Here we hypothesize that such mechanisms are relevant to routine storage in the blood bank.Study Design and Methods: Within the framework of the REDS-III RBC-Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell-Omics) study, packed RBC units (n = 599) were stored under blood bank conditions for 10, 23, and 42 days and profiled for oxidative hemolysis and time-dependent metabolic dysregulation of the trans-sulfuration pathway.Results: In these units, methionine consumption positively correlated with storage age and oxidative hemolysis. Mechanistic studies show that this phenomenon is favored by oxidative stress or hyperoxic storage (sulfur dioxide >95%), and prevented by hypoxia or methyltransferase inhibition. Through a combination of proteomics approaches and 13 C-methionine tracing, we observed oxidation-induced increases in both Asn deamidation to Asp and formation of methyl-Asp on key structural proteins and enzymes, including Band 3, hemoglobin, ankyrin, 4.1, spectrin beta, aldolase, glyceraldehyde 3-phosphate dehydrogenase, biphosphoglycerate mutase, lactate dehydrogenase and catalase. Methylated regions tended to map proximal to the active site (e.g., N316 of glyceraldehyde 3-phosphate dehydrogenase) and/or residues interacting with the N-terminal cytosolic domain of Band 3.Conclusion: While methylation of basic amino acid residues serves as an epigenetic modification in nucleated cells, protein methylation at carboxylate side chains and deamidated asparagines is a nonepigenetic posttranslational sensor of oxidative stress and refrigerated storage in anucleated human RBCs. [ABSTRACT FROM AUTHOR]

Published
2018
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38. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Author

Baillie, J. Kenneth, Bretherick, Andrew, Haley, Christopher S., Clohisey, Sara, Gray, Alan, Neyton, Lucile P. A., Barrett, Jeffrey, Stahl, Eli A., Tenesa, Albert, Andersson, Robin, Brown, J. Ben, Faulkner, Geoffrey J., Lizio, Marina, Schaefer, Ulf, Daub, Carsten, Itoh, Masayoshi, Kondo, Naoto, Lassmann, Timo, Kawai, Jun, and null, null

Subjects
DNA probes, GENE expression, RNA, RIBOSE, RIBOSOMAL DNA
Abstract

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn’s disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits. [ABSTRACT FROM AUTHOR]

Published
2018
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39. Draft Horse Team and Plow on Dunham Farm

Author

Dunham, Egbert Harold, 1867-1957 (photographer) and Dunham, Egbert Harold, 1867-1957 (photographer)

Abstract

Farmer, likely a member of the Dunham family, seated on a wheeled plow behind two draft horses. Photo was taken between 1912-1927 by Egbert Dunham., Andrew Dunham

Published
1920

40. Dunham Farm Barn

Author

Dunham, Egbert Harold, 1867-1957 (photographer) and Dunham, Egbert Harold, 1867-1957 (photographer)

Abstract

The barn on the Dunham farm, named Elm Grove, in Chester Township near Grinnell, Iowa. Photo shows the silo in front of the end of the barn. An automobile is in the foreground. A water pump is in the foreground., Andrew Dunham

Published
1920

43. To Succeed in Manufacturing, Focus on Your People First.

Author

Naitove, Matthew H.

Subjects
MAINTENANCE, TOTAL quality management, MACHINE molding (Founding), MANUFACTURING processes, PERSONNEL management, BUSINESS development
Abstract

The article discusses qualities which make Natech Plastics Inc. a successful custom injection molder in New York City. According to David Kachoui, director of business development at Natech, the firm is focused on management of product, project and talent to be successful. He said that the firm ensures high standards of product quality and plant safety by encouraging staff by continuous training, collaboration and mutual respect.

Published
2019

45. Management of Obstructive Sleep Apnea in Children with Cerebral Palsy.

Author

Munson, Patrick D., Dunham, Andrew, Bower, Charles M., Richter, Gresham T., Hartzell, Larry D., and Guillory, Ryan

Abstract

Objective: 1) Determine the efficacy of combined surgical techniques for improving obstructive sleep apnea (OSA) in pediatric patients with cerebral palsy (CP). 2) Evaluate the addition of tongue base suspension for children with CP that have moderate to severe OSA. Method: Seven‐year retrospective chart review of 14 children with CP undergoing surgical management of OSA, including adenotonsillectomy (T&A) and uvulopalatopharyngoplasty (UPPP), with or without tongue base suspension (TBS). Response to treatment was determined by its impact on PSG parameters: apnea/hypopnea index (AHI) and arousal index (AI). Results: Children with CP who received TBS had a mean preoperative AHI of 27.2 compared with an AHI of 6.8 in the group that underwent only T&A and UPPP (non‐TBS). AHI decreased by a mean of 16.5 (TBS) vs 5.0 (non‐TBS); (P value. 03 vs 04). AI also improved in both groups (33.1 to 20.7 and 11.0 to 5.8); (P value. 05 vs 10). Hospital length of stay was slightly longer for the TBS groups than the non‐TBS groups (mean 9.3 days and 6.6 days) but was not statistically significant (P =. 09). Average length of follow‐up was 52 months with no surgical complications. Conclusion: Combined surgical therapy improves OSA in children with CP. Children with CP and moderate to severe OSA (AHI>15) may safely benefit from the addition of tongue base suspension to T&A and UPPP to maximize treatment. [ABSTRACT FROM AUTHOR]

Published
2011
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46. The Origins, Development, and Passage of Medicare’s Revolutionary Prospective Payment System.

Author

MAYES, RICK

Subjects
MEDICARE, HEALTH insurance, MEDICAL care for older people, PROSPECTIVE payment systems, HEALTH insurance reimbursement
Abstract

This article explains the origins, development, and passage of the single most influential postwar innovation in medical financing: Medicare’s prospective payment system (PPS). Inexorably rising medical inflation and deep economic deterioration forced policymakers in the late 1970s to pursue radical reform of Medicare to keep the program from insolvency. Congress and the Reagan administration eventually turned to the one alternative reimbursement system that analysts and academics had studied more than any other and had even tested with apparent success in New Jersey: prospective payment with diagnosis-related groups (DRGs). Rather than simply reimbursing hospitals whatever costs they charged to treat Medicare patients, the new model paid hospitals a predetermined, set rate based on the patient’s diagnosis. The most significant change in health policy since Medicare and Medicaid’s passage in 1965 went virtually unnoticed by the general public. Nevertheless, the change was nothing short of revolutionary. For the first time, the federal government gained the upper hand in its financial relationship with the hospital industry. Medicare’s new prospective payment system with DRGs triggered a shift in the balance of political and economic power between the providers of medical care (hospitals and physicians) and those who paid for it—power that providers had successfully accumulated for more than half a century. [ABSTRACT FROM PUBLISHER]

Published
2007
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47. Recent Trends in U.S. Social Welfare Policy.

Author

Quadagno, Jill and Street, Debra

Subjects
WELFARE state, ECONOMIC policy, PUBLIC welfare, SOCIAL policy, WELFARE economics, CODEPENDENCY, PUBLIC welfare administration
Abstract

Many scholars have characterized the United States as a welfare state "laggard" less generous than most other nations because of a peculiarly American set of historical circumstances and values. This article explores "American exceptionalism" in the context of welfare state reforms over the past two decades. The authors first describe recent social policy innovations in Western democracies, considering two competing views of welfare state change. The first asserts that welfare states have been fundamentally transformed into "enabling" states, characterized by efforts to promote work, privatize benefits and services, and target benefits to the most needy. The second holds that policy structures have remained essentially intact because of "path-dependent" processes that create institutional continuity. Although evidence for the United States is somewhat mixed, the general direction of policy decisions and current frameworks of policy debates is consistent with a transition toward an enabling state. [ABSTRACT FROM AUTHOR]

Published
2006
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