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155. An empirical exploration of the relationship between manufacturing strategy and environmental management: two complementary models

Author

Newman, W. Rocky and Hanna, Mark D.

Subjects
Strategic planning (Business) -- Research, Production planning -- Research, Environmental engineering -- Research, Production management -- Research, Business, Business, international, Research
Abstract

Introduction Business concern for the environment is not a passing fad. This is clearly verified by the recent world summit in Rio de Janeiro, where the Business Council for Sustainable [...]

Published
1996

157. Integrated manufacturing strategy: a prerequisite for environmental excellence

Author

Newman, W. Rocky, Hanna, Mark D., and Youngdahl, William E.

Subjects
Manufacturing processes -- Production management, Business planning -- Management, Environmental protection -- Management, Business, Business, regional
Abstract

This paper is based upon a framework which links the effective integration of manufacturing strategy into overall corporate strategy (Wheelwright and Hayes 1985) and corporate attainment of environmental excellence (Winsemius and Guntram 1992). By exploring the practical implications of this framework, the paper suggests that improvement of environmental performance may depend on adequate integration of manufacturing strategy into overall corporate strategy. Hence, situations may commonly exist where corporate goals for environmental excellence remain unachieved due to insufficient development of manufacturing strategy, and manufacturing strategy integration may be a critical prerequisite to environmental excellence.

Published
1994

158. Including equipment flexibility in break-even analysis: two examples

Author

Newman, W. Rocky and Hanna, Mark D.

Subjects
Break-even analysis -- Usage, Flexible manufacturing systems -- Management, Automobile industry, Business, Human resources and labor relations, Metals, metalworking and machinery industries
Abstract

When making initial comparisons between process technology alternatives, managers want a quick, logical, and easily communicated model that makes the relevant trade-offs evident. This article is a description of two examples of a simple extension of cost-volume break-even analysis which can include flexibility-related costs. In both cases management considered flexibility a key strategic variable.

Published
1994

159. Evaluating the Impact of Financial Management Practices on an Organization’s Financial Performance: A Case Study of Hwange Colliery Company

Author

Newman Wadesango, Justice Walter Ruwende, and Lovemore Sitsha

Subjects
Financial Management Practices, Fixed Assets Management, Capital Structure, Investment Practices, Business, HF5001-6182, Economics as a science, HB71-74
Abstract

The purpose of the study was to establish the impact of financial management practices on an organization’s financial performance. This analysis was driven by the organization’s declining profitability despite the efforts to deploy cost-cutting initiatives. As a consequence, the research looked into the impact of existing procedures in working capital management, fixed assets management, capital structure and investment practices. The descriptive research design was used in the study and quantitative research approach was adopted. The administrative personnel at Hwange Colliery Company, which numbered forty six, comprised the population and a sample of 30 was used. A questionnaire survey with structured questions was utilized. In the study, regression analysis and Pearson coefficient of correlation were employed to determine the link between the factors of financial performance and financial management techniques. It emerged that the financial management strategies had a substantial impact on Hwange Colliery Company financial performance. To maintain resource efficiency, the research recommends improvements in the areas of accounts receivable management and investment decision that is leading to losses if wrong decision are made.

Published
2023
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160. Implosive accretion and outbursts of active galactic nuclei

Author

Lovelace, R. V. E, Romanova, M. M, and Newman, W. I

Subjects
Astrophysics
Abstract

A model and simulation code have been developed for time-dependent axisymmetric disk accretion onto a compact object including for the first time the influence of an ordered magnetic field. The accretion rate and radiative luminosity of the disk are naturally coupled to the rate of outflow of energy and angular momentum in magnetically driven (+/- z) winds. The magnetic field of the wind is treated in a phenomenological way suggested by self-consistent wind solutions. The radial accretion speed u(r, t) of the disk matter is shown to be the sum of the usual viscous contribution and a magnetic contribution proportional to r(exp 3/2)(B(sub p exp 2))/sigma, where B(sub p)(r,t) is the poloidal field threading the disk and sigma(r,t) is the disk's surface mass density. An enhancement or variation in B(sub p) at a large radial distance leads to the formation of a soliton-like structure in the disk density, temperature, and B-field which propagates implosively inward. The implosion gives a burst in the power output in winds or jets and a simultaneous burst in the disk radiation. The model is pertinent to the formation of discrete fast-moving components in jets observed by very long baseline interferometry. These components appear to originate at times of optical outbursts of the active galactic nucleus.

Published
1994
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161. Adapting traditional breakeven analysis to modern production economics: simultaneously modeling economies of scale and scope

Author

Hanna, Mark D., Newman, W. Rocky, and Sridharan, Sri V.

Subjects
Flexible manufacturing systems -- Models, Manufacturing industry -- Management, Break-even analysis -- Models, Business, Business, international, Engineering and manufacturing industries
Abstract

Cost volume breakdown analysis (CVBA) is a simple method for considering the basic costs and benefits of equipment alternatives in a flexible manufacturing set-up. However, a comparison with the cost volume flexibility breakeven analysis (CVFBA) shows that the latter is better suited to reflect the economics of modern technology selection decisions. CVFBA is thus a better alternative than CVBA in the capital budgeting process for new manufacturing technology.

Published
1993

162. Dealing with the uncertainties of manufacturing; flexibility, buffers and integration

Author

Newman, W. Rocky, Hanna, Marcus Alonzo, and Maffei, Mary Jo

Subjects
Uncertainty -- Management, Manufacturing industry -- Management, Flexible manufacturing systems -- Research, Capacity management (Computers) -- Research, Business, Business, international
Abstract

An analysis of manufacturing firm management of uncertainties is presented. It is shown that most manufacturing firms face uncertainty by applying flexible manufacturing systems. A dynamic equilibrium model is developed and presented as a possible aid in describing tradeoffs involving process and infrastructure flexibility, firm uncertainty and buffer effects of inventory, lead time and capacity.

Published
1993

163. Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Author

Heathfield, Sarah, Parker, Ben, Zeef, Leo, Bruce, Ian, Alexander, Yvonne, Collins, Fraser, Stone, Michael, Wang, Edward, Williams, Anwen S., Wright, Helen L., Thomas, Huw B., Moots, Robert J., Edwards, Steven W., Bullock, Craig, Chapman, Victoria, Walsh, David A., Mobasheri, Ali, Kendall, David, Kelly, Sara, Bayley, Rachel, Buckley, Chris D., Young, Stephen P., Rump-Goodrich, Lisa, Middleton, Jim, Chen, Liye, Fisher, Roman, Kollnberger, Simon, Shastri, Nilabh, Kessler, Benedikt M., Bowness, Paul, Nazeer Moideen, Abdul, Evans, Laura, Osgood, Louise, Jones, Simon A., Nowell, Mari A., Mahadik, Younis, Young, Stephen, Morgan, Matthew, Gordon, Caroline, Harper, Lorraine, Giles, Joanna L., Paul Morgan, B., Harris, Claire L., Rysnik, Oliwia J., McHugh, Kirsty, Payeli, Sravan, Marroquin, Osiris, Shaw, Jacqueline, Renner, Christoph, Nayar, Saba, Cloake, Tom, Bombardieri, Michele, Pitzalis, Costantino, Buckley, Chris, Barone, Francesca, Lane, Peter, Coles, Mark, Williams, Emma L., Edwards, Christopher J., Cooper, Cyrus, Oreffo, Richard O., Dunn, Sara, Crawford, Aileen, Wilkinson, Mark, Le Maitre, Christine, Bunning, Rowena, Daniels, Jodie, Phillips, Kate L. E., Chiverton, Neil, Le Maitre, Christine L., Shaw, Jackie, Ridley, Anna, Wong-Baeza, Isabel, Keidel, Sarah, Chan, Antoni, Gullick, Nicola J., Abozaid, Hanan S., Jayaraj, David M., Evans, Hayley G., Scott, David L., Choy, Ernest H., Taams, Leonie S., Hickling, M., Golor, G., Jullion, A., Shaw, S., Kretsos, K., Bari, Syed F., Rhys-Dillon, Brian, Amos, Nicholson, Siebert, Stefan, Bunning, Rowena D., Haddock, Gail, Cross, Alison K., Kate, I., Phillips, E., Cross, Alison, Bunning, Rowena A. D., Ceeraz, Sabrina, Spencer, Jo, Choy, Ernest, Corrigall, Valerie, Crilly, Anne, Palmer, Helen, Lockhart, John, Plevin, Robin, Ferrell, William R., McInnes, Iain, Hutchinson, David, Perry, Liz, DiCicco, Maria, Humby, Frances, Kelly, Stephen, Hands, Rebecca, McInnes, Ian, Taylor, Peter, Mehta, Puja, Mitchell, Adam, Tysoe, Carolyn, Caswell, Richard, Owens, Martina, Vincent, Tonia, Hashmi, Tahir M., Price-Forbes, Alec, Sharp, Charlotte A., Murphy, Helen, Wood, Elizabeth F., Doherty, Teresa, Sheldon, Jo, Sofat, Nidhi, Goff, Iain, Platt, Philip N., Abdulkader, Rita, Clunie, Gavin, Ismajli, Mediola, Nikiphorou, Elena, Young, Adam, Tugnet, Nicola, Dixey, Josh, Banik, Snehashish, Alcorn, Desmond, Hunter, John, Win Maw, Win, Patil, Pravin, Hayes, Fiona, Main Wong, Way, Borg, Frances A., Dasgupta, Bhaskar, Malaviya, Anshuman P., Ostor, Andrew J., Chana, Jasroop K., Ahmed, Azeem A., Edmonds, Sally, Coward, Lucy, Borg, Frances, Heaney, Jonathan, Amft, Nicole, Simpson, John, Dhillon, Veena, Ayalew, Yezenash, Khattak, Fazlihakim, Gayed, Mary, Amarasena, Roshan I., McKenna, Frank, Mc Laughlin, Maeve, Baburaj, Krishnan, Fattah, Zozik, Ng, Nora, Wilson, Jo, Colaco, Bernard, Williams, Mark R., Adizie, Tochukwu, Casey, Matthew, Lip, Stefanie, Tan, Shaun, Anderson, David, Robertson, Calum, Devanny, Ian, Field, Max, Walker, David, Robinson, Sandra, Ryan, Sarah, Hassell, Andrew, Bateman, James, Allen, Maggie, Davies, David, Crouch, Carina, Walker-Bone, Karen, Gainsborough, Nicola, Lutalo, Pamela M., Davies, Ursula M., Mckew, Jennifer R., Millar, Auleen M., Wright, Stephen A., Bell, Aubrey L., Thapper, Muryum, Roussou, Thalia, Cumming, Jo, Hull, Richard G., McKeogh, John, O'Connor, Mortimer B., Hassan, Ahmed I., Bond, Ursula, Swan, Joan, Phelan, Mark J., Coady, David, Kumar, Namita, Farrow, Luke, Bukhari, Marwan, Oldroyd, Alexander G., Greenbank, Cathi, McBeth, John, Duncan, Rosie, Brown, Deborah, Horan, Michael, Pendleton, Neil, Littlewood, Alison, Cordingley, Lis, Mulvey, Matthew, Curtis, Elizabeth M., Cole, Zoe A., Crozier, Sarah R., Georgia, Ntani, Robinson, Siân M., Godfrey, Keith M., Sayer, Avan A., Inskip, Hazel M., Harvey, Nicholas C., Davies, Rebecca, Mercer, Louise, Galloway, James, Low, Audrey, Watson, Kath, Lunt, Mark, Symmons, Deborah, Hyrich, Kimme, Chitale, Sarang, Estrach, Cristina, Goodson, Nicola J., Rankin, Elizabeth, Jiang, C. Q., Cheng, K. K., Lam, T. H., Adab, Peymané, Ling, Stephanie, Humphreys, Jennifer, Ellis, Corrinne, Bunn, Diane, Verstappen, Suzanne M., Fluess, Elisa, Macfarlane, Gary J., Bond, Christine, Jones, Gareth T., Scott, Ian C., Steer, Sophia, Lewis, Cathryn M., Cope, Andrew, Mulvey, Matthew R., Lovell, Karina, Keeley, Philip, Woby, Steve, Beasley, Marcus, Viatte, Sebastien, Plant, Darren, Fu, Bo, Solymossy, Csilla, Worthington, Jane, Barton, Anne, Williams, Frances M., Osei-Bordom, Daniel-Clement, Popham, Maria, MacGregor, Alex, Spector, Tim, Little, Jayne, Herrick, Ariane, Pushpakom, S., Ennis, H., McBurney, H., Worthington, J., Newman, W., Ibrahim, Ibrahim, Morgan, Anne, Wilson, Anthony, Isaacs, John, Sanderson, Tessa, Hewlett, Sarah, Calnan, Michael, Morris, Marianne, Raza, Karim, Kumar, Kanta, Cardy, Caroline M., Pauling, John D., Jenkins, Jessica, Brown, Sue J., McHugh, Neil, Mugford, Miranda, Davies, Charlotte, Cooper, Nicola, Brooksby, Alan, Dures, Emma, Ambler, Nick, Fletcher, Debbie, Pope, Denise, Robinson, Frances, Rooke, Royston, Gorman, Claire L., Reynolds, Piero, Hakim, Alan J., Bosworth, Ailsa, Weaver, Dan, Kiely, Patrick D., Skeoch, Sarah, Jani, Meghna, Amarasena, Roshan, Rao, Chandini, Macphie, Elizabeth, McLoughlin, Yokemei, Shah, Preeti, Else, Sara, Semenova, Olga, Thompson, Helen, Ogunbambi, Olabambo, Kallankara, Sathish, Patel, Yusuf, Baguley, Elaine, Halsey, John, Severn, Andrew, Selvan, Shilpa, Price, Elizabeth, Husain, Muhammad J., Brophy, Sinead, Phillips, Ceri J., Cooksey, Roxanne, Irvine, Elizabeth, Lendrem, Dennis, Mitchell, Sheryl, Bowman, Simon, Pease, Colin T., Emery, Paul, Andrews, Jacqueline, Sutcliffe, Nurhan, Lanyon, Peter, Gupta, Monica, McLaren, John, Regan, Marian, Cooper, Annie, Giles, Ian, Isenberg, David, Griffiths, Bridget, Foggo, Heather, Edgar, Suzanne, Vadivelu, Saravanan, Ng, Wan-Fai, Iqbal, Itrat, Heron, Louise, Pilling, Claire, Marks, Jonathan, Hull, Richard, Ledingham, Jo, Han, Chenglong, Gathany, Tim, Tandon, Neeta, Hsia, Elizabeth, Taylor, P., Strand, V., Sensky, T., Harta, N., Fleming, S., Kay, Lesley, Rutherford, Michelle, Nicholl, Karl, Eyre, Tracey, Wilson, Gillian, Johnson, Phil, Russell, M., Timoshanko, J., Duncan, G., Spandley, A., Roskell, S., West, Louise, Adshead, Rebecca, Donnelly, Simon P., Ashton, Simon, Tahir, Hasan, Patel, Dipti, Darroch, James, Boulton, John, Ellis, Benjamin, Finlay, Ron, Murray-Brown, William, Priori, R., Tappuni, T., Vartoukian, S., Seoudi, N., Picarelli, G., Fortune, F., Valesini, G., Pitzalis, C., Bombardieri, M., Ball, Elisabeth, Rooney, Madeleine, Bell, Aubrey, Mérida, Angeles Acosta, Tarelli, Edward, Axford, John, Pericleous, Charis, Pierangeli, Silvia S., Ioannou, John, Rahman, Anisur, Alavi, Azita, Hughes, Michael, Evans, Bronwen, Zaki, Awal, Hui, Michelle, Garner, Rozeena, Rees, Frances, Bavakunji, Riaz, Daniel, Priya, Varughese, Sneha, Srikanth, Asha, Andres, Mariano, Pearce, Fiona, Leung, Jansen, Lim, Ken, Oomatia, Amin, Petri, Michelle, Fang, Hong, Birnbaum, Julius, Amissah-Arthur, Maame, Stewart, Kirsty, Jennens, Hannah, Braude, Simon, Sutton, Emily J., Watson, Kath D., Yee, Chee-Seng, Jayne, David, Akil, Mohammed, Ahmad, Yasmeen, D'Cruz, David, Khamashta, Munther, Teh, Lee-Suan, Zoma, Asad, Dey, Ida D., Kenu, Ernest, Garza-Garcia, Acely, Murfitt, Lucy, Driscoll, Paul C., Pierangeli, Silvia, Ioannou, Yiannis, Reynolds, John A., Ray, David W., O'Neill, Terence, Segeda, Iuliia, Shevchuk, Sergii, Kuvikova, Inna, Brown, Nina, Venning, Michael, Dhanjal, Mandish, Mason, Justin, Nelson-Piercy, Catherine, Basu, Neil, Paudyal, Priya, Stockton, Marie, Lawton, Sally, Dent, Caroline, Kindness, Kathy, Meldrum, Gillian, John, Elizabeth, Arthur, Catherine, West, Lucy, Macfarlane, Matthew V., Reid, David M., Yates, Max, Loke, Yoon, Watts, Richard, Christidis, Dimitrios, Williams, Mark, Sivakumar, Rajappa, Misra, Ramnath, Danda, Debashish, Mahendranath, K. M., Bacon, Paul A., and Mackie, Sarah L.

Abstract

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q < 0.00005). This was supported by qPCR analysis at 6 hrs (E-selectin and VCAM-1; 208.5 fold and 40.5, respectively above control) and also at 1, 3 and 24 hrs (E-selectin; 25.6, 93.5, 12.7 fold, respectively) (VCAM-1; 4.7, 47.2, 17.6 fold) (n = 3; p < 0.05). In contrast, HAoECs treated with TNF in combination with CZP exhibited control levels of E-selectin and VCAM-1 transcript (p > 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interest

Published
2017

164. Extending cost-volume breakeven analysis to include flexibility

Author

Hanna, Mark D., Newman, W. Rocky, and Sridharan, Sri V.

Subjects
Break-even analysis -- Models, Flexible manufacturing systems -- Economic aspects, Business, Business, regional
Abstract

Manufacturers who seek to enhance customer service through increased manufacturing flexibility often utilize cost-volume breakeven analysis to justify their capital investment decisions. Changing market demands place new emphasis on flexibility and customer responsiveness. An equally simple justification formula based on economic rationality that also measures flexibility as a component in breakeven analysis is presented and explained.

Published
1992

165. Magellan observations of extended impact crater related features on the surface of Venus

Author

Campbell, D. B, Stacy, N. J. S, Newman, W. I, Arvidson, R. E, Jones, E. M, Musser, G. S, Roper, A. Y, and Schaller, C

Subjects
Lunar And Planetary Exploration
Abstract

The hydrodynamic evolution of an incompressible plane mixing layer is addressed to elucidate scalar mixing in free shear flows. A detailed description of the onset of three-dimensionality in a mixing layer before or in the absence of pairing is presented. Various simulations were performed to investigate the sensitivity of these results to variations in initial conditions. These variations included changes in amplitude, wavelength, functional form, and relative phasing of the initial low-wavenumber disturbances. Pierrehumber & Widnall's (1982) translative instability eigenfunctions are found to include rib vortices in the braid region and oppositely signed streamwise vorticity in the roller core. The translative instability is an instability of the late-time oversaturated flow. Three-dimensional perturbation growth similar to that of the translative instability can occur whenever spanwise vorticity is present in the braid region. The nonlinear effects that occur when the initial rib circulation is sufficiently high are discussed.

Published
1992

166. A model for the formation of the extended paraboloidal halos around some impact craters on Venus

Author

Newman, W. I, Jones, E. M, Campbell, D. B, and Stacy, N. J. S

Subjects
Lunar And Planetary Exploration
Abstract

Many parabolic-shaped extended impact crater-related features have been found in Magellan synthetic aperture radar and emissivity data covering much of the surface of Venus. They are oriented east-west with the apex to the east and the impact crater located just west of the apex. A model for the formation of the parabolic features is developed based on the injection of small particles into the upper atmosphere at the time of impact, and their subsequent transport to the west by the east-west zonal winds. Fallout times from 50 km in the Venus atmosphere for particles of this size are about two hours, allowing westerly drifts of several hundred kilometers for zonal winds of 50 to 100 m s(exp -1).

Published
1992

170. Cascade model for fluvial geomorphology

Author

Newman, W. I and Turcotte, D. L

Subjects
Earth Resources And Remote Sensing
Abstract

Erosional landscapes are generally scale invariant and fractal. Spectral studies provide quantitative confirmation of this statement. Linear theories of erosion will not generate scale-invariant topography. In order to explain the fractal behavior of landscapes a modified Fourier series has been introduced that is the basis for a renormalization approach. A nonlinear dynamical model has been introduced for the decay of the modified Fourier series coefficients that yield a fractal spectra. It is argued that a physical basis for this approach is that a fractal (or nearly fractal) distribution of storms (floods) continually renews erosional features on all scales.

Published
1990

171. A computer search for stable orbits between Jupiter and Saturn

Author

Weibel, W. M, Kaula, W. M, and Newman, W. I

Subjects
Lunar And Planetary Exploration
Abstract

The present experiment with test particles placed in orbits at uniform intervals between 5.7 and 8.8 AU, with randomly distributed eccentricities between 0.0 and 0.02 and inclinations between 0.0 and 0.063 rad, leads to the perception that no stable niches exist in the Jupiter-Saturn zone other than the Lagrangian points of Jupiter. These points are populated by at least 26 Trojan asteroids. The primary implication of these results for future investigations of the Saturn-Uranus-Neptune zone is that experimental design should be as selective as the dynamics of the planetary system have been shown to be.

Published
1990
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175. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Author

Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J.M., Winkler, J., Yilmaz, O., Pleschka, M., Cao, J., Kockum, C.C., Barker, G., Holmdahl, G., Beaman, G., Keene, D., Woolf, A.S., Cervellione, R.M., Cheng, W., Wilkins, S., Gearhart, J.P., Sirchia, F., Grazia, M. Di, Ebert, A.K., Rosch, W., Ellinger, J., Jenetzky, E., Zwink, N., Feitz, W.F.J., Marcelis, C.L., Schumacher, J., Martinon-Torres, F., Hibberd, M.L., Khor, C.C., Heilmann-Heimbach, S., Barth, S., Boyadjiev, S.A., Brusco, A., Ludwig, M., Newman, W., Nordenskjold, A., Yamada, G., Odermatt, B., Reutter, H., Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J.M., Winkler, J., Yilmaz, O., Pleschka, M., Cao, J., Kockum, C.C., Barker, G., Holmdahl, G., Beaman, G., Keene, D., Woolf, A.S., Cervellione, R.M., Cheng, W., Wilkins, S., Gearhart, J.P., Sirchia, F., Grazia, M. Di, Ebert, A.K., Rosch, W., Ellinger, J., Jenetzky, E., Zwink, N., Feitz, W.F.J., Marcelis, C.L., Schumacher, J., Martinon-Torres, F., Hibberd, M.L., Khor, C.C., Heilmann-Heimbach, S., Barth, S., Boyadjiev, S.A., Brusco, A., Ludwig, M., Newman, W., Nordenskjold, A., Yamada, G., Odermatt, B., and Reutter, H.

Abstract

Contains fulltext : 173200.pdf (publisher's version ) (Open Access), Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 x 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 x 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Published
2017

176. A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Author

Palmer, EE, Kumar, R, Gordon, CT, Shaw, M, Hubert, L, Carroll, R, Rio, M, Murray, L, Leffler, M, Dudding-Byth, T, Oufadem, M, Lalani, SR, Lewis, AM, Xia, F, Tam, A, Webster, R, Brammah, S, Filippini, F, Pollard, J, Spies, J, Minoche, AE, Cowley, MJ, Risen, S, Powell-Hamilton, NN, Tusi, JE, Immken, LD, Nagakura, H, Bole-Feysot, C, Nitschké, P, Garrigue, A, de Saint Basile, G, Kivuva, E, Scott, RH, Rendon, A, Munnich, A, Newman, W, Kerr, B, Besmond, C, Rosenfeld, JA, Amiel, J, Field, M, Gecz, J, Palmer, EE, Kumar, R, Gordon, CT, Shaw, M, Hubert, L, Carroll, R, Rio, M, Murray, L, Leffler, M, Dudding-Byth, T, Oufadem, M, Lalani, SR, Lewis, AM, Xia, F, Tam, A, Webster, R, Brammah, S, Filippini, F, Pollard, J, Spies, J, Minoche, AE, Cowley, MJ, Risen, S, Powell-Hamilton, NN, Tusi, JE, Immken, LD, Nagakura, H, Bole-Feysot, C, Nitschké, P, Garrigue, A, de Saint Basile, G, Kivuva, E, Scott, RH, Rendon, A, Munnich, A, Newman, W, Kerr, B, Besmond, C, Rosenfeld, JA, Amiel, J, Field, M, and Gecz, J

Abstract

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Published
2017

182. Measurement of Human Atherosclerosis

Author

Newman, W. P., III, Malcom, G. T., McMahan, L. H., Tracy, R. E., Schettler, F. Gotthard, editor, Gotto, Antonio M., Jr., editor, Middelhoff, Gert, editor, Habenicht, Andreas J. R., editor, and Jurutka, Klara R., editor

Published
1983
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190. Proposed Medical Benefit Society

Author

MacCarthy, Ffennell, Lke, Francis Boynton, Walter, William, Henry, Geo. Fraser, Stephens, William J., and Newman, W.

Published
1883

197. Lumbago

Author

Newman, W.

Published
1859

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