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2. An architecture to facilitate the integration of human workers in Industry 4.0 environments.

Author

Sparrow, D. E., Kruger, K., and Basson, A. H.

Subjects
INDUSTRY 4.0, MANUFACTURING processes, HUMAN beings, CYBER physical systems
Abstract

While Industry 4.0 research has predominantly focussed on the connection of machines and digital systems and solutions, it is important to consider the role of human workers within the envisaged Industry 4.0 environments. This paper presents the concept of a digital administration shell to support the integration of humans in Industry 4.0 environments and an architecture for the development of such an administration shell. The Biography-Attributes-Schedule-Execution (BASE) architecture builds on holonic systems principles and is guided by the requirements and responsibilities of the Resource Holon, as developed in the Holonic Manufacturing Systems paradigm. The functionality and value of the BASE architecture administration shell is demonstrated by means of a case study implementation. [ABSTRACT FROM AUTHOR]

Published
2022
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6. Crucial functions of alpha-actinin 2 in the embryonic heart

Author

Gehmlich, K, primary, Jiang, A, additional, Wadmore, K, additional, Hooper, C, additional, Douglas, G, additional, Ehler, E, additional, Broadway-Stringer, S, additional, Kalisch-Smith, J, additional, Sparrow, D, additional, Gautel, M, additional, Davies, B, additional, and Watkins, H, additional

Published
2022
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7. Using expert-elicitation to deliver biodiversity monitoring priorities on a Mediterranean island

Author

Peyton, J, Hadjistylli, M., Tziortzis, I., Erotokritou, E., Demetriou M., Samuel, Y., Anastasi, V., Fyttis, G., Hadjioannou, L., Kassinis, N., Kleitou, P., Kletou, D., Mandoulaki, A., Michailidis, N., Papatheodoulou, A., Payiattas, G., Sparrow, D., Sparrow, R., Turvey, K., Tzirkalli, E., Varnava, A.I., and Pescott, O.L.

Abstract

Biodiversity monitoring plays an essential role in tracking changes in ecosystems, species distributions and abundances across the globe. Data collected through both structured and unstructured biodiversity recording can inform conservation measures designed to reduce, prevent, and reverse declines in valued biodiversity of many types. However, given that resources for biodiversity monitoring are limited, it is important that funding bodies prioritise investments relative to the requirements in any given region. We addressed this prioritisation requirement for a biodiverse Mediterranean island (Cyprus) using a three-stage process of expert-elicitation. This resulted in a structured list of twenty biodiversity monitoring needs; specifically, a hierarchy of three groups of these needs was created using a consensus approach. The most highly prioritised biodiversity monitoring needs were those related to the development of robust survey methodologies, and those ensuring that sufficiently skilled citizens are available to contribute. We discuss ways that the results of our expert-elicitation process could be used to support current and future biodiversity monitoring in Cyprus.

Published
2022

8. Using expert-elicitation to deliver biodiversity monitoring priorities on a Mediterranean island

Author

Peyton, J., Hadjistylli, M., Tziortzis, I., Erotokritou, E., Demetriou, M., Samuel, Y., Anastasi, V., Fyttis, G., Hadjioannou, L., Ieronymidou, C., Kassinis, N., Kleitou, P., Kletou, D., Mandoulaki, A., Michailidis, N., Papatheodoulou, A., Payiattas, G., Sparrow, D., Sparrow, R., Turvey, K., Tzirkalli, E., Varnava, A.I., Pescott, O.L., Peyton, J., Hadjistylli, M., Tziortzis, I., Erotokritou, E., Demetriou, M., Samuel, Y., Anastasi, V., Fyttis, G., Hadjioannou, L., Ieronymidou, C., Kassinis, N., Kleitou, P., Kletou, D., Mandoulaki, A., Michailidis, N., Papatheodoulou, A., Payiattas, G., Sparrow, D., Sparrow, R., Turvey, K., Tzirkalli, E., Varnava, A.I., and Pescott, O.L.

Abstract

Biodiversity monitoring plays an essential role in tracking changes in ecosystems, species distributions and abundances across the globe. Data collected through both structured and unstructured biodiversity recording can inform conservation measures designed to reduce, prevent, and reverse declines in valued biodiversity of many types. However, given that resources for biodiversity monitoring are limited, it is important that funding bodies prioritise investments relative to the requirements in any given region. We addressed this prioritisation requirement for a biodiverse Mediterranean island (Cyprus) using a three-stage process of expert-elicitation. This resulted in a structured list of twenty biodiversity monitoring needs; specifically, a hierarchy of three groups of these needs was created using a consensus approach. The most highly prioritised biodiversity monitoring needs were those related to the development of robust survey methodologies, and those ensuring that sufficiently skilled citizens are available to contribute. We discuss ways that the results of our expert-elicitation process could be used to support current and future biodiversity monitoring in Cyprus.

Published
2022

9. Using expert-elicitation to deliver biodiversity monitoring priorities on a Mediterranean island

Author

Peyton, J., primary, Hadjistylli, M., additional, Tziortzis, I., additional, Erotokritou, E., additional, Demetriou, M., additional, Samuel, Y., additional, Anastasi, V., additional, Fyttis, G., additional, Hadjioannou, L., additional, Ieronymidou, C., additional, Kassinis, N., additional, Kleitou, P., additional, Kletou, D., additional, Mandoulaki, A., additional, Michailidis, N., additional, Papatheodoulou, A., additional, Payiattas, G., additional, Sparrow, D., additional, Sparrow, R., additional, Turvey, K., additional, Tzirkalli, E., additional, Varnava, A. I., additional, and Pescott, O. L., additional

Published
2022
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13. Using expert-elicitation to deliver biodiversity monitoring priorities on a Mediterranean island

Author

Peyton, J., Hadjistylli, M., Tziortzis, I., Erotokritou, E., Demetriou, M., Samuel, Y., Anastasi, V., Fyttis, G., Hadjioannou, L., Ieronymidou, C., Kassinis, N., Kleitou, P., Kletou, D., Mandoulaki, A., Michailidis, N., Papatheodoulou, A., Payiattas, G., Sparrow, D., Sparrow, R., Turvey, K., Tzirkalli, E., Varnava, A. I., and Pescott, O. L.

Subjects
Conservation of Natural Resources, Mediterranean Islands, Multidisciplinary, Biodiversity, Investments, Ecology and Environment, Ecosystem
Abstract

Biodiversity monitoring plays an essential role in tracking changes in ecosystems, species distributions and abundances across the globe. Data collected through both structured and unstructured biodiversity recording can inform conservation measures designed to reduce, prevent, and reverse declines in valued biodiversity of many types. However, given that resources for biodiversity monitoring are limited, it is important that funding bodies prioritise investments relative to the requirements in any given region. We addressed this prioritisation requirement for a biodiverse Mediterranean island (Cyprus) using a three-stage process of expert-elicitation. This resulted in a structured list of twenty biodiversity monitoring needs; specifically, a hierarchy of three groups of these needs was created using a consensus approach. The most highly prioritised biodiversity monitoring needs were those related to the development of robust survey methodologies, and those ensuring that sufficiently skilled citizens are available to contribute. We discuss ways that the results of our expert-elicitation process could be used to support current and future biodiversity monitoring in Cyprus.

Published
2021

15. Using expert-elicitation to deliver biodiversity monitoring priorities on a Mediterranean island

Author

Peyton, J., primary, Hadjistylli, M., additional, Tziortzis, I., additional, Erotokritou, E., additional, Demetriou, M., additional, Samuel-Rhoads, Y., additional, Anastasi, V., additional, Fyttis, G., additional, Hadjioannou, L., additional, Ieronymidou, C., additional, Kassinis, N., additional, Kleitou, P., additional, Kletou, D., additional, Mandoulaki, A., additional, Michailidis, N., additional, Papatheodoulou, A., additional, Payiattas, G., additional, Sparrow, D., additional, Sparrow, R., additional, Turvey, K., additional, Tzirkalli, E., additional, Varnava, A.I., additional, and Pescott, O.L., additional

Published
2021
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17. The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition

Author

Azzoni, E, Frontera, V, Anselmi, G, Rode, C, James, C, Deltcheva, E, Demian, A, Brown, J, Barone, C, Patelli, A, Harman, J, Nicholls, M, Conway, S, Morrissey, E, Jacobsen, S, Sparrow, D, Harris, A, Enver, T, de Bruijn, M, Azzoni, Emanuele, Frontera, Vincent, Anselmi, Giorgio, Rode, Christina, James, Chela, Deltcheva, Elitza M, Demian, Atanasiu S, Brown, John, Barone, Cristiana, Patelli, Arianna, Harman, Joe R, Nicholls, Matthew, Conway, Simon J, Morrissey, Edward, Jacobsen, Sten Eirik W, Sparrow, Duncan B, Harris, Adrian L, Enver, Tariq, de Bruijn, Marella F T R, Azzoni, E, Frontera, V, Anselmi, G, Rode, C, James, C, Deltcheva, E, Demian, A, Brown, J, Barone, C, Patelli, A, Harman, J, Nicholls, M, Conway, S, Morrissey, E, Jacobsen, S, Sparrow, D, Harris, A, Enver, T, de Bruijn, M, Azzoni, Emanuele, Frontera, Vincent, Anselmi, Giorgio, Rode, Christina, James, Chela, Deltcheva, Elitza M, Demian, Atanasiu S, Brown, John, Barone, Cristiana, Patelli, Arianna, Harman, Joe R, Nicholls, Matthew, Conway, Simon J, Morrissey, Edward, Jacobsen, Sten Eirik W, Sparrow, Duncan B, Harris, Adrian L, Enver, Tariq, and de Bruijn, Marella F T R

Abstract

Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1−/− mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1−/− cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.

Published
2021

21. Tamoxifen administration in pregnant mice can be deleterious to both mother and embryo

Author

Ved, N, Curran, A, Ashcroft, FM, and Sparrow, D

Subjects
Selective Estrogen Receptor Modulators, experimental design, ethics and welfare, Case Reports, laboratory animal welfare, Embryo, Mammalian, organisms and models, 3Rs, Mice, Tamoxifen, Pregnancy, rodents, Animals, genetics, Female, techniques
Abstract

Since it was introduced 20 years ago, tamoxifen-inducible genetic recombination in vivo has become a standard tool in many fields. This technique has great utility, allowing precise temporal and spatial gene recombination mediated by expression of a Cre recombinase-oestrogen receptor hormone binding domain fusion protein. It is frequently used in developmental biology, either for accurate spatio-temporal gene deletion or for lineage-labelling. Administration of high doses of tamoxifen can rapidly induce abortion in pregnant mice but this can be partially overcome by progesterone co-administration. However, administration of tamoxifen to pregnant mice early in pregnancy may have potentially lethal effects on the mother independently of abortion, and can also severely perturb embryonic development. Despite this, only a few published studies mention this fact in passing, and standard parameters for successful or unsuccessful use of tamoxifen in pregnant mice have not been reported. Therefore, in the interests of providing a framework for more humane animal research, we describe our experiences of tamoxifen administration during early gestation in mice. These observations should assist the design of future studies in accordance with the principles of the three Rs (Replacement, Reduction and Refinement of Animals in Research).

Published
2019

24. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author

Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), Wain, L. V. (Louise, V), Shrine, N. (Nick), Guyatt, A. L. (Anna L.), Erzurumluoglu, A. M. (A. Mesut), Jackson, V. E. (Victoria E.), Hobbs, B. D. (Brian D.), Melbourne, C. A. (Carl A.), Batini, C. (Chiara), Fawcett, K. A. (Katherine A.), Song, K. (Kijoung), Sakornsakolpat, P. (Phuwanat), Li, X. (Xingnan), Boxall, R. (Ruth), Reeve, N. F. (Nicola F.), Obeidat, M. (Ma'en), Zhao, J. H. (Jing Hua), Wielscher, M. (Matthias), Weiss, S. (Stefan), Kentistou, K. A. (Katherine A.), Cook, J. P. (James P.), Sun, B. B. (Benjamin B.), Zhou, J. (Jian), Hui, J. (Jennie), Karrasch, S. (Stefan), Imboden, M. (Medea), Harris, S. E. (Sarah E.), Marten, J. (Jonathan), Enroth, S. (Stefan), Kerr, S. M. (Shona M.), Surakka, I. (Ida), Vitart, V. (Veronique), Lehtimäki, T. (Terho), Allen, R. J. (Richard J.), Bakke, P. S. (Per S.), Beaty, T. H. (Terri H.), Bleecker, E. R. (Eugene R.), Bosse, Y. (Yohan), Brandsma, C.-A. (Corry-Anke), Chen, Z. (Zhengming), Crapo, J. D. (James D.), Danesh, J. (John), DeMeo, D. L. (Dawn L.), Dudbridge, F. (Frank), Ewert, R. (Ralf), Gieger, C. (Christian), Gulsvik, A. (Amund), Hansell, A. L. (Anna L.), Hao, K. (Ke), Hoffman, J. D. (Joshua D.), Hokanson, J. E. (John E.), Homuth, G. (Georg), Joshi, P. K. (Peter K.), Joubert, P. (Philippe), Langenberg, C. (Claudia), Li, X. (Xuan), Li, L. (Liming), Lin, K. (Kuang), Lind, L. (Lars), Locantore, N. (Nicholas), Luan, J. (Jian'an), Mahajan, A. (Anubha), Maranville, J. C. (Joseph C.), Murray, A. (Alison), Nickle, D. C. (David C.), Packer, R. (Richard), Parker, M. M. (Margaret M.), Paynton, M. L. (Megan L.), Porteous, D. J. (David J.), Prokopenko, D. (Dmitry), Qiao, D. (Dandi), Rawal, R. (Rajesh), Runz, H. (Heiko), Sayers, I. (Ian), Sin, D. D. (Don D.), Smith, B. H. (Blair H.), Artigas, M. S. (Maria Soler), Sparrow, D. (David), Tal-Singer, R. (Ruth), Timmers, P. R. (Paul R. H. J.), Van den Berge, M. (Maarten), Whittaker, J. C. (John C.), Woodruff, P. G. (Prescott G.), Verges-Armstrong, L. M. (Laura M.), Troyanskaya, O. G. (Olga G.), Raitakari, O. T. (Olli T.), Kähönen, M. (Mika), Polasek, O. (Ozren), Gyllensten, U. (Ulf), Rudan, I. (Igor), Deary, I. J. (Ian J.), Probst-Hensch, N. M. (Nicole M.), Schulz, H. (Holger), James, A. L. (Alan L.), Wilson, J. F. (James F.), Stubbe, B. (Beate), Zeggini, E. (Eleftheria), Järvelin, M.-R. (Marjo-Riitta), Wareham, N. (Nick), Silverman, E. K. (Edwin K.), Hayward, C. (Caroline), Morris, A. P. (Andrew P.), Butterworth, A. S. (Adam S.), Scott, R. A. (Robert A.), Walters, R. G. (Robin G.), Meyers, D. A. (Deborah A.), Cho, M. H. (Michael H.), Strachan, D. P. (David P.), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), and Wain, L. V. (Louise, V)

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Published
2019

35. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, BD, de Jong, K, Lamontagne, M, Bossé, Y, Shrine, N, Artigas, MS, Wain, LV, Hall, IP, Jackson, VE, Wyss, AB, London, SJ, North, KE, Franceschini, N, Strachan, DP, Beaty, TH, Hokanson, JE, Crapo, JD, Castaldi, PJ, Chase, RP, Bartz, TM, Heckbert, SR, Psaty, BM, Gharib, SA, Zanen, P, Lammers, JW, Oudkerk, M, Groen, HJ, Locantore, N, Tal-Singer, R, Rennard, SI, Vestbo, J, Timens, W, Paré, PD, Latourelle, JC, Dupuis, J, O'Connor, GT, Wilk, JB, Kim, WJ, Lee, MK, Oh, Y-M, Vonk, JM, de Koning, HJ, Leng, S, Belinsky, SA, Tesfaigzi, Y, Manichaikul, A, Wang, X-Q, Rich, SS, Barr, RG, Sparrow, D, Litonjua, AA, Bakke, P, Gulsvik, A, Lahousse, L, Brusselle, GG, Stricker, BH, Uitterlinden, AG, Ampleford, EJ, Bleecker, ER, Woodruff, PG, Meyers, DA, Qiao, D, Lomas, DA, Yim, J-J, Kim, DK, Hawrylkiewicz, I, Sliwinski, P, Hardin, M, Fingerlin, TE, Schwartz, DA, Postma, DS, MacNee, W, Tobin, MD, Silverman, EK, Boezen, HM, Cho, MH, COPDGene Investigators, ECLIPSE Investigators, LifeLines Investigators, SPIROMICS Research Group, International COPD Genetics Network Investigators, UK BiLEVE Investigators, and International COPD Genetics Consortium

Subjects
respiratory tract diseases
Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017

36. Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

Author

Farahi, N, Paige, E, Balla, J, Prudence, E, Ferreira, RC, Southwood, M, Appleby, SL, Bakke, P, Gulsvik, A, Litonjua, AA, Sparrow, D, Silverman, EK, Cho, MH, Danesh, J, Paul, DS, Freitag, DF, Chilvers, ER, Danesh, John [0000-0003-1158-6791], Paul, Dirk [0000-0002-8230-0116], Chilvers, Edwin [0000-0002-4230-9677], and Apollo - University of Cambridge Repository

Subjects
SOLUBLE RECEPTOR, Male, Biochemistry & Molecular Biology, ADAM PROTEASES, in vitro study, AIRWAY INFLAMMATION, Neutrophils, monocyte chemoattractant protein-1, chronic obstructive airway disease, lung, DOUBLE-BLIND, Pulmonary Disease, Chronic Obstructive, respiration disorders, tocilizumab, pulmonary artery, Humans, PRO-INFLAMMATORY ACTIVITIES, genes, interleukin 6 receptor, METAANALYSIS, Genetic Association Studies, squamous intraepithelial lesion, Genetics & Heredity, Science & Technology, interleukin-6, neutrophil, 11 Medical And Health Sciences, 06 Biological Sciences, asthma, Receptors, Interleukin-6, endothelial cells, respiratory tract diseases, RHEUMATOID-ARTHRITIS, LUNG-FUNCTION, homozygote, INTERLEUKIN-6 RECEPTOR, alleles, pmel17, biobanks, Female, LEUKOCYTE RECRUITMENT, Life Sciences & Biomedicine, signal transduction, extrinsic asthma
Abstract

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.

Published
2017

37. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), Cho, M.H. (Michael), Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), and Cho, M.H. (Michael)

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017
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41. Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Author

Hansel, N.N., Pare, P.D., Rafaels, N., Sin, D.D., Sandford, A., Daley, D., Vergara, C., Huang, L.L., Elliott, W.M., Pascoe, C.D., Arsenault, B.A., Postma, D.S., Boezen, H.M., Bosse, Y., Berge, M. van den, Hiemstra, P.S., Cho, M.H., Litonjua, A.A., Sparrow, D., Ober, C., Wise, R.A., Connett, J., Neptune, E.R., Beaty, T.H., Ruczinski, I., Mathias, R.A., Barnes, K.C., Lung Hlth Study, Groningen Research Institute for Asthma and COPD (GRIAC), and Life Course Epidemiology (LCE)

Subjects
Risk, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Quantitative Trait Loci, Clinical Biochemistry, Genome-wide association study, Quantitative trait locus, LUNG HEALTH, VARIANTS, delta-sarcoglycan, EARLY INTERVENTION, eQTL, Polymorphism, Single Nucleotide, bronchial responsiveness, Pulmonary Disease, Chronic Obstructive, Sarcoglycans, airway reactivity, Genotype, medicine, Humans, COPD, Genetic Predisposition to Disease, CORONARY-HEART-DISEASE, 1000 Genomes Project, Molecular Biology, Original Research, Lung, Myosin Heavy Chains, business.industry, SMOOTH-MUSCLE, Cell Biology, SMOKING-CESSATION, medicine.disease, respiratory tract diseases, medicine.anatomical_structure, Expression quantitative trait loci, Immunology, BRONCHIAL HYPERRESPONSIVENESS, RISK-FACTORS, METHACHOLINE, business, Imputation (genetics), Genome-Wide Association Study
Abstract

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.

Published
2015

46. Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging

Author

Poon, AH, Houseman, EA, Ryan, L, Sparrow, D, Vokonas, PS, Litonjua, AA, Poon, AH, Houseman, EA, Ryan, L, Sparrow, D, Vokonas, PS, and Litonjua, AA

Abstract

Background. A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men. Methods. We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time. Results. One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time. Conclusions. Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes. © The Author 2013.

Published
2014

47. Step growth polymerization

Author

Jenkins, A. D., primary, Kennedy, J. F., additional, Ferguson, J., additional, Sparrow, D. J., additional, and Walton, I. G., additional

Published
1984
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48. Step growth polymerization

Author

Jenkins, A. D., primary, Kennedy, J. F., additional, Ferguson, J., additional, Sparrow, D. J., additional, and Walton, J. G., additional

Published
1982
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49. Structural patterns for soundness of business process models

Author

Dongen, van, B.F., Mendling, J., Aalst, van der, W.M.P., Hung, P., Li, Q., Sparrow, D., and Information Systems IE&IS

Subjects
Soundness, Correctness, Process modeling, Programming language, computer.internet_protocol, Computer science, Activity diagram, Deadlock, Petri net, Business process modeling, computer.software_genre, Business Process Execution Language, Data mining, computer
Abstract

The correctness of business process models is of paramount importance for the application on an enterprise level. A severe problem is that several languages for business process modelling do not have formal execution semantics which is a prerequisite to check correctness criteria. In this context, soundness defines a minimum correctness criterion that a process model should fulfill. In this paper we present a novel approach to reason about soundness based on so-called causal footprints. A causal footprint represents a set of conditions on the order of activities that holds for every case of a process model. We identify three kinds of error patterns that affect the soundness of a process model, namely the deadlock pattern, the multiple termination pattern, and the trap pattern. We use Eventdriven Process Chains (EPCs) and Petri nets to demonstrate the applicability of our approach for both conceptual as for formal process modelling languages. Furthermore, it can easily be applied to other languages, such as UML activity diagrams or BPEL. Based on the trap pattern, we prove that the .vicious circle., that is heavily discussed in EPC literature, is unsound.

Published
2006

50. Towards advanced interaction design concepts

Author

Dijkman, R.M., Dirgahayu, T., Quartel, D.A.C., Hung, P., Li, Q., Sparrow, D., and Information Systems IE&IS

Subjects
Computer science, Distributed computing, Message passing, Interaction design, Petri net, computer.software_genre, EWI-7031, Consistency (database systems), Common Object Request Broker Architecture, IR-57707, Callback, METIS-238688, METIS-238269, Polling, Web service, EWI-7962, IR-63455, computer
Abstract

In this paper we analyse the interaction mechanisms provided by Web Services technology and by CORBA. Specifically we analyse the request/response, callback, polling and (multicasr) message passing mechanisms. As a result we present Coloured Petri Nets that capture the behaviour of these mechanisms precisely. Based on our analysis we define concepts for representing the Web Services and CORBA interactions in a suitable and platform independent manner. These concepts can be used for platfonn independent design of distributed applications, while they (provably) maintain the consistency with platform specific implementations. Because their behaviour is defined by Petri Nets, the concepts also support simulation, validation and verification of designs. We also evaluate the suitability of Urn's concepts for representing the mechanisms and the degree of platform independence that these concepts can achieve.

Published
2006

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