57 results on '"David DC"'
Search Results
2. Conservation of caspase substrates across metazoans suggests hierarchical importance of signaling pathways over specific targets and cleavage site motifs in apoptosis
- Author
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Crawford, ED, Seaman, JE, Barber, AE, David, DC, Babbitt, PC, Burlingame, AL, and Wells, JA
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Biochemistry and Cell Biology ,Biological Sciences ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Animals ,Apoptosis ,Caenorhabditis elegans ,Caspases ,Cell Line ,Drosophila ,Humans ,Mass Spectrometry ,Mice ,Signal Transduction ,Substrate Specificity ,caspase ,apoptosis ,PTM ,proteomics ,evolution ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Caspases, cysteine proteases with aspartate specificity, are key players in programmed cell death across the metazoan lineage. Hundreds of apoptotic caspase substrates have been identified in human cells. Some have been extensively characterized, revealing key functional nodes for apoptosis signaling and important drug targets in cancer. But the functional significance of most cuts remains mysterious. We set out to better understand the importance of caspase cleavage specificity in apoptosis by asking which cleavage events are conserved across metazoan model species. Using N-terminal labeling followed by mass spectrometry, we identified 257 caspase cleavage sites in mouse, 130 in Drosophila, and 50 in Caenorhabditis elegans. The large majority of the caspase cut sites identified in mouse proteins were found conserved in human orthologs. However, while many of the same proteins targeted in the more distantly related species were cleaved in human orthologs, the exact sites were often different. Furthermore, similar functional pathways are targeted by caspases in all four species. Our data suggest a model for the evolution of apoptotic caspase specificity that highlights the hierarchical importance of functional pathways over specific proteins, and proteins over their specific cleavage site motifs.
- Published
- 2012
3. The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics
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David Dc Kaslow, Katherine L. O'Brien, Andrew C Steer, Jerome H. Kim, Fernando Gouvea-Reis, Jean-Louis Excler, Jonathan R. Carapetis, Pierre R. Smeesters, Chris A. Van Beneden, and Johan Vekemans
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0301 basic medicine ,Microbiology (medical) ,Biomedical Research ,Streptococcus pyogenes ,media_common.quotation_subject ,Global Health ,World Health Organization ,World health ,03 medical and health sciences ,Strategic goal ,0302 clinical medicine ,Cost of Illness ,Streptococcal Infections ,vaccine ,Global health ,Humans ,Medicine ,030212 general & internal medicine ,Antibiotic use ,Policy Making ,media_common ,business.industry ,group A Streptococcus ,Streptococcal Vaccines ,pharyngitis ,Sciences bio-médicales et agricoles ,rheumatic heart disease ,Product characteristics ,Vaccine efficacy ,3. Good health ,Viewpoints ,030104 developmental biology ,Infectious Diseases ,Risk analysis (engineering) ,Technology roadmap ,business ,Diversity (politics) - Abstract
Group A Streptococcus (GAS) infections result in a considerable underappreciated burden of acute and chronic disease globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important World Health Organization (WHO) activity, influencing prioritization of investments. Here, the role, status, and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision making, availability, and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitutes a key near-term strategic goal. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed., Group A Streptococcus causes a wide spectrum of acute and chronic human disease and considerable antibiotic use. Through a consensus-building consultation process, the World Health Organization developed a vision for vaccine development, highlighting strategic targets, product preferences, and priority research/development activities.
- Published
- 2019
4. Re-examining manufacturing strategy from knowledge advantages
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David Dc Tarn and Juefan Jf Wang
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Knowledge management ,Computer science ,business.industry ,Strategy and Management ,Knowledge economy ,05 social sciences ,Knowledge value chain ,General Decision Sciences ,Procedural knowledge ,Competitive advantage ,Empirical research ,Management of Technology and Innovation ,0502 economics and business ,Organizational learning ,Personal knowledge management ,050211 marketing ,business ,Empirical evidence ,050203 business & management - Abstract
Purpose During this current era of the knowledge economy, knowledge activities have greatly impacted manufacturing activities, with knowledge being treated as a critical factor that creates and sustains competitive advantages. Past studies tended to relate knowledge works with organizational tasks and assumed that knowledge workers implement those tasks to achieve organizational goals. Accordingly, the purpose of this paper is to employ the perspective of task domain as the basis to clarify the impact of manufacturing task domains on the manufacturing strategy, as well as the mediating effects of knowledge advantage on such an impact. Design/methodology/approach The authors follow Becerra-Fernandez and Sabherwal’s (2001) task which focus/task breadth dichotomy as the basis to define market-based task domains, employs Leonard-Barton’s (1995) T-shaped skill as the theoretical base to construct knowledge advantages, i.e., knowledge depth (I-shaped skill), diversity (hyphened skill), and convergence (T-shaped skill), and uses the conventional typology to measure the manufacturing strategy (i.e. cost, quality, flexibility, and delivery). The empirical study is conducted via a questionnaire survey and selects Taiwan’s top 600 manufacturers as the population and accordingly collects 131 effective observations. Findings The empirical evidence indicates that firms’ priorities on cost and delivery are positively caused by the focus orientation of the tasks, while their priorities on quality and flexibility are positively caused by both focus and diversity orientations of the tasks. The results also signify that knowledge advantages perform complete mediation on the previous relationships. In more detail, knowledge depth presents mediation on focus orientation, and knowledge convergence exhibits mediating effects both on focus and breadth orientations. The statistics point out that knowledge depth has the highest impact on the manufacturing strategy, but knowledge diversity fails to significantly explain the manufacturing strategy. Originality/value Literature assumed that knowledge activities are task-driven issue; this study hence examines knowledge advantage based on the task domain perspective to clarify the architecture and contents of knowledge advantages.
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- 2017
5. The path to group A Streptococcus vaccines: WHO research and development technology roadmap and preferred product characteristics
- Author
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Vekemans, Johan, Gouvea-Reis, Fernando, Kim, Jerome H, Excler, Jean-Louis, Smeesters, Pierre, O'Brien, Katherine L, Van Beneden, Chris C.A., Steer, Andrew C, Carapetis, Jonathan Rhys, and Kaslow, David DC
- Subjects
group A Streptococcus ,vaccine ,pharyngitis ,Sciences bio-médicales et agricoles ,rheumatic heart disease - Abstract
Group A Streptococcus (GAS) infections result in a considerable under-appreciated burden of acute and chronic disease, globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important WHO activity, influencing prioritization of investments. Here, the role, status and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision-making, availability and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitute key near-term strategic goals. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed., SCOPUS: re.j, info:eu-repo/semantics/published
- Published
- 2019
6. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
- Author
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Jansen, IE, Ye, H, Heetveld, S, Lechler, MC, Michels, H, Seinstra, RI, Lubbe, SJ, Drouet, V, Lesage, S, Majounie, E, Gibbs, JR, Nalls, MA, Ryten, M, Botia, JA, Vandrovcova, J, Simon-Sanchez, J, Castillo-Lizardo, M, Rizzu, P, Blauwendraat, C, Chouhan, AK, Li, Y, Yogi, P, Amin, N, van Duijn, CM, Morris, HR, Brice, A, Singleton, AB, David, DC, Nollen, EA, Jain, S, Shulman, JM, Heutink, P, Hernandez, DG, Arepalli, S, Brooks, J, Price, R, Nicolas, A, Chong, S, Cookson, MR, Dillman, A, Moore, M, Traynor, BJ, Plagnol, V, Nicholas, WW, Sheerin, UM, Jose, MB, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier, S-S, Schulte, C, Corvol, JC, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline, HW-G, Ben-Shlomo, Y, Berendse, HW, van Dijk, KD, Berg, D, Brockmann, K, Wurster, I, Mätzler, W, Gasser, T, Martinez, M, de Bie, RMA, Biffi, A, and Velseboer, D
- Abstract
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
- Published
- 2017
7. TECHNIQUE WORKSHOP: DEFENCE AGAINST A ROUNDHOUSE KICK WHILE SEATED.
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CHRISTOPHER, DAVID 'DC', WILLIAMS, MIKE, and BARDOS, DAVID
- Published
- 2018
8. Similar Agendas, Diverse Strategies: The Quest for a Regional Hub of Higher Education in Hong Kong and Singapore.
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David DC Chan and Pak Tee PN Ng
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HIGHER education , *POSTSECONDARY education , *EDUCATION , *SEGREGATION in higher education - Abstract
This article examines the approaches that Hong Kong and Singapore are taking to develop themselves as ‘regional hubs of higher education’ and the implications of their approaches. It starts with a delineation of how the internationalization of higher education structurally alters the landscape of the global higher education market. These changes drive both Hong Kong and Singapore to compete for the higher education pie. Despite many similarities in the vision and policy instruments, the article argues that there are significant differences in terms of their implementation approaches. More importantly, such differences reflect the different mindsets of the two governments in their governance of the university sector.Higher Education Policy (2008) 21, 487–503. doi:10.1057/hep.2008.19 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
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9. European Foreign Policy and American Primacy.
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David DC Clark
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INTERNATIONAL relations ,POLITICAL science ,POWER (Social sciences) ,EUROPE-United States relations - Abstract
The ideology of American primacy is not new with the Bush administration. Rather it draws upon a long tradition of American exceptionalism. Yet, the unilateralism built into this ideology is not viable as a foundation on which to build a global order, since it assumes that US behaviour is based on broadly-held values and interests, not those of a single state. With the end of the cold war many of the factors that tied the United States to Europe dissolved; moreover, the United States in effect, as its demographic and political centre moved south and west, abandoned many of the values that it shared with Europe. In many ways America's repudiation of multilateralism and welfare capitalism could be seen as a return to the default setting of its founding values. Some analysts argue that Europe faces but two alternative paths in its relationship with the United States — to accept a subservient position, while attempting to broaden Washington's agenda, or a form of ‘Euro-Gaullism’ in which Europe would break free from US domination. In fact, a third, and preferable approach, exists that would be based on strengthening Europe's position vis-à-vis the United States, while working with the United States in those areas where common values and interests exist. There is no doubt that a united Europe has the potential to play a more independent global role if it is willing to create the necessary decision-making structure and deploy its collective resources more efficiently.International Politics (2008) 45, 276–291. doi:10.1057/ip.2008.4 [ABSTRACT FROM AUTHOR]
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- 2008
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10. The security–development nexus and the rise of ‘anti-foreign policy’.
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David DC Chandler
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INTERNATIONAL relations ,POLICY sciences ,AUTOPOIESIS ,INTERNATIONAL security ,POLITICAL science - Abstract
Current debates and discussions of the emerging security–development nexus tend to portray this as signifying the increased importance of the problems of non-Western states to Western policy-makers. This article seeks to challenge this perspective and analyses how the policy ‘nexus’ reflects a retreat from strategic policy-making and a more inward-looking approach to foreign policy, more concerned with self-image than the policy consequences in the areas concerned. Rather than demonstrating a new seriousness of approach to tackling the security and development problems of the non-Western world, the discussions around this framework betray the separation between policy rhetoric and policy planning. This reflects the rise of anti-foreign policy: attempts to use the international sphere as an arena for self-referential statements of political mission and purpose, decoupled from their subject matter, resulting in ad hoc and arbitrary foreign policy-making.Journal of International Relations and Development (2007) 10, 362–386. doi:10.1057/palgrave.jird.1800135 [ABSTRACT FROM AUTHOR]
- Published
- 2007
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11. The Social Basis of Developmental Capitalism in Japan: From Post-war Mobilization to Current Stress Symptoms and Future Disintegration.
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David DC Chiavacci
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CAPITALISM ,SOCIOECONOMICS ,WELL-being ,QUALITY of life ,DEMOGRAPHIC change ,UPWARD mobility (Social sciences) - Abstract
Developmental capitalism is not only a question of a shared vision of economic nationalism and a shared strategy of national growth among economic and political elites, and their cooperation. Its success also depends on the degree of mobilization and integration in the population. Post-war Japan saw little continuity in the social basis of developmental capitalism, which was institutionalized in two steps following the socio-political crisis of 1960. In the first period of 1960â1973, national economic growth was redefined from a project for national greatness depending on individual sacrifice into a path of shared growth towards general well-being. Then, during the late 1970s and 1980s, the social basis was strengthened through the institutionalization of the Japanese way of life. The social basis of developmental capitalism in Japan is showing symptoms of stress. Provided that the current return to growth is not a short-term interlude, these symptoms may be overcome and an adapted version of developmental capitalism reestablished. However, in the medium term, demographic development and the end of general social upward mobility may well lead to a disintegration of the social basis of developmental capitalism.Asian Business & Management (2007) 6, 35â55. doi:10.1057/palgrave.abm.9200207 [ABSTRACT FROM AUTHOR]
- Published
- 2007
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12. A method for designing electromagnetic resonance enhanced silicon-on-insulatormetal–semiconductor–metal photodetectors.
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David DC Crouse and Pavan PK Keshavareddy
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- 2006
13. Culture Wars and International Intervention: An ‘Inside/Out’ View of the Decline of National Interest.
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David DC Chandler
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CONSENSUS (Social sciences) ,INTERNATIONAL relations ,SELF-interest ,ETHICS ,VALUES (Ethics) ,HUMAN rights ,GLOBALIZATION - Abstract
Today there is a consensus that the foreign policy of leading Western powers cannot be understood by considering nation states as egoistic actors pursing narrow self-interest. Since the end of the Cold War, major states have increasingly stressed the importance of ethics and values in the shaping of international goals and have intervened internationally on the basis of ‘other-regarding’ concerns such as human rights and international justice. Many commentators have understood this shift to ‘value-led’ or ‘ethical’ foreign policy through an ‘outside/in’ approach to the question, viewing this value shift as a response to international pressures of globalization and the creation of new cosmopolitan constituencies. This article instead employs an ‘inside/out’ approach, which suggests that the shift away from the articulation of national interests and the drive to defend ‘values’ through international intervention can be understood as products of and responses to the domestic political malaise at the heart of Western politics, often referred to in the US as an outcome of the ‘Culture Wars’.International Politics (2004) 41, 354–374. doi:10.1057/palgrave.ip.8800082 [ABSTRACT FROM AUTHOR]
- Published
- 2004
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14. Exploration of tradeoffs in intensity-modulated radiotherapy
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Craft, David DC, Halabi, Tarek TH, and Bortfeld, Thomas TB
- Abstract
The purpose of this study is to calculate Pareto surfaces in multi-criteria radiation treatment planning and to analyse the dependency of the Pareto surfaces on the objective functions used for the volumes of interest. We develop a linear approach that allows us to calculate truly Pareto optimal treatment plans, and we apply it to explore the tradeoff between tumour dose homogeneity and critical structure sparing. We show that for two phantom and two clinical cases, a smooth (as opposed to kinked) Pareto tradeoff curve exists. We find that in the paraspinal cases the Pareto surface is invariant to the response function used on the spinal cord: whether the mean cord dose or the maximum cord dose is used, the Pareto plan database is similar. This is not true for the lung studies, where the choice of objective function on the healthy lung tissue influences the resulting Pareto surface greatly. We conclude that in the special case when the tumour wraps around the organ at risk, e.g. prostate cases and paraspinal cases, the Pareto surface will be largely invariant to the objective function used to model the organ at risk.
- Published
- 2005
15. Everyday abstraction: geographical knowledge in the art of Peter Lanyon
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Crouch, David DC and Toogood, Mark MT
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Drawing on the painting, constructions and writing of the British artist Peter Lanyon, we explore how geographical knowledge is represented in modern abstract art. Lanyon had a deeply felt sense of Cornish identity and attachment to the history, people and place of West Cornwall. He also adopted particular practices - such as gliding - in which he experimented with bodily position and experience. We examine how these practices and cultural identity flowed together, constituting a kind of knowledge which was transposed into his art, the making of which was also an integral part of this dynamic process. We conclude that Lanyon’s perspective departs from the surveying gaze of traditional landscape representation, and also from the autonomous aesthetic common to abstract expressionists. Lanyon’s historical and cultural conception of landscape, as well as his spatial practices, suggest an awareness of landscape as socially defined. So, in a wider sense, we regard Lanyon’s geographical knowledge as a distinctive exploration of the relationship between individual, society and space.
- Published
- 1999
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16. MANUAL OF PHYSIOLOGY
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H. Willoughby Lyle and David dc Souza
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General Medicine - Published
- 1930
17. The Politics of Marketing the Labour Party
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Coates, David DC
- Published
- 2006
18. PASREG 2003: International Workshop on Processing and Applications of Superconducting (RE)BCO Large Grain Materials
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Murakami, Masato MM, Cardwell, David DC, Salama, Kamel KS, Krabbes, Gernot GK, Habisreuther, Tobias TH, and Gawalek, Wolfgang WG
- Abstract
Superconducting melt-textured bulk (RE)BCO large grain materials are one of the most promising materials for power applications of high temperature superconductivity at the liquid nitrogen temperature range. Industrial applications are expected in high-speed low-loss magnetic bearings for flywheel energy storage devices, high-dynamic high-torque electric reluctance motors, and MAGLEV transportation systems. The material has high magnetic field trapping capability and therefore a new class of high-field superconducting permanent magnets will soon appear. However, there is still the need to improve the magnetic and mechanical material properties, as well as to increase the single domain size.This special issue contains papers concerning these topics presented at the International Workshop on the Processing and Applications of Superconducting (RE)BCO Large Grain Materials. The workshop was held on the 30 June-2 July 2003 in Jena, Germany, and was organized by the Institut fuer Physikalische Hochtechnologie, Jena. It was the fourth in the series of PASREG workshops after Cambridge, UK (1997), Morioka, Japan (1999), and Seattle, USA (2001). Sixty two contributions were presented at the workshop, 38 oral presentations and 24 poster presentations. This special issue contains 42 papers.The editors are grateful for the support of many colleagues who reviewed the manuscripts to guarantee their high technical quality. The editors also wish to thank Doris Litzkendorf and Tobias Habisreuther from Institut fuer Physikalische Hochtechnologie, Jena, for their assistance with the organization and handling of the manuscripts. Many thanks to the workshop co-chairman Gernot Krabbes from Leibniz-Institut fuer Festkoerper und Werkstoffforschung, Dresden, for hosting the workshop participants in Dresden. Finally, all attendees wish to acknowledge the efforts of Wolfgang Gawalek, Tobias Habisreuther, Doris Litzkendorf and the Team of Department Magnetics from the Institut fuer Physikalische Hochtechnologie, Jena, for being generous hosts during the workshop.The International PASREG Board selected the following distinguished researchers as recipients of the 2003 PASREG Award for Excellence to acknowledge their contribution to the development of bulk high-temperature superconductors: Masato Murakami, ISTEC Tokyo; Günter Fuchs, IFW Dresden; Uichiro Mitzutani, Nagoya University; Bernhard Oswald, OSWALD Electric Motors Co. Miltenberg; Anna E Carillo, Teresa Puig and Xavier Obradors, ICMAB Barcelona.
- Published
- 2005
19. An investigation into the potential use of poly(vinylphosphonic acid-co-acrylic acid) in bone tissue scaffolds
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Dey, Rebecca, GOUGH, JULIE JE, WATTS, DAVID DC, Budd, Peter, Gough, Julie, and Watts, David
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poly(vinylphosphonic acid-co-acrylic acid) ,bone tissue engineering ,hydrogels - Abstract
Bone undergoes constant turnover throughout life and has the capacity to regenerate itself. However, the repair of critical size defects, caused by bone diseases such as osteoporosis, can be more problematic. Therefore, there is a clinical need for a bone graft substitute that can be used at sites of surgical intervention to enhance bone regeneration. Poly(vinylphosphonic acid-co-acrylic acid) (PVPA-co-AA) has recently been identified as a potential candidate for use in bone tissue scaffolds. It is hypothesised that PVPA-co-AA can mimic the action of bisphosphonates â a class of drugs used in the treatment of osteoporosis â by binding to calcium ions from bone mineral surfaces. In this way, bisphosphonates can affect bone turnover by increasing the activity of osteoblasts and reducing osteoclast activity. Although PVPA-co-AA has been shown to improve bone formation, the mechanism of action has so far not been fully elucidated. Therefore, this work aims to understand the effect of copolymer composition on the properties of PVPA-co-AA, and thus to determine its effect on osteoblast adhesion and proliferation. PVPA-co-AA copolymers have been synthesised with a range of monomer feed ratios. It was found that a VPA content of 30 mol % led to the greatest calcium binding affinity of the copolymer and is thus expected to lead to enhanced bone formation and mineralisation of the matrix produced by osteoblast cells. The release profile of PVPA-co-AA from electrospun PCL scaffolds was investigated. It was shown that all of the PVPA-co-AA was released into aqueous media within 8 h of immersion. It was also found that the calcium chelation from osteogenic differentiation media significantly increased within the first 8 h. Therefore, it was concluded that PVPA-co-AA is released from the scaffolds, where it can then bind to calcium ions from the bone mineral surface to promote mineralisation, thus acting as a mimic of non-collagenous proteins, which are present in the extracellular matrix (ECM) of bone. Hydrogels of PVPA-co-AA have been produced and the effect of monomer feed ratio (0-50 mol % VPA) on the properties of the gels was explored. It was found that an increase in VPA content led to greater hydrogel swelling and increased porosities. Hydrogels that contained 30 and 50 mol % VPA were shown to have similar morphologies to the native ECM of bone. Rheological testing showed that hydrogels with higher VPA contents were more flexible and could be deformed to a large extent without permanent deformation of their structure. An increase in osteoblast adhesion and proliferation was observed for hydrogels with 30 and 50 mol % VPA content as well as superior cell spreading. Osteoblast cell metabolic activity also increased as a function of VPA content in the hydrogels. This work indicates that hydrogels of PVPA-co-AA, with VPA contents of 30 or 50 mol %, are ideal for use as bone tissue scaffolds. Furthermore, the mechanical and cell adhesion properties of the gels can be tuned by altering the copolymer composition. Finally, composite hydrogels of PVPA-co-AA and hydroxyapatite (HA) have been produced and investigated for their ability to remove fluoride ions from groundwater. It was found that the fluoride uptake ability of PVPA-HA hydrogels was significantly enhanced when compared with HA powder alone. Furthermore, the fluoride uptake was dependent on many factors, including pH, contact time and the presence of competing ions. It was possible to regenerate the hydrogel to remove the fluoride ions, and thus it was shown that the material can be used a number of times with only a slight reduction in its fluoride uptake capacity.
- Published
- 2017
20. 'The State of Society is Awful': Poor Whites, Class, Mobility, and the Mixed-Labour Economy of New Orleans, 1820-1835
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Stallard, Matthew Robert, BROWN, DAVID DC, Zacek, Natalie, and Brown, David
- Abstract
The rapid economic development of the South Western United States transformed the city of New Orleans into a thriving commercial centre and led to unprecedented demographic growth. Highly innovative digital techniques are pioneered in this thesis and combined with a plethora of legal and governmental records and traditional qualitative primary sources to investigate for the first time the development of a white working class in 1820s and 1830s New Orleans.South and North, the antebellum period was defined by the increasing penetration of the global and national capitalistic market system into everyday life and economic activity, which created a large white waged labouring population who were unable to attain the markers of independence and mastery, such as slave ownership, property ownership, heading a household, mastering a trade, directing and controlling dependents, and exercising democratic political rights, which supposedly bound all adult white men together as equal citizens in the age of white supremacist Jacksonian Democracy.By transcribing every entry from the 1820 and 1830s censuses of the city and combining them in a unique linked database with transcriptions from the 1822 and 1832 city directories, this thesis is able to show that poor whites were decreasingly likely to exercise these rights in 1830 than in 1820, were unlikely to remain resident in New Orleans over an extended period of time, and were far more likely to perish in the city’s pestilential disease environment than the more affluent classes of society. The increasing reach of the capitalist market across continents and oceans facilitated the migration of thousands of poor whites from their economically disadvantaged homes to the sites where labour was required. Mobile networks of working class migration which spanned the Atlantic, the Caribbean, the Mississippi Valley, and the eastern United States overlapped at New Orleans, which became a major transport hub for itinerant and indigent arrivals.The alienation of poor whites from basic markers of manhood was compounded by having to acquire the necessities and pleasures of domestic life in the marketplace, denying them the private and familial life which was the cultural norm for republican men. On top of the detrimental impacts of class amongst the white population, the use of a mixed-labour system which combined various slavery arrangements with waged and indentured free black and white labour led to a situation where poor whites were forced to compete with both enslaved and free blacks for jobs, and at times be requested to work in subordination to free black workers. The use of the mixed-labour system was promoted by the property owning and slaveholding elite as it maximised their returns on profit but it simultaneously drove down remuneration for white workers. In a city with a large, affluent, and confident free black population, which included many master craftsmen, slaveholders, and property owners, poor whites found themselves in a position in which the dominant social ideologies of race were undermined. Poor whites reacted to this with violence and protest, whilst elite whites also recognised the anomalous position of the poorest and responded by doubting their commitment to racial solidarity in the summer of 1835 when southern society was tested by insurrectionary panic.
- Published
- 2017
21. Phosphonated Polymers for Nanofibrous Tissue Scaffolds
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Youle, Peter, GOUGH, JULIE JE, WATTS, DAVID DC, Gough, Julie, Watts, David, and Budd, Peter
- Abstract
This thesis, entitled “Phosphonated polymers for nanofibrous tissue scaffolds”, was written by Peter James Youle at the University of Manchester for the degree of Doctor of Philosophy and was submitted in 2016. The work contained within concerns itself with the synthesis and characterisation of phosphonated polymers intended for application as nanofibrous tissue scaffolds for improving the healing of bone; it is based on previous work performed in the University of Manchester that identified poly(ε-caprolactone) (PCL) nanofibres coated with poly(vinylphosphonic acid-co-acrylic acid) (PVPA-co-AA) as a promising material for enhancing bone healing. This thesis initially focuses on the characterisation of a commercially sourced PVPA-co-AA by defining its composition and molar mass using quantitative 31P NMR and aqueous gel permeation chromatography. A method of synthesising the copolymer by free radical polymerization, with controlled rates of monomer addition, was developed to produce PVPA-co-AA copolymers with a range of compositions. Additionally, nanofibres of PVPA-co-AA were then formed by electrospinning and crosslinked with ethylene glycol; the subsequent nanofibres were found to be water stable and retain their structure after hydration and subsequent drying. A block copolymer, polycaprolactone-b-poly(acrylic acid) (PCL-b-PAA), was synthesised by four-step ATRP and two-step NMP based approaches, with the block character of the resulting copolymer being demonstrated by GPC and dynamic light scattering. The PCL-b-PAA was subsequently used as a compatibiliser for PCL and PVPA-co-AA emulsions, which were used to create composite nanofibres by electrospinning. These nanofibre were in turn characterized by scanning electron microscopy and compared to nanofibres formed using a surfactant, Span® 80, and the original dip-coated nanofibres. Finally, a small portion of work was undertaken to develop phosphonated PCL analogues, by attempting to synthesise phosphonated ε-caprolactone monomers.
- Published
- 2017
22. The Vietnam War and the U.S. South:Regional Perspectives on a National War
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Dixon, Lee Russell, BROWN, DAVID DC, Carden-Coyne, Ana, and Brown, David
- Subjects
The Vietnam War ,The U.S. South - Abstract
The American South’s cultural distinctiveness has been a central historiographical issue debated by scholars since the first decades of the country’s inception. Implicitly or explicitly, this debate centres largely on one question – why has the South retained its distinct identity for cultural, social, political and economic exclusivity? This thesis examines southern distinctiveness with specific reference to America’s military involvement in Vietnam during the 1960s and 1970s, providing new insights upon an old question. Although a national effort, which encompassed the service over three million men, America’s 16 year involvement in their war against the communist-backed North Vietnamese Army (NVA) and Viet Minh/Vietcong (VC) forces was shaped by distinct southern influences attributed to the region’s history and culture. This thesis demonstrates that the southern influence over America’s political, economic and military theatres profoundly shaped the direction and administration of the Vietnam War. Southerners occupied crucial leadership roles throughout the Vietnam war era, including the presidency and Secretary of State, while both the Senate and the House of Representatives were led by men from South of the Mason-Dixon Line.
- Published
- 2016
23. Ebony Magazine, Lerone Bennett, Jr., and the Making and Selling of Modern Black History, 1958-1987
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West, James James, BROWN, DAVID DC, Brown, David, and Quinn, Eithne
- Subjects
Lerone Bennett ,Black Popular Culture ,Black Press ,Black History ,Ebony Magazine - Abstract
This thesis is concerned with the ways in which Ebony magazine sought to recover, popularise and utilise black history between the late 1950s and the late 1980s. The dominant scholarly approach to Ebony has focused on the magazine’s bourgeois values and visual aesthetics, and has ignored its importance as a creator and disseminator of black history. By contrast, I highlight the multiple ways in which black history became central to Ebony’s content from the late 1950s onwards. Far from viewing Ebony as peripheral to or simply reflective of popular debates into the black past, I place the magazine at the heart of contestations between the corporate, philosophical and political uses of black history during the second half of the twentieth century. In Ebony, this shift was quarterbacked by Lerone Bennett Jr., the magazine’s senior editor and in-house historian. Bennett’s emergence as a prominent black historian and intellectual, and his increased desire to present history ‘from a black perspective’, was paralleled by Ebony’s broader move from a more politicised to a more market-driven moment. Rooted in my unique position as the first scholar to look at Bennett’s unprocessed papers at Chicago State University, and one of the first researchers to examine Bennett’s collections at Emory University, this thesis sheds new light on the work of Bennett, on Ebony’s significance as a ‘history book’ for millions of readers, and on the magazine’s place at the centre of post-war debates into the form and function of African-American history.
- Published
- 2015
24. An Evaluation of Handling and Physico - Mechanical Properties of Resin-Composite Materials
- Author
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Alahdal, Khold Yahya m, WATTS, DAVID DC, CUNLIFFE, JOANNE J, Silikas, Nikolaos, Watts, David, and Cunliffe, Joanne
- Subjects
Degree of conversion ,Viscosity ,Polymerization kinetics ,Mechanical properties ,Creep ,Depth of cure, mechanical properties ,Handling behaviour ,Speedmixer ,Bulk-fill ,Resin composites ,Visco-elasticity ,Consistency ,Stickiness ,Rheology - Abstract
Resin composites are the most commonly used material in restorative dentistry. They have been used initially for aesthetical reasons, but afterwards were modified to be used widely for their good aesthetic and mechanical properties performance. They are classified as visco-elastic materials which are composed of inorganic fillers and organic matrix.The aim of this study was to investigate some handling properties of uncured resin composites such as stickiness, consistency and rheology. Also, to measure the degree of conversion and creep behaviour under static loading of some resin composites.In the pre-cure stage, their handling properties are very essential to achieve a successful dental restoration. Therefore, dental practitioners are very critical in choosing the resin composite restorative material. A texture analyser was used to measure the stickiness and consistency of some commercial resin composites. Also, the rheology of different commercial and model resin composites were investigated using the Bohlin Rheometer in two different temperatures (room and body temperature).Moreover, Fourier transform infrared spectroscopy (FTIR) was used to determine the degree of conversion of several bulk-fill resin composites (DC) at 4 mm depth at different periods during 24 h post-irradiation.Also, the visco-elastic stability of cured resin composites with different resin matrices was investigated under static load at different maturation times (1 h and 24 h).
- Published
- 2015
25. Shell’s England:Corporate Patronage and English Art in the Shell Posters of the 1930s
- Author
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Speakman, Malcolm V, LOMAS, DAVID DC, Crinson, Mark, and Lomas, David
- Subjects
Posters ,Shell Oil ,Interwar - Abstract
This thesis establishes why the Shell Oil Company produced a series of seventy-one posters of the British landscape in the 1930s. Through an examination of the 76 cm. x 114cm. posters that were attached to the sides and backs of the company’s delivery lorries, the thesis determines why Shell chose this form of publicity. The thesis examines the posters as historical, if ephemeral, artefacts and analyses the social, economic and cultural context of their production. Whilst there has been some historical analysis of poster design within the field of design history, the significance of the poster within these contexts has been largely neglected. The unique hybrid nature of the Shell posters as advertising based upon fine art using over fifty artists and designers makes them a unique repository of British visual culture of the 1930s.This thesis describes how Shell created three landscape poster campaigns, not through the enlightened patronage of its publicity manager, Jack Beddington, but through a complex set of circumstances that included: the cartel that was formed by the oil companies supplying Britain; the development and encouragement of motoring tourism and its effect on the countryside; the middle-class rejection of working class holiday destinations; concern about the preservation of the countryside; the effect of the ‘slump’ on the working lives of artists; economic and aesthetic arguments about the relationship between fine and commercial art and the relationship between landscape and national identity. Chapter 1 explores the background and influences that led to the creation of the posters, including the precursors of Beddington and the development of the poster as a medium. Chapter 2 investigates the inter-war debate that exposed the uneasy relationship between fine art, commercial art and industry. Chapter 3 investigates the concept of ‘place’ and uses case studies of places Shell wished to portray as destinations. Chapter 4 examines, through case studies, how the landscape, as portrayed by the posters, is represented for tourists and also the posters’ function within tourism.
- Published
- 2014
26. Eduardo Paolozzi and JG Ballard: Representing New British Modernities, c. 1966 - 1980
- Author
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Huston, Carol, LOMAS, DAVID DC, Crinson, Mark, and Lomas, David
- Abstract
The significance of the relationship between Scottish artist Sir Eduardo Paolozzi (1924-2005) and English novelist J.G. Ballard (1930-2009) has previously been overlooked in art historical and literary scholarship. This thesis fills this research gap through the analysis of how the pair’s works overlapped thematically to represent a particular strain of British modernity. By looking at shared cultural circumstances after World War II, parallels will be drawn between the work of Paolozzi and Ballard in the late years of British modernism. Drawing upon the topics of science fiction, Surrealism, the neo-avant-garde and militaristic and crash aesthetics, this thesis explores the various themes which Paolozzi and Ballard encountered during the period of their friendship.Overall, this comparative analysis reveals that despite dissimilar upbringings, Paolozzi and Ballard’s harrowing experiences of the Second World War culminated in a dual reaction against the stagnant flow of British modernism during the late postwar era. My thesis demonstrates this through their involvement with literary magazines as well as their mutually shared interests as expressed in their works of art and writings. By creating works which appropriated early twentieth century traditions, Paolozzi and Ballard rejected their immediate modernist inheritance and turned to the modernist past with renewed avant-garde intent. As exemplified in their works, the pair together represented the late postwar transition of British modernity during the dawn of what would come to be called ‘postmodernism’.
- Published
- 2013
27. Temperature-dependent properties of resin-composites before and during the setting process
- Author
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Alnazzawi, Ahmad, WATTS, DAVID DC, Watts, David, and Silikas, Nikolaos
- Abstract
Dental Resin-Composites contain inorganic particles, coated with organic coupling agent, dispersed in an organic resin-matrix. In their precured state they are viscous pastes that change rapidly to a hardened mass after photo-activation. Temperature change is expected to modify several physical properties.The aims were to determine the extent to which increasing temperature from ambient (23 oC) to body temperature (37 oC) may affect properties before and during the setting process. Six representative resin-composites were selected [GRO, GCK, VDD, FXE, GDP, and GDA].Temperature-dependence of handling properties (packing stress and viscosity) of pre-cured resin composites was examined using a penetrometer instrument at 23 oC, 30 oC, and 37 oC. Viscosity was reduced significantly by up to 93 % at 37 oC compared to 23 oC. Temperature-dependence of degree-of-conversion (DC) was measured by FTIR spectroscopy at 23 oC and 37 oC. DC was also time-dependent after photo-activation at both temperatures, with all examined materials having higher DC at 1 h than 0 h.A modified bonded-disk instrument was used for simultaneous measurement of: shrinkage-strain, exotherm, and Coefficient of Thermal Expansion (CTE) at 23 oC. Shrinkage-strain, exotherm, and CTE were all found to correlate negatively with filler-load. Positive correlation was found also between shrinkage-strain and CTE.Temperature-dependence of shrinkage-strain kinetics, at 23 oC and 37 oC, was examined with the bonded-disk instrument. Mean 1h shrinkage-strains at 37 oC were numerically and significantly greater (p
- Published
- 2012
28. Physical properties of dental resin nanocomposites
- Author
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Nuri Khaled, Asma Khiri, WATTS, DAVID DC, Watts, David, and Silikas, Nikolaos
- Subjects
microhybrid composites ,Nanocomposites - Abstract
Objectives: (1) To evaluate and compare the flexural strength, flexural modulus, compressive strength, surface roughness, and gloss for two nanohybrid composites (Herculite XRV Ultra, and Tetric Evo Ceram) and two microhybrid composites (Filtek Z250, and Venus). (2) To evaluate the differences in surface roughness and gloss between the materials. (3) To evaluate the effect of polishing and toothbrushing abrasive on surface roughness and gloss. (4) To assess the relationship between 2D surface roughness and 3D surface roughness parameters.Materials and methods: Compressive strength, Flexural strength, and Flexural Modulus of each material were determined using a universal testing machine (each test n=10). Flexural strength and flexural modulus were evaluated by using a three-point bending test. The results were statistically analyzed, with p≤ 0.05. Surface roughness and gloss of each material were evaluated by a 2D contact stylus profilometer: before polishing, after polishing, and after abrasive toothbrushing. Three surface roughness parameter were used in this study (Ra, Rt, Rsm). The results were analysed to evaluate the effect of polishing and toothbrushing abrasive by t-test for paired data and Oneway (ANOVA) test, followed by Tukey`s post hoc test, for multiple comparisons. 3D surface roughness measurements (Sa, St, Sds) were recorded using 3D non contact stylus profilometer. 3D surface roughness (Sa) and 2D surface roughness (Ra) for all tested materials were plotted to show the relationship between Sa and Ra after polishing and after brushing.Results: For the mechanical tests, Filtek Z250 exhibited the highest flexural strength (136.71 MPa), flexural modulus (7.9 GPa), and compressive strength (405.33 MPa) among all materials tested, while Tetric Evo Ceram showed the lowest mean values for compressive strength (237.74 MPa) and flexural strength (83.75 MPa).For Surface roughness after polishing, Ra, Rt, aand Rsm of the materials did not differ significantly from each other, whereas after brushing there were significant differences between the materials. Tetric Evo Ceram exhibited the rougher surface after brushing. The gloss results showed significant differences in gloss between the materials tested after polishing and after brushing. Herculite XRV exhibited the highest surface gloss after polishing (74.85) and was the best at retaining the gloss after brushing, whereas Venus recorded the lowest result for gloss after polishing (52.28). However, Filtek Z250 had the lowest gloss retention after brushing. Also the results showed a positive correlation between 3D surface roughness (Sa) and 2D surface roughness (Ra) for all materials tested after polishing: r2=0.9 and after brushing: r2=1. Conclusion: While nanohybrid composites may have certain advantage, such as higher gloss, over microhybrid composite resin, their mechanical properties were not superior to those of the microhybrid composites which were tested.
- Published
- 2012
29. Teaching Christianity in the face of adversity: African American religious leaders in the late antebellum South
- Author
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Strange, Thomas, BROWN, DAVID DC, Ward, Brian, and Brown, David
- Subjects
Slave religion ,African American history - Abstract
Religious leaders were key figures within African American society in the late antebellum South. They undertook a vital religious function within both the plantation slave community and the institutionalised biracial and independent black church and many became a focal point for African American Christianity amongst slaves and free blacks. These religious leaders also took on a number of secular responsibilities, becoming counsellors, mediators, and advisors, individuals that blacks would frequently seek out for their opinion, advice and solace. African American religious leaders held a position considered to be vital and prestigious. But such a position was also perilous. Black religious leaders had to reconcile the conflicting demands of two groups whose needs were almost diametrically opposed. Slaves and free blacks wanted to hear a message of hope, but the Southern elite wanted to hear a message of obedience to ensure that their authority remained unchallenged. Appeasing both groups was an almost impossible task. Failing to meet their demands, however, could be disastrous for black religious leaders. Slaves and free blacks who heard a message of obedience to the Southern white elite rejected the authority of the black preacher, who was then often unable to continue his ministrations. Conversely, those who were considered to be teaching a message that was undermining the planter’s authority faced reprisals from white society. These reprisals could be violent. In order to survive, black religious leaders had to chart a difficult course between the two groups, giving a sense of hope to the enslaved but in a manner that did not appear to undermine white authority. Within historical scholarship, it has been argued that African American religious leaders shared a common role. By the late antebellum period, however, a divide had emerged amongst black religious leaders. Although they continued to share many of the same goals, responsibilities, and challenges, the form of Christianity practiced by black preachers on the plantation was not the same as that practiced by licensed black ministers in the biracial and independent black church. Christianity within the plantation slave community continued to include African traditions and rituals that had survived the transatlantic crossing. Christianity within the biracial and independent black church, however, had begun to reject these African traditions as backward and outdated, and had moved instead towards a form of religion that, whilst still emotional and uplifting, was also more formal and hierarchical, resembling the Christianity of white Southern evangelicals.Black preachers and licensed black ministers were preaching Christianity in the face of adversity and had the potential to become political leaders within the African American community. The realisation of this potential was hindered, not only by the constant supervision of these religious leaders by the white elite but also through the refusal of black preachers and ministers to use Christianity to justify acts of resistance. This research adds new insight to the role of African American religious leaders through a detailed understanding of their different approaches in delivering the Christian message.
- Published
- 2011
30. Application of Bayesian Networks to Problems within Obesity Epidemiology
- Author
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Harding, Nicholas John, HOYLE, DAVID DC, Hoyle, David, and Buchan, Iain
- Abstract
Obesity is a significant public health problem in the United Kingdom and many other parts of the world, including some low-income settings. Although obesity prevalence has been rising for several decades, governments have been slow to implement policies that may have an impact at a population level. Numerous socio-demographic factors have been linked with obesity, but are highly intercorrelated, and identifying relevant factors or at-risk population groups is difficult.This thesis uses a graphical modelling approach, specifically Bayesian networks, to model the joint distribution of socio-demographic factors and obesity related behaviour. The key advantages of graphical models in this context are their ability to model highly correlated data, and to represent complex relationships efficiently as network structure.Three separate pieces of work comprise this thesis. The first uses a sampling technique to identify the networks that best explain the observed data, and employs the common structural features of these networks to infer conditional dependencies present between socio-demographic variables and obesity related behaviour indicators. We find determinants of recreational physical activity differ between males and females, and age and ethnicity have a significant influence on snacking behaviour. The second piece of work usesBayesian networks to build a model of health behaviour given socio demographic input, and then applies this to data from the 2001 census in order to provide an estimate of the health behaviour of a real population. The final analysis uses Bayesian network structure to explore potential determinants of body fat deposition patterns and compares the results tothose derived from a Generalized Linear Model (GLM). Our approach successfully identifies the main determinants, age and Body Mass Index, although is not a genuine alternative due to a lack of sensitivity to less important determinants.Beyond the application to obesity, results of this thesis are of a wider relevance to epidemiology as the field moves towards an increased use of Machine Learning techniques. The work conducted has also met and overcome several technical issues that are likely to be of relevance to others exploring similar approaches. C# Metropolis Hastings implementation available from:http://personalpages.manchester.ac.uk/postgrad/nicholas.harding/njharding_thesis_samplingoverBNtopologies.rar
- Published
- 2011
31. A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans.
- Author
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Jung R, Lechler MC, Fernandez-Villegas A, Chung CW, Jones HC, Choi YH, Thompson MA, Rödelsperger C, Röseler W, Kaminski Schierle GS, Sommer RJ, and David DC
- Subjects
- Animals, Aging, Proteasome Endopeptidase Complex, Proteostasis, Caenorhabditis elegans, Protein Aggregates
- Abstract
During aging, proteostasis capacity declines and distinct proteins become unstable and can accumulate as protein aggregates inside and outside of cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of cytoplasmic protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of 3 core protein quality control systems, namely chaperones, the proteasome, and macroautophagy, leads to lower levels of age-dependent protein aggregation in Caenorhabditis elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism that selectively targets newly synthesized proteins to suppress their aggregation and associated proteotoxicity. The safety mechanism relies on macroautophagy-independent lysosomal degradation and involves several previously uncharacterized components of the intracellular pathogen response (IPR). We propose that this protective mechanism engages an anti-aggregation machinery targeting aggregating proteins for lysosomal degradation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
- View/download PDF
32. Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.
- Author
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Cable J, Weber-Ban E, Clausen T, Walters KJ, Sharon M, Finley DJ, Gu Y, Hanna J, Feng Y, Martens S, Simonsen A, Hansen M, Zhang H, Goodwin JM, Reggio A, Chang C, Ge L, Schulman BA, Deshaies RJ, Dikic I, Harper JW, Wertz IE, Thomä NH, Słabicki M, Frydman J, Jakob U, David DC, Bennett EJ, Bertozzi CR, Sardana R, Eapen VV, and Carra S
- Subjects
- Autophagy physiology, Humans, Organelles, Proteins metabolism, Proteolysis, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics., (© 2022 New York Academy of Sciences.)
- Published
- 2022
- Full Text
- View/download PDF
33. Evaluation of antiangiogenic and antiproliferative potential of ethanolic extracts of Andrographis echioides using in vitro and in ovo assays.
- Author
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Muralidharan K, Kumaravelu P, and David DC
- Subjects
- Angiogenesis Inhibitors isolation & purification, Animals, Antineoplastic Agents, Phytogenic isolation & purification, Cell Proliferation drug effects, Chick Embryo, Chorioallantoic Membrane, Drug Screening Assays, Antitumor, Ethanol chemistry, Humans, MCF-7 Cells, Neoplasms blood supply, Neoplasms drug therapy, Neovascularization, Pathologic drug therapy, Plant Extracts isolation & purification, Andrographis chemistry, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Plant Extracts pharmacology
- Abstract
Introduction: Andrographis echioides is a prevalently used medicinal herb in South Asian countries. Scientific researches with the extracts of A. echioides revealed its antipyretic, anti-inflammatory, antimicrobial, ulceroprotective, and hepatoprotective properties. This study was done to elucidate antiproliferative and antiangiogenic potential of ethanolic extracts of A. echioides (EEAE) by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and chorioallantoic membrane (CAM) assay., Materials and Methods: EEAE was prepared using Soxhlet apparatus with ethanol after being sun-dried and powdered. MCF 7 (human invasive breast ductal carcinoma) cell lines retaining attributes of differentiated mammary epithelium with both estrogen and progesterone receptors were treated with EEAE, and antiproliferative effect was seen using Mosmann method of MTT assay using 5-fluorouracil (5-FU) as a comparator. The evaluation of antiangiogenic potential of EEAE was done by comparing mean vessel density (MVD) in chick CAM after treatment with EEAE, thalidomide, and vascular endothelial growth factor (VEGF) using CAM assay, an in ovo assay., Results: EEAE displayed antiproliferative activity from low to high concentrations with MTT assay. The IC
50 of EEAE and 5-FU was 62.5 and 15.6 μg/ml, respectively (P < 0.05). The exhibition of its antiangiogenic activity increased proportionately with increasing concentration. VEGF increased MVD by 45.94%; thalidomide decreased it by 53.76%. There was a decrease of MVD by 5.91%, 20.46%, and 35.95% at concentrations of 25, 50, and 100 μg of EEAE, respectively., Conclusion: EEAE possessed significant antiangiogenic and antiproliferative activity, making them a promising substrate in the development of a novel anticancer drug and can be successfully used in the therapy of various cancers after establishment of the anticancer effects in animal models and subsequently in clinical trials., Competing Interests: None- Published
- 2021
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- View/download PDF
34. Extracellular proteostasis prevents aggregation during pathogenic attack.
- Author
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Gallotta I, Sandhu A, Peters M, Haslbeck M, Jung R, Agilkaya S, Blersch JL, Rödelsperger C, Röseler W, Huang C, Sommer RJ, and David DC
- Subjects
- Aging metabolism, Animals, Caenorhabditis elegans cytology, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins metabolism, Fatty Acid-Binding Proteins metabolism, MAP Kinase Signaling System, Protein Aggregation, Pathological prevention & control, Proteome genetics, Proteome metabolism, RNA Interference, Caenorhabditis elegans metabolism, Caenorhabditis elegans microbiology, Extracellular Space metabolism, Protein Aggregates, Proteostasis
- Abstract
In metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery. Until now, only a few bona fide extracellular chaperones and proteases have been shown to limit the aggregation of extracellular proteins
1-5 . Here we performed a systematic analysis of the extracellular proteostasis network in Caenorhabditis elegans with an RNA interference screen that targets genes that encode the secreted proteome. We discovered 57 regulators of extracellular protein aggregation, including several proteins related to innate immunity. Because intracellular proteostasis is upregulated in response to pathogens6-9 , we investigated whether pathogens also stimulate extracellular proteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we found that C. elegans responded by increasing the expression of components of extracellular proteostasis and by limiting aggregation of extracellular proteins. The activation of extracellular proteostasis was dependent on stress-activated MAP kinase signalling. Notably, the overexpression of components of extracellular proteostasis delayed ageing and rendered worms resistant to intoxication. We propose that enhanced extracellular proteostasis contributes to systemic host defence by maintaining a functional secreted proteome and avoiding proteotoxicity.- Published
- 2020
- Full Text
- View/download PDF
35. Molecular modeling and docking analysis of aspirin with pde7b in the context of neuro-inflammation.
- Author
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Balasundaram A and David DC
- Abstract
The PDE7B gene encodes 3'5'-cyclic nucleotide phosphodiesterase (PDE) and a known target in cognitive impairments. Therefore, it is of interest to design and development of potential inhibitors with PDE7B with improved binding features. We document that the amino acid residues such as H186, K190, and G113 of PDE7B protein showed crucial interactions with aspirin for further consideration in this context., (© 2020 Biomedical Informatics.)
- Published
- 2020
- Full Text
- View/download PDF
36. Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans .
- Author
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Huang C, Wagner-Valladolid S, Stephens AD, Jung R, Poudel C, Sinnige T, Lechler MC, Schlörit N, Lu M, Laine RF, Michel CH, Vendruscolo M, Kaminski CF, Kaminski Schierle GS, and David DC
- Subjects
- Animals, Aging, Amyloid metabolism, Caenorhabditis elegans physiology, Caenorhabditis elegans Proteins metabolism, Protein Aggregates
- Abstract
Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans . Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life., Competing Interests: CH, SW, AS, RJ, CP, TS, ML, NS, ML, RL, CM, MV, CK, GK, DD No competing interests declared, (© 2019, Huang et al.)
- Published
- 2019
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- View/download PDF
37. Antimicrobial Resistance of Thermotolerant Campylobacter Species Isolated from Humans, Food-Producing Animals, and Products of Animal Origin: A Worldwide Meta-Analysis.
- Author
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Signorini ML, Rossler E, Díaz David DC, Olivero CR, Romero-Scharpen A, Soto LP, Astesana DM, Berisvil AP, Zimmermann JA, Fusari ML, Frizzo LS, and Zbrun MV
- Subjects
- Animals, Campylobacter drug effects, Campylobacter Infections, Food Microbiology, Humans, Microbial Sensitivity Tests methods, Anti-Bacterial Agents pharmacology, Campylobacter genetics, Campylobacter isolation & purification, Drug Resistance, Multiple, Bacterial drug effects, Drug Resistance, Multiple, Bacterial genetics
- Abstract
The objective of this meta-analysis was to summarize available information on the prevalence of antimicrobial-resistant Campylobacter species in humans, food-producing animals, and products of animal origin. A number of multilevel random-effect meta-analysis models were fitted to estimate mean occurrence rate of antimicrobial-resistant thermotolerant Campylobacter and to compare them throughout the years and among the species, food-producing animals (i.e., bovine, pigs, broilers, hen, goat, and sheep), country of origin, sample type, methodology to determine the antimicrobial susceptibility, and the species of Campylobacter. Among the considered antibiotics, thermotolerant Campylobacter showed the highest resistance to tetracycline (pool estimate [PE] = 0.493; 95% CI 0.466-0.519), nalidixic acid (PE = 0.385; 95% CI 0.348-0.423), and ciprofloxacin (PE = 0.376; 95% CI 0.339-0.415). In general, the prevalence of antimicrobial-resistant Campylobacter spp. was higher in hen, broilers, and swine. Campylobacter coli showed a higher prevalence of antimicrobial resistance than Campylobacter jejuni. Independent of the antimicrobial evaluated, the disk diffusion method showed higher prevalence of antimicrobial-resistant Campylobacter than the methods based on the minimum inhibitory concentration estimation. The meta-analysis showed that the prevalence of antimicrobial-resistant Campylobacter is relevant essentially in foods derived from hens and broilers, and it was observed worldwide. The prevalence of this pathogen is of public health importance and the increase in the prevalence of Campylobacter strains resistant to the antimicrobial of choice worsens the situation, hence, national authorities must monitor the situation in each country with the aim to establish the appropriate risk management measures.
- Published
- 2018
- Full Text
- View/download PDF
38. Methods to Study Changes in Inherent Protein Aggregation with Age in Caenorhabditis elegans.
- Author
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Groh N, Gallotta I, Lechler MC, Huang C, Jung R, and David DC
- Subjects
- Age Factors, Animals, Animals, Genetically Modified, Caenorhabditis elegans chemistry, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins chemistry, Caenorhabditis elegans Proteins genetics, Models, Animal, Protein Aggregates, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins metabolism
- Abstract
In the last decades, the prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), has grown. These age-associated disorders are characterized by the appearance of protein aggregates with fibrillary structure in the brains of these patients. Exactly why normally soluble proteins undergo an aggregation process remains poorly understood. The discovery that protein aggregation is not limited to disease processes and instead part of the normal aging process enables the study of the molecular and cellular mechanisms that regulate protein aggregation, without using ectopically expressed human disease-associated proteins. Here we describe methodologies to examine inherent protein aggregation in Caenorhabditis elegans through complementary approaches. First, we examine how to grow large numbers of age-synchronized C. elegans to obtain aged animals and we present the biochemical procedures to isolate highly-insoluble-large aggregates. In combination with a targeted genetic knockdown, it is possible to dissect the role of a gene of interest in promoting or preventing age-dependent protein aggregation by using either a comprehensive analysis with quantitative mass spectrometry or a candidate-based analysis with antibodies. These findings are then confirmed by in vivo analysis with transgenic animals expressing fluorescent-tagged aggregation-prone proteins. These methods should help clarify why certain proteins are prone to aggregate with age and ultimately how to keep these proteins fully functional.
- Published
- 2017
- Full Text
- View/download PDF
39. More stressed out with age? Check your RNA granule aggregation.
- Author
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Lechler MC and David DC
- Subjects
- Animals, Caenorhabditis elegans genetics, Forkhead Transcription Factors metabolism, Humans, Longevity, Neurodegenerative Diseases metabolism, Poly(A)-Binding Protein I metabolism, Protein Aggregation, Pathological metabolism, Proteome chemistry, RNA metabolism, Transcription Factors metabolism, Aging metabolism, Caenorhabditis elegans Proteins metabolism, Cytoplasmic Granules metabolism, Prions metabolism, RNA-Binding Proteins metabolism, Stress, Physiological
- Abstract
Low complexity (LC) prion-like domains are over-represented among RNA-binding proteins (RBPs) and contribute to the dynamic nature of RNA granules. Importantly, several neurodegenerative diseases are characterized by cytoplasmic "solid" aggregates formed by mainly nuclear RBPs harboring LC prion-like domains. Although RBP aggregation in disease has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. Our recent study revealed that RNA granule components including 2 key stress granule RBPs with LC prion-like domains, PAB-1 and TIAR-2, aggregate in aged Caenorhabditis elegans in the absence of disease. Here we present new evidence showing that sustained stress granule formation triggers RBP aggregation. In addition, we demonstrate that mild chronic stress during aging promotes mislocalization of nuclear RBPs. We discuss the consequences of aberrant interactions between age-related RBP aggregation and disease-associated RBP aggregation. In particular, we show that FUST-1 and PAB-1 co-localize in aberrant cytoplasmic accumulations. Significantly, long-lived animals with reduced insulin/IGF-1 signaling abrogate stress granule RBP aggregation through activation of the transcription factors HSF-1 and DAF-16. We evaluate the different mechanisms that could maintain dynamic stress granules. Together these findings highlight how changes with age could contribute to pathogenesis in neurodegenerative diseases and disruption of RNA homeostasis.
- Published
- 2017
- Full Text
- View/download PDF
40. Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation.
- Author
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Groh N, Bühler A, Huang C, Li KW, van Nierop P, Smit AB, Fändrich M, Baumann F, and David DC
- Abstract
Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro . We tested the seeding potential at four different ages across the adult lifespan of C. elegans . Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.
- Published
- 2017
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41. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
- Author
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Jansen IE, Ye H, Heetveld S, Lechler MC, Michels H, Seinstra RI, Lubbe SJ, Drouet V, Lesage S, Majounie E, Gibbs JR, Nalls MA, Ryten M, Botia JA, Vandrovcova J, Simon-Sanchez J, Castillo-Lizardo M, Rizzu P, Blauwendraat C, Chouhan AK, Li Y, Yogi P, Amin N, van Duijn CM, Morris HR, Brice A, Singleton AB, David DC, Nollen EA, Jain S, Shulman JM, and Heutink P
- Subjects
- Adolescent, Adult, Animals, Animals, Genetically Modified, Caenorhabditis elegans genetics, Case-Control Studies, Cells, Cultured, Child, Disease Models, Animal, Drosophila melanogaster genetics, Exome, Humans, Middle Aged, RNA Interference, Young Adult, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing methods, Parkinson Disease genetics, Sequence Analysis, DNA methods, alpha-Synuclein genetics
- Abstract
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models., Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication., Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
- Published
- 2017
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42. Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging.
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Lechler MC, Crawford ED, Groh N, Widmaier K, Jung R, Kirstein J, Trinidad JC, Burlingame AL, and David DC
- Subjects
- Animals, Longevity, Mutation genetics, Protein Aggregates, RNA metabolism, RNA-Binding Proteins metabolism, Receptor, Insulin metabolism, Solubility, Aging metabolism, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins metabolism, Cytoplasmic Granules metabolism, Heat-Shock Proteins metabolism, Insulin metabolism, Insulin-Like Growth Factor I metabolism, Signal Transduction
- Abstract
Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1) is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule-related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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43. Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.
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Sugumar R, Adithavarman AP, Dakshinamoorthi A, David DC, and Ragunath PK
- Abstract
Introduction: Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia., Aim: To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool., Materials and Methods: The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals., Results: Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87., Conclusion: Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies.
- Published
- 2016
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44. Therapeutic drug monitoring of antiepileptic drugs in a tertiary care hospital in India.
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Harivenkatesh N, Haribalaji N, David DC, and Kumar CM
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- Adolescent, Adult, Anticonvulsants blood, Child, Dose-Response Relationship, Drug, Epilepsy blood, Female, Humans, India, Longitudinal Studies, Male, Middle Aged, Retrospective Studies, Tertiary Healthcare statistics & numerical data, Young Adult, Anticonvulsants therapeutic use, Drug Monitoring, Epilepsy drug therapy
- Abstract
Introduction: Therapeutic drug monitoring (TDM) helps to optimize the dose of antiepileptic drugs. Only limited information is available about the clinical utility of TDM of antiepileptic drugs in India. Hence, we aimed to study the clinical utility of antiepileptic TDM in a tertiary care hospital in India and to explore the association between the plasma drug levels and the occurrence of breakthrough seizures and drug toxicity., Methods: All patients taking antiepileptic drugs for whom TDM was done from January 2008 to December 2010 were included in the study. All relevant information was obtained from patient medical records. Trough levels were measured for all drugs using chemiluminescence assay. Drug levels were interpreted as within, below, and above the reference range, as recommended by the International League Against Epilepsy guidelines., Results: Of the 420 samples analyzed during this period, 396 samples were included in this study for analysis. The maximum number of requests was for phenytoin (50%) followed by valproic acid (26%). The most common indication for TDM was dosage adjustment (38%) followed by breakthrough seizures (34%). Among the 135 samples received with breakthrough seizures as indication, more than 50% had drug levels either within or above the reference range. Among the 62 samples referred with clinical symptoms of suspected toxicity, drug levels were above the reference range in only 52% of the samples., Conclusions: Therapeutic drug monitoring was found to be useful in practice, in tailoring drug dosage in accordance with the needs of individual patient, in distinguishing nonresponders from noncompliants, and in aiding in making critical decisions. However, the "reference range" of these antiepileptic drugs was not reliable in predicting the occurrence of breakthrough seizures and clinical symptoms of suspected drug toxicity.
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- 2015
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45. Efficacy and safety of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia: a randomized controlled trial.
- Author
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Harivenkatesh N, David DC, Haribalaji N, and Sudhakar MK
- Subjects
- Adult, Atorvastatin, Cholesterol blood, Cost-Benefit Analysis, Drug Administration Schedule, Drug Combinations, Drug Therapy, Combination, Dyslipidemias economics, Female, Fenofibrate administration & dosage, Fenofibrate adverse effects, Heptanoic Acids administration & dosage, Heptanoic Acids adverse effects, Humans, Hypolipidemic Agents administration & dosage, Hypolipidemic Agents adverse effects, Male, Middle Aged, Pyrroles administration & dosage, Pyrroles adverse effects, Triglycerides blood, Dyslipidemias drug therapy, Fenofibrate therapeutic use, Heptanoic Acids therapeutic use, Hypolipidemic Agents therapeutic use, Pyrroles therapeutic use
- Abstract
Introduction: The long half-life of atorvastatin and fenofibrate makes them suitable for alternate day therapy. Hence, we aimed to study the efficacy, safety, and cost-effectiveness of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia., Methods: Eligible patients with mixed dyslipidemia were randomly allotted into 2 equal parallel groups-alternate day therapy group (group 1) and daily therapy group (group 2). Patients in groups 1 and 2 received fixed dose combination of atorvastatin 10 mg and fenofibrate 160 mg on alternate days and daily, respectively, for 12 weeks. Mean percentage change from baseline in triglycerides (TGLs), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and TC-HDL ratio, incidence of adverse effects, and cost-effectiveness were compared in both the groups., Results: Among 110 patients randomized, 99 completed the study till 12 weeks treatment duration. The TGLs, non-HDL-C, TC, and LDL-C decreased by 56.4%, 49.7%, 36.5%, and 39.2%, respectively, in alternate day therapy group and by 57.5%, 51.2%, 37.5%, and 39.4%, respectively, in daily therapy group. The HDL-C levels increased by 20.1% in alternate day therapy group compared to 21.8% in daily therapy group. No statistically significant difference was seen between both the groups in mean percentage change in lipid parameters from baseline to end of 12 weeks. Incidence of adverse events was reasonably less in alternate day therapy group., Conclusion: Alternate day therapy with atorvastatin-fenofibrate combination is an effective and safe alternative to daily therapy in mixed dyslipidemia. Apart from significant cost savings, reasonable reduction in the incidence of adverse events is seen with alternate day regimen. However, larger studies are needed to more reliably confirm our interesting but preliminary results.
- Published
- 2014
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46. Aging and the aggregating proteome.
- Author
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David DC
- Abstract
For all organisms promoting protein homeostasis is a high priority in order to optimize cellular functions and resources. However, there is accumulating evidence that aging leads to a collapse in protein homeostasis and widespread non-disease protein aggregation. This review examines these findings and discusses the potential causes and consequences of this physiological aggregation with age in particular in relation to disease protein aggregation and toxicity. Importantly, recent evidence points to unexpected differences in protein-quality-control and susceptibility to protein aggregation between neurons and other cell types. In addition, new insight into the cell-non-autonomous coordination of protein homeostasis by neurons will be presented.
- Published
- 2012
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47. Widespread protein aggregation as an inherent part of aging in C. elegans.
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David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, and Kenyon C
- Subjects
- Aging physiology, Animals, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Disease Models, Animal, Humans, Huntington Disease metabolism, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases physiopathology, Proteins genetics, Proteins metabolism, Proteomics, Aging metabolism, Caenorhabditis elegans physiology, Caenorhabditis elegans Proteins metabolism, Huntington Disease physiopathology
- Abstract
Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in beta-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2010
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48. Use of cholinesterase activity in monitoring chlorpyrifos exposure of steer cattle after topical administration.
- Author
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Picco EJ, Fernández HR, David DC, San Andrés MI, Boggio JC, and Rodríguez C
- Subjects
- Animals, Cattle, Chromatography, Gas, Erythrocytes enzymology, Erythrocytes metabolism, Kinetics, Acetylcholinesterase blood, Administration, Topical, Butyrylcholinesterase blood, Chlorpyrifos administration & dosage, Erythrocytes drug effects, Insecticides administration & dosage
- Abstract
The aim of this work was to study the pharmacokinetic behavior and the inhibitory effect of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities of chlorpyrifos (CPF) in steer cattle after pour-on administration. Determination of cholinesterase activity in plasma and erythrocyte was carried out according to Ellman kinetic method. CPF was analyzed by gas chromatography. AChE was the predominant form of cholinesterase analyzed, with low levels of BChE in plasma. Following the treatment with CPF, the maximum inhibitory effect on AChE or BChE were 50.88 +/- 11.57 and 42.66 +/- 12.01%, respectively. The chlorpyrifos plasma concentrations observed were low and they presented a high variability. Chlorpyrifos peak plasma concentration (10.42 +/- 4.76 micro g/L) was reached at 8.42 +/- 13.97 h. The pesticide was not detected in plasma after 48 h post treatment. The values of area under the curve (AUC) were 118.48 +/- 87.46 micro g x h/L and mean resistance time (MRT) were 13.38 +/- 10.41 h. The pour-on exposure to the organophosphate chlorpyrifos significantly reduced AChE and BChE activity in steer cattle and the recovery was not reached on 50 days post-treatment.
- Published
- 2008
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49. Pharmacokinetics and pharmacodynamics of chlorpyrifos in male and female cattle after topical administration.
- Author
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Picco EJ, Rubio MR, David DC, Rodríguez C, and Boggio JC
- Subjects
- Acetylcholinesterase metabolism, Administration, Topical, Animals, Butyrylcholinesterase metabolism, Chlorpyrifos administration & dosage, Chlorpyrifos blood, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors blood, Female, Insecticides administration & dosage, Insecticides blood, Male, Sex Factors, Cattle metabolism, Chlorpyrifos pharmacokinetics, Enzyme Inhibitors pharmacokinetics, Insecticides pharmacokinetics
- Abstract
The aim of this work was to study the pharmacokinetic behaviour and the inhibitory effect on acetylcholinesterase and butyrylcholinesterase activities of chlorpyrifos in male and female cattle after pour-on administration. Determination of cholinesterase activity in plasma and erythrocyte was carried out according to Ellman kinetic method. The mean baseline activities were 9338.39 +/- 1331.61 and 13220.69 +/- 2274.18 to acetylcholinesterase and 624.65 +/- 39.32 and 641.68 +/- 88.08 IU/L to butyrylcholinesterase in females and males, respectively. Acetylcholinesterase was the predominant form of cholinesterase analyzed, with low levels of butyrylcholinesterase. The basal acetylcholinesterase activities of the bulls were significantly greater than those of cows. The inhibitory effect of topical chlorpyrifos administration was lower on butyrylcholinesterase than on acetylcholinesterase. Chlorpyrifos peak plasma concentration (male:10.920 +/- 4.18; female:12.12 +/- 3.88 microg/L) were reached at 11.92 +/- 9.19 and 8.17 +/- 7.67 h in male and female, respectively. The values of area under curve were 185.96 +/- 168.45 and 278.89 +/- 270.00 microg h/L and mean residence time were 13.95 +/- 8.10 and 14.90 +/- 9.80 h in male and female, respectively.
- Published
- 2008
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50. Beta-amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes.
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David DC, Ittner LM, Gehrig P, Nergenau D, Shepherd C, Halliday G, and Götz J
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- Alzheimer Disease etiology, Animals, Brain metabolism, Cell Line, Tumor, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Mutation, Nerve Tissue Proteins isolation & purification, Nerve Tissue Proteins metabolism, Protein Folding, Proteomics, Recombinant Proteins genetics, Recombinant Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid beta-Peptides pharmacology, tau Proteins genetics, tau Proteins metabolism
- Abstract
Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.
- Published
- 2006
- Full Text
- View/download PDF
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