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Roger Spear 《Systemic Practice and Action Research》1993,6(2):139-153
Conventional OR/systems practice, it is argued in this paper, is based upon assumptions which make it unsuitable for guiding interventions in nontraditional organizations. Any methodology or method rests upon a social theory,upon craft knowledge, and upon a theory of how change can and should be brought about. Conventional OR/systems is not explicit about any of these matters. Reflecting on why conventional methods often fail to work with nontraditional organizations, however, enables us to get beneath the iceberg and unearth what is being taken for granted. It is then obvious that the nature of many organizations in the social economy requires a different type of practice. Soft OR/systems is a response to the failings of the traditional approach, but goes only some way toward meeting the criticisms. 相似文献
86.
Hans-J?rg Schek Heiko Schuldt Christoph Schuler Roger Weber 《Cellular and molecular life sciences : CMLS》1991,47(7):643-643
Science Policy News
United Kingdom: The Science and Engineering Research Council (SERC): A Report on Research in the United Kingdom, France and Germany (W) 相似文献87.
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Albert Lee Stephanie L. Rayner Serene S. L. Gwee Alana De Luca Hamideh Shahheydari Vinod Sundaramoorthy Audrey Ragagnin Marco Morsch Rowan Radford Jasmin Galper Sarah Freckleton Bingyang Shi Adam K. Walker Emily K. Don Nicholas J. Cole Shu Yang Kelly L. Williams Justin J. Yerbury Ian P. Blair Julie D. Atkin Mark P. Molloy Roger S. Chung 《Cellular and molecular life sciences : CMLS》2018,75(2):335-354
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. 相似文献
89.
Charlier C Coppieters W Rollin F Desmecht D Agerholm JS Cambisano N Carta E Dardano S Dive M Fasquelle C Frennet JC Hanset R Hubin X Jorgensen C Karim L Kent M Harvey K Pearce BR Simon P Tama N Nie H Vandeputte S Lien S Longeri M Fredholm M Harvey RJ Georges M 《Nature genetics》2008,40(4):449-454
The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings. 相似文献
90.
DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis 总被引:14,自引:0,他引:14
Lorenz-Depiereux B Bastepe M Benet-Pagès A Amyere M Wagenstaller J Müller-Barth U Badenhoop K Kaiser SM Rittmaster RS Shlossberg AH Olivares JL Loris C Ramos FJ Glorieux F Vikkula M Jüppner H Strom TM 《Nature genetics》2006,38(11):1248-1250
Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression. 相似文献