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Houlden H Johnson J Gardner-Thorpe C Lashley T Hernandez D Worth P Singleton AB Hilton DA Holton J Revesz T Davis MB Giunti P Giunti P Wood NW 《Nature genetics》2007,39(12):1434-1436
The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration. 相似文献
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Gerald Holton 《自然辩证法通讯》2005,27(1):2-8
Historians of moden science have good reasons to be grateful to Paul Arthur Schilpp, professor of philosophy and Methodist clergyman but better known as the editor of a series of volumes on “Living Philosophers,” including several on scientist - philosophers. His motto was:“The asking of questions about a philosopher‘s meaning while he is alive.” And to his everlasting credit, 相似文献
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Ubiquitin-like proteins (UBLs) are conjugated by dynamic E1-E2-E3 enzyme cascades. E1 enzymes activate UBLs by catalysing UBL carboxy-terminal adenylation, forming a covalent E1 throught UBL thioester intermediate, and generating a thioester-linked E2 throught UBL product, which must be released for subsequent reactions. Here we report the structural analysis of a trapped UBL activation complex for the human NEDD8 pathway, containing NEDD8's heterodimeric E1 (APPBP1-UBA3), two NEDD8s (one thioester-linked to E1, one noncovalently associated for adenylation), a catalytically inactive E2 (Ubc12), and MgATP. The results suggest that a thioester switch toggles E1-E2 affinities. Two E2 binding sites depend on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1 conformational change. The other comes directly from the thioester-bound NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1 conformation would facilitate release of the E2 throught NEDD8 thioester product. Thus, transferring the UBL's thioester linkage between successive conjugation enzymes can induce conformational changes and alter interaction networks to drive consecutive steps in UBL cascades. 相似文献
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Gerald Holton 《自然科学史研究》2005,24(B07):75-82
Historians of modem science have good reasons to be grateful to Paul Arthur Schilpp, professor of philosophy and Methodist clergyman but better known as the editor of a series of volumes on“ Living Philosophers”, including several on scientist-philosophers. His motto was: “The asking of questions about a philosopher's meaning while he is alive.” 相似文献
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Gerald Holton 《自然科学史研究》2005,24(Z1):75-82
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Historians of modern science have good reasons to be grateful to Paul Arthur Schilpp, professor of philosophy and Methodist clergyman but better known as the editor of a series of volumes on" Living Philosophers", including several on scientist-philosophers. His motto was:"The asking of questions about a philosopher's meaning while he is alive." And to his everlasting credit, he persuaded Albert Einstein to do what he had resisted all his years: to sit down to write, in 1946 at age sixty-seven, an extensive autobiography-forty-five pages long in print. 相似文献
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A. Rostagno J. L. Holton T. Lashley T. Revesz Jorge Ghiso 《Cellular and molecular life sciences : CMLS》2010,67(4):581-600
Cerebral amyloid diseases are part of a complex group of chronic and progressive entities bracketed together under the common
denomination of protein folding disorders and characterized by the intra- and extracellular accumulation of fibrillar aggregates.
Of the more than 25 unrelated proteins known to produce amyloidosis in humans only about a third of them are associated with
cerebral deposits translating in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination
thereof. The familial forms reviewed herein, although infrequent, provide unique paradigms to examine the role of amyloid
in the mechanism of disease pathogenesis and to dissect the link between vascular and parenchymal amyloid deposition and their
differential contribution to neurodegeneration. 相似文献
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Rostagno A Tomidokoro Y Lashley T Ng D Plant G Holton J Frangione B Revesz T Ghiso J 《Cellular and molecular life sciences : CMLS》2005,62(16):1814-1825
The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid β(Aβ) and its role in the neuronal loss characteristic of Alzheimer’s disease, the most common form of human cerebral amyloidosis. Two non-Aβ cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer’s disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.Received 4 March 2005; received after revision 24 April 2005; accepted 26 April 2005 相似文献
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