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排序方式: 共有226条查询结果,搜索用时 15 毫秒
181.
Ali MM Roe SM Vaughan CK Meyer P Panaretou B Piper PW Prodromou C Pearl LH 《Nature》2006,440(7087):1013-1017
Hsp90 (heat shock protein of 90 kDa) is a ubiquitous molecular chaperone responsible for the assembly and regulation of many eukaryotic signalling systems and is an emerging target for rational chemotherapy of many cancers. Although the structures of isolated domains of Hsp90 have been determined, the arrangement and ATP-dependent dynamics of these in the full Hsp90 dimer have been elusive and contentious. Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1. The structure reveals the complex architecture of the 'closed' state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1. Contrary to expectations, the closed Hsp90 would not enclose its client proteins but provides a bipartite binding surface whose formation and disruption are coupled to the chaperone ATPase cycle. 相似文献
182.
This research proposes a prediction model of multistage financial distress (MSFD) after considering contextual and methodological issues regarding sampling, feature and model selection criteria. Financial distress is defined as a three‐stage process showing different nature and intensity of financial problems. It is argued that applied definition of distress is independent of legal framework and its predictability would provide more practical solutions. The final sample is selected after industry adjustments and oversampling the data. A wrapper subset data mining approach is applied to extract the most relevant features from financial statement and stock market indicators. An ensemble approach using a combination of DTNB (decision table and naïve base hybrid model), LMT (logistic model tree) and A2DE (alternative N dependence estimator) Bayesian models is used to develop the final prediction model. The performance of all the models is evaluated using a 10‐fold cross‐validation method. Results showed that the proposed model predicted MSFD with 84.06% accuracy. This accuracy increased to 89.57% when a 33.33% cut‐off value was considered. Hence the proposed model is accurate and reliable to identify the true nature and intensity of financial problems regardless of the contextual legal framework. 相似文献
183.
184.
Systemic Practice and Action Research - Action research studies in education often address learners’ needs and empower practitioners to effectively change instructional practices and school... 相似文献
185.
Eeles RA Kote-Jarai Z Giles GG Olama AA Guy M Jugurnauth SK Mulholland S Leongamornlert DA Edwards SM Morrison J Field HI Southey MC Severi G Donovan JL Hamdy FC Dearnaley DP Muir KR Smith C Bagnato M Ardern-Jones AT Hall AL O'Brien LT Gehr-Swain BN Wilkinson RA Cox A Lewis S Brown PM Jhavar SG Tymrakiewicz M Lophatananon A Bryant SL;UK Genetic Prostate Cancer Study Collaborators;British Association of Urological Surgeons' Section of Oncology;UK ProtecT Study Collaborators Horwich A Huddart RA 《Nature genetics》2008,40(3):316-321
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at =60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3. 相似文献
186.
Barak T Kwan KY Louvi A Demirbilek V Saygı S Tüysüz B Choi M Boyacı H Doerschner K Zhu Y Kaymakçalan H Yılmaz S Bakırcıoğlu M Cağlayan AO Oztürk AK Yasuno K Brunken WJ Atalar E Yalçınkaya C Dinçer A Bronen RA Mane S Ozçelik T Lifton RP Sestan N Bilgüvar K Günel M 《Nature genetics》2011,43(6):590-594
The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations. 相似文献
187.
ATM protein kinase: the linchpin of cellular defenses to stress 总被引:1,自引:1,他引:0
Bhatti S Kozlov S Farooqi AA Naqi A Lavin M Khanna KK 《Cellular and molecular life sciences : CMLS》2011,68(18):2977-3006
ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly
challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated
early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the
damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration.
Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating
diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we
have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying
the complex phenotypes observed in AT patients. 相似文献
188.
Syed Zahid Ali Shah Tariq Hussain Deming Zhao Lifeng Yang 《Cellular and molecular life sciences : CMLS》2017,74(6):1061-1074
Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca2+) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca2+ in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca2+ storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases. 相似文献
189.
Adel Alahmadi Husain Alhazmi Shakir Ali Tor Helleseth Rola Hijazi Chunlei Li Patrick Solé 《系统科学与复杂性》2017,30(4):950-966
This paper constructs a cyclic ?4-code with a parity-check matrix similar to that of Goethals code but in length 2m + 1, for all m ≥ 4. This code is a subcode of the lifted Zetterberg code for m even. Its minimum Lee weight is shown to be at least 10, in general, and exactly 12 in lengths 33, 65. The authors give an algebraic decoding algorithm which corrects five errors in these lengths for m = 5, 6 and four errors for m > 6. 相似文献
190.
Crow YJ Leitch A Hayward BE Garner A Parmar R Griffith E Ali M Semple C Aicardi J Babul-Hirji R Baumann C Baxter P Bertini E Chandler KE Chitayat D Cau D Déry C Fazzi E Goizet C King MD Klepper J Lacombe D Lanzi G Lyall H Martínez-Frías ML Mathieu M McKeown C Monier A Oade Y Quarrell OW Rittey CD Rogers RC Sanchis A Stephenson JB Tacke U Till M Tolmie JL Tomlin P Voit T Weschke B Woods CG Lebon P Bonthron DT Ponting CP Jackson AP 《Nature genetics》2006,38(8):910-916
Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation. 相似文献