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排序方式: 共有115条查询结果,搜索用时 15 毫秒
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Tatham MH Geoffroy MC Shen L Plechanovova A Hattersley N Jaffray EG Palvimo JJ Hay RT 《Nature cell biology》2008,10(5):538-546
In acute promyelocytic leukaemia (APL), the promyelocytic leukaemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). This disease can be treated effectively with arsenic, which induces PML modification by small ubiquitin-like modifiers (SUMO) and proteasomal degradation. Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro. In the absence of RNF4, arsenic failed to induce degradation of PML and SUMO-modified PML accumulated in the nucleus. These results demonstrate that poly-SUMO chains can act as discrete signals from mono-SUMOylation, in this case targeting a poly-SUMOylated substrate for ubiquitin-mediated proteolysis. 相似文献
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The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis
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Besser RE Jones AG McDonald TJ Shields BM Knight BA Hattersley AT 《Diabetic medicine : a journal of the British Diabetic Association》2012,29(10):1279-1284
Diabet. Med. 29, 1279-1284 (2012) ABSTRACT: Aims The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. Methods Ninety-one adults with insulin-treated diabetes (Type?1 n?=?56, Type?2 n?=?35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. Results The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r?=?0.98, P?0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P?=?0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥?0.2?nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r?=?0.97, P?0.0001). A fasting serum C-peptide ≥?0.07?nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥?0.2?nmol/l). Conclusions Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients. 相似文献
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Mark W. Moyle Taekyung Kim Neil Hattersley Julien Espeut Dhanya K. Cheerambathur Karen Oegema Arshad Desai 《The Journal of cell biology》2014,204(5):647-657
Recruitment of Mad1–Mad2 complexes to unattached kinetochores is a central event in spindle checkpoint signaling. Despite its importance, the mechanism that recruits Mad1–Mad2 to kinetochores is unclear. In this paper, we show that MAD-1 interacts with BUB-1 in Caenorhabditis elegans. Mutagenesis identified specific residues in a segment of the MAD-1 coiled coil that mediate the BUB-1 interaction. In addition to unattached kinetochores, MAD-1 localized between separating meiotic chromosomes and to the nuclear periphery. Mutations in the MAD-1 coiled coil that selectively disrupt interaction with BUB-1 eliminated MAD-1 localization to unattached kinetochores and between meiotic chromosomes, both of which require BUB-1, and abrogated checkpoint signaling. The identified MAD-1 coiled-coil segment interacted with a C-terminal region of BUB-1 that contains its kinase domain, and mutations in this region prevented MAD-1 kinetochore targeting independently of kinase activity. These results delineate an interaction between BUB-1 and MAD-1 that targets MAD-1–MAD-2 complexes to kinetochores and is essential for spindle checkpoint signaling. 相似文献
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David A. Scott Kirsten J. Bell Cheryl T. Campbell Donald J. Cook Les A. Dakin David J. Del Valle Lisa Drew Thomas W. Gero Maureen M. Hattersley Charles A. Omer Boris Tyurin Xiaolan Zheng 《Bioorganic & medicinal chemistry letters》2009,19(3):701-705
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified. 相似文献
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Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals 总被引:7,自引:0,他引:7 下载免费PDF全文
Freathy RM Weedon MN Bennett A Hypponen E Relton CL Knight B Shields B Parnell KS Groves CJ Ring SM Pembrey ME Ben-Shlomo Y Strachan DP Power C Jarvelin MR McCarthy MI Davey Smith G Hattersley AT Frayling TM 《American journal of human genetics》2007,80(6):1150-1161
The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation. 相似文献
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DON AT AGOSTI 《Systematic Entomology》1994,19(2):93-117
Abstract. The holarctic ant tribe Formicini is revised, the new genus Bajcaridris described, and possible phylogenetic relationships are discussed. The subgenus Iberoformica is synonymized with Formica. A synopsis, diagnosis and keys to the genera are provided. 相似文献
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