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排序方式: 共有595条查询结果,搜索用时 31 毫秒
131.
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Georgette M. Castanedo Shumei Wang Kirk D. Robarge Elizabeth Blackwood Daniel Burdick Christine Chang Gerrit J.P. Dijkgraaf Stephen Gould Janet Gunzner Oivin Guichert Jason Halladay Cyrus Khojasteh Leslie Lee James C. Marsters Lesley Murray David Peterson Emile Plise Laurent Salphati Frederic J. de Sauvage Susan Wong Daniel P. Sutherlin 《Bioorganic & medicinal chemistry letters》2010,20(22):6748-6753
Potent and efficacious inhibitors of the hedgehog pathway for the treatment of cancer have been prepared using the 2-pyridyl biphenyl amide scaffold common to the clinical lead GDC-0449. Analogs with polar groups in the para-position of the aryl amide ring optimized potency, had minimal CYP inhibition, and possessed good exposure in rats. Compounds 9d and 14f potently inhibited hedgehog signaling as measured by Gli1 mRNA and were found to be equivalent or more potent than GDC-0449, respectively, when studied in a Ptch+/? medulloblastoma allograft model, that is, highly dependent on hedgehog signaling. 相似文献
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135.
Maria Veiga-da-Cunha Donatienne Tyteca Vincent Stroobant Pierre J. Courtoy Fred R. Opperdoes Emile Van Schaftingen 《The Journal of biological chemistry》2010,285(24):18888-18898
Our goal was to identify the reaction catalyzed by NAT8 (N-acetyltransferase 8), a putative N-acetyltransferase homologous to the enzyme (NAT8L) that produces N-acetylaspartate in brain. The almost exclusive expression of NAT8 in kidney and liver and its predicted association with the endoplasmic reticulum suggested that it was cysteinyl-S-conjugate N-acetyltransferase, the microsomal enzyme that catalyzes the last step of mercapturic acid formation. In agreement, HEK293T extracts of cells overexpressing NAT8 catalyzed the N-acetylation of S-benzyl-l-cysteine and leukotriene E4, two cysteine conjugates, but were inactive on other physiological amines or amino acids. Confocal microscopy indicated that NAT8 was associated with the endoplasmic reticulum. Neither of the two frequent single nucleotide polymorphisms found in NAT8, E104K nor F143S, changed the enzymatic activity or the expression of the protein by ≥2-fold, whereas a mutation (R149K) replacing an extremely conserved arginine suppressed the activity. Sequencing of genomic DNA and EST clones corresponding to the NAT8B gene, which resulted from duplication of the NAT8 gene in the primate lineage, disclosed the systematic presence of a premature stop codon at codon 16. Furthermore, truncated NAT8B and NAT8 proteins starting from the following methionine (Met-25) showed no cysteinyl-S-conjugate N-acetyltransferase activity when transfected in HEK293T cells. Taken together, these findings indicate that NAT8 is involved in mercapturic acid formation and confirm that NAT8B is an inactive gene in humans. NAT8 homologues are found in all vertebrate genomes, where they are often encoded by multiple, tandemly repeated genes as many other genes encoding xenobiotic metabolism enzymes. 相似文献
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137.
Profiling of the tetraspanin web of human colon cancer cells 总被引:1,自引:0,他引:1
Le Naour F André M Greco C Billard M Sordat B Emile JF Lanza F Boucheix C Rubinstein E 《Molecular & cellular proteomics : MCP》2006,5(5):845-857
Tetraspanins are integral membrane proteins involved in a variety of physiological and pathological processes. In cancer, clinical and experimental studies have reported a link between tetraspanin expression levels and metastasis. Tetraspanins play a role as organizers of multimolecular complexes in the plasma membrane. Indeed each tetraspanin associates specifically with one or a few other membrane proteins forming primary complexes. Thus, tetraspanin-tetraspanin associations lead to a molecular network of interactions, the "tetraspanin web." We performed a proteomic characterization of the tetraspanin web using a model of human colon cancer consisting of three cell lines derived from the primary tumor and two metastases (hepatic and peritoneal) from the same patient. The tetraspanin complexes were isolated after immunoaffinity purification using monoclonal antibodies directed against the tetraspanin CD9, and the associated proteins were separated by SDS-PAGE and identified by mass spectrometry using LC-MS/MS. This allowed the identification of 32 proteins including adhesion molecules (integrins, proteins with Ig domains, CD44, and epithelial cell adhesion molecule) (EpCAM), membrane proteases (ADAM10, TADG-15, and CD26/dipeptidyl peptidase IV), and signaling proteins (heterotrimeric G proteins). Importantly some components were differentially detected in the tetraspanin web of the three cell lines: the laminin receptor Lutheran/B-cell adhesion molecule (Lu/B-CAM) was expressed only on the primary tumor cells, whereas CD26/dipeptidyl peptidase IV and tetraspanin Co-029 were observed only on metastatic cells. Concerning Co-029, immunohistofluorescence showed a high expression of Co-029 on epithelial cells in normal colon and a lower expression in tumors, whereas heterogeneity in terms of expression level was observed on metastasis. Finally we demonstrated that epithelial cell adhesion molecule and CD9 form a new primary complex in the tetraspanin web. 相似文献
138.
Veronica Vinciotti Xiaohui Liu Rolf Turk Emile J de Meijer Peter AC 't Hoen 《BMC bioinformatics》2006,7(1):183-12
Background
The identification of biologically interesting genes in a temporal expression profiling dataset is challenging and complicated by high levels of experimental noise. Most statistical methods used in the literature do not fully exploit the temporal ordering in the dataset and are not suited to the case where temporal profiles are measured for a number of different biological conditions. We present a statistical test that makes explicit use of the temporal order in the data by fitting polynomial functions to the temporal profile of each gene and for each biological condition. A Hotelling T 2-statistic is derived to detect the genes for which the parameters of these polynomials are significantly different from each other. 相似文献139.
Identification of fructosamine residues deglycated by fructosamine-3-kinase in human hemoglobin 总被引:3,自引:0,他引:3
Delpierrre G Vertommen D Communi D Rider MH Van Schaftingen E 《The Journal of biological chemistry》2004,279(26):27613-27620
Fructosamine-3-kinase (FN3K) phosphorylates fructosamine residues, leading to their destabilization and their shedding from protein. Support for the occurrence of this deglycation mechanism in intact cells has been obtained by showing that hemoglobin is significantly more glycated when human erythrocytes are incubated with an elevated glucose concentration in the presence of 1-deoxy-1-morpholinofructose (DMF), a cell-permeable inhibitor of FN3K, than in its absence. The aim of this work was to identify the fructosamine residues on hemoglobin that are removed as a result of the action of FN3K in intact erythrocytes. Highly glycated hemoglobin derived from intact human erythrocytes incubated for 48 h with 200 mm glucose and DMF was incubated in vitro with FN3K and [gamma-(32)P]ATP. After reduction of fructosamine 3-phosphates with borohydride, the protein was digested with trypsin. Peptides were separated by reversed-phase high-performance liquid chromatography, and the radioactive peaks were analyzed by mass spectrometry. Nine different modified residues were identified. These were Lys-alpha-16, Lys-alpha-61, Lys-alpha-139, Val-beta-1, Lys-beta-17, Lys-beta-59, Lys-beta-66, Lys-beta-132, and Lys-beta-144. Some (e.g. Lys-alpha-139) were readily phosphorylated to a maximal extent by FN3K in vitro whereas others (e.g. Val-beta-1) were slowly and only very partially phosphorylated. The radiolabeled peptides containing reduced fructosamine 3-phosphates bound to Lys-alpha-16, Lys-alpha-139, and Lys-beta-17 were much less abundant if the hemoglobin substrate used for the in vitro phosphorylation with FN3K and [gamma-(32)P]ATP came from erythrocytes incubated with an elevated glucose concentration in the absence of DMF, indicating that these lysine residues had been substantially deglycated in intact cells when FN3K action was unrefrained. Other residues (e.g. Val-beta-1, Lys-alpha-61) seemed to be insignificantly deglycated in intact cells. 相似文献
140.
Stimulation of angiogenesis by Ras proteins 总被引:12,自引:0,他引:12