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71.
Rodriguez D Ramesh C Henson LH Wilmeth L Bryant BK Kadavakollu S Hirsch R Montoya J Howell PR George JM Alexander D Johnson DL Arterburn JB Shuster CB 《Bioorganic & medicinal chemistry》2011,19(18):5446-5453
Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents. 相似文献
72.
Background
A recent epidemiological study demonstrated a reduced risk of lung cancer mortality in breast cancer patients using antiestrogens. These and other data implicate a role for estrogens in lung cancer, particularly nonsmall cell lung cancer (NSCLC). Approximately 61% of human NSCLC tumors express nuclear estrogen receptor β (ERβ); however, the role of ERβ and estrogens in NSCLC is likely to be multifactorial. Here we tested the hypothesis that proteins interacting with ERβ in human lung adenocarcinoma cells that respond proliferatively to estradiol (E2) are distinct from those in non-E2-responsive cells.Methods
FLAG affinity purification of FLAG-ERβ-interacting proteins was used to isolate ERβ-interacting proteins in whole cell extracts from E2 proliferative H1793 and non-E2-proliferative A549 lung adenocarcinoma cell lines. Following trypsin digestion, proteins were identified using liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). Proteomic data were analyzed using Ingenuity Pathway Analysis. Select results were confirmed by coimmunoprecipitation.Results
LC-MS/MS identified 27 non-redundant ERβ-interacting proteins. ERβ-interacting proteins included hsp70, hsp60, vimentin, histones and calmodulin. Ingenuity Pathway Analysis of the ERβ-interacting proteins revealed differences in molecular and functional networks between H1793 and A549 lung adenocarcinoma cells. Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E2 or EGF. BRCA1 interacted with ERβ in A549 cell lines and in human lung adenocarcinoma tumors, but not normal lung tissue.Conclusion
Our results identify specific differences in ERβ-interacting proteins in lung adenocarcinoma cells corresponding to ligand-dependent differences in estrogenic responses.73.
Bakker MF Verstappen SM Welsing PM Jacobs JW Jahangier ZN van der Veen MJ Bijlsma JW Lafeber FP;Utrecht Arthritis Cohort study group 《Arthritis research & therapy》2011,13(3):R70
Introduction
The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA). 相似文献74.
George S. Mahuku María Antonia Henríquez Carmenza Montoya Carlos Jara Henry Teran Stephen Beebe 《Molecular breeding : new strategies in plant improvement》2011,28(1):57-71
Angular leaf spot (ALS) is one of the major diseases of the common bean (Phaseolus vulgaris L.). Different sources of resistance have been identified but few have been characterized. Studies were conducted to elucidate
the inheritance of ALS resistance in the bean accession G10909 and to identify molecular markers linked to these genes. Evaluation
of parental genotypes, F1, F2 and backcross to susceptible parent (Sprite) populations revealed that two dominant and complementary genes conditioned ALS
resistance. Allelism tests showed that the ALS resistance genes in G10909 were different from those in the Mesoamerican cultivars
Mexico 54, MAR 2, G10474 and Cornell 49-242. Three sequence-characterized amplified region (SCAR) markers, PF13310, PF9260 and OPE04709, and a microsatellite, Pv-gaat001, segregated in coupling with the resistance genes in G10909. Pairwise segregation analysis
revealed that markers PF13310, PF9260 and OPE04709 were linked, while Pv-gaat001 segregated in a 9:3:3:1 ratio from all markers. Markers PF13310, PF9260 and OPE04709 were mapped to linkage group B08, and segregated with resistance gene Phg
G10909B
at 4.9, 7.4 and 9.9 cM, respectively. Pv-gaat001, previously mapped to linkage group B04, segregated with resistance gene
Phg
G10909A
at 13 cM. The potential utility of these markers to aid breeding for ALS resistance is discussed. 相似文献
75.
76.
siRNA (small interfering RNA) and shRNA (small hairpin RNA) are powerful and commonly used tools in biomedical research. Currently, siRNAs are generally designed as two 21 nt strands of RNA that include a 19 nt completely complementary part and a 2 nt overhang. However, since the si/shRNAs use the endogenous miRNA machinery for gene silencing and the miRNAs are generally 22 nt in length and contain multiple internal mismatches, we tested if the functionality can be increased by designing the si/shRNAs to mimic a miRNA structure. We systematically investigated the effect of single or multiple mismatches introduced in the passenger strand at different positions on siRNA functionality. Mismatches at certain positions could significantly increase the functionality of siRNAs and also, in some cases decreased the unwanted passenger strand functionality. The same strategy could also be used to design shRNAs. Finally, we showed that both si and miRNA structured oligos (siRNA with or without mismatches in the passenger strand) can repress targets in all individual Ago containing cells, suggesting that the Ago proteins do not differentiate between si/miRNA-based structure for silencing activity. 相似文献
77.
78.
Reactions of ligands 1-ethyl-5-methyl-3-phenyl-1H-pyrazole (L1) and 5-methyl-1-octyl-3-phenyl-1H-pyrazole (L2) with [PdCl2(CH3CN)2 and K2PtCl4 gave complexes trans-[MCl2(L)2] (L = L1, L2). The new complexes were characterised by elemental analyses, conductivity measurements, infrared, 1H and 13C{1H} NMR spectroscopies and X-ray diffraction. The NMR study of the complex [PdCl2(L1)2], in CDCl3 solution, is consistent with a very slow rotation of ligands around the Pd-N bond, so that two conformational isomers can be observed in solution (syn and anti). Different behaviour is observed for complexes [PdCl2(L2)2] and [PtCl2(L)2] (L = L1, L2), which present an isomer in solution at room temperature (anti). The crystal structure of [PdCl2(L1)2] complex is described, where the Pd(II) presents a square planar geometry with the ligands coordinated in a trans disposition. 相似文献
79.
Two new pyrazole-derived ligands, 1-ethyl-3,5-bis(2-pyridyl)pyrazole (L1) and 1-octyl-3,5-bis(2-pyridyl)pyrazole (L2), both containing alkyl groups at position 1 were prepared by reaction between 3,5-bis(2-pyridyl) pyrazole and the appropriate bromoalkane in toluene using sodium ethoxide as base.The reaction between L1, L2 and [MCl2(CH3CN)2] (M = Pd(II), Pt(II)) resulted in the formation complexes of formula [MCl2(L)] (M = Pd(II), L = L1 (1); M = Pd(II), L = L2 (2); M = Pt(II), L = L1 (3); M = Pt(II), L = L2 (4)). These complexes were characterised by elemental analyses, conductivity measurements, infrared, 1H, 13C{1H} NMR and HMQC spectroscopies. The X-ray structure of the complex [PtCl2(L2)] (4) was determined. In this complex, Npyridine and Npyrazole donor atoms coordinate the ligand to the metal, which complete its coordination with two chloro ligands in a cis disposition. 相似文献
80.