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101.
Barrese AA Genis C Fisher SZ Orwenyo JN Kumara MT Dutta SK Phillips E Kiddle JJ Tu C Silverman DN Govindasamy L Agbandje-McKenna M McKenna R Tripp BC 《Biochemistry》2008,47(10):3174-3184
This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791 . Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect. 相似文献
102.
Chikara Murakata Masami Kaneko George Gessner Thelma S Angeles Mark A Ator Teresa M O'Kane Beth Ann W McKenna Beth Ann Thomas Joanne R Mathiasen Michael S Saporito Donna Bozyczko-Coyne Robert L Hudkins 《Bioorganic & medicinal chemistry letters》2002,12(2):147-150
The MLK1-3 activity for a series of analogues of the indolocarbazole K-252a is reported. Addition of 3,9-bis-alkylthiomethyl groups to K-252a results in potent and selective MLK inhibitors. The in vitro and in vivo survival promoting activity of bis-isopropylthiomethyl-K-252a (16, CEP-11004/KT-8138) is reported. 相似文献
103.
104.
Spontaneous mutation at the adenine phosphoribosyl transferase (APRT) locus in clone 707 of the Friend cell line was examined. The frequency of cells resistant to 2,6-diaminopurine (DAP) was found to be 2.6 × 10−5 with a mutation rate of 1.81 × 10−6 cell−1 generation−1. APRT activities in 9 DAP-resistant clones were found to vary between 0 and 27% the level observed in wild-type cells. It is suggested that clone 707 cells are heterozygous or functionally hemizygous at the APRT locus. 相似文献
105.
H Haines T M McKenna R M Edwards 《Comparative biochemistry and physiology. A, Comparative physiology》1987,87(3):597-601
1. Total water (TW), and extracellular water (ECW) (as sodium and chloride space) were determined in skeletal muscle and carcass of Mus musculus acclimated to long-term water shortage. 2. The presence of fat in control mice and those in early stages of acclimation resulted in an apparent increase in TW and ECW as acclimation proceeded. 3. In contrast, fluid volumes per fat-free weight were either unchanged from controls or reduced. 4. Sodium space exceeded chloride space. 5. Muscle and carcass had essentially the same pattern of fluid shifts. 6. We conclude that ECW maintenance is a preeminent component of the acclimation process in this species. 相似文献
106.
H. J. McKenna 《Cancer immunology, immunotherapy : CII》1999,48(6):281-286
flt3 ligand (FL) is a growth factor that induces hematopoietic progenitor cell and dendritic cell (DC) expansion when administered
to mice. Lymphoid-related (CD8α+) and myeloid-related (CD8α−) DC are transiently expanded in multiple tissues. Treatment of tumor-bearing mice with FL results in slower tumor growth
and, in some cases, tumor rejection and the development of tumor-specific T cell immunity. The clinical use of DC as cellular
vehicles for tumor antigen presentation to generate a tumor-specific T cell response is under investigation. DC are currently
generated ex vivo, pulsed with antigen, and then infused into patients, and much effort is being directed toward optimizing
each of these steps. Administration of FL to humans induces a profound increase in circulating DC. The availability of a large
number of DC generated in vivo has important implications for tumor immunotherapy approaches.
Received: 13 May 1999 / Accepted: 14 June 1999 相似文献
107.
108.
Nor F Rajab Declan J McKenna Jim Diamond Kate Williamson Peter W Hamilton Valerie J McKelvey-Martin 《Cytometry. Part A》2006,69(10):1077-1085
BACKGROUND: Nuclear texture analysis measures phenotypic changes in chromatin distribution within a cell nucleus, while the alkaline Comet assay is a sensitive method for measuring the extent of DNA breakage in individual cells. The authors aim to use both methods to provide information about the sensitivity of cells to ionizing radiation. METHODS: The alkaline Comet assay was performed on six human bladder carcinoma cell lines and one human urothelial cell line exposed to gamma-radiation doses from 0 to 10 Gy. Nuclear chromatin texture analysis of 40 features was then performed in the same cell lines exposed to 0, 2, and 6 Gy to explore if nuclear phenotype was related to radiation sensitivity. RESULTS: Comet assay results demonstrated that the cell lines exhibited different levels of radiosensitivity and could be divided into a radiosensitive and a radioresistant group at >6 Gy. Using stepwise discriminant analysis, a subset of important nuclear texture features that best discriminated between sensitive and resistant cell lines were identified A classification function, defined using these features, correctly classified 81.75% of all cells into their radiosensitive or radioresistant groups based on their pretreatment chromatin phenotype. Posttreatment chromatin changes also varied between cell lines, with sensitive cell lines showing a relaxed chromatin conformation following radiation, whereas resistant cell lines exhibited chromatin condensation. CONCLUSIONS: The authors conclude that the alkaline Comet assay and nuclear texture methodologies may prove to be valuable aids in predicting the response of tumor cells to radiotherapy. 相似文献
109.
T. J. McKenna J. F. Donohoe T. G. Brien J. J. Healy B. St. J. Canning F. P. Muldowney 《BMJ (Clinical research ed.)》1971,2(5764):739-741
Three pharmacological agents in use as “potassium-sparing” drugs have been tested by serial measurements of total exchangeable potassium (KE) during 4 to 12 weeks of oral diuretic therapy in hypertensive subjects. Triamterene seemed ineffective in the dosage used (50 mg twice daily). Spironolactone (25 mg twice daily) reduced K loss to a considerable extent, while Slow-K (32 mEq daily) completely reversed previous KE deficits. Plasma K levels were a poor indication of degree of KE restoration. 相似文献
110.