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61.
Kinetic and immunologic evidence for the absence of glucose-6-phosphatase in early human chorionic villi and term placenta. 总被引:1,自引:0,他引:1
V Barash A Riskin E Shafrir I D Waddell A Burchell 《Biochimica et biophysica acta》1991,1073(1):161-167
The existence of the enzyme glucose-6-phosphatase (G6Pase) in early and term human placenta was investigated by comparing the characteristics of placental microsomal glucose 6-phosphate (G6P) hydrolytic activity and liver G6Pase. Placental microsomes exhibited similar apparent Km values for G6P and beta-glycerophosphate in intact and deoxycholate-treated microsomes, heat stability at acidic pH, low latency of mannose 6-phosphate hydrolysis, very low activity of pyrophosphate: glucose phosphotransferase, and undetectable [U-14C]G6P transport into the placental microsomes, all of which indicated that specific G6Pase activity does not exist in placenta. Immunological evidence of the absence of both 36.5 kDa and T2 proteins, which represent the G6Pase catalytic protein and the phosphate/pyrophosphate transporter protein, respectively, confirmed that early and term human placenta are devoid of the multicomponent G6Pase enzyme. 相似文献
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A medium for the detection of Lancefield Group D cocci in skimmed milk powder by measurement of conductivity changes 总被引:1,自引:0,他引:1
A selective medium for the detection of Lancefield Group D cocci in skimmed milk powder by conductivity measurements was developed and evaluated using the Bactometer M123 and Malthus 128H systems. This medium promoted large changes in conductance and capacitance. The calibration curve of detection times vs concentration of Lancefield Group D cocci showed a linear correlation coefficient of 0.93 and the method gave comparable results in both conductivity instruments. Naturally contaminated samples containing c. 103 cfu/g of Lancefield Group D cocci gave detection times within 16–18 h which was sufficiently rapid for the medium to be used for the routine screening of skimmed milk powder. 相似文献
65.
Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease 下载免费PDF全文
The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA‐DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X‐ray structures of APTX engaging nicked RNA‐DNA substrates that provide direct evidence for a wedge‐pivot‐cut strategy for 5′‐AMP resolution shared with the alternate 5′‐AMP processing enzymes POLβ and FEN1. Our results uncover a DNA‐induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X‐ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations. 相似文献
66.
William R. Shadrick Peter J. Slavish Sergio C. Chai Brett Waddell Michele Connelly Jonathan A. Low Cynthia Tallant Brandon M. Young Nagakumar Bharatham Stefan Knapp Vincent A. Boyd Marie Morfouace Martine F. Roussel Taosheng Chen Richard E. Lee R. Kiplin Guy Anang A. Shelat Philip M. Potter 《Bioorganic & medicinal chemistry》2018,26(1):25-36
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates. 相似文献
67.
Antibody-selected variation and reversion in Sindbis virus neutralization epitopes. 总被引:12,自引:9,他引:3 下载免费PDF全文
Sindbis virus variants evidencing a complex and bidirectional tendency toward spontaneous antigenic change were isolated and characterized. Variants were selected on the basis of their escape from neutralization by individual monoclonal antibodies to either of the two envelope glycoproteins, E2 and E1. Multisite variants, including one altered in three neutralization sites, were obtained by selecting mutants consecutively in the presence of different neutralizing monoclonal antibodies. Two phenotypic revertants, each of which reacquired prototype antigenicity, were back-selected on the basis of their reactivity with a neutralizing monoclonal antibody. An incidental oligonucleotide marker distinguished these and the variant from which they arose from parental Sindbis virus and other mutants, thereby confirming that the revertants were true progeny of the antigenic variant. Prototype Sindbis virus and variants derived from it were compared on the basis of their reactivities with each of a panel of monoclonal antibodies; patterns revealed a minimum of five independently mutable Sindbis virus neutralization epitopes, segregating as three antigenic sites (two E2 and one E1). 相似文献
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A medium for the detection of Lancefield Group D cocci in skimmed milk powder by measurement of conductivity changes 总被引:1,自引:0,他引:1
A selective medium for the detection of Lancefield Group D cocci in skimmed milk powder by conductivity measurements was developed and evaluated using the Bactometer M123 and Malthus 128H systems. This medium promoted large changes in conductance and capacitance. The calibration curve of detection times vs concentration of Lancefield Group D cocci showed a linear correlation coefficient of 0.93 and the method gave comparable results in both conductivity instruments. Naturally contaminated samples containing c. 10(3) cfu/g of Lancefield Group D cocci gave detection times within 16-18 h which was sufficiently rapid for the medium to be used for the routine screening of skimmed milk powder. 相似文献
70.
The identification of T2; the phosphate/pyrophosphate transport protein of the hepatic microsomal glucose-6-phosphatase system 总被引:1,自引:0,他引:1
The phosphate/pyrophosphate translocase protein (T2) of the hepatic microsomal glucose-6-phosphatase system was identified and then purified using antibodies raised against the rat mitochondrial phosphate/hydroxyl ion antiport protein. The T2 protein was shown to be absent in the microsomes isolated from a patient previously diagnosed as having type lc glycogen storage disease. 相似文献