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151.
152.
Sequence-selective DNA cleavage by a chimeric metallopeptide 总被引:3,自引:0,他引:3
A chimeric metallopeptide derived from the sequences of two structurally superimposable motifs was designed as an artificial nuclease. Both DNA recognition and nuclease activity have been incorporated into a small peptide sequence. P3W, a 33-mer peptide comprising helices alpha2 and alpha3 from the engrailed homeodomain and the consensus EF-hand Ca-binding loop binds one equivalent of lanthanides or calcium and folds upon metal binding. The conditional formation constants (in the presence of 50 mM Tris) of P3W for Eu(III) (K(a) = (2.1 +/- 0.1) x 10(5) M(-1)) and Ce(IV) (K(a) = (2.6 +/- 0.1) x 10(5) M(-1)) are typical of isolated EF-hand peptides. Circular dichroism studies show that 1:1 CeP3W is 26% alpha-helical and EuP3W is up to 40% alpha-helical in the presence of excess metal. The predicted helicity of the folded peptide based on helix length and end effects is about 50%, showing the metallopeptides are significantly folded. EuP3W has considerably more secondary structure than our previously reported chimeras (Welch, J. T.; Sirish, M.; Lindstrom, K. M.; Franklin, S. J. Inorg. Chem. 2001, 40, 1982-1984). Eu(III)P3W and Ce(IV)P3W nick supercoiled DNA at pH 6.9, although EuP3W is more active at pH 8. CeP3W cleaves linearized, duplex DNA as well as supercoiled plasmid. The cleavage of a 5'-(32)P-labeled 121-mer DNA fragment was followed by polyacrylamide gel electrophoresis. The cleavage products are 3'-OPO(3) termini exclusively, suggesting a regioselective or multistep mechanism. In contrast, uncomplexed Ce(IV) and Eu(III) ions produce both 3'-OPO(3) and 3'-OH, and no evidence of 4'-oxidative cleavage termini with either metal. The complementary 3'-(32)P-labeled oligonucleotide experiment also showed both 5'-OPO(3) and 5'-OH termini were produced by the free ions, whereas CeP3W produces only 5'-OPO(3) termini. In addition to apparent regioselectivity, the metallopeptides cut DNA with modest sequence discrimination, which suggests that the HTH motif binds DNA as a folded domain and thus cleaves selected sequences. The de novo artificial nuclease LnP3W represents the first small, underivatized peptide that is both active as a nuclease and sequence selective. 相似文献
153.
We propose that supercoiling energizes double-stranded DNA (dsDNA) so as to facilitate thermal fluctuations to an unzipped state. We support this with a model of two elastic rods coupled via forces that represent base-pair interactions. Supercoiling is shown to lead to a distention of base pairs over a short span of dsDNA. This enhances the thermal probability for their disruption. The localized region of distention is analogous to a soliton. Our theory permits the development of an analogy between the unzipping transition and a second-order phase transition, for which the possibility of a new set of critical exponents is identified. 相似文献
154.
Sharma V Beatty A Wey SP Dahlheimer J Pica CM Crankshaw CL Bass L Green MA Welch MJ Piwnica-Worms D 《Chemistry & biology》2000,7(5):335-343
BACKGROUND: Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy. RESULTS: Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo. CONCLUSIONS: These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET. 相似文献
155.
J. Michael Robinson Masood Ahmed Nicky J. Alaniz Timothy R. Boyles Chris D. Brasher Kimberly A. Floyd Preston L. Holland Laura D. Maruffo Terry L. Mcmahan Stan Middleton Kevin D. O'Hara Marcia J. Pack Brandon D. Reynolds Romelia R. Rodriquez Dennis E. Sawyer Elena Sharp Sharai L. Simpson Clint L. Vanlandingham Rebecca S. Velasquez Brian M. Welch C. David Wright 《Journal of heterocyclic chemistry》1998,35(1):65-69
Alternative complimentary syntheses of penta-substituted pyridine rings with full regiochemical control of substituents were studied as a method for the synthesis of Streptonigrin ( 1 ). Various α-substituted acetophenones 2 were reacted with enones 3 in acetic acid/ammonium acetate and air to afford penta-substituted pyridines 4 . α-Substituents that could provide a source of exocyclic nitrogen at position 3 of these Steptonigrin ring-C models proved to be the limiting factor. However, an inverse “3+2+1” cyclocondensation of α-cyanochalcone 5c with 2-furyl ethyl ketone ( 6b ) afforded the desired model 6-(2-furyl)-5-methyl2,4-diphenyl-3-pyridinecarbonitrile ( 4g ) in 75% yield. 相似文献
156.
A. Cohen E. White V B. Coxon R. G. Christensen M. J. Welch R. C. Paule D. A. Becker 《Fresenius' Journal of Analytical Chemistry》1990,338(4):426-429
Summary The process used to certify Standard Reference Material (SRM) 916a Bilirubin is described. The certification involved the use of various analytical techniques to detect or quantitate impurities, as well as to characterize the SRM itself. Bilirubin (BR) is believed to exist, in human serum, as the IX isomer. Samples prepared commercially, including this SRM, also contain the III and XIII isomers which are believed to be formed during purification. For the SRM, the three isomers were measured by HPLC and TLC. 1H NMR was used to detect and quantitate chloroform in the BR. Biliverdine and mesobilirubin were not detected. Impurities insoluble in chloroform, the residue from the ashing of BR, and volatiles were measured, in addition to non-acidic impurities and impurities more acidic than BR. The absorptivity of BR in chloroform was measured. A pink fluorescent impurity was detected and measured by TLC. From these analyses, a best estimate of the total amount of impurities was determined, and the BR was issued as SRM 916a with a certified purity of 98.3±0.3%. 相似文献
157.
158.
159.
The cathodic reduction of HCl dissolved in molten LiCl+KCl eutectic with the presence of up to 19 mol %ZnCl2 was investigated chronopotentiometrically and voltammetrically. On glassy carbon electrodes the reduction is a reversible, one-electron charge transfer forming soluble product and without kinetic complications. While the ZnCl2 causes an increase in solubility of the HCl, it also causes a decrease in the diffusion coefficient of the reduced species. Results obtained when using a platinum working electrode contrasted with those for the same solvent when using a glassy carbon electrode. The difference is probably due to adsorption occurring on the working electrode, the degree of adsorption approximating to monolayer coverage. The adsorption can be explained by either an AR, SR model or an SAR model and while the accuracy is insufficient to enable differentiation betwen the two, the latter mechanism is favoured. 相似文献
160.