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Abstract: Native chemical ligation has proven to be a powerful method for the synthesis of small proteins and the semisynthesis of larger ones. The essential synthetic intermediates, which are C‐terminal peptide thioesters, cannot survive the repetitive piperidine deprotection steps of Nα‐9‐fluorenylmethoxycarbonyl (Fmoc) chemistry. Therefore, peptide scientists who prefer to not use Nα‐t‐butyloxycarbonyl (Boc) chemistry need to adopt more esoteric strategies and tactics in order to integrate ligation approaches with Fmoc chemistry. In the present work, side‐chain and backbone anchoring strategies have been used to prepare the required suitably (partially) protected and/or activated peptide intermediates spanning the length of bovine pancreatic trypsin inhibitor (BPTI). Three separate strategies for managing the critical N‐terminal cysteine residue have been developed: (i) incorporation of Nα‐9‐fluorenylmethoxycarbonyl‐S‐(N‐methyl‐N‐phenylcarbamoyl)sulfenylcysteine [Fmoc‐Cys(Snm)‐OH], allowing creation of an otherwise fully protected resin‐bound intermediate with N‐terminal free Cys; (ii) incorporation of Nα‐9‐fluorenylmethoxycarbonyl‐S‐triphenylmethylcysteine [Fmoc‐Cys(Trt)‐OH], generating a stable Fmoc‐Cys(H)‐peptide upon acidolytic cleavage; and (iii) incorporation of Nα‐t‐butyloxycarbonyl‐S‐fluorenylmethylcysteine [Boc‐Cys(Fm)‐OH], generating a stable H‐Cys(Fm)‐peptide upon cleavage. In separate stages of these strategies, thioesters are established at the C‐termini by selective deprotection and coupling steps carried out while peptides remain bound to the supports. Pilot native chemical ligations were pursued directly on‐resin, as well as in solution after cleavage/purification. 相似文献
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SEVERO SALVADORI REMO GUERRINI PIERO ANDREA BOREA ROBERTO TOMATIS 《Chemical biology & drug design》1992,40(5):437-444
The synthesis of pseudotetrapeptides H-Tyr-D-Ala-Phe-NH-(CH2)2-NH2 (1a), H-Tyr-D-Ala-Phe-ψ(CH2-NH)-Gly-NH2 (2a), H-Tyr-D-Ala-ψ(CH2-NH)-Phe-Gly-NH2 (3a), and H-Tyr-ψ(CH2-NH)-D-Ala-Phe-Gly-NH2 (4a), representing the N-terminal tetrapeptide sequence of dermorphin, in which amide bonds are replaced by CH2-NH bond, is described. N-acetyl-Tyr and desamino-Tyr pseudopeptide analogs (1-4b), (1-3c) are also described. The analogs were assayed in binding studies based on displacement of μ and δ-receptor selective radiolabels from rat brain membrane and in a bioassay using guinea pig ileum (GPI). Pseudopeptides in which the C-terminal (1a) or D-Ala-Phe (3a) amide bond are substituted, exhibit higher μ-affinities and μ-receptor selectivity than the corresponding Phe-Gly or Tyr-D-Ala analogs (2a, 4a). Acetyl-and desamino-Tyr pseudopeptide analogs (1-4b) and (1-3c) did not exhibit μ and δ-opioid receptor affinity at nM concentration. The relevance of the single peptide replacement and of its association to acetylation or amino group elimination of Tyr, is discussed on the basis of a receptor model for μ and δ opioids. 相似文献
5.
The previously described cyclic delta opioid receptor-selective tetrapeptide H-Tyr-d -Cys-Phe-d -Pen-OH (JOM-13) was modified at residue 3 by incorporation of both natural and unnatural amino acids with varying steric, electronic, and lipophilic properties. Effects on mu and delta opioid receptor binding affinities were evaluated by testing the compounds for displacement of radiolabeled receptor-selective ligands in a guinea pig brain receptor binding assay. Results obtained with the bulky aromatic 1-Nal3 and 2-Nal3 substitutions suggest that the shape of the receptor subsite with which the side chain of the internal aromatic residue interacts differs for delta and mu receptors. This subsite of either receptor can accommodate the transverse steric bulk of the 1-Nal3 side chain but only the delta receptor can readily accept the more elongated 2-Nal3 side chain. Several analogs with pi-excessive heteroaromatic side chains in residue 3 were examined. In general, these analogs display diminished binding to mu and delta receptors, consistent with previous findings for analogs with residue 3 substitutions of modified electronic character. Several analogs with alkyl side chains in residue 3 were also examined. While delta receptor binding affinity is severely diminished with Val3, Ile3, and Leu3 substitutions, Cha3 substitution is very well tolerated, indicating that, contrary to the widely held belief, an aromatic side chain in this portion of the ligand is not required for delta receptor binding. Where possible, comparison of results in this delta-selective tetrapeptide series with those reported for analogous modification in the cyclic delta-selective pentapeptide [d -Pen2, d -Pen5]enkephalin (DPDPE) and linear pentapeptide enkephalins reveals similar trends. 相似文献
6.
CHRISTIANE MENDRE VERONIQUE SARRADE BERNARD CALAS 《Chemical biology & drug design》1992,39(3):278-284
The continuous flow syntheses of endothelin 1, proendothelin 2. ATP binding site of the CDC2 kinase 3, and fragment 18-30 of an actin 4, have been performed by using a polyacrylamide gel resin Expansin? (about 0.6 mmol NH2/g) with the glycolamidic ester handle as labile anchorage. In addition, we report here a method of air oxidation which reduces the formation of side-products related to the formation of intermolecular disulfide bridges. 相似文献
7.
用酸蚀法提高纯钛与光固化冠桥树脂粘结强度的研究 总被引:5,自引:1,他引:4
目的:研究用酸蚀法提高钛与光固化复合树脂剪切粘结强度的可行性,并观察表面粗糙度与剪切粘结强度之间的关系。方法:采用不同浓度的酸蚀剂对钛铸件表面进行酸蚀,并与artglass光固化复合树脂进行粘结,以单纯喷砂组为对照,比较剪切粘结强度的差异。对酸蚀后及剪切试验后的金属表面进行扫描电镜观察,并测定其表面粗糙度。结果:用酸蚀法可以显著提高钛与复合树脂的粘结强度,HF浓度为4%时粘结强度最高。表面粗糙度随酸蚀剂的浓度增高而下降。结论:纯钛铸件用酸蚀法处理后可以获得较高的粘结强度,HF酸浓度以4%为宜。表面粗糙度对粘结强度不起决定性作用。 相似文献
8.
Peter E. Jensen 《Seminars in immunology》1995,7(6)
CD4+ helper T cells recognize short peptides stably associated with class II MHC molecules displayed on the surface of antigen presenting cells. Very little is known about the sequence of events that lead to the generation of these peptides from protein antigens. It is likely that native proteins must partially unfold before they are cleaved by endopeptidases or bind to MHC proteins. For many antigens, the rate-limiting step in unfolding may involve reduction of disulfide bonds. Evidence that disulfide reduction occurs in endocytic compartments is reviewed and potential mechanisms for the reduction of antigen disulfide bonds are proposed. 相似文献
9.
Chemical catalysis, an effector mechanism utilized by fully assembled antibodies, can also be mediated by the isolated antibody subunits. Because trace amounts of free light chains (L chains) are present in IgG preparations, a detailed study was undertaken to identify the constituents responsible for the polyreactive proteolytic activity of IgG purified from human sera, determined as the extent of cleavage of the model peptide substrate Pro-Phe-Arg-methylcoumarinamide. Two proteolytic species with approximate mass of 50 kD and 150 kD were separated by repetitive gel filtration in a denaturing solvent (6 M guanidine hydrochloride). The activity of the renatured 50-kD fraction (in fluorescence units/microg protein) was more than 45-fold greater than of the 150-kD fraction. Both fractions lost the activity following immunoadsorption on immobilized anti-IgG antibody. Fab fragments prepared from the 150-kD IgG fraction retained the activity. Reducing and non-reducing SDS-electrophoresis suggested the 50-kD fraction isolated from the IgG preparations to be a mixture of heavy chain (H chain) monomers and disulphide bonded L chain dimers. Electrophoretically homogeneous monomers of 50-kD H chains and 25-kD L chains were prepared by gel filtration of reduced and alkylated IgG from seven human subjects. Each of the alkylated L chain preparations displayed the proteolytic activity. The activity in alkylated H chains was undetectable or only marginally greater than the background values. L chain dimers appear to be the major species responsible for the polyreactive proteolytic activity of serum IgG preparations, with a smaller contribution furnished by tetrameric IgG. 相似文献
10.
The O-alkyl-N-aryl thiocarbamate, I, (2-chloro-5-[[(l-methyl-ethoxy)thioxomethyl]amino]benzoic acid, 1-methylethylester, NSC 629243, also known as Uniroyal Jr.) is an experimental anti-HIV drug with very low water solubility (1.5 µg/mL). Early clinical studies required an injectable solution at 15 mg/mL, representing a solubility increase of 104-fold. Adequate solubilization of this hydrophobic drug was achieved in 20% lipid emulsions. Extemporaneous emulsions were prepared by adding a concentrated drug solution to a commercially available parenteral emulsion. Various methods of preparation to minimize drug precipitation during its addition and enhance redissolution of precipitated drug were evaluated. The stability and mechanism(s) of decomposition of NSC 629243 in both 20% lipid emulsions and in natural oil vehicles were examined. In lipid emulsions, the shelf life at 25°C varied from 1 to >10 weeks, depending on the extent to which air was excluded from the preparation. The shelf life of 50 mg/mL solutions in natural oils at 25°C varied from <1 to >100 days depending on the oil and its supplier. A qualitative correlation was found between the initial rate of oxidation and the peroxide concentration in the oil. The primary degradation product in both systems was shown to be a disulfide dimer, II, formed via oxidation. Oxidation was inhibited by vacuum-sealing of emulsion formulations or incorporation of an oil-soluble thiol, thioglycolic acid (TGA), into oil formulations. TGA may inhibit oxidation by consuming free radicals or peroxide initiators or by reacting with the disulfide, II, to regenerate the starting drug. 相似文献