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171.
Peptidyl alpha-aminoalkylphosphonate diphenyl esters have been synthesized and shown to be effective inhibitors of serine proteases. Extending the peptide chain from a single alpha-aminoalkylphosphonate residue (kobs/[I] = 2.5-260 M-1 s-1) to a tripeptide or tetrapeptide derivative (kobs/[I] = 7,000-17,000 M-1 s-1) resulted in 65-2800 improvement in inhibitory potency and increased specificity. The rate of inactivation of chymotrypsin by MeO-Suc-Ala-Ala-Pro-HNCH(CH2Ph)P(O)(OPh)2 was decreased 5 fold in the presence of the substrate Suc-Val-Pro-Phe-NA (0.119 mM). Phosphonylated serine proteases are extremely stable since the half-life for reactivation was greater than 48 hrs for the inhibited elastases and at least 10 hrs for chymotrypsin. 相似文献
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Use of N,O-bis-Fmoc-D-Tyr-ONSu for introduction of an oxidative iodination site into cholecystokinin family peptides 总被引:2,自引:0,他引:2
S P Powers D I Pinon L J Miller 《International journal of peptide and protein research》1988,31(5):429-434
We report the synthesis of a new reagent for the introduction of an oxidative iodination site into the amino terminus of acid-labile peptides, and the use of this reagent to synthesize a novel affinity-labeling probe for the cholecystokinin (CCK) receptor. The acylation reagent, N,O-bis-fluorenylmethyloxycarbonyl-D-tyrosine hydroxysuccinimide ester, utilizes base-labile protection of both the alpha amino group and the aromatic ring hydroxyl. This can be safely removed to expose a cross-linkable free amino group on the aminopeptidase-resistant D-enantiomer of tyrosine. The synthetic probe, D-Tyr-Gly-Asp-Tyr(OSO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2, was fully biologically active, could be radioiodinated to high-specific radioactivity (2000 Ci/mmol), bound with high affinity to the pancreatic CCK receptor, and covalently labeled the hormone-binding site. This reagent should be useful for the synthesis of a wide variety of analogues of CCK and other acid-labile peptides. 相似文献
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W E Blumberg P R Desai L Powers J H Freedman J J Villafranca 《The Journal of biological chemistry》1989,264(11):6029-6032
X-ray absorption spectroscopy has been used to investigate the local environment of the copper sites in bovine dopamine beta-hydroylase, the enzyme that catalyzes the conversion of dopamine to norepinephrine in the adrenal medulla and noradrenergic nerve cells. The marked similarity of the x-ray absorption edge features of the oxidized and ascorbate-reduced forms of the enzyme with those of the corresponding Cu(imidazole)4 complexes suggests that the ligation in both cases is very similar. Furthermore, this similarity is found for the extended x-ray absorption fine structure data, and analysis shows only nitrogen (or oxygen) ligation for both enzyme forms. Thus, four nitrogen atoms provide the best fit to the data at an average distance of 1.97 +/- 0.02 A for the oxidized enzyme and four nitrogen atoms at 2.05 +/- 0.02 A for the ascorbate-reduced form. The present data analysis also indicates that there is little change in the average copper ligand environment upon reduction of the enzyme-bound copper from Cu(II) to the Cu(I). The data for the oxidized form of the enzyme are in agreement with previous spin-echo EPR experiments that show three to four imidazole nitrogen ligands for each copper (McCracken, J., Desai, P. R., Papadopoulos, N. J., Villafranca, J. J., and Peisach, J. (1988) Biochemistry 27, 4133-4137). In addition, the data do not indicate the presence of any heavy atom (sulfur or chlorine) ligation to the ascorbate-reduced form of the enzyme as reported by Scott et al. (Scott, R. A., Sullivan, R. J., DeWolf, W. E., Jr., Dolle, R. E., and Kruse, L. I. (1988) Biochemistry 27, 5411-5417). 相似文献
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Eric C. Mossel Jeremy P. Ledermann Aaron T. Phillips Erin M. Borland Ann M. Powers Ken E. Olson 《PloS one》2013,8(3)
Western equine encephalitis virus (WEEV) is a naturally occurring recombinant virus derived from ancestral Sindbis and Eastern equine encephalitis viruses. We previously showed that infection by WEEV isolates McMillan (McM) and IMP-181 (IMP) results in high (∼90–100%) and low (0%) mortality, respectively, in outbred CD-1 mice when virus is delivered by either subcutaneous or aerosol routes. However, relatively little is known about specific virulence determinants of WEEV. We previously observed that IMP infected Culex tarsalis mosquitoes at a high rate (app. 80%) following ingestion of an infected bloodmeal but these mosquitoes were infected by McM at a much lower rate (10%). To understand the viral role in these phenotypic differences, we characterized the pathogenic phenotypes of McM/IMP chimeras. Chimeras encoding the E2 of McM on an IMP backbone (or the reciprocal) had the most significant effect on infection phenotypes in mice or mosquitoes. Furthermore, exchanging the arginine, present on IMP E2 glycoprotein at position 214, for the glutamine present at the same position on McM, ablated mouse mortality. Curiously, the reciprocal exchange did not confer mouse virulence to the IMP virus. Mosquito infectivity was also determined and significantly, one of the important loci was the same as the mouse virulence determinant identified above. Replacing either IMP E2 amino acid 181 or 214 with the corresponding McM amino acid lowered mosquito infection rates to McM-like levels. As with the mouse neurovirulence, reciprocal exchange of amino acids did not confer mosquito infectivity. The identification of WEEV E2 amino acid 214 as necessary for both IMP mosquito infectivity and McM mouse virulence indicates that they are mutually exclusive phenotypes and suggests an explanation for the lack of human or equine WEE cases even in the presence of active transmission. 相似文献