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121.
CYP2E1 substrate inhibition. Mechanistic interpretation through an effector site for monocyclic compounds 总被引:1,自引:0,他引:1
Collom SL Laddusaw RM Burch AM Kuzmic P Perry MD Miller GP 《The Journal of biological chemistry》2008,283(6):3487-3496
In this study we offer a mechanistic interpretation of the previously known but unexplained substrate inhibition observed for CYP2E1. At low substrate concentrations, p-nitrophenol (pNP) was rapidly turned over (47 min(-1)) with relatively low K(m) (24 microM); nevertheless, at concentrations of >100 microM, the rate of pNP oxidation gradually decreased as a second molecule bound to CYP2E1 through an effector site (K(ss) = 260 microm), which inhibited activity at the catalytic site. 4-Methylpyrazole (4MP) was a potent inhibitor for both sites through a mixed inhibition mechanism. The K(i) for the catalytic site was 2.0 microM. Although we were unable to discriminate whether an EIS or ESI complex formed, the respective inhibition constants were far lower than K(ss). Bicyclic indazole (IND) inhibited catalysis through a single CYP2E1 site (K(i) = 0.12 microM). Similarly, 4MP and IND yielded type II binding spectra that reflected the association of either two 4MP or one IND molecule(s) to CYP2E1, respectively. Based on computational docking studies with a homology model for CYP2E1, the two sites for monocyclic molecules, pNP and 4MP, exist within a narrow channel connecting the active site to the surface of the enzyme. Because of the presence of the heme iron, one site supports catalysis, whereas the other more distal effector site binds molecules that can influence the binding orientation and egress of molecules for the catalytic site. Although IND did not bind these sites simultaneously, the presence of IND at the catalytic site blocked binding at the effector site. 相似文献
122.
Shao L Hewitt M Jerussi TP Wu F Malcolm S Grover P Fang K Koch P Senanayake C Bhongle N Ribe S Bakale R Currie M 《Bioorganic & medicinal chemistry letters》2008,18(5):1674-1680
Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency. 相似文献
123.
Hypersensitive response of wheat to the Hessian fly 总被引:3,自引:0,他引:3
Paul B. Grover Jr. 《Entomologia Experimentalis et Applicata》1995,74(3):283-294
Hessian flyMayetiola destructor (Say) larvae are able to obtain food from their host plant without inflicting mechanical damage to the plant surface, apparently
by secreting substances which elicit release of nutrients from plant cells surrounding the feeding site. Cells of fully susceptible
plants retain their normal appearances, while in resistant plants extensive areas of cellular collapse occur. These responses
indicate that hypersensitivity is the basis of wheat's resistance to the Hessian fly. The fly's feeding mechanism more closely
resembles that of a pathogen than of a phytophagous insect; correspondingly, both the genetic relationship and resistance
mechanism of the host plant to the parasite are of the sorts commonly associated with bacterial and fungal pathogens. 相似文献
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We examined the effects of peroxide on the sarco(endo)plasmicreticulum Ca2+ (SERCA) pump in pigcoronary artery endothelium and smooth muscle at three organizationallevels: Ca2+ transport inpermeabilized cells, cytosolicCa2+ concentration in intactcells, and contractile function of artery rings. We monitored theATP-dependent, azide-insensitive, oxalate-stimulated 45Ca2+uptake by saponin-permeabilized cultured cells. Low concentrations ofperoxide inhibited the uptake less effectively in endothelium than insmooth muscle whether we added the peroxide directly to theCa2+ uptake solution or treatedintact cells with peroxide and washed them before the permeabilization.An acylphosphate formation assay confirmed the greater resistance ofthe SERCA pump in endothelial cells than in smooth muscle cells.Pretreating smooth muscle cells with 300 µM peroxide inhibited (by 77 ± 2%) the cyclopiazonic acid (CPA)-induced increase in cytosolicCa2+ concentration in aCa2+-free solution, but it did notaffect the endothelial cells. Peroxide pretreatment inhibited theCPA-induced contraction in deendothelialized arteries with a 50%inhibitory concentration of 97 ± 13 µM, but up to 500 µMperoxide did not affect the endothelium-dependent, CPA-inducedrelaxation. Similarly, 500 µM peroxide inhibited the angiotensin-induced contractions in deendothelialized arteries by 93 ± 2%, but it inhibited the bradykinin-induced,endothelium-dependent relaxation by only 40 ± 13%. The greaterresistance of the endothelium to reactive oxygen may be importantduring ischemia-reperfusion or in the postinfection immune response. 相似文献
128.
Cytogenetic investigations of 5 diploid Argemone species and their hybrids were undertaken. Correlative informations on the morphology, cytology, crossability and interfertility have been secured to understand the mechanism crossability and interfertility have been secured to understand the mechanism of speciation in the genus.All species studied possess 14 bivalents, normal meiosis and perfect pollen and seed fertility.Statistical comparisons regarding two meiotic metrics (frequency of ring bivalents; chiasma frequency) between some of the species revealed significant differences.Crosses were attempted in all species combinations, and hybrids were obtained in several. On the basis of pollen and seed fertility these were classified as fortile (mexicana × subfusiformis; subjusiformis × mexicana f. leiocarpa) and semifertile (mexicana × albiflora; subjusiformis × platyceras; mexicana f. leiocarpa × platyceras) hybrids. F1's are intermediate, qualitatively they exhibit heterosis.Meiosis was analysed in all hybrids (pachynema; M-I, A-I) and several metrics e.g. ring bivalent frequency, chiasma frequency were taken as indices of genome affinity.It is suggested that mexicana, mexicana f. leiocarpa and subfusiformis are taxonomically close and display only allelic differentiation: albiflora and platyceras are structurally distinct from each other. Several structural changes e.g. duplications, inversions, translocations etc. were involved in their differentiation.The role of isolation barriers in maintaining species differentiation is discussed. 相似文献
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