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941.
Enzymatic catalysis has conflicting structural requirements of the enzyme. In order for the enzyme to form a Michaelis complex, the enzyme must be in an open conformation so that the substrate can get into its active center. On the other hand, in order to maximize the stabilization of the transition state of the enzymatic reaction, the enzyme must be in a closed conformation to maximize its interactions with the transition state. The conflicting structural requirements can be resolved by a flexible active center that can sample both open and closed conformational states. For a bisubstrate enzyme, the Michaelis complex consists of two substrates in addition to the enzyme. The enzyme must remain flexible upon the binding of the first substrate so that the second substrate can get into the active center. The active center is fully assembled and stabilized only when both substrates bind to the enzyme. However, the side-chain positions of the catalytic residues in the Michaelis complex are still not optimally aligned for the stabilization of the transition state, which lasts only approximately 10(-13) s. The instantaneous and optimal alignment of catalytic groups for the transition state stabilization requires a dynamic enzyme, not an enzyme which undergoes a large scale of movements but an enzyme which permits at least a small scale of adjustment of catalytic group positions. This review will summarize the structure, catalytic mechanism, and dynamic properties of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and examine the role of protein conformational dynamics in the catalysis of a bisubstrate enzymatic reaction. 相似文献
942.
Miao J Choi SE Seok SM Yang L Zuercher WJ Xu Y Willson TM Xu HE Kemper JK 《Molecular endocrinology (Baltimore, Md.)》2011,25(7):1159-1169
943.
Tichotová L Matoušová E Spulák M Kuneš J Votruba I Buchta V Pour M 《Bioorganic & medicinal chemistry letters》2011,21(20):6062-6066
A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of Ti(iPrO)(4)-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity. The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of the compound to influence cell proliferation using two different assays showed that 2-benzylidenecyclopent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product. 相似文献
944.
Gao J Li X Gu G Sun B Cui M Ji M Lou HX 《Bioorganic & medicinal chemistry letters》2011,21(2):622-627
To investigate the relationship of cytotoxicity and saponins with varied aglycones, based on the structure of indioside E 1, a natural derived anti-tumor active ingredient from Chinese medicinal plant Solanum indicum L., five novel saponins 2-6 bearing the same trisaccharide moiety together with 1 were efficiently synthesized via a transglycosylation strategy. MTT assay revealed the killing effects to tumor cells of the synthesized saponins are varied with the change of aglycones. Furthermore, time-lapse microscopy, LDH release, PI staining, and immunocytochemical investigations demonstrated that the cell death caused by neosaponin 2 was through oncotic necrosis involving plasma membrane perturbation and destruction of cytoskeleton. 相似文献
945.
Jin M Kleinberg A Cooke A Gokhale PC Foreman K Dong H Siu KW Bittner MA Mulvihill KM Yao Y Landfair D O'Connor M Mak G Pachter JA Wild R Rosenfeld-Franklin M Ji Q Mulvihill MJ 《Bioorganic & medicinal chemistry letters》2011,21(4):1176-1180
Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model. 相似文献
946.
Zhiguo WuYalong Liu Ji ZhangWeiliang Shen Wenxiang LuQing Hong Shunpeng Li 《International biodeterioration & biodegradation》2011,65(6):871-876
Strain D4 was isolated from the sludge of the wastewater treating system of a 4-Chloronitrobenzene (4-CNB) manufacturer. It was able to utilize 4-CNB as the sole carbon and nitrogen source for growth. Strain D4 was preliminarily identified as Cupriavidus sp. based on its physiological & biochemical characteristics and 16S rRNA gene sequence analysis. It could completely degrade 300 mg L−1 of 4-CNB within 25 h under the condition of 30 °C and pH 7.0. Strain D4 could also degrade 4-CNB in presence of heavy metals including Co2+, Cd2+, Pb2+, Zn2+, Mn2+and so on, therefore it was an excellent candidate for the bio-treatment of 4-CNB and heavy metals co-contaminated environments. The main 4-CNB degrading related genes (cnb A, B, Cab, D, G, Z) and arsenate resistance gene fragment of strain D4 were cloned, sequenced and analyzed, which showed high similarity with the corresponding genes of a reported 4-CNB-degrader, strain CNB-1. The cnb genes of strain D4 were located on two plasmids. This is the first report on the degradation of 4-CNB by the strain from the genus of Cupriavidus sp. 相似文献
947.
Lü S Luo Q Hao X Li X Ji L Zheng W Wang F 《Bioorganic & medicinal chemistry letters》2011,21(23):6964-6968
Six analogs of imatinib, an Abl kinase inhibitor clinically used as a first-line therapeutic agent for chronic myeloid leukaemia (CML), have been synthesized and characterized. And their potency as Abl kinase inhibitors have been screened by a robust virtual screening method developed based on the crystal structure (PDB code 2hyy) of Abl-imatinib complex using Surflex-Docking. The docking results are consistent with the inhibitory potency of the compounds characterized by MS method. And the H-bonds between imatinib analogs and Thr315 and Met318 residues in Abl kinase are shown to be crucial for achieving accurate poses and high binding affinities for the ATP-competitive kinase inhibitors. 相似文献
948.
949.
抗吡虫啉单克隆抗体的制备及鉴定 总被引:1,自引:0,他引:1
为制备灵敏度高,特异性强的抗吡虫啉单克隆抗体,建立经济、快速、准确的吡虫啉残留免疫学分析方法,采用分子模拟技术分析吡虫啉及其类似农药的电荷分布后,选择1-[6-(2-羧乙硫基-3-吡啶)甲基]-N-硝基-2-咪唑啉亚胺 (H1) 作为免疫半抗原,1-(6-氯-3-吡啶甲基)-3-羧丙基-N-硝基-2-咪唑啉亚胺 (H2) 作为包被半抗原,利用NHS酯法将H1和H2分别与牛血清蛋白 (BSA) 和卵清蛋白 (OVA) 偶联合成免疫原与包被原。免疫BALB/c小鼠后,采用常规杂交瘤技术共获得2株稳定分泌抗吡虫 相似文献
950.
NaCl胁迫下高纬度移植桐花树幼苗的生理生态效应 总被引:1,自引:0,他引:1
通过砂培试验,研究了不同浓度NaCl(0、100、200、300和400 mmol·L-1)处理对高纬度移植桐花树幼苗生物量、离子吸收、碳氮代谢、叶片光合色素和叶片抗氧化系统的影响.结果表明:100 mmol·L-1NaCl处理对桐花树生长有轻微的促进作用,当NaCl浓度达到300mmol·L-1时,桐花树根、茎、叶器官的干鲜质量、根冠比、株高和基径均显著下降.高盐胁迫抑制了叶片抗氧化系统中超氧化物歧化酶(SOD)和过氧化物酶(POD)的活性,提高了丙二醛含量,降低了叶片中叶绿素、类胡萝卜素总量以及根茎叶的可溶性总糖和游离氨基酸总量.不同浓度NaCl胁迫下,桐花树根茎叶中Na+含量快速上升,K+含量相对下降,K+/Na+快速下降,导致各器官中离子平衡失调.当NaCl浓度高于300 mmol·L-1时,桐花树根茎叶的碳氮代谢运转失调,抑制了植株的正常生长,导致各器官的生物量显著下降. 相似文献