全文获取类型
收费全文 | 21542篇 |
免费 | 940篇 |
国内免费 | 680篇 |
专业分类
23162篇 |
出版年
2024年 | 15篇 |
2023年 | 250篇 |
2022年 | 408篇 |
2021年 | 519篇 |
2020年 | 487篇 |
2019年 | 714篇 |
2018年 | 736篇 |
2017年 | 392篇 |
2016年 | 519篇 |
2015年 | 654篇 |
2014年 | 1335篇 |
2013年 | 1552篇 |
2012年 | 856篇 |
2011年 | 1333篇 |
2010年 | 945篇 |
2009年 | 1030篇 |
2008年 | 1199篇 |
2007年 | 1193篇 |
2006年 | 1098篇 |
2005年 | 963篇 |
2004年 | 868篇 |
2003年 | 725篇 |
2002年 | 705篇 |
2001年 | 439篇 |
2000年 | 395篇 |
1999年 | 402篇 |
1998年 | 431篇 |
1997年 | 356篇 |
1996年 | 308篇 |
1995年 | 316篇 |
1994年 | 286篇 |
1993年 | 223篇 |
1992年 | 189篇 |
1991年 | 166篇 |
1990年 | 143篇 |
1989年 | 122篇 |
1988年 | 109篇 |
1987年 | 106篇 |
1986年 | 80篇 |
1985年 | 85篇 |
1984年 | 109篇 |
1983年 | 97篇 |
1982年 | 86篇 |
1981年 | 67篇 |
1980年 | 62篇 |
1979年 | 41篇 |
1978年 | 19篇 |
1977年 | 13篇 |
1976年 | 5篇 |
1973年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 9 毫秒
991.
应用RT-PCR、Westem blot、免疫组化分别检测甲状腺乳头状癌组织与癌旁正常甲状腺组织标本中DcR3mRNA及蛋白的表达情况,探讨DcR3在甲状腺乳头状癌组织中的表达及,临床意义。RT-PCR检测显示,甲状腺乳头状癌中DcR3 mRNA的表达明显高于正常甲状腺组织(P〈0.05):Western blot提示,DcR3蛋白在甲状腺乳头状癌中表达比正常甲状腺组织高(P〈0.05);免疫组化显示,DcR3蛋白在甲状腺乳头状癌中高表达(P〈0.05)。DcR3mRNA及蛋白质在甲状腺乳头状癌及正常甲状腺组织间的表达差异有统计学意义(P〈0.05)。DcR3基因及蛋白在甲状腺乳头状癌中高表达,提示DcR3可能促进了甲状腺乳头状癌的发生发展。 相似文献
992.
目的研究促甲状腺激素受体(TSHR)在子宫颈癌组织的表达及其与乳头瘤病毒(HPV-16)的关系。方法应用免疫组织化学链霉菌抗生物素过氧化物酶(SP)法检测79例子宫颈癌和30例子宫颈炎组织HPV-16与TSHR蛋白表达。79例癌症患者中病理分级〈Ⅱ级33例,≥Ⅱ级46例;病理分期〈Ⅱ期56例,≥Ⅱ期23例;无淋巴结转移66例,有淋巴结转移13例;肿瘤大小〈3cm44例,肿瘤大小≥3cm35例。结果HPV-16在子宫颈癌表达率55.70%明显高于宫颈炎5%(P〈0.05),TSHR在子宫颈癌表达率68.35%明显高于宫颈炎26.67%(P〈0.05)。HPV-16表达与肿瘤的大小、肿瘤分级、分期、淋巴结转移不相关。TSHR表达与肿瘤的大小呈正相关,P〈0.05,与肿瘤分级、分期及淋巴结转移不相关。HPV-16与TSHR在宫颈癌表达呈正相关。结论HPV感染对宫颈癌病变起到强烈的预警作用。TSHR不仅在甲状腺滤泡上皮细胞表达,在子宫颈癌细胞也表达,TSHR过表达能促进宫颈细胞的异常增殖,其异常功能可能是恶性肿瘤特定的临床表型。HPV与TSHR在子宫颈癌变过程中起协同作用。 相似文献
993.
994.
Takashi Uemura Manami Fujimori Ho-Hi Lee Sakio Ikeda Keiichi Aso 《Bioscience, biotechnology, and biochemistry》2013,77(9):2277-2281
Comparative studies were made of the polymerization of l-aspartic and l-glutamic acid dialkyl esters using polyethylene glycol–modified papain as a catalyst in phosphate buffer (pH 7.5) and in benzene. Changes in the substrate specificity of papain and in the composition of oligomerized products were observed. In the buffer, the diethyl and di-n-propyl esters of l-glutamic acid were sufficiently converted to high molecular weight oligomers with the accumulation of dimer and trimer, but l-aspartic acid esters were very poor substrates. In benzene, l-aspartic acid esters became more reactive than L-glutamic acid esters. In particular, from l-aspartic acid dimethyl ester the product, which was mainly composed of heptamer to decamer, was obtained in a 90% yield. The reaction in benzene required desalted substrates and a small amount of water to proceed extensively. 相似文献
995.
Zhongli Gao William J. Hurst Etienne Guillot Werngard Czechtizky Ulrike Lukasczyk Raisa Nagorny Marie-Pierre Pruniaux Lothar Schwink Juan Antonio Sanchez Siegfried Stengelin Lei Tang Irvin Winkler James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(11):3416-3420
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. 相似文献
996.
Yan Zhang Orgil Elbegdorj Yunyun Yuan Irina O. Beletskaya Dana E. Selley 《Bioorganic & medicinal chemistry letters》2013,23(13):3719-3722
Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the 35S-GTP[γS] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. 相似文献
997.
Keisuke Maruyama Masaharu Nakamura Shusuke Tomoshige Kazuyuki Sugita Makoto Makishima Yuichi Hashimoto Minoru Ishikawa 《Bioorganic & medicinal chemistry letters》2013,23(14):4031-4036
Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERβ subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERβ and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer. 相似文献
998.
Frauke Steindel Raissa Lerner Martin Häring Sabine Ruehle Giovanni Marsicano Beat Lutz Krisztina Monory 《Journal of neurochemistry》2013,124(6):795-807
Type 1 cannabinoid receptor (CB1) is expressed in different neuronal populations in the mammalian brain. In particular, CB1 on GABAergic or glutamatergic neurons exerts different functions and display different pharmacological properties in vivo. This suggests the existence of neuron‐type specific signalling pathways activated by different subpopulations of CB1. In this study, we analysed CB1 expression, binding and signalling in the hippocampus of conditional mutant mice, bearing CB1 deletion in GABAergic (GABA‐CB1‐KO mice) or cortical glutamatergic neurons (Glu‐CB1‐KO mice). Compared to their wild‐type littermates, Glu‐CB1‐KO displayed a small decrease of CB1 mRNA amount, immunoreactivity and [³H]CP55,940 binding. Conversely, GABA‐CB1‐KO mice showed a drastic reduction of these parameters, confirming that CB1 is present at much higher density on hippocampal GABAergic interneurons than glutamatergic neurons. Surprisingly, however, saturation analysis of HU210‐stimulated [35S]GTPγS binding demonstrated that ‘glutamatergic’ CB1 is more efficiently coupled to G protein signalling than ‘GABAergic’ CB1. Thus, the minority of CB1 on glutamatergic neurons is paradoxically several fold more strongly coupled to G protein signalling than ‘GABAergic’ CB1. This selective signalling mechanism raises the possibility of designing novel cannabinoid ligands that differentially activate only a subset of physiological effects of CB1 stimulation, thereby optimizing therapeutic action. 相似文献
999.
Nicolás Fuenzalida‐Uribe Rodrigo C. Meza Hernán A. Hoffmann Rodrigo Varas Jorge M. Campusano 《Journal of neurochemistry》2013,125(2):281-290
Biogenic amines (BAs) play a central role in the generation of complex behaviors in vertebrates and invertebrates, including the fly Drosophila melanogaster. The comparative advantages of Drosophila as a genetic model to study the contribution of BAs to behaviors stumble upon the difficulty to access the fly brain to ask relevant physiological questions. For instance, it is not known whether the activation of nicotinic acetylcholine receptors (nAChRs) induces the release of BAs in fly brain, a phenomenon associated to several behaviors in vertebrates. Here, we describe a new preparation to study the efflux of BAs in the adult fly brain by in vitro chronoamperometry. Using this preparation we show that nAChR agonists including nicotine induce a fast, transient, dose‐dependent efflux of endogenous BAs, an effect mediated by α‐bungarotoxin‐sensitive nAChRs. By using different genetic tools we demonstrate that the BA whose efflux is induced by nAChR activation is octopamine (Oct). Furthermore, we show that the impairment of a mechanically induced startle response after nicotine exposure is not observed in flies deficient in Oct transmission. Thus, our data show that the efflux of BAs in Drosophila brain is increased by nAChR activation as in vertebrates, and that then AChR‐induced Oct release could have implications in a nicotine‐induced behavioral response. 相似文献
1000.
Jeremy Celver Meenakshi Sharma Vaidehi Thanawala J. Christopher Octeau Abraham Kovoor 《Journal of neurochemistry》2013,127(1):57-65
We reconstituted D2 like dopamine receptor (D2R) and the delta opioid receptor (DOR) coupling to G‐protein gated inwardly rectifying potassium channels (Kir3) and directly compared the effects of co‐expression of G‐protein coupled receptor kinase (GRK) and arrestin on agonist‐dependent desensitization of the receptor response. We found, as described previously, that co‐expression of a GRK and an arrestin synergistically increased the rate of agonist‐dependent desensitization of DOR. In contrast, only arrestin expression was required to produce desensitization of D2R responses. Furthermore, arrestin‐dependent GRK‐independent desensitization of D2R‐Kir3 coupling could be transferred to DOR by substituting the third cytoplasmic loop of DOR with that of D2R. The arrestin‐dependent GRK‐independent desensitization of D2R desensitization was inhibited by staurosporine treatment, and blocked by alanine substitution of putative protein kinase C phosphorylation sites in the third cytoplasmic loop of D2R. Finally, the D2R construct in which putative protein kinase C phosphorylation sites were mutated did not undergo significant agonist‐dependent desensitization even after GRK co‐expression, suggesting that GRK phosphorylation of D2R does not play an important role in uncoupling of the receptor.