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941.
Amy D. Gelinas Douglas R. Davies Thomas E. Edwards John C. Rohloff Jeffrey D. Carter Chi Zhang Shashi Gupta Yuichi Ishikawa Masao Hirota Yuichiro Nakaishi Thale C. Jarvis Nebojsa Janjic 《The Journal of biological chemistry》2014,289(12):8720-8734
IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (Kd = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets. 相似文献
942.
并系同源(paralog)和直系同源(ortholog)是物种进化过程中产生的两种基本的同源序列类型.目前判断ortholog的方法已经基本确立,而paralog的判断却还没有统一的标准.番茄全基因组测序正在进行中,利用GenBank中已有的番茄BAC序列进行一系列不同参数下的比对(blastn),根据比对结果确定了paralog预测的最佳参数,分别是E值为10-40,匹配序列长度为200 bp,序列一致率为80%.这些参数值的确定为以后在番茄BAC序列中进行paralog预测提供了适用的参数. 相似文献
943.
944.
Chi‐Pin Lee Srinivasan Nithiyanantham Hui‐Ting Hsu Kun‐Tu Yeh Tzer‐Min Kuo Ying‐Chin Ko 《Journal of cellular and molecular medicine》2019,23(11):7699-7708
ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up‐regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin‐treated wild‐type mice (WT‐STZ) and streptozotocin‐treated ALPK1 transgenic mice (TG‐STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP‐1, CCL5/Rantes and G‐CSF expression in TG‐STZ compared with the WT‐STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney‐2 cells. The protein expression of ALPK1, NFkB and lectin was up‐regulated in glucose‐treated HK‐2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up‐regulation involving in diabetic nephropathies induction. 相似文献
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946.
947.
Chemical studies of the antioxidant mechanism of tea catechins: radical reaction products of epicatechin with peroxyl radicals 总被引:4,自引:0,他引:4
Sang S Tian S Wang H Stark RE Rosen RT Yang CS Ho CT 《Bioorganic & medicinal chemistry》2003,11(16):3371-3378
Tea catechins, an important class of polyphenols, have been shown to have antioxidant activity and are thought to act as antioxidants in biological systems. However, the mechanisms of their antioxidant reactions remain unclear. The objective of this study was to characterize the reaction products of epicatechin with peroxyl radicals generated by thermolysis of the azo initiator azo-bisisobutyrylnitrile (AIBN). Structural elucidation of these products can provide insights into specific mechanisms of antioxidant reactions. Eight reaction products were isolated and identified using high-field 1D and 2D NMR spectral analysis. The observation of these compounds confirmed that the B-ring is the initial site for formation of reaction products in the peroxyl radical oxidant system. 相似文献
948.
Chunling Yuan Xiaoli Guo Qifan Zhou Fangyu Du Wei Jiang Xiaoyu Zhou Peng Liu Tianyan Chi Xuefei Ji Jinheng Gao Chengwen Chen Hongli Lang Jia Xu Danyang Liu Yang Yang Shimeng Qiu Xing Tang Guoliang Chen Libo Zou 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):161-180
The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting Aβ production (such as β- and γ-secretase inhibitors) make people suspect the Aβ hypothesis, in which the neurotoxicity of Aβ is undoubtedly involved. According to studies, >95% of AD patients with sporadic AD are primarily associated with abnormal Aβ clearance. Therefore, drugs that increase Aβ clearance are becoming new prospects for the treatment of AD. Here, the novel small molecule OAB-14, designed using bexarotene as the lead compound, significantly alleviated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice after administration for 15?days or 3?months. OAB-14 rapidly cleared 71% of Aβ by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of Aβ accumulation, such as synaptic degeneration, neuronal loss, tau hyperphosphorylation and neuroinflammation in APP/PS1 mice. Moreover, OAB-14 had no significant effect on body weight or liver toxicity after acute and chronic treatment. OAB-14 was well tolerated and its maximum-tolerated dose in mice was >4.0?g/kg. Based on these findings, OAB-14 represents a promising new candidate for AD treatment. 相似文献
949.
广东横石水河大型底栖动物群落与环境因子的关系 总被引:1,自引:0,他引:1
应用典范对应分析(CCA)对横石水河流域14个样点中的大型底栖动物与环境因子的关系进行了研究。结果表明,枯水期和丰水期的物种与环境因子的相关性均在90%以上,说明大型底栖动物在横石水河的分布很大程度上受到环境因子的影响。化学需氧量(COD)和pH值是影响枯水期大型底栖动物分布的两个主要因子,浊度和重金属Cu、Pb浓度对大型底栖动物分布也有一定程度的影响。在丰水期,重金属Cu、Pb浓度和pH值是影响大型底栖动物分布的关键因子。从种类水平看,耐污种类如蠓类、摇蚊和大蚊的丰富度与COD和重金属浓度的环境轴呈正相关,而敏感种类如腹足纲、毛翅目以及蜉蝣目昆虫与COD和重金属浓度的环境轴呈负相关。 相似文献
950.
The mammalian proprotein convertase furin has been found to play an important role in diverse physiological and pathological events, such as the activation of viral glycoproteins and bacterial exotoxins. Small, non-toxic and highly active, furin inhibitors are considered to be attractive drug candidates for diseases caused by virus and bacteria. In this study, a series of peptide inhibitors were designed and synthesized based on the C-terminal fragment of histone H1.2, which has an inhibitory effect on furin. Replacing the reactive site of inhibitors with the consensus substrate recognition sequence of furin has been found to increase inhibitory activity greatly. The most potent inhibitor, I4, with 14 amino acid residues has a Ki value of 17 nM for furin. Although most of the synthesized peptides were temporary inhibitors, the inhibitor I5, with nine amino acids, retained its full potency, even after a 3 h incubation period with furin at 37 degrees C. These inhibitors may potentially lead to the development of anti-viral and anti-bacterial drug compounds. 相似文献