全文获取类型
收费全文 | 12253篇 |
免费 | 1183篇 |
国内免费 | 1293篇 |
专业分类
14729篇 |
出版年
2024年 | 31篇 |
2023年 | 235篇 |
2022年 | 524篇 |
2021年 | 774篇 |
2020年 | 533篇 |
2019年 | 635篇 |
2018年 | 579篇 |
2017年 | 443篇 |
2016年 | 561篇 |
2015年 | 819篇 |
2014年 | 977篇 |
2013年 | 940篇 |
2012年 | 1161篇 |
2011年 | 966篇 |
2010年 | 607篇 |
2009年 | 552篇 |
2008年 | 652篇 |
2007年 | 511篇 |
2006年 | 449篇 |
2005年 | 331篇 |
2004年 | 307篇 |
2003年 | 309篇 |
2002年 | 196篇 |
2001年 | 195篇 |
2000年 | 166篇 |
1999年 | 184篇 |
1998年 | 103篇 |
1997年 | 92篇 |
1996年 | 102篇 |
1995年 | 90篇 |
1994年 | 79篇 |
1993年 | 42篇 |
1992年 | 85篇 |
1991年 | 63篇 |
1990年 | 54篇 |
1989年 | 40篇 |
1988年 | 35篇 |
1987年 | 47篇 |
1986年 | 25篇 |
1985年 | 50篇 |
1984年 | 15篇 |
1983年 | 16篇 |
1982年 | 11篇 |
1981年 | 10篇 |
1980年 | 9篇 |
1978年 | 9篇 |
1977年 | 9篇 |
1974年 | 9篇 |
1973年 | 10篇 |
1971年 | 12篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
111.
112.
Jeffrey A. Pfefferkorn Meihua Tu Kevin J. Filipski Angel Guzman-Perez Jianwei Bian Gary E. Aspnes Matthew F. Sammons Wei Song Jian-Cheng Li Christopher S. Jones Leena Patel Tim Rasmusson Dongxiang Zeng Kapil Karki Michael Hamilton Richard Hank Karen Atkinson John Litchfield Robert Aiello Levenia Baker Alan Robertson 《Bioorganic & medicinal chemistry letters》2012,22(23):7100-7105
Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy. 相似文献
113.
Yi Ting Zhou Li Li Chew Sheng-cai Lin Boon Chuan Low 《Molecular biology of the cell》2010,21(18):3232-3246
The BNIP-2 and Cdc42GAP homology (BCH) domain is a novel regulator for Rho GTPases, but its impact on p50-Rho GTPase-activating protein (p50RhoGAP or Cdc42GAP) in cells remains elusive. Here we show that deletion of the BCH domain from p50RhoGAP enhanced its GAP activity and caused drastic cell rounding. Introducing constitutively active RhoA or inactivating GAP domain blocked such effect, whereas replacing the BCH domain with endosome-targeting SNX3 excluded requirement of endosomal localization in regulating the GAP activity. Substitution with homologous BCH domain from Schizosaccharomyces pombe, which does not bind mammalian RhoA, also led to complete loss of suppression. Interestingly, the p50RhoGAP BCH domain only targeted RhoA, but not Cdc42 or Rac1, and it was unable to distinguish between GDP and the GTP-bound form of RhoA. Further mutagenesis revealed a RhoA-binding motif (residues 85-120), which when deleted, significantly reduced BCH inhibition on GAP-mediated cell rounding, whereas its full suppression also required an intramolecular interaction motif (residues 169-197). Therefore, BCH domain serves as a local modulator in cis to sequester RhoA from inactivation by the adjacent GAP domain, adding to a new paradigm for regulating p50RhoGAP signaling. 相似文献
114.
115.
Deborah Merrick Tao Ting Lukas Kurt Josef Stadler Janet Smith 《BMC developmental biology》2007,7(1):65
Background
Fibre type specification is a poorly understood process beginning in embryogenesis in which skeletal muscle myotubes switch myosin-type to establish fast, slow and mixed fibre muscle groups with distinct function. Growth factors are required to establish slow fibres; it is unknown how fast twitch fibres are specified. Igf-2 is an embryonically expressed growth factor with established in vitro roles in skeletal muscle. Its localisation and role in embryonic muscle differentiation had not been established. 相似文献116.
Hong Er Tian Yong Sheng Gao Feng Min Li Fuli Zeng 《Biological trace element research》2003,93(1-3):257-269
Scanning electron microscopic and energy-dispersive X-ray analyses were used to study the distributions of different types
of elements in the epidermis, exodermis, endodermis, and vascular cylinder of the fracture face in the Lathyrus sativus L. roots in the presence or absence of Eu3+. Some index of the biological activity related to the elements binding with protein were determined also. The results showed
that the tissular distributions of elements in the fracture face are different in the presence and absence of Eu3+. The atomic percentages of P, S, Ca, and Mn were influenced more than those of other elements. Eu3+ promoted the biological activities of various kinds of element. The one possible mechanism changing the biological activities
was that the reaction of Eu3+
Eu2+ would influence the electron capture or transport in elements of binding protein. Another mechanism was that CaM-Ca2+ becoming CaM-Eu3+ through Eu3+ instead of Ca2+ would affect the biological activity of elements by regulating the Ca2+ level in the plant cell. 相似文献
117.
The connectivity structure,giant strong component and centrality of metabolic networks 总被引:14,自引:0,他引:14
MOTIVATION: Structural and functional analysis of genome-based large-scale metabolic networks is important for understanding the design principles and regulation of the metabolism at a system level. The metabolic network is conventionally considered to be highly integrated and very complex. A rational reduction of the metabolic network to its core structure and a deeper understanding of its functional modules are important. RESULTS: In this work, we show that the metabolites in a metabolic network are far from fully connected. A connectivity structure consisting of four major subsets of metabolites and reactions, i.e. a fully connected sub-network, a substrate subset, a product subset and an isolated subset is found to exist in metabolic networks of 65 fully sequenced organisms. The largest fully connected part of a metabolic network, called 'the giant strong component (GSC)', represents the most complicated part and the core of the network and has the feature of scale-free networks. The average path length of the whole network is primarily determined by that of the GSC. For most of the organisms, GSC normally contains less than one-third of the nodes of the network. This connectivity structure is very similar to the 'bow-tie' structure of World Wide Web. Our results indicate that the bow-tie structure may be common for large-scale directed networks. More importantly, the uncovered structure feature makes a structural and functional analysis of large-scale metabolic network more amenable. As shown in this work, comparing the closeness centrality of the nodes in the GSC can identify the most central metabolites of a metabolic network. To quantitatively characterize the overall connection structure of the GSC we introduced the term 'overall closeness centralization index (OCCI)'. OCCI correlates well with the average path length of the GSC and is a useful parameter for a system-level comparison of metabolic networks of different organisms. SUPPLEMENTARY INFORMATION: http://genome.gbf.de/bioinformatics/ 相似文献
118.
Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex 总被引:8,自引:0,他引:8 下载免费PDF全文
Yuan Z Cai T Tian J Ivanov AV Giovannucci DR Xie Z 《Molecular biology of the cell》2005,16(9):4034-4045
We have shown that the caveolar Na/K-ATPase transmits ouabain signals via multiple signalplexes. To obtain the information on the composition of such complexes, we separated the Na/K-ATPase from the outer medulla of rat kidney into two different fractions by detergent treatment and density gradient centrifugation. Analysis of the light fraction indicated that both PLC-gamma1 and IP3 receptors (isoforms 2 and 3, IP3R2 and IP3R3) were coenriched with the Na/K-ATPase, caveolin-1 and Src. GST pulldown assays revealed that the central loop of the Na/K-ATPase alpha1 subunit interacts with PLC-gamma1, whereas the N-terminus binds IP3R2 and IP3R3, suggesting that the signaling Na/K-ATPase may tether PLC-gamma1 and IP3 receptors together to form a Ca(2+)-regulatory complex. This notion is supported by the following findings. First, both PLC-gamma1 and IP3R2 coimmunoprecipitated with the Na/K-ATPase and ouabain increased this interaction in a dose- and time-dependent manner in LLC-PK1 cells. Depletion of cholesterol abolished the effects of ouabain on this interaction. Second, ouabain induced phosphorylation of PLC-gamma1 at Tyr(783) and activated PLC-gamma1 in a Src-dependent manner, resulting in increased hydrolysis of PIP2. It also stimulated Src-dependent tyrosine phosphorylation of the IP3R2. Finally, ouabain induced Ca(2+) release from the intracellular stores via the activation of IP3 receptors in LLC-PK1 cells. This effect required the ouabain-induced activation of PLC-gamma1. Inhibition of Src or depletion of cholesterol also abolished the effect of ouabain on intracellular Ca(2+). 相似文献
119.
该文利用FIASCO法(fast isolation by AFLP of sequences containing repeats)和GenBank数据库搜索法开发花鲈微卫星标记,并对筛选的标记进行多态性检测.两种方法共获得54条能够设计引物的序列,扩增结果显示15对引物具有多态性,多态性微卫星位点的等位基因数为2~10个.15个多态性位点中,4个位点偏离了Hardy-Weinberg平衡;各位点间没有连锁不平衡现象;仅位点SP52可能存在无效等位基因;除SP17和SP468外,其余引物的P1C值均在0.5以上,可用于花鲈群体遗传分析等研究. 相似文献
120.
X Luo W Zeng X Xu S Popov I Davignon T M Wilkie S M Mumby S Muallem 《The Journal of biological chemistry》1999,274(25):17684-17690
Many Gs-coupled receptors can activate both cAMP and Ca2+ signaling pathways. Three mechanisms for dual activation have been proposed. One is receptor coupling to both Gs and G15 (a Gq class heterotrimeric G protein) to initiate independent signaling cascades that elevate intracellular levels of cAMP and Ca+2, respectively. The other two mechanisms involve cAMP-dependent protein kinase-mediated activation of phospholipase Cbeta either directly or by switching receptor coupling from Gs to Gi. These mechanisms were primarily inferred from studies with transfected cell lines. In native cells we found that two Gs-coupled receptors (the vasoactive intestinal peptide and beta-adrenergic receptors) in pancreatic acinar and submandibular gland duct cells, respectively, evoke a Ca2+ signal by a mechanism involving both Gs and Gi. This inference was based on the inhibitory action of antibodies specific for Galphas, Galphai, and phosphatidylinositol 4,5-bisphosphate, pertussis toxin, RGS4, a fragment of beta-adrenergic receptor kinase and inhibitors of cAMP-dependent protein kinase. By contrast, Ca2+ signaling evoked by Gs-coupled receptor agonists was not blocked by Gq class-specific antibodies and was unaffected in Galpha15 -/- knockout mice. We conclude that sequential activation of Gs and Gi, mediated by cAMP-dependent protein kinase, may represent a general mechanism in native cells for dual stimulation of signaling pathways by Gs-coupled receptors. 相似文献