全文获取类型
收费全文 | 56245篇 |
免费 | 4706篇 |
国内免费 | 49篇 |
专业分类
61000篇 |
出版年
2023年 | 200篇 |
2022年 | 584篇 |
2021年 | 1003篇 |
2020年 | 556篇 |
2019年 | 741篇 |
2018年 | 1133篇 |
2017年 | 889篇 |
2016年 | 1566篇 |
2015年 | 2585篇 |
2014年 | 2875篇 |
2013年 | 3368篇 |
2012年 | 4342篇 |
2011年 | 4153篇 |
2010年 | 2637篇 |
2009年 | 2319篇 |
2008年 | 3337篇 |
2007年 | 3100篇 |
2006年 | 2833篇 |
2005年 | 2558篇 |
2004年 | 2502篇 |
2003年 | 2226篇 |
2002年 | 1897篇 |
2001年 | 1645篇 |
2000年 | 1536篇 |
1999年 | 1218篇 |
1998年 | 528篇 |
1997年 | 468篇 |
1996年 | 401篇 |
1995年 | 393篇 |
1994年 | 305篇 |
1993年 | 298篇 |
1992年 | 639篇 |
1991年 | 515篇 |
1990年 | 474篇 |
1989年 | 479篇 |
1988年 | 405篇 |
1987年 | 390篇 |
1986年 | 318篇 |
1985年 | 329篇 |
1984年 | 270篇 |
1983年 | 224篇 |
1982年 | 189篇 |
1981年 | 162篇 |
1980年 | 160篇 |
1979年 | 220篇 |
1978年 | 197篇 |
1977年 | 179篇 |
1976年 | 170篇 |
1974年 | 196篇 |
1972年 | 155篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
921.
Multiple murine models have proven useful in studying the natural history of neovessel development in the tissue engineering of vascular grafts. Nevertheless, to better understand longitudinal changes in the biomechanics of such neovessels, we must first quantify native tissue structure and properties. In this paper, we present the first biaxial mechanical data for, and nonlinear constitutive modeling of, &QJ;the inferior vena cava from two models used in tissue engineering: wild-type C57BL/6 and immunodeficient CB-17 SCID/bg mice. Results show that inferior vena cava from the latter are significantly stiffer in the circumferential direction, both materially (as assessed by a stored energy function) and structurally (as assessed by the compliance), despite a lower intramural content of fibrillar collagen and similar wall thickness. Quantifying the natural history of neovessel development in different hosts could lead to increased insight into the mechanisms by which cells fashion and maintain extracellular matrix in order to match best the host stiffness while ensuring sufficient vascular integrity. 相似文献
922.
923.
Sohee Baek Nam Joo Kang Grzegorz M. Popowicz Marcelino Arciniega Sung Keun Jung Sanguine Byun Nu Ry Song Yong-Seok Heo Bo Yeon Kim Hyong Joo Lee Tad A. Holak Martin Augustin Ann M. Bode Robert Huber Zigang Dong Ki Won Lee 《Journal of molecular biology》2013,425(2):411-423
c-Jun NH2-terminal kinases (JNKs) and phosphatidylinositol 3-kinase (PI3-K) play critical roles in chronic diseases such as cancer, type II diabetes, and obesity. We describe here the binding of quercetagetin (3,3′,4′,5,6,7-hydroxyflavone), related flavonoids, and SP600125 to JNK1 and PI3-K by ATP-competitive and immobilized metal ion affinity-based fluorescence polarization assays and measure the effect of quercetagetin on JNK1 and PI3-K activities. Quercetagetin attenuated the phosphorylation of c-Jun and AKT, suppressed AP-1 and NF-κB promoter activities, and also reduced cell transformation. It attenuated tumor incidence and reduced tumor volumes in a two-stage skin carcinogenesis mouse model.Our crystallographic structure determination data show that quercetagetin binds to the ATP-binding site of JNK1. Notably, the interaction between Lys55, Asp169, and Glu73 of JNK1 and the catechol moiety of quercetagetin reorients the N-terminal lobe of JNK1, thereby improving compatibility of the ligand with its binding site. The results of a theoretical docking study suggest a binding mode of PI3-K with the hydroxyl groups of the catechol moiety forming hydrogen bonds with the side chains of Asp964 and Asp841 in the p110γ catalytic subunit. These interactions could contribute to the high inhibitory activity of quercetagetin against PI3-K. Our study suggests the potential use of quercetagetin in the prevention or therapy of cancer and other chronic diseases. 相似文献
924.
925.
Ching-Hung Lee Yen-Wei Chen Yun-Tzu Huang Yih-Jiuan Pan Chien-Hsien Lee Shih-Ming Lin Lin-Kun Huang Yueh-Yu Lo Yu-Fen Huang Yu-Di Hsu Shih-Chung Yen Jenn-Kang Hwang Rong-Long Pan 《The Journal of membrane biology》2013,246(12):959-966
H+-translocating pyrophosphatase (H+-PPase, EC 3.6.1.1) plays an important role in acidifying vacuoles by transporting protons across membranes at the expense of pyrophosphate (PPi) hydrolysis. Vigna radiata H+-PPase (VrH+-PPase) contains 16 transmembrane helices (TMs). The hydrophobicity of TM3 is relatively lower than that of most other TMs, and the amino acids in this TM are highly conserved in plants. Furthermore, TM5 and -6, which are the core TMs involving in H+-PPase functions, are near TM3. It is thus proposed that TM3 is associated with H+-PPase activity. To address this possibility, site-directed mutagenesis was applied in this investigation to determine the role of TM3 in VrH+-PPase. Upon alanine/serine substitution, T138 and S142, whose side chains face toward the center TMs, were found to be involved in efficient proton transport. G149/S153 and G160/A164 pairs at the crucial termini of the two GxxxG-like motifs are indispensable in maintaining enzymatic activities and conformational stability. Moreover, stability in the vicinity surrounding G149 is pivotal for efficient expression. S153, M161 and A164 are critical for the K+-mediated stimulation of H+-PPase. Taken together, our results demonstrate that TM3 plays essential roles in PPi hydrolysis, proton transport, expression, and K+ stimulation of H+-PPase. 相似文献
926.
Nazzareno D'Avanzo Sun-Joo Lee Wayland W. L. Cheng Colin G. Nichols 《The Journal of biological chemistry》2013,288(23):16726-16737
Kir2.1 channels are uniquely activated by phosphoinositide 4,5-bisphosphate (PI(4,5)P2) and can be inhibited by other phosphoinositides (PIPs). Using biochemical and computational approaches, we assess PIP-channel interactions and distinguish residues that are energetically critical for binding from those that alter PIP sensitivity by shifting the open-closed equilibrium. Intriguingly, binding of each PIP is disrupted by a different subset of mutations. In silico ligand docking indicates that PIPs bind to two sites. The second minor site may correspond to the secondary anionic phospholipid site required for channel activation. However, 96–99% of PIP binding localizes to the first cluster, which corresponds to the general PI(4,5)P2 binding location in recent Kir crystal structures. PIPs can encompass multiple orientations; each di- and triphosphorylated species binds with comparable energies and is favored over monophosphorylated PIPs. The data suggest that selective activation by PI(4,5)P2 involves orientational specificity and that other PIPs inhibit this activation through direct competition. 相似文献
927.
Hiroaki Tanaka Ken-ichi Akagi Chitose Oneyama Masakazu Tanaka Yuichi Sasaki Takashi Kanou Young-Ho Lee Daisuke Yokogawa Marc-Werner Dobenecker Atsushi Nakagawa Masato Okada Takahisa Ikegami 《The Journal of biological chemistry》2013,288(21):15240-15254
Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling. Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated. However, these analyses have been performed using short peptides consisting of phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites. Here, we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from the Csk-binding protein (Cbp). This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine 314-binding site of Cbp. Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction. Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the βB/βC loop of the SH2 domain. 相似文献
928.
Van Anthony M. Villar John Edward Jones Ines Armando Laureano D. Asico Crisanto S. Escano Jr. Hewang Lee Xiaoyan Wang Yu Yang Annabelle M. Pascua-Crusan Cynthia P. Palmes-Saloma Robin A. Felder Pedro A. Jose 《The Journal of biological chemistry》2013,288(1):152-163
The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D5R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D5R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D5R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D5R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D5R trafficking and that SNX1 depletion results in D5R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension. 相似文献
929.
930.
Yong-Hak Kim Woo-Seok Song Hayoung Go Chang-Jun Cha Cheolju Lee Myeong-Hee Yu Peter C. K. Lau Kangseok Lee 《Journal of bacteriology》2013,195(2):180-192
2-Nitrobenzoate 2-nitroreductase (NbaA) of Pseudomonas fluorescens strain KU-7 is a unique enzyme, transforming 2-nitrobenzoic acid (2-NBA) and 2,4-dinitrobenzoic acid (2,4-DNBA) to the 2-hydroxylamine compounds. Sequence comparison reveals that NbaA contains a conserved cysteine residue at position 141 and two variable regions at amino acids 65 to 74 and 193 to 216. The truncated mutant Δ65-74 exhibited markedly reduced activity toward 2,4-DNBA, but its 2-NBA reduction activity was unaffected; however, both activities were abolished in the Δ193-216 mutant, suggesting that these regions are necessary for the catalysis and specificity of NbaA. NbaA showed different lag times for the reduction of 2-NBA and 2,4-DNBA with NADPH, and the reduction of 2,4-DNBA, but not 2-NBA, failed in the presence of 1 mM dithiothreitol or under anaerobic conditions, indicating oxidative modification of the enzyme for 2,4-DNBA. The enzyme was irreversibly inhibited by 5,5′-dithio-bis-(2-nitrobenzoic acid) and ZnCl2, which bind to reactive thiol/thiolate groups, and was eventually inactivated during the formation of higher-order oligomers at high pH, high temperature, or in the presence of H2O2. SDS-PAGE and mass spectrometry revealed the formation of intermolecular disulfide bonds by involvement of the two cysteines at positions 141 and 194. Site-directed mutagenesis indicated that the cysteines at positions 39, 103, 141, and 194 played a role in changing the enzyme activity and specificity toward 2-NBA and 2,4-DNBA. This study suggests that oxidative modifications of NbaA are responsible for the differential specificity for the two substrates and further enzyme inactivation through the formation of disulfide bonds under oxidizing conditions. 相似文献