全文获取类型
收费全文 | 10709篇 |
免费 | 532篇 |
国内免费 | 689篇 |
出版年
2023年 | 86篇 |
2022年 | 169篇 |
2021年 | 192篇 |
2020年 | 172篇 |
2019年 | 283篇 |
2018年 | 309篇 |
2017年 | 209篇 |
2016年 | 216篇 |
2015年 | 258篇 |
2014年 | 533篇 |
2013年 | 742篇 |
2012年 | 453篇 |
2011年 | 596篇 |
2010年 | 420篇 |
2009年 | 507篇 |
2008年 | 549篇 |
2007年 | 602篇 |
2006年 | 497篇 |
2005年 | 511篇 |
2004年 | 443篇 |
2003年 | 413篇 |
2002年 | 344篇 |
2001年 | 233篇 |
2000年 | 187篇 |
1999年 | 200篇 |
1998年 | 192篇 |
1997年 | 177篇 |
1996年 | 150篇 |
1995年 | 174篇 |
1994年 | 159篇 |
1993年 | 156篇 |
1992年 | 145篇 |
1991年 | 126篇 |
1990年 | 114篇 |
1989年 | 88篇 |
1988年 | 87篇 |
1987年 | 90篇 |
1986年 | 81篇 |
1985年 | 120篇 |
1984年 | 151篇 |
1983年 | 114篇 |
1982年 | 150篇 |
1981年 | 112篇 |
1980年 | 91篇 |
1979年 | 76篇 |
1978年 | 44篇 |
1977年 | 56篇 |
1976年 | 46篇 |
1975年 | 40篇 |
1973年 | 25篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
P2X receptor (P2XR) is a family of the ATP-gated ion channel family and can permeabilize the plasma membrane to small cations
such as potassium, sodium, and calcium, resulting in cellular depolarization. There are seven P2XR that have been described
and cloned, with 45% identity in amino acid sequence. Each P2X receptors has two transmembrane domains that are separated
by an extracellular loop and an intracellular N and C terminus. Unlike the other P2X receptors, the P2X7R has a larger C terminus
with an extra 200 amino acid residues compared with the other receptors. The C terminus of the P2X7R has been implicated in
regulating receptor function including signaling pathway activation, cellular localization, protein–protein interactions,
and post-translational modification (PTM). In the present review, we discuss the role of the P2X7R C terminus in regards to
receptor function, describe the specific domains and motifs found therein and compare the C terminus sequence with others
proteins to discover predicted domains or sites of PTM. 相似文献
992.
Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express
three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective
cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in
the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses
to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1
receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism
induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute
more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution
to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near
sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques. 相似文献
993.
994.
Feng DD Zhang H Zhang P Zheng YS Zhang XJ Han BW Luo XQ Xu L Zhou H Qu LH Chen YQ 《Journal of cellular and molecular medicine》2011,15(10):2164-2175
Multidrug resistance (MDR) and disease relapse are challenging clinical problems in the treatment of leukaemia. Relapsed disease is frequently refractory to chemotherapy and exhibits multiple drug resistance. Therefore, it is important to identify the mechanism by which cancer cells develop resistance. In this study, we used microRNA (miRNA) microarray and qRT-PCR approaches to investigate the expression of miRNAs in three leukaemia cell lines with different degrees of resistance to doxorubicin (DOX) compared with their parent cell line, K562. The expression of miR-331-5p and miR-27a was inversely correlated with the expression of a drug-resistant factor, P-glycoprotein (P-gp), in leukaemia cell lines with gradually increasing resistance. The development of drug resistance is regulated by the expression of the P-gp. Transfection of the K562 and, a human promyelocytic cell line (HL) HL60 DOX-resistant cells with miR-331-5p and miR-27a, separately or in combination, resulted in the increased sensitivity of cells to DOX, suggesting that correction of altered expression of miRNAs may be used for therapeutic strategies to overcome leukaemia cell resistance. Importantly, miR-331-5p and miR-27a were also expressed at lower levels in a panel of relapse patients compared with primary patients at diagnosis, further illustrating that leukaemia relapse might be a consequence of deregulation of miR-331-5p and miR-27a. 相似文献
995.
We report the crystal structure of the 5-residue peptide acetyl-YEQGL-amide, determined directly from powder X-ray diffraction data recorded on a conventional laboratory X-ray powder diffractometer. The YEQGL motif has a known biological role, as a trafficking motif in the C-terminus of mammalian P2X4 receptors. Comparison of the crystal structure of acetyl-YEQGL-amide determined here and that of a complex formed with the μ2 subunit of the clathrin adaptor protein complex AP2 reported previously, reveals differences in conformational properties, although there are nevertheless similarities concerning aspects of the hydrogen-bonding arrangement and the hydrophobic environment of the leucine sidechain. Our results demonstrate the potential for exploiting modern powder X-ray diffraction methodology to achieve complete structure determination of materials of biological interest that do not crystallize as single crystals of suitable size and quality for single-crystal X-ray diffraction. 相似文献
996.
Chinese hamster ovary (CHO) cells are the main platform for production of biotherapeutics in the biopharmaceutical industry. However, relatively little is known about the metabolism of CHO cells in cell culture. In this work, metabolism of CHO cells was studied at the growth phase and early stationary phase using isotopic tracers and mass spectrometry. CHO cells were grown in fed-batch culture over a period of six days. On days 2 and 4, [1,2-13C] glucose was introduced and the labeling of intracellular metabolites was measured by gas chromatography-mass spectrometry (GC–MS) at 6, 12 and 24 h following the introduction of tracer. Intracellular metabolic fluxes were quantified from measured extracellular rates and 13C-labeling dynamics of intracellular metabolites using non-stationary 13C-metabolic flux analysis (13C-MFA). The flux results revealed significant rewiring of intracellular metabolic fluxes in the transition from growth to non-growth, including changes in energy metabolism, redox metabolism, oxidative pentose phosphate pathway and anaplerosis. At the exponential phase, CHO cell metabolism was characterized by a high flux of glycolysis from glucose to lactate, anaplerosis from pyruvate to oxaloacetate and from glutamate to α-ketoglutarate, and cataplerosis though malic enzyme. At the stationary phase, the flux map was characterized by a reduced flux of glycolysis, net lactate uptake, oxidative pentose phosphate pathway flux, and reduced rate of anaplerosis. The fluxes of pyruvate dehydrogenase and TCA cycle were similar at the exponential and stationary phase. The results presented here provide a solid foundation for future studies of CHO cell metabolism for applications such as cell line development and medium optimization for high-titer production of recombinant proteins. 相似文献
997.
Pao PC Huang NK Liu YW Yeh SH Lin ST Hsieh CP Huang AM Huang HS Tseng JT Chang WC Lee YC 《Cell death and differentiation》2011,18(11):1791-1804
Znf179 is a member of the RING finger protein family. During embryogenesis, Znf179 is expressed in a restricted manner in the brain, suggesting a potential role in nervous system development. In this report, we show that the expression of Znf179 is upregulated during P19 cell neuronal differentiation. Inhibition of Znf179 expression by RNA interference significantly attenuated neuronal differentiation of P19 cells and a primary culture of cerebellar granule cells. Using a microarray approach and subsequent functional annotation analysis, we identified differentially expressed genes in Znf179-knockdown cells and found that several genes are involved in development, cellular growth, and cell cycle control. Flow cytometric analyses revealed that the population of G0/G1 cells decreased in Znf179-knockdown cells. In agreement with the flow cytometric data, the number of BrdU-incorporated cells significantly increased in Znf179-knockdown cells. Moreover, in Znf179-knockdown cells, p35, a neuronal-specific Cdk5 activator that is known to activate Cdk5 and may affect the cell cycle, and p27, a cell cycle inhibitor, also decreased. Collectively, these results show that induction of the Znf179 gene may be associated with p35 expression and p27 protein accumulation, which lead to cell cycle arrest in the G0/G1 phase, and is critical for neuronal differentiation of P19 cells. 相似文献
998.
999.
Ribonuclease P (RNase P) is an essential endoribonuclease for which the best-characterized function is processing the 5' leader of pre-tRNAs. Compared to bacterial RNase P, which contains a single small protein subunit and a large catalytic RNA subunit, eukaryotic nuclear RNase P is more complex, containing nine proteins and an RNA subunit in Saccharomyces cerevisiae. Consistent with this, nuclear RNase P has been shown to possess unique RNA binding capabilities. To understand the unique molecular recognition of nuclear RNase P, the interaction of S. cerevisiae RNase P with single-stranded RNA was characterized. Unstructured, single-stranded RNA inhibits RNase P in a size-dependent manner, suggesting that multiple interactions are required for high affinity binding. Mixed-sequence RNAs from protein-coding regions also bind strongly to the RNase P holoenzyme. However, in contrast to poly(U) homopolymer RNA that is not cleaved, a variety of mixed-sequence RNAs have multiple preferential cleavage sites that do not correspond to identifiable consensus structures or sequences. In addition, pre-tRNA(Tyr), poly(U)(50) RNA, and mixed-sequence RNA cross-link with purified RNase P in the RNA subunit Rpr1 near the active site in "Conserved Region I," although the exact positions vary. Additional contacts between poly(U)(50) and the RNase P proteins Rpr2p and Pop4p were identified. We conclude that unstructured RNAs interact with multiple protein and RNA contacts near the RNase P RNA active site, but that cleavage depends on the nature of interaction with the active site. 相似文献
1000.
Hendrik Schewe Marco Antonio Mirata Dirk Holtmann Jens Schrader 《Process Biochemistry》2011,46(10):1885-1899
Biotechnological monoterpene oxidation has a considerable economic potential as an alternative route to natural monoterpenoid compounds with desirable organoleptic and pharmaceutical properties. Bacterial cytochrome P450 monooxygenases (CYPs) constitute ideal catalysts for monoterpene oxidation due to their pronounced selectivities, comparably high activities and ease of recombinant expression. Research activities of the recent decades resulted in the identification and characterization of many monoterpene oxidizing bacterial CYPs, often together with their electron transfer partners. To the authors’ knowledge, no industrial process of bacterial monoterpene oxidation has been established up to date. However, the last decade has seen movement away from small scale test tube sized reactions to research activities focusing on more sophisticated processes in larger volumes and in bioreactors. These research activities successfully combined improvements on all levels of a biotransformation process. Activity, selectivity and stability of bacterial CYPs were enhanced by rational protein design, substrate and product toxicity was counteracted with the development of feeding strategies and in situ product removal techniques. The disadvantage of costly cofactors was bypassed by the application of cofactor regeneration systems and by electrochemical substitution of cofactors. 相似文献