全文获取类型
收费全文 | 9116篇 |
免费 | 697篇 |
国内免费 | 754篇 |
出版年
2024年 | 14篇 |
2023年 | 108篇 |
2022年 | 262篇 |
2021年 | 502篇 |
2020年 | 308篇 |
2019年 | 438篇 |
2018年 | 402篇 |
2017年 | 254篇 |
2016年 | 425篇 |
2015年 | 588篇 |
2014年 | 696篇 |
2013年 | 785篇 |
2012年 | 884篇 |
2011年 | 760篇 |
2010年 | 439篇 |
2009年 | 434篇 |
2008年 | 454篇 |
2007年 | 398篇 |
2006年 | 357篇 |
2005年 | 258篇 |
2004年 | 248篇 |
2003年 | 202篇 |
2002年 | 148篇 |
2001年 | 133篇 |
2000年 | 121篇 |
1999年 | 103篇 |
1998年 | 101篇 |
1997年 | 95篇 |
1996年 | 83篇 |
1995年 | 72篇 |
1994年 | 66篇 |
1993年 | 46篇 |
1992年 | 78篇 |
1991年 | 47篇 |
1990年 | 33篇 |
1989年 | 37篇 |
1988年 | 22篇 |
1987年 | 25篇 |
1986年 | 25篇 |
1985年 | 24篇 |
1984年 | 11篇 |
1983年 | 9篇 |
1982年 | 10篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 9篇 |
1976年 | 4篇 |
1973年 | 5篇 |
1971年 | 4篇 |
1968年 | 6篇 |
排序方式: 共有10000条查询结果,搜索用时 156 毫秒
951.
Chaoyang Li Shuiliang Yu Fumihiko Nakamura Olli T. Pentik?inen Neena Singh Shaoman Yin Wei Xin Man-Sun Sy 《The Journal of biological chemistry》2010,285(39):30328-30339
Filamin A (FLNA) is an integrator of cell mechanics and signaling. The spreading and migration observed in FLNA sufficient A7 melanoma cells but not in the parental FLNA deficient M2 cells have been attributed to FLNA. In A7 and M2 cells, the normal prion (PrP) exists as pro-PrP, retaining its glycosylphosphatidyl-inositol (GPI) anchor peptide signal sequence (GPI-PSS). The GPI-PSS of PrP has a FLNA binding motif and binds FLNA. Reducing PrP expression in A7 cells alters the spatial distribution of FLNA and organization of actin and diminishes cell spreading and migration. Integrin β1 also binds FLNA. In A7 cells, FLNA, PrP, and integrin β1 exist as two independent, yet functionally linked, complexes; they are FLNA with PrP or FLNA with integrin β1. Reducing PrP expression in A7 cells decreases the amount of integrin β1 bound to FLNA. A PrP GPI-PSS synthetic peptide that crosses the cell membrane inhibits A7 cell spreading and migration. Thus, in A7 cells FLNA does not act alone; the binding of pro-PrP enhances association between FLNA and integrin β1, which then promotes cell spreading and migration. Pro-PrP is detected in melanoma in situ but not in melanocyte. Invasive melanoma has more pro-PrP. The binding of pro-PrP to FLNA, therefore, contributes to melanomagenesis. 相似文献
952.
Xiaoqiu Yuan Ping Yin Qi Hao Chuangye Yan Jiawei Wang Nieng Yan 《The Journal of biological chemistry》2010,285(37):28953-28958
Abscisic acid (ABA) is one of the most important phytohormones in plant. PYL proteins were identified to be ABA receptors in Arabidopsis thaliana. Despite the remarkably high degree of sequence similarity, PYL1 and PYL2 exhibit distinct responses toward pyrabactin, an ABA agonist. PYL1 inhibits protein phosphatase type 2C upon binding of pyrabactin. In contrast, PYL2 appears relatively insensitive to this compound. The crystal structure of pyrabactin-bound PYL1 revealed that most of the PYL1 residues involved in pyrabactin binding are conserved, hence failing to explain the selectivity of pyrabactin for PYL1 over PYL2. To understand the molecular basis of pyrabactin selectivity, we determined the crystal structure of PYL2 in complex with pyrabactin at 1.64 Å resolution. Structural comparison and biochemical analyses demonstrated that one single amino acid alteration between a corresponding valine and isoleucine determines the distinct pyrabactin selectivity by PYL1 and PYL2. These characterizations provide an important clue to dissecting the redundancy of PYL proteins. 相似文献
953.
Xiaogang Gu John Glushka Yanbin Yin Ying Xu Timothy Denny James Smith Yingnan Jiang Maor Bar-Peled 《The Journal of biological chemistry》2010,285(12):9030-9040
The UDP-sugar interconverting enzymes involved in UDP-GlcA metabolism are well described in eukaryotes but less is known in prokaryotes. Here we identify and characterize a gene (RsU4kpxs) from Ralstonia solanacearum str. GMI1000, which encodes a dual function enzyme not previously described. One activity is to decarboxylate UDP-glucuronic acid to UDP-β-l-threo-pentopyranosyl-4″-ulose in the presence of NAD+. The second activity converts UDP-β-l-threo-pentopyranosyl-4″-ulose and NADH to UDP-xylose and NAD+, albeit at a lower rate. Our data also suggest that following decarboxylation, there is stereospecific protonation at the C5 pro-R position. The identification of the R. solanacearum enzyme enables us to propose that the ancestral enzyme of UDP-xylose synthase and UDP-apiose/UDP-xylose synthase was diverged to two distinct enzymatic activities in early bacteria. This separation gave rise to the current UDP-xylose synthase in animal, fungus, and plant as well as to the plant Uaxs and bacterial ArnA and U4kpxs homologs. 相似文献
954.
Wen Yin Jialing Wang Linling Jiang Y James Kang 《Experimental biology and medicine (Maywood, N.J.)》2021,246(16):1791
Being the second leading cause of death globally, cancer has been a long-standing and rapidly evolving focus of biomedical research and practice in the world. A tremendous effort has been made to understand the origin of cancer cells, the formation of cancerous tissues, and the mechanism by which they spread and relapse, but the disease still remains mysterious. Here, we made an attempt to scrutinize evidences that indicate the role of stem cells in tumorigenesis and metastasis, and cancer relapse. We also looked into the influence of cancers on stem cells, which in turn represent a major constituent of tumor microenvironment. Based on current understandings of the properties of (cancer) stem cells and their relation to cancers, we can foresee that novel therapeutic approaches would become the next wave of cancer treatment. 相似文献
955.
956.
130-kDa smooth muscle myosin light chain kinase is transcribed from a CArG-dependent, internal promoter within the mouse mylk gene 总被引:1,自引:0,他引:1
Yin F Hoggatt AM Zhou J Herring BP 《American journal of physiology. Cell physiology》2006,290(6):C1599-C1609
The 130-kDa smooth muscle myosin light chain kinase (smMLCK) is a Ca2+/CaM-regulated enzyme that plays a pivotal role in the initiation of smooth muscle contraction and regulation of cellular migration and division. Despite the critical importance of smMLCK in these processes, little is known about the mechanisms regulating its expression. In this study, we have identified the proximal promoter of smMLCK within an intron of the mouse mylk gene. The mylk gene encodes at least two isoforms of MLCK (130 and 220 kDa) and telokin. Luciferase reporter gene assays demonstrated that a 282-bp fragment (-167 to +115) of the smMLCK promoter was sufficient for maximum activity in A10 smooth muscle cells and 10T1/2 fibroblasts. Deletion of the 16 bp between -167 and -151, which included a CArG box, resulted in a nearly complete loss of promoter activity. Gel mobility shift assays and chromatin immunoprecipitation assays demonstrated that serum response factor (SRF) binds to this CArG box both in vitro and in vivo. SRF knockdown by short hairpin RNA decreased endogenous smMLCK expression in A10 cells. Although the SRF coactivator myocardin induced smMLCK expression in 10T1/2 cells, myocardin activated the promoter only two- to fourfold in reporter gene assays. Addition of either intron 1 or 6 kb of the 5' upstream sequence did not lead to any further activation of the promoter by myocardin. The proximal smMLCK promoter also contains a consensus GATA-binding site that bound GATA-6. GATA-6 binding to this site decreased endogenous smMLCK expression, inhibited promoter activity in smooth muscle cells, and blocked the ability of myocardin to induce smMLCK expression. Altogether, these data suggest that SRF and SRF-associated factors play a key role in regulating the expression of smMLCK. 相似文献
957.
Shi L Yue J You Y Yin B Gong Y Xu C Qiang B Yuan J Liu Y Peng X 《Cellular signalling》2006,18(11):1995-2003
Tropomyosin-related kinase (Trk) family receptors are a group of high affinity receptors for neurotrophin growth factors, which have pivotal functions in many physiological processes of nervous system. Trk receptors can dimerize and autophosphorylate upon neurotrophin stimulation, then recruit multiple adaptor proteins to transduct signal. In this report, we identified Dok5, a member of Dok family, as a new substrate of TrkB/C receptors. In yeast two-hybrid assay, Dok5 can interact with intracellular domain of TrkB and TrkC receptor through its PTB domain, but not with that of TrkA receptor. The interaction was then confirmed by GST pull-down assay and Co-IP experiment. Dok5 co-localized with TrkB and TrkC in differentiated PC12 cells, providing another evidence for their interaction. By using mutational analysis, we characterized that Dok5 PTB domain bound to Trk receptor NPQY motif in a kinase-activity-dependent manner. Furthermore, competition experiment indicated that Dok5 competed with N-shc for binding to the receptors at the same site. Finally, we showed that Dok5 was involved in the activation of MAPK pathway induced by neurotrophin stimulation. Taken together, these results suggest that Dok5 acts as substrate of TrkB/C receptors and is involved in neurotrophin induced MAPK signal pathway activation. 相似文献
958.
959.
Yin X Baek RC Kirschner DA Peterson A Fujii Y Nave KA Macklin WB Trapp BD 《The Journal of cell biology》2006,172(3):469-478
The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when a tetraspan membrane protein, myelin proteolipid protein (PLP), replaced the type I integral membrane protein, P0, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P0 instead of PLP in CNS myelin. In the absence of PLP, the ancestral P0 provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P0 is the major structural protein today. The PLP-P0 shift resulted in reduced myelin internode length, degeneration of myelinated axons, severe neurological disability, and a 50% reduction in lifespan. Mice with equal amounts of P0 and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia. 相似文献
960.
Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ 总被引:5,自引:0,他引:5
Yan P Hu X Song H Yin K Bateman RJ Cirrito JR Xiao Q Hsu FF Turk JW Xu J Hsu CY Holtzman DM Lee JM 《The Journal of biological chemistry》2006,281(34):24566-24574
The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAbeta and that this ability is not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAbeta was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAbeta breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAbeta were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Abeta that are cleaved during its degradation. Only MMP-9 digests contained fragments (Abeta(1-20) and Abeta(1-30)) from fAbeta(1-42) substrate; the corresponding cleavage sites are thought to be important for beta-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fAbeta and may contribute to ongoing clearance of plaques from amyloid-laden brains. 相似文献