全文获取类型
收费全文 | 7233篇 |
免费 | 278篇 |
国内免费 | 116篇 |
专业分类
7627篇 |
出版年
2024年 | 6篇 |
2023年 | 52篇 |
2022年 | 84篇 |
2021年 | 115篇 |
2020年 | 97篇 |
2019年 | 169篇 |
2018年 | 178篇 |
2017年 | 124篇 |
2016年 | 124篇 |
2015年 | 164篇 |
2014年 | 307篇 |
2013年 | 425篇 |
2012年 | 270篇 |
2011年 | 364篇 |
2010年 | 205篇 |
2009年 | 290篇 |
2008年 | 367篇 |
2007年 | 382篇 |
2006年 | 333篇 |
2005年 | 303篇 |
2004年 | 290篇 |
2003年 | 246篇 |
2002年 | 238篇 |
2001年 | 167篇 |
2000年 | 164篇 |
1999年 | 164篇 |
1998年 | 155篇 |
1997年 | 134篇 |
1996年 | 141篇 |
1995年 | 150篇 |
1994年 | 141篇 |
1993年 | 123篇 |
1992年 | 124篇 |
1991年 | 122篇 |
1990年 | 109篇 |
1989年 | 108篇 |
1988年 | 95篇 |
1987年 | 64篇 |
1986年 | 81篇 |
1985年 | 93篇 |
1984年 | 98篇 |
1983年 | 56篇 |
1982年 | 59篇 |
1981年 | 55篇 |
1980年 | 27篇 |
1979年 | 18篇 |
1978年 | 18篇 |
1977年 | 7篇 |
1976年 | 8篇 |
1971年 | 4篇 |
排序方式: 共有7627条查询结果,搜索用时 15 毫秒
91.
Shin-Ae Kang Eun-Saem Lee Hye-Young Yoon Paul A. Randazzo Seung-Taek Lee 《The Journal of biological chemistry》2010,285(34):26013-26021
PTK6 (also known as Brk) is a non-receptor-tyrosine kinase containing SH3, SH2, and catalytic domains, that is expressed in more than 60% of breast carcinomas but not in normal mammary tissues. To analyze PTK6-interacting proteins, we have expressed Flag-tagged PTK6 in HEK293 cells and performed co-immunoprecipitation assays with Flag antibody-conjugated agarose. A 164-kDa protein in the precipitated fraction was identified as ARAP1 (also known as centaurin δ-2) by MALDI-TOF mass analysis. ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg105 residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr231 in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. Silencing of endogenous PTK6 expression in breast carcinoma cells decreased EGFR levels. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells. 相似文献
92.
Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABA(A) receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and degradation are found in brain tissue of several species including human and rat, and up to 5 nM PS has been detected in extracts of postmortem human brain. Here, we ask whether PS could modulate transmitter release from nerve terminals located in the striatum. Superfusion of a preparation of striatal nerve terminals comprised of mixed synaptosomes and synaptoneurosomes with brief-duration (2 min) pulses of 25 nM PS demonstrates that PS increases the release of newly accumulated [3H]dopamine ([3H]DA), but not [14C]glutamate or [3H]GABA, whereas pregnenolone is without effect. PS does not affect dopamine transporter (DAT) mediated uptake of [3H]DA, demonstrating that it specifically affects the transmitter release mechanism. The PS-induced [3H]DA release occurs via an NMDA receptor (NMDAR) dependent mechanism as it is blocked by D-2-amino-5-phosphonovaleric acid. PS modulates DA release with very high potency, significantly increasing [3H]DA release at PS concentrations as low as 25 pM. This first report of a selective direct enhancement of synaptosomal dopamine release by PS at picomolar concentrations via an NMDAR dependent mechanism raises the possibility that dopaminergic axon terminals may be a site of action for this neurosteroid. 相似文献
93.
Hyung‐Ju Cho Jae Young Choi Yu‐Mi Yang Jeong Hee Hong Chang‐Hoon Kim Heon Young Gee Hyun Jae Lee Dong Min Shin Joo‐Heon Yoon 《Journal of cellular biochemistry》2010,109(6):1254-1263
Adequate fluid secretion from airway mucosa is essential for maintaining mucociliary clearance, and fluid hypersecretion is a prominent feature of inflammatory airway diseases such as allergic rhinitis. House dust mite extract (HDM) has been reported to activate protease‐activated receptors (PARs), which play various roles in airway epithelia. However, the role of HDM in regulating ion transporters and fluid secretion has not been investigated. We examined the effect of HDM on ion transport in human primary nasal epithelial cells. The Ca2+‐sensitive dye Fura2‐AM was used to determine intracellular Ca2+ concentration ([Ca2+]i) by means of spectrofluorometry in human normal nasal epithelial cells (NHNE). Short‐circuit current (Isc) was measured using Ussing chambers. Fluid secretion from porcine airway mucosa was observed by optical measurement. HDM extract (10 µg/Ml) effectively cleaved the PAR‐2 peptide and induced an increase of [Ca2+]i that was abolished by desensitization with trypsin, but not with thrombin. Apical application of HDM‐induced Isc sensitive to both a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor and a Ca2+‐activated Cl? channel (CaCC) inhibitor. HDM extract also stimulated fluid secretion from porcine airway mucosa. HDM extract activated PAR‐2 and apical Cl? secretion via CaCC and CFTR, and HDM‐induced fluid secretion in porcine airway mucosa. Our results suggest a role for PAR‐2 in mucociliary clearance and fluid hypersecretion of airway mucosa in response to air‐borne allergens such as HDM. J. Cell. Biochem. 109: 1254–1263, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
94.
Yang X Harkins LK Zubanova O Harrington A Kovalenko D Nadeau RJ Chen PY Toher JL Lindner V Liaw L Friesel R 《Developmental biology》2008,321(1):64-76
The FGF signaling pathway plays essential roles in endochondral ossification by regulating osteoblast proliferation and differentiation, chondrocyte proliferation, hypertrophy, and apoptosis. FGF signaling is controlled by the complementary action of both positive and negative regulators of the signal transduction pathway. The Spry proteins are crucial regulators of receptor tyrosine kinase-mediated MAPK signaling activity. Sprys are expressed in close proximity to FGF signaling centers and regulate FGFR-ERK-mediated organogenesis. During endochondral ossification, Spry genes are expressed in prehypertrophic and hypertrophic chondrocytes. Using a conditional transgenic approach in chondrocytes in vivo, the forced expression of Spry1 resulted in neonatal lethality with accompanying skeletal abnormalities resembling thanatophoric dysplasia II, including increased apoptosis and decreased chondrocyte proliferation in the presumptive reserve and proliferating zones. In vitro chondrocyte cultures recapitulated the inhibitory effect of Spry1 on chondrocyte proliferation. In addition, overexpression of Spry1 resulted in sustained ERK activation and increased expression of p21 and STAT1. Immunoprecipitation experiments revealed that Spry1 expression in chondrocyte cultures resulted in decreased FGFR2 ubiquitination and increased FGFR2 stability. These results suggest that constitutive expression of Spry1 in chondrocytes results in attenuated FGFR2 degradation, sustained ERK activation, and up-regulation of p21Cip and STAT1 causing dysregulated chondrocyte proliferation and terminal differentiation. 相似文献
95.
Space exploration by dendritic cells requires maintenance of myosin II activity by IP3 receptor 1 下载免费PDF全文
Paola Solanes Marine Bretou Franziska Lautenschlaeger Paolo Maiuri Emmanuel Terriac Maria‐Isabel Thoulouze Pierre Launay Matthieu Piel Pablo Vargas Ana‐Maria Lennon‐Duménil 《The EMBO journal》2015,34(6):798-810
Dendritic cells (DCs) patrol the interstitial space of peripheral tissues. The mechanisms that regulate their migration in such constrained environment remain unknown. We here investigated the role of calcium in immature DCs migrating in confinement. We found that they displayed calcium oscillations that were independent of extracellular calcium and more frequently observed in DCs undergoing strong speed fluctuations. In these cells, calcium spikes were associated with fast motility phases. IP3 receptors (IP3Rs) channels, which allow calcium release from the endoplasmic reticulum, were identified as required for immature DCs to migrate at fast speed. The IP3R1 isoform was further shown to specifically regulate the locomotion persistence of immature DCs, that is, their capacity to maintain directional migration. This function of IP3R1 results from its ability to control the phosphorylation levels of myosin II regulatory light chain (MLC) and the back/front polarization of the motor protein. We propose that by upholding myosin II activity, constitutive calcium release from the ER through IP3R1 maintains DC polarity during migration in confinement, facilitating the exploration of their environment. 相似文献
96.
Aditya Sharma Chandan K. Maurya Deepti Arha Amit K. Rai Sushmita Singh Salil Varshney Jonathan D. Schertzer Akhilesh K. Tamrakar 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):136-146
Chronic inflammation contributes to obesity mediated metabolic disturbances, including insulin resistance. Obesity is associated with altered microbial load in metabolic tissues that can contribute to metabolic inflammation. Different bacterial components such as, LPS, peptidoglycans have been shown to underpin metabolic disturbances through interaction with host innate immune receptors. Activation of Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) with specific peptidoglycan moieties promotes insulin resistance, inflammation and lipolysis in adipocytes. However, it was not clear how Nod1-mediated lipolysis and inflammation is linked. Here, we tested if Nod1-mediated lipolysis caused accumulation of lipid intermediates and promoted cell autonomous inflammation in adipocytes. We showed that Nod1-mediated lipolysis caused accumulation of diacylglycerol (DAG) and activation of PKCδ in 3T3-L1 adipocytes, which was prevented with a Nod1 inhibitor. Nod1-activated PKCδ caused downstream stimulation of IRAK1/4 and was associated with increased expression of proinflammatory cytokines such as, IL-1β, IL-18, IL-6, TNFα and MCP-1. Pharmacological inhibition or siRNA mediated knockdown of IRAK1/4 attenuated Nod1-mediated activation of NF-κB, JNK, and the expression of proinflammatory cytokines. These results reveal that Nod1-mediated lipolysis promoted accumulation of DAG, which engaged PKCδ and IRAK1/4 to augment inflammation in 3T3-L1 adipocytes. 相似文献
97.
The presence of serotonin 5-HT1A receptors and their physiological role were further characterized in the goldfish retina. The effects of the 5-HT6/7 receptor antagonists pimozide, fluphenazine and amoxapine, the 5-HT1A receptor antagonist WAY-100,135, and the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, on the 5-HT1A receptor agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to retinal membranes, were evaluated. In addition, the effects of serotonin, 8-hydroxy-2-(di-n-propylamino)tetralin, WAY-100,135, the adenylate cyclase inhibitors SQ22536 and MDL12330A, and the cyclic AMP analog 8-bromoadenosine-3:5 cyclic monophosphate were also studied on neuritic outgrowth from retinal explants. WAY-100,135 but not 5-HT6/7receptor antagonists inhibited [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to retinal membranes N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline decreased [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding sites up to 70%, while receptor turnover was similar to that reported in other tissues. Serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin stimulated cyclic AMP production, both ex vivo and in vitro, and these increases were related to inhibition of neuritic outgrowth. The inhibitory effect was reduced by SQ22536 and by WAY-100,135, and was mimicked by 8-bromoadenosine-3:5cyclic monophosphate. This study supports previous findings about the role of serotonin as a regulator of axonal outgrowth during in vitro regeneration of the goldfish retina and demonstrates that this effect is mediated, at least in part, by 5-HT1A receptors through a mechanism which involves an increase of cyclic AMP levels. 相似文献
98.
Maria Steblyanko Nadia Anikeeva Kerry S. Campbell James H. Keen Yuri Sykulev 《The Journal of biological chemistry》2015,290(19):11833-11842
Integrin engagement on lymphocytes initiates “outside-in” signaling that is required for cytoskeleton remodeling and the formation of the synaptic interface. However, the mechanism by which the “outside-in” signal contributes to receptor-mediated intracellular signaling that regulates the kinetics of granule delivery and efficiency of cytolytic activity is not well understood. We have found that variations in ICAM-1 expression on tumor cells influence killing kinetics of these cells by CD16.NK-92 cytolytic effectors suggesting that changes in integrin ligation on the effector cells regulate the kinetics of cytolytic activity by the effector cells. To understand how variations of the integrin receptor ligation may alter cytolytic activity of CD16.NK-92 cells, we analyzed molecular events at the contact area of these cells exposed to planar lipid bilayers that display integrin ligands at different densities and activating CD16-specific antibodies. Changes in the extent of integrin ligation on CD16.NK-92 cells at the cell/bilayer interface revealed that the integrin signal influences the size and the dynamics of activating receptor microclusters in a Pyk2-dependent manner. Integrin-mediated changes of the intracellular signaling significantly affected the kinetics of degranulation of CD16.NK-92 cells providing evidence that integrins regulate the rate of target cell destruction in antibody-dependent cell cytotoxicity (ADCC). 相似文献
99.
G蛋白偶联受体(G-protein-coupled receptors,GPCRs)作为跨膜蛋白,其结构和功能同时受相互作用的蛋白质和脂质分子调控.S-棕榈酰化(S-palmitoylation)能够影响GPCRs与信号蛋白及膜脂分子的相互作用,在GPCRs相关的多项生理进程中发挥重要调节作用.棕榈酸与GPCRs的半胱氨酸间形成不稳定的硫酯键,其修饰动力学过程受棕榈酰转移酶(protein acly transferases,PATs)与硫酯酶(thioesterases)之间的可逆性双重调控,与受体活性及生理状态密切相关.棕榈酰化修饰多发生在GPCRs的C末端,通过棕榈酸侧链插入到质膜内侧而形成第4和/或第5个胞内环,从而影响GPCRs的构象,促进其正确折叠与成熟,并对GPCRs胞内转运、分选、下游信号转导、失敏、内化、寡聚化等活动产生影响.此外,棕榈酰化还与磷酸化、泛素化及亚硝基化等多种翻译后修饰机制相互作用,共同参与调节GPCRs的功能.GPCRs的棕榈酰化修饰酶学机制以及GPCRs蛋白复合体棕榈酰化修饰胞内动力学过程将是未来的研究热点. 相似文献
100.