全文获取类型
收费全文 | 6748篇 |
免费 | 528篇 |
国内免费 | 1篇 |
专业分类
7277篇 |
出版年
2023年 | 42篇 |
2022年 | 116篇 |
2021年 | 192篇 |
2020年 | 118篇 |
2019年 | 132篇 |
2018年 | 155篇 |
2017年 | 124篇 |
2016年 | 218篇 |
2015年 | 394篇 |
2014年 | 422篇 |
2013年 | 494篇 |
2012年 | 625篇 |
2011年 | 560篇 |
2010年 | 368篇 |
2009年 | 353篇 |
2008年 | 456篇 |
2007年 | 417篇 |
2006年 | 359篇 |
2005年 | 300篇 |
2004年 | 266篇 |
2003年 | 288篇 |
2002年 | 258篇 |
2001年 | 50篇 |
2000年 | 36篇 |
1999年 | 65篇 |
1998年 | 50篇 |
1997年 | 46篇 |
1996年 | 27篇 |
1995年 | 35篇 |
1994年 | 36篇 |
1993年 | 31篇 |
1992年 | 28篇 |
1991年 | 17篇 |
1990年 | 8篇 |
1989年 | 12篇 |
1988年 | 19篇 |
1987年 | 7篇 |
1986年 | 11篇 |
1985年 | 5篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 10篇 |
1981年 | 6篇 |
1979年 | 7篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1974年 | 9篇 |
1973年 | 5篇 |
1970年 | 5篇 |
1969年 | 8篇 |
排序方式: 共有7277条查询结果,搜索用时 0 毫秒
281.
282.
283.
Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells 总被引:7,自引:0,他引:7
Chen HL Demiralp B Schneider A Koh AJ Silve C Wang CY McCauley LK 《The Journal of biological chemistry》2002,277(22):19374-19381
During bone formation, multipotential mesenchymal cells proliferate and differentiate into osteoblasts, and subsequently many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors. Furthermore, the effects of PTH and PTHrP on apoptosis were dramatically dependent on cell status. In preconfluent C3H10T1/2 and MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced reduction in cell viability, which was dependent on cAMP activation. Conversely, PTH and PTHrP resulted in reduced cell viability in postconfluent cells, which was also dependent on cAMP activation. Further, the proapoptotic-like effects were associated with an inhibition of Akt phosphorylation. These data suggest that parathyroid hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at least in part via the protein kinase A pathway. 相似文献
284.
285.
Elliott-Hunt CR Kazlauskaite J Wilde GJ Grammatopoulos DK Hillhouse EW 《Journal of neurochemistry》2002,80(3):416-425
In several neurological disorders including cerebral ischaemia, glutamate has been implicated as a neurotoxic agent in the mechanisms leading to neuronal cell death. The role of corticotrophin-releasing hormone (CRH), the 41-amino acid peptide, which activates the HPA axis in response to stressful stimuli, remains controversial. In this study, we report that CRH in low physiological concentrations (2 pM), prevented glutamate-induced neurotoxicity via receptor-mediated mechanisms when administered to organotypic hippocampal cultures both during and after the glutamate-induced insult. Detailed investigations on the mechanisms mediating this neuroprotective effect showed that activation of the adenylate cyclase pathway and induction of MAP kinase phosphorylation mediate the CRH action. In addition we showed that CRH can inhibit the phosphorylation of JNK/SAPK by glutamate. Most importantly, we showed that CRH can afford neuroprotection against neurotoxicity up to 12 h following the insult, suggesting that CRH is acting at a late stage in the neuronal death cycle, and this might be important in the development of novel neuroprotective agents in order to improve neuronal survival following the insult. 相似文献
286.
Welz-Voegele C Stone JE Tran PT Kearney HM Liskay RM Petes TD Jinks-Robertson S 《Genetics》2002,162(3):1131-1145
Mismatch-repair (MMR) systems promote eukaryotic genome stability by removing errors introduced during DNA replication and by inhibiting recombination between nonidentical sequences (spellchecker and antirecombination activities, respectively). Following a common mismatch-recognition step effected by MutS-homologous Msh proteins, homologs of the bacterial MutL ATPase (predominantly the Mlh1p-Pms1p heterodimer in yeast) couple mismatch recognition to the appropriate downstream processing steps. To examine whether the processing steps in the spellchecker and antirecombination pathways might differ, we mutagenized the yeast PMS1 gene and screened for mitotic separation-of-function alleles. Two alleles affecting only the antirecombination function of Pms1p were identified, one of which changed an amino acid within the highly conserved ATPase domain. To more specifically address the role of ATP binding/hydrolysis in MMR-related processes, we examined mutations known to compromise the ATPase activity of Pms1p or Mlh1p with respect to the mitotic spellchecker and antirecombination activities and with respect to the repair of mismatches present in meiotic recombination intermediates. The results of these analyses confirm a differential requirement for the Pms1p ATPase activity in replication vs. recombination processes, while demonstrating that the Mlh1p ATPase activity is important for all examined MMR-related functions. 相似文献
287.
Yarov-Yarovoy V McPhee JC Idsvoog D Pate C Scheuer T Catterall WA 《The Journal of biological chemistry》2002,277(38):35393-35401
Alanine-scanning mutagenesis of transmembrane segments IS6 and IIS6 of the rat brain Na(v)1.2 channel alpha subunit identified mutations N418A in IS6 and L975A in IIS6 as causing strong positive shifts in the voltage dependence of activation. In contrast, mutations V424A in IS6 and L983A in IIS6 caused strong negative shifts. Most IS6 mutations opposed inactivation from closed states, but most IIS6 mutations favored such inactivation. Mutations L421C and L983A near the intracellular ends of IS6 and IIS6, respectively, exhibited significant sustained Na(+) currents at the end of 30-ms depolarizations, indicating a role for these residues in Na(+) channel fast inactivation. These residues, in combination with residues at the intracellular end of IVS6, are well situated to form an inactivation gate receptor. Mutation I409A in IS6 reduced the affinity of the local anesthetic etidocaine for the inactivated state by 6-fold, and mutations I409A and N418A reduced use-dependent block by etidocaine. No IS6 or IIS6 mutations studied affected inactivated-state affinity or use-dependent block by the neuroprotective drug sipatrigine (compound 619C89). These results suggest that the local anesthetic receptor site is formed primarily by residues in segments IIIS6 and IVS6 with the contribution of a single amino acid in segment IS6. 相似文献
288.
The activation of monocytes involves a stimulation of glycolysis, release of potent inflammatory mediators, and alterations in gene expression. All of these processes are known to be further increased under hypoxic conditions. The activated monocytes express inducible 6-phosphofructo-2-kinase (iPFK-2), which synthesizes fructose 2,6-bisphosphate, a stimulator of glycolysis. During ischemia, AMP-activated protein kinase (AMPK) activates the homologous heart 6-phosphofructo-2-kinase isoform by phosphorylating its Ser-466. Here, we studied the involvement of AMPK and iPFK-2 in the stimulation of glycolysis in activated monocytes under hypoxia. iPFK-2 was phosphorylated on the homologous serine (Ser-461) and activated by AMPK in vitro. The activation of human monocytes by lipopolysaccharide induced iPFK-2 expression and increased fructose 2,6-bisphosphate content and glycolysis. The incubation of activated monocytes with oligomycin, an inhibitor of oxidative phosphorylation, or under hypoxic conditions activated AMPK and further increased iPFK-2 activity, fructose 2,6-bisphosphate content, and glycolysis. In cultured human embryonic kidney 293 cells, the expression of a dominant-negative AMPK prevented both the activation and phosphorylation of co-transfected iPFK-2 by oligomycin. It is concluded that the stimulation of glycolysis by hypoxia in activated monocytes requires the phosphorylation and activation of iPFK-2 by AMPK. 相似文献
289.
Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells 总被引:8,自引:0,他引:8
Oberholzer A Oberholzer C Bahjat KS Ungaro R Tannahill CL Murday M Bahjat FR Abouhamze Z Tsai V LaFace D Hutchins B Moldawer LL Clare-Salzler MJ 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(7):3412-3418
The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells. Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses. In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs. Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression. However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node. The extent of IL-10 expression is dose dependent; transduction with low particle numbers (10(5)) yields only local expression, while transduction with higher particle numbers (10(7) and 10(10)) leads additionally to IL-10 appearance in the circulation. Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (10(5)) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response. 相似文献
290.
Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28 总被引:2,自引:0,他引:2
Srinivasan M Gienapp IE Stuckman SS Rogers CJ Jewell SD Kaumaya PT Whitacre CC 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(4):2180-2188
The B7:CD28/CTLA-4 costimulatory pathway plays a critical role in regulating the immune response and thus provides an ideal target for therapeutic manipulation of autoimmune disease. Previous studies have shown that blockade of CD28 signaling by mAbs can both prevent and exacerbate experimental autoimmune encephalomyelitis (EAE). In this study, we have designed two CD28 peptide mimics that selectively block B7:CD28 interactions. By surface plasmon resonance, both the end group-blocked CD28 peptide (EL-CD28) and its retro-inverso isomer (RI-CD28) compete effectively with the extracellular domain of CD28 for binding to B7-1. Both the CD28 peptide mimics inhibited expansion of encephalitogenic T cells in vitro. A single administration of EL-CD28 or RI-CD28 peptide significantly reduced disease severity in EAE. Importantly, we show that either CD28 peptide mimic administered during acute disease dramatically improved clinical signs of EAE, suppressing ongoing disease. The ratio of CD80:CD86 expression was significantly lower on CD4(+) and F4/80(+) spleen cells in CD28 peptide-treated mice. Peripheral deletion of Ag-specific CD4(+) T cells occurs following in vivo blockade of CD28 with synthetic CD28 peptides. 相似文献