全文获取类型
收费全文 | 203568篇 |
免费 | 12426篇 |
国内免费 | 11076篇 |
出版年
2023年 | 2254篇 |
2022年 | 2536篇 |
2021年 | 4755篇 |
2020年 | 4856篇 |
2019年 | 6527篇 |
2018年 | 5270篇 |
2017年 | 4182篇 |
2016年 | 5047篇 |
2015年 | 7961篇 |
2014年 | 12579篇 |
2013年 | 15223篇 |
2012年 | 9924篇 |
2011年 | 12636篇 |
2010年 | 9228篇 |
2009年 | 9852篇 |
2008年 | 10266篇 |
2007年 | 10751篇 |
2006年 | 9011篇 |
2005年 | 7971篇 |
2004年 | 6730篇 |
2003年 | 5933篇 |
2002年 | 5338篇 |
2001年 | 3945篇 |
2000年 | 3512篇 |
1999年 | 3335篇 |
1998年 | 3027篇 |
1997年 | 2613篇 |
1996年 | 2418篇 |
1995年 | 2856篇 |
1994年 | 2651篇 |
1993年 | 2479篇 |
1992年 | 2420篇 |
1991年 | 2094篇 |
1990年 | 1864篇 |
1989年 | 1755篇 |
1988年 | 1735篇 |
1987年 | 1587篇 |
1986年 | 1264篇 |
1985年 | 1952篇 |
1984年 | 2611篇 |
1983年 | 1863篇 |
1982年 | 2438篇 |
1981年 | 1893篇 |
1980年 | 1672篇 |
1979年 | 1573篇 |
1978年 | 961篇 |
1977年 | 852篇 |
1976年 | 733篇 |
1975年 | 497篇 |
1973年 | 536篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
2.
Andrea Dichlberger Stefanie Schlager Katariina Maaninka Wolfgang J. Schneider Petri T. Kovanen 《Journal of lipid research》2014,55(12):2471-2478
Human mast cells (MCs) contain TG-rich cytoplasmic lipid droplets (LDs) with high arachidonic acid (AA) content. Here, we investigated the functional role of adipose TG lipase (ATGL) in TG hydrolysis and the ensuing release of AA as substrate for eicosanoid generation by activated human primary MCs in culture. Silencing of ATGL in MCs by siRNAs induced the accumulation of neutral lipids in LDs. IgE-dependent activation of MCs triggered the secretion of the two major eicosanoids, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4). The immediate release of PGD2 from the activated MCs was solely dependent on cyclooxygenase (COX) 1, while during the delayed phase of lipid mediator production, the inducible COX-2 also contributed to its release. Importantly, when ATGL-silenced MCs were activated, the secretion of both PGD2 and LTC4 was significantly reduced. Interestingly, the inhibitory effect on the release of LTC4 was even more pronounced in ATGL-silenced MCs than in cytosolic phospholipase A2-silenced MCs. These data show that ATGL hydrolyzes AA-containing TGs present in human MC LDs and define ATGL as a novel regulator of the substrate availability of AA for eicosanoid generation upon MC activation. 相似文献
3.
4.
Bong Jin Kim Kyung Seob Song Hyun-Hee Kong Hee-Jae Cha Meesun Ock 《The Korean journal of parasitology》2014,52(1):85-87
We encountered a patient with heavy Hymenolepis nana infection. The patient was a 44-year-old Korean man who had suffered from chronic hepatitis (type B) for 15 years. A large number of H. nana adult worms were found during colonoscopy that was performed as a part of routine health screening. The parasites were scattered throughout the colon, as well as in the terminal ileum, although the patient was immunocompetent. Based on this study, colonoscopy may be helpful for diagnosis of asymptomatic H. nana infections. 相似文献
5.
6.
Laura C. Burzynski Melanie Humphry Martin R. Bennett Murray C. H. Clarke 《The Journal of biological chemistry》2015,290(41):25188-25196
Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection. 相似文献
7.
Theofilos Papadopoulos Rudolf Schemm Helmut Grubmüller Nils Brose 《The Journal of biological chemistry》2015,290(13):8256-8270
Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects—or synaptopathies—are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the CbR290H mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans. 相似文献
8.
Mohamed M. Eid Samy I. El-Kowrany Ahmad A. Othman Dina I. El Gendy Eman M. Saied 《The Korean journal of parasitology》2015,53(1):51-58
Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection. 相似文献
9.
NKG2D ligand RAE1ε induces generation and enhances the inhibitor function of myeloid‐derived suppressor cells in mice 下载免费PDF全文
Li Qian Weijuan Gong Xiaoqin Jia Lu Liu Feng Ye Jingjuan Ding Yuwei Xu Yi Fu Fang Tian 《Journal of cellular and molecular medicine》2017,21(9):2046-2054
Expression of surface NKG2D ligands on tumour cells, which activates nature killer (NK) cells and CD8+ T cells, is crucial in antitumour immunity. Some types of tumours have evolved mechanisms to suppress NKG2D‐mediated immune cell activation, such as tumour‐derived soluble NKG2D ligands or sustained NKG2D ligands produced by tumours down‐regulate the expression of NKG2D on NK cells and CD8+ T cells. Here, we report that surface NKG2D ligand RAE1ε on tumour cells induces CD11b+Gr‐1+ myeloid‐derived suppressor cell (MDSC) via NKG2D in vitro and in vivo. MDSCs induced by RAE1ε display a robust induction of IL‐10 and arginase, and these MDSCs show greater suppressive activity by inhibiting antigen‐non‐specific CD8+ T‐cell proliferation. Consistently, upon adoptive transfer, MDSCs induced by RAE1ε significantly promote CT26 tumour growth in IL‐10‐ and arginase‐dependent manners. RAE1ε moves cytokine balance towards Th2 but not Th1 in vivo. Furthermore, RAE1ε enhances inhibitory function of CT26‐derived MDSCs and promotes IL‐4 rather than IFN‐γ production from CT26‐derived MDSCs through NKG2D in vitro. Our study has demonstrated a novel mechanism for NKG2D ligand+ tumour cells escaping from immunosurveillance by facilitating the proliferation and the inhibitory function of MDSCs. 相似文献
10.
Circulating long non‐coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure 下载免费PDF全文