全文获取类型
收费全文 | 2151篇 |
免费 | 47篇 |
国内免费 | 30篇 |
专业分类
2228篇 |
出版年
2023年 | 9篇 |
2022年 | 13篇 |
2021年 | 16篇 |
2020年 | 13篇 |
2019年 | 18篇 |
2018年 | 24篇 |
2017年 | 16篇 |
2016年 | 21篇 |
2015年 | 112篇 |
2014年 | 329篇 |
2013年 | 269篇 |
2012年 | 355篇 |
2011年 | 356篇 |
2010年 | 240篇 |
2009年 | 35篇 |
2008年 | 35篇 |
2007年 | 35篇 |
2006年 | 28篇 |
2005年 | 32篇 |
2004年 | 21篇 |
2003年 | 22篇 |
2002年 | 12篇 |
2001年 | 16篇 |
2000年 | 12篇 |
1999年 | 7篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 10篇 |
1993年 | 8篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 9篇 |
1986年 | 4篇 |
1985年 | 8篇 |
1984年 | 13篇 |
1983年 | 6篇 |
1982年 | 9篇 |
1981年 | 10篇 |
1980年 | 6篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1973年 | 4篇 |
1970年 | 4篇 |
排序方式: 共有2228条查询结果,搜索用时 10 毫秒
91.
Doi S Zou Y Togao O Pastor JV John GB Wang L Shiizaki K Gotschall R Schiavi S Yorioka N Takahashi M Boothman DA Kuro-o M 《The Journal of biological chemistry》2011,286(10):8655-8665
Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby inhibiting TGF-β1 signaling. Klotho suppresses TGF-β1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-β1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously. 相似文献
92.
Kadono S Sakamoto A Kikuchi Y Oh-eda M Yabuta N Koga T Hattori K Shiraishi T Haramura M Kodama H Esaki T Sato H Watanabe Y Itoh S Ohta M Kozono T 《Biochemical and biophysical research communications》2004,324(4):1227-1233
The 3D structure of human factor VIIa/soluble tissue factor in complex with a peptide mimetic inhibitor, propylsulfonamide-D-Thr-Met-p-aminobenzamidine, is determined by X-ray crystallography. As compared with the interactions between thrombin and thrombin inhibitors, the interactions at S2 and S3 sites characteristic of factor VIIa and factor VIIa inhibitors are revealed. The S2 site has a small pocket, which is filled by the hydrophobic methionine side chain in P2. The small S3 site fits the small size residue, D-threonine in P3. The structural data and SAR data of the peptide mimetic inhibitor show that these interactions in the S2 and S3 sites play an important role for the improvement of selectivity versus thrombin. The results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF. 相似文献
93.
Mark W. Zimmerman Kelley E. McQueeney Jeffrey S. Isenberg Bruce R. Pitt Karla A. Wasserloos Gregg E. Homanics John S. Lazo 《The Journal of biological chemistry》2014,289(9):5904-5913
Protein-tyrosine phosphatase 4A3 (PTP4A3) is highly expressed in multiple human cancers and is hypothesized to have a critical, albeit poorly defined, role in the formation of experimental tumors in mice. PTP4A3 is broadly expressed in many tissues so the cellular basis of its etiological contributions to carcinogenesis may involve both tumor and stromal cells. In particular, PTP4A3 is expressed in the tumor vasculature and has been proposed to be a direct target of vascular endothelial growth factor (VEGF) signaling in endothelial cells. We now provide the first in vivo experimental evidence that PTP4A3 participates in VEGF signaling and contributes to the process of pathological angiogenesis. Colon tumor tissue isolated from Ptp4a3-null mice revealed reduced tumor microvessel density compared with wild type controls. Additionally, vascular cells derived from Ptp4a3-null tissues exhibited decreased invasiveness in an ex vivo wound healing assay. When primary endothelial cells were isolated and cultured in vitro, Ptp4a3-null cells displayed greatly reduced migration compared with wild type cells. Exposure to VEGF led to an increase in Src phosphorylation in wild type endothelial cells, a response that was completely ablated in Ptp4a3-null cells. In loss-of-function studies, reduced VEGF-mediated migration was also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. VEGF-mediated in vivo vascular permeability was significantly attenuated in PTP4A3-deficient mice. These findings strongly support a role for PTP4A3 as an important contributor to endothelial cell function and as a multimodal target for cancer therapy and mitigating VEGF-regulated angiogenesis. 相似文献
94.
用生物活性法和双抗体夹心桥联酶免疫吸附(ELISA)法检测了人类疱疹病素6型(HHV-6)GS株和南京地方株CN5,8,10感染的淋巴细胞培养上清中的肿瘤坏死因子(TNF)的水平,发现培养24h即可检出高水平的TNF,48~72h述到峰值,此后逐渐下降,与未感染耐照组比较有及其显著的差异(P<0.001)。GS株与地方株同诱生TNF水平无儿著性差异(P>0.1),三株地方株诱生TNF也无显著性差异(P>0.05)。TNF-α单抗可以完全中和培养上清中TNF的活性,证实上清中有TNF-α。与LPS比较,HHV-6诱生TNF-α的能力要强得多。 相似文献
95.
Peng C Zhu F Wen W Yao K Li S Zykova T Liu K Li X Ma WY Bode AM Dong Z 《The Journal of biological chemistry》2012,287(31):25881-25892
TRAF2 has an important function in mediating the TNF-R signaling pathway toward activation of NF-κB and JNKs. Here we reveal a novel function of TRAF2 in the epidermal growth factor (EGF) signaling pathway. Knockdown of TRAF2 blocked EGF-induced AP-1 activity and anchorage- independent cell transformation. Notably, we showed that EGF induces ribosomal S6 kinase 2 (RSK2) ubiquitination, and knocking down TRAF2 suppresses ubiquitination of RSK2 induced by EGF. We also found that TRAF2 affects RSK2 activity through RSK2 ubiquitination. RSK2 plays a critical role in AP-1 activity mediated through CREB and c-Fos, which regulates anchorage-independent cell transformation. In addition, TRAF2 is overexpressed in colon cancer and required for colon cancer development, suggesting that TRAF2 might be a potential molecular target for cancer prevention and treatment. 相似文献
96.
Specificity and Structure of a High Affinity Activin Receptor-like Kinase 1 (ALK1) Signaling Complex
Townson SA Martinez-Hackert E Greppi C Lowden P Sako D Liu J Ucran JA Liharska K Underwood KW Seehra J Kumar R Grinberg AV 《The Journal of biological chemistry》2012,287(33):27313-27325
Activin receptor-like kinase 1 (ALK1), an endothelial cell-specific type I receptor of the TGF-β superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis. As such, ALK1 is an important therapeutic target. Thus, several ALK1-directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics. Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling. The TGF-β family ligands BMP9 and BMP10 as well as the three type II TGF-β family receptors ActRIIA, ActRIIB, and BMPRII have been implicated in ALK1 signaling. Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors. Our data show that BMP9 displays a significant discrimination in type II receptor binding, whereas BMP10 does not. We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB. The structure reveals that the high specificity of ALK1 for BMP9/10 is determined by a novel orientation of ALK1 with respect to BMP9, which leads to a unique set of receptor-ligand interactions. In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors. Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies. 相似文献
97.
98.
Kjaersgaard T Jensen MK Christiansen MW Gregersen P Kragelund BB Skriver K 《The Journal of biological chemistry》2011,286(41):35418-35429
99.
100.