全文获取类型
收费全文 | 4540篇 |
免费 | 109篇 |
国内免费 | 119篇 |
出版年
2023年 | 21篇 |
2022年 | 51篇 |
2021年 | 60篇 |
2020年 | 79篇 |
2019年 | 112篇 |
2018年 | 125篇 |
2017年 | 58篇 |
2016年 | 67篇 |
2015年 | 135篇 |
2014年 | 329篇 |
2013年 | 279篇 |
2012年 | 246篇 |
2011年 | 339篇 |
2010年 | 261篇 |
2009年 | 222篇 |
2008年 | 235篇 |
2007年 | 218篇 |
2006年 | 241篇 |
2005年 | 213篇 |
2004年 | 202篇 |
2003年 | 166篇 |
2002年 | 109篇 |
2001年 | 43篇 |
2000年 | 89篇 |
1999年 | 83篇 |
1998年 | 69篇 |
1997年 | 58篇 |
1996年 | 61篇 |
1995年 | 65篇 |
1994年 | 58篇 |
1993年 | 60篇 |
1992年 | 53篇 |
1991年 | 42篇 |
1990年 | 37篇 |
1989年 | 24篇 |
1988年 | 24篇 |
1987年 | 21篇 |
1986年 | 26篇 |
1985年 | 27篇 |
1984年 | 28篇 |
1983年 | 8篇 |
1982年 | 26篇 |
1981年 | 16篇 |
1980年 | 19篇 |
1979年 | 15篇 |
1978年 | 6篇 |
1976年 | 9篇 |
1972年 | 5篇 |
1971年 | 6篇 |
1970年 | 5篇 |
排序方式: 共有4768条查询结果,搜索用时 15 毫秒
161.
162.
163.
《Cytokine》2016
Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1−/−Ifng−/− mice with dimethylnitrosamine or carbon tetrachloride. Ifng−/− and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1−/−Ifng−/− mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng−/− mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability. 相似文献
164.
165.
《Molecular & cellular proteomics : MCP》2019,18(10):2108-2120
- Download : Download high-res image (74KB)
- Download : Download full-size image
- •Bayesian Beta-Binomial model integrates ion statistics with peptide ratio agreement.
- •Model appropriately interprets information from low signal peptides.
- •Confidence can be assigned even without replicates.
- •Model adds sensitivity to detection of small changes.
166.
《Bioorganic & medicinal chemistry》2019,27(24):115157
N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site. 相似文献
167.
Hippo信号通路在哺乳动物肝脏发育、动态平衡、再生和疾病中发挥非常重要的作用。大肿瘤抑制基因1/2(large tumor suppressor 1/2, LATS1/2)激酶是Hippo信号通路的关键激酶,可以磷酸化YES相关蛋白(yes-associated protein,YAP),从而调节YAP的核质定位和降解。本文采用CRISPR/Cas9方法构建慢病毒介导的Last1/2基因敲除的载体,通过包装、感染和嘌呤霉素筛选,获得LATS1/2部分敲除的人卵巢癌ES-2和H08910细胞,免疫印迹方法检测LATS1/2表达明显减少。细胞增殖实验检测LATS1/2缺失明显抑制ES-2和HO8910细胞增殖。软琼脂克隆形成实验表明,LATS1/2缺失抑制卵巢癌ES-2细胞的克隆形成能力。细胞划痕和Transwell实验证明,LATS1/2缺失明显抑制卵巢癌ES-2细胞迁移。流式细胞检测发现,LATS1/2敲除促进卵巢癌ES-2细胞凋亡并影响细胞周期。裸鼠成瘤实验表明,LATS1/2缺失明显抑制体内肿瘤组织增殖。分子机制研究表明, LATS1/2敲除促进卵巢癌ES-2细胞中胶原I型α1(collagen type I α1,ColIα1)基因表达量增加,在卵巢癌ES-2细胞中同时敲除LATS1/2和COL1A1,可以促进细胞克隆形成。综上结果,人卵巢癌ES-2细胞中LATS1/2缺失能促进COL1A1表达增加, 从而抑制细胞增殖、转移和克隆形成,并影响细胞周期和促进细胞凋亡。 相似文献
168.
Amanda Rui En Woo Siu Kwan Sze Hwa Hwa Chung Valerie C-L Lin 《Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms》2019,1862(4):522-533
The activation functions AF1 and AF2 of nuclear receptors mediate the recruitment of coregulators in gene regulation. AF1 is mapped to the highly variable and intrinsically unstructured N terminal domain and AF2 lies in the conserved ligand binding domain. The unstructured nature of AF1 offers structural plasticity and hence functional versatility in gene regulation. However, little is known about the key functional residues of AF1 that mediates its interaction with coregulators. This study focuses on the progesterone receptor (PR) and reports the identification of K464, K481 and R492 (KKR) as the key functional residues of PR AF1. The KKR are monomethylated and function cooperatively. The combined mutations of KKR to QQQ render PR isoform B (PRB) hyperactive, whereas KKR to FFF mutations abolishes as much as 80% of PR activity. Furthermore, the hyperactive QQQ mutation rescues the loss of PR activity due to E911A mutation in AF2. The study also finds that the magnitudes of the mutational effect differ in different cell types as a result of differential effects on the functional interaction with coregulators. Furthermore, KKR provides the interface for AF1 to physically interact with p300 and SRC-1, and with AF2 at E911. Intriguingly, the inactive FFF mutant interacts strikingly stronger with both SRC-1 and AF2 than wt PRB. We propose a tripartite model to describe the dynamic interactions between AF1, AF2 and SRC-1 with KKR of AF1 and E911 of AF2 as the interface. An overly stable interaction would hamper the dynamics of disassembly of the receptor complex. 相似文献
169.
170.
Inflammation facilitates tumor progression including metastasis. Interleukin-8 (IL-8) is a chemokine that regulates polymorphonuclear neutrophil (PMN) mobilization and activity and we hypothesize that this cytokine influences tumor behavior. We have demonstrated that IL-8 is crucial for PMN-mediated melanoma extravasation under flow conditions. In addition, IL-8 is up-regulated in PMNs upon co-culturing with melanoma cells. Melanoma cells induce IkappaB-alpha degradation in PMNs indicating that NF-kappaB signaling is active in PMNs. Furthermore, the production of IL-8 in PMNs is NF-kappaB dependent. We have further identified that interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) from PMN-melanoma co-cultures synergistically contribute to IkappaB-alpha degradation and IL-8 synthesis in PMNs. Taken together, these findings show that melanoma cells induce PMNs to secrete IL-8 through activation of NF-kappaB and suggest a model in which this interaction promotes a microenvironment that is favorable for metastasis. 相似文献