全文获取类型
收费全文 | 1139篇 |
免费 | 60篇 |
国内免费 | 22篇 |
出版年
2024年 | 1篇 |
2023年 | 6篇 |
2022年 | 4篇 |
2021年 | 29篇 |
2020年 | 28篇 |
2019年 | 45篇 |
2018年 | 50篇 |
2017年 | 17篇 |
2016年 | 31篇 |
2015年 | 47篇 |
2014年 | 89篇 |
2013年 | 110篇 |
2012年 | 87篇 |
2011年 | 132篇 |
2010年 | 84篇 |
2009年 | 71篇 |
2008年 | 86篇 |
2007年 | 78篇 |
2006年 | 60篇 |
2005年 | 59篇 |
2004年 | 34篇 |
2003年 | 24篇 |
2002年 | 19篇 |
2001年 | 13篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1994年 | 1篇 |
排序方式: 共有1221条查询结果,搜索用时 109 毫秒
71.
Planar cell polarity or PCP refers to a uniform cellular organization within the plan, typically orthogonal to the apico-basal polarity axis. As such, PCP provides directional cues that control and coordinate the integration of cells in tissues to build a living organism. Although dysfunctions of this fundamental cellular process have been convincingly linked to the etiology of various pathologies such as cancer and developmental defects, the molecular mechanisms governing its establishment and maintenance remain poorly understood. Here, we review some aspects of invertebrate and vertebrate PCPs, highlighting similarities and differences, and discuss the prevalence of the non-canonical Wnt signaling as a central PCP pathway, as well as recent findings on the importance of cell contractility and cilia as promising avenues of investigation. 相似文献
72.
Death receptor 6 (DR6) is a member of the death domain-containing receptors that belong to the TNFR superfamily. To date, the ligand for DR6 is still not clearly defined. Here, we developed a functional agonist monoclonal antibody (DQM3) against DR6, which bound to the first cysteine-rich domain. Importantly, DR6 signaling could be clearly activated by DQM3, which was dependent on its intracellular death domain. In addition, we demonstrated that the association between DR6 and TRADD was enhanced upon DQM3 stimulation and TRADD was involved in DR6-induced signaling activation. Taken together, our findings provide new insight into a novel mechanism by which DR6 induces downstream signaling in response to an agonist antibody. 相似文献
73.
Gokul Swaminathan Daniel Pascual Germaine Rival Renzo Perales-Linares Julio Martin-Garcia Sonia Navas-Martin 《FEBS letters》2014
Despite their differential cell tropisms, HIV-1 and HCV dramatically influence disease progression in coinfected patients. Macrophages are important target cells of HIV-1. We hypothesized that secreted HCV core protein might modulate HIV-1 replication. We demonstrate that HCV core significantly enhances HIV-1 replication in human macrophages by upregulating TNF-α and IL-6 via TLR2-, JNK-, and MEK1/2-dependent pathways. Furthermore, we show that TNF-α and IL-6 secreted from HCV core-treated macrophages reactivates monocytic U1 cells latently infected with HIV-1. Our studies reveal a previously unrecognized role of HCV core by enhancing HIV-1 infection in macrophages. 相似文献
74.
75.
Jolanta Szenajch Gabriel Wcislo Jee-Yeong Jeong Cezary Szczylik Laurie Feldman 《生物化学与生物物理学报:癌评论》2010
Recombinant human erythropoietin (rhEPO) has been used clinically to alleviate cancer- and chemotherapy-related anemia. However, recent clinical trials have reported that rhEPO also may adversely impact disease progression and survival. The expression of functional EPO receptors (EPOR) has been demonstrated in many human cancer cells where, at least in vitro, rhEPO can stimulate cell growth and survival and may induce resistance to selected therapies. 相似文献
76.
L. M. Tai K. A. Holloway D. K. Male A. J. Loughlin I. A. Romero 《Journal of cellular and molecular medicine》2010,14(5):1101-1112
Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer’s disease (AD). A leaky blood–brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid β (Aβ) peptides of 1–40 and 1–42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Aβ 1–40, the Aβ variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Aβ 1–40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC‐dextran when compared with cells incubated with the scrambled Aβ 1–40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin‐5 and ZO‐1 were unaffected. JNK and p38MAPK inhibition prevented both Aβ 1–40‐mediated down‐regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD. 相似文献
77.
Wenfeng Li Bin Yu Mengmeng Li Yanjun Hu Cai-Bin Cui 《Biochemical and biophysical research communications》2010,391(2):1228-66
Osteogenesis associated with persistent inflammation or infection exists in a broad range of conditions including rheumatoid arthritis and traumatic bone fracture. The poor outcomes of these conditions will benefit from more effective treatments. Here we investigated the molecular mechanisms and tested NEMO-binding domain peptide as a new approach of circumventing TNF-α inhibition of osteoblast differentiation. Our results showed: TNF-α markedly decreased BMP-2-induced alkaline phosphatase activity in the multipotent myoblast C2C12 cells in a dose dependent manner; stepwise experiments demonstrated that BMP-2-induced Smad1 activity was abrogated by addition of exogenous TNF-α or overexpression of NF-κB, and it was significantly elevated by overexpression of IκBα, an inhibitor of NF-κB; Western blotting showed that TNF-α markedly decreased the amount of phospho-Smad1 in BMP-2-activated C2C12 cells, but it did not alter Smad1 mRNA abundance as measured by real-time PCR; addition of a functional cell-permeable NEMO-binding domain (NBD) peptide antagonized NF-κB activity and ameliorated TNF-α inhibition of osteoblast differentiation. Taken together, our study reveals for the first time that NF-κB activation inhibits osteoblast differentiation by attenuating Smad1 activity and application of NBD peptide ameliorates this inhibitory effect. This could lead to new therapeutic drugs that circumvent the inflammatory inhibition of osteogenesis for treatment of traumatic open fractures with infection, rheumatoid arthritis and other bone loss disorders. 相似文献
78.
Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress
Yeon Yi Lee Shin Hee Hong Ye Jin Lee Sung Soo Chung Hye Seung Jung Sang Gyu Park Kyong Soo Park 《Biochemical and biophysical research communications》2010,397(4):735-739
The exposure to acute or chronic endoplasmic reticulum (ER) stress has been known to induce dysfunction of islets, leading to apoptosis. The reduction of ER stress in islet isolation for transplantation is critical for islet protection. In this study, we investigated whether tauroursodeoxycholate (TUDCA) could inhibit ER stress induced by thapsigargin, and restore the decreased glucose stimulation index of islets. In pig islets, thapsigargin decreased the insulin secretion by high glucose stimulation in a time-dependent manner (1 h, 1.35 ± 0.16; 2 h, 1.21 ± 0.13; 4 h, 1.17 ± 0.16 vs. 0 h, 1.81 ± 0.15, n = 4, p < 0.05, respectively). However, the treatment of TUDCA restored the decreased insulin secretion index induced by thapsigargin (thapsigargin, 1.25 ± 0.12 vs. thapsigargin + TUDCA, 2.13 ± 0.19, n = 5, p < 0.05). Furthermore, the culture of isolated islets for 24 h with TUDCA significantly reduced the rate of islet regression (37.4 ± 5.8% vs. 14.5 ± 6.4%, n = 12, p < 0.05). The treatment of TUDCA enhanced ATP contents in islets (27.2 ± 3.2 pmol/20IEQs vs. 21.7 ± 2.8 pmol/20IEQs, n = 9, p < 0.05). The insulin secretion index by high glucose stimulation is also increased by treatment of TUDCA (2.42 ± 0.15 vs. 1.92 ± 0.12, n = 12, p < 0.05). Taken together, we suggest that TUDCA could be a useful agent for islet protection in islet isolation for transplantation. 相似文献
79.
Takashi Matsumoto Takayoshi Kinoshita Koichi Yokota Toshiji Tada 《Biochemical and biophysical research communications》2010,400(3):369-373
MKK4 activates both JNKs and p38s. We determined the crystal structures of human non-phosphorylated MKK4 kinase domain (npMKK4) complexed with AMP-PNP (npMKK4/AMP) and a ternary complex of npMKK4, AMP-PNP and p38α peptide (npMKK4/AMP/p38). These crystal structures revealed that the p38α peptide-bound npMKK4 at the allosteric site rather than at the putative substrate binding site and induced an auto-inhibition state. While the activation loop of the npMKK4/AMP complex was disordered, in the npMKK4/AMP/p38 complex it configured a long α-helix, which prevented substrate access to the active site and αC-helix movement to the active configuration of MKK4. 相似文献
80.
Kendra S. Carmon 《Analytical biochemistry》2010,401(2):288-294
Wnts are secreted lipid-modified glycoproteins that carry out various signaling functions during development and in adult tissue. Wnt signaling is mediated by frizzled receptors (Fzds) at the cell surface and can be modulated by the secreted frizzled-related proteins (SFRPs) and other molecular antagonists. Abnormal Wnt signaling has been implicated in several diseases. However, due to the complexity of the Wnt signal and the lack of knowledge pertaining to the binding properties of different Wnt ligands, no therapeutic agents that target this pathway exist. Using a novel enzyme-linked immunosorbent assay (ELISA)-based technique, we were able to determine the first measurements of binding affinity for specific Wnt interactions. This study shows that purified Wnt3a, Wnt7a, and Wnt5a have different binding specificities for Fzds and SFRPs. 相似文献