全文获取类型
收费全文 | 4303篇 |
免费 | 288篇 |
国内免费 | 6篇 |
出版年
2024年 | 1篇 |
2023年 | 15篇 |
2022年 | 8篇 |
2021年 | 80篇 |
2020年 | 48篇 |
2019年 | 80篇 |
2018年 | 113篇 |
2017年 | 104篇 |
2016年 | 168篇 |
2015年 | 214篇 |
2014年 | 275篇 |
2013年 | 317篇 |
2012年 | 384篇 |
2011年 | 394篇 |
2010年 | 209篇 |
2009年 | 210篇 |
2008年 | 306篇 |
2007年 | 253篇 |
2006年 | 192篇 |
2005年 | 188篇 |
2004年 | 182篇 |
2003年 | 186篇 |
2002年 | 140篇 |
2001年 | 125篇 |
2000年 | 107篇 |
1999年 | 76篇 |
1998年 | 34篇 |
1997年 | 19篇 |
1996年 | 28篇 |
1995年 | 17篇 |
1994年 | 13篇 |
1993年 | 12篇 |
1992年 | 26篇 |
1991年 | 25篇 |
1990年 | 10篇 |
1989年 | 14篇 |
1988年 | 8篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1979年 | 1篇 |
1975年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1965年 | 1篇 |
1963年 | 1篇 |
排序方式: 共有4597条查询结果,搜索用时 15 毫秒
51.
Jihwa Chung Kyoung Hwa Kim Seok Cheol Lee Shung Hyun An Kihwan Kwon 《Molecules and cells》2015,38(10):851-858
Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis. 相似文献
52.
Tae Hoon Kwon Hyunwoo Jung Eun Jeong Cho Ji Hoon Jeong Uy Dong Sohn 《Molecules and cells》2015,38(7):616-623
P2 receptors are membrane-bound receptors for extracellular nucleotides such as ATP and UTP. P2 receptors have been classified as ligand-gated ion channels or P2X receptors and G protein-coupled P2Y receptors. Recently, purinergic signaling has begun to attract attention as a potential therapeutic target for a variety of diseases especially associated with gastroenterology. This study determined the ATP and UTP-induced receptor signaling mechanism in feline esophageal contraction. Contraction of dispersed feline esophageal smooth muscle cells was measured by scanning micrometry. Phosphorylation of MLC20 was determined by western blot analysis. ATP and UTP elicited maximum esophageal contraction at 30 s and 10 μM concentration. Contraction of dispersed cells treated with 10 μM ATP was inhibited by nifedipine. However, contraction induced by 0.1 μM ATP, 0.1 μM UTP and 10 μM UTP was decreased by , chelerythrine, ML-9, PTX and GDPβS. Contraction induced by 0.1 μM ATP and UTP was inhibited by Gαi3 or Gαq antibodies and by PLCβ1 or PLCβ3 antibodies. Phosphorylated MLC20 was increased by ATP and UTP treatment. In conclusion, esophageal contraction induced by ATP and UTP was preferentially mediated by P2Y receptors coupled to Gαi3 and G q proteins, which activate PLCβ1 and PLCβ3. Subsequently, increased intracellular Ca2+ and activated PKC triggered stimulation of MLC kinase and inhibition of MLC phosphatase. Finally, increased pMLC20 generated esophageal contraction. U73122相似文献
53.
54.
Won Gi Yoo Sanghyun Lee Myoung-Ro Lee Mi-Ran Yun Taesoo Kwon Dae-Won Kim 《Bioinformation》2015,11(1):17-20
The increase in prevalence of antimicrobial resistance makes the search for new antibiotic agents imperative. Antimicrobial
peptides (AMPs) from natural resources have been recognized as suitable tools to combat antibiotic-resistant bacteria. The liver
fluke Clonorchis sinensis living in germ-filled environments could be a good source of antimicrobials. Here, we report the use of a
rational protocol that combines AMP predictions based on their physicochemical properties and their in vivo stability to discover
AMP candidates from the entire genome of C. sinensis. To screen AMP candidates, in silico analyses based on the physicochemical
properties of known AMPs, such as length, charge, isoelectric point, and in vitro and in vivo aggregation values were performed. To
enhance their in vivo stability, proteins having proteolytic cleavage sites were excluded. As a consequence, four high-activity, highstability
peptides were identified. These peptides could be potential starting materials for the development of new AMPs via
structural modification and optimization. Thus, this study proposes a refined computational method to develop new AMPs and
identifies four AMP candidates, which could serve as templates for further development of peptide antibiotics. 相似文献
55.
Biomimetic repeat protein derived from Xenopus tropicalis for fibrous scaffold fabrication 下载免费PDF全文
Yunkyeoung Kwon Yun Jung Yang Dooyup Jung Byeong Hee Hwang Hyung Joon Cha 《Biopolymers》2015,103(12):659-664
Collagen, silk, and elastin are the fibrous proteins consist of representative amino acid repeats. Because these proteins exhibited distinguishing mechanical properties, they have been utilized in diverse applications, such as fiber‐based sensors, filtration membranes, supporting materials, and tissue engineering scaffolds. Despite their infinite prevalence and potential, most studies have only focused on a few repeat proteins. In this work, the hypothetical protein with a repeat motif derived from the frog Xenopus tropicalis was obtained and characterized for its potential as a novel protein‐based material. The codon‐optimized recombinant frog repeat protein, referred to as ‘xetro’, was produced at a high rate in a bacterial system, and an acid extraction‐based purified xetro protein was successfully fabricated into microfibers and nanofibers using wet spinning and electrospinning, respectively. Specifically, the wet‐spun xetro microfibers demonstrated about 2‐ and 1.5‐fold higher tensile strength compared with synthetic polymer polylactic acid and cross‐linked collagen, respectively. In addition, the wet‐spun xetro microfibers showed about sevenfold greater stiffness than collagen. Therefore, the mass production potential and greater mechanical properties of the xetro fiber may result in these fibers becoming a new promising fiber‐based material for biomedical engineering. © 2015 Wiley Periodicals, Inc. Biopolymers 103: 659–664, 2015. 相似文献
56.
Young-Lai Cho Sung-Mo Hur Ji-Yoon Kim Ji-Hee Kim Dong-Keon Lee Jongeon Choe Moo-Ho Won Kwon-Soo Ha Dooil Jeoung Sanghwa Han Sungwoo Ryoo Hansoo Lee Jeong-Ki Min Young-Guen Kwon Dong-Hyun Kim Young-Myeong Kim 《The Journal of biological chemistry》2015,290(1):467-477
Ginsenoside Rg5 is a compound newly synthesized during the steaming process of ginseng; however, its biological activity has not been elucidated with regard to endothelial function. We found that Rg5 stimulated in vitro angiogenesis of human endothelial cells, consistent with increased neovascularization and blood perfusion in a mouse hind limb ischemia model. Rg5 also evoked vasorelaxation in aortic rings isolated from wild type and high cholesterol-fed ApoE−/− mice but not from endothelial nitric-oxide synthase (eNOS) knock-out mice. Angiogenic activity of Rg5 was highly associated with a specific increase in insulin-like growth factor-1 receptor (IGF-1R) phosphorylation and subsequent activation of multiple angiogenic signals, including ERK, FAK, Akt/eNOS/NO, and Gi-mediated phospholipase C/Ca2+/eNOS dimerization pathways. The vasodilative activity of Rg5 was mediated by the eNOS/NO/cGMP axis. IGF-1R knockdown suppressed Rg5-induced angiogenesis and vasorelaxation by inhibiting key angiogenic signaling and NO/cGMP pathways. In silico docking analysis showed that Rg5 bound with high affinity to IGF-1R at the same binding site of IGF. Rg5 blocked binding of IGF-1 to its receptor with an IC50 of ∼90 nmol/liter. However, Rg5 did not induce vascular inflammation and permeability. These data suggest that Rg5 plays a novel role as an IGF-1R agonist, promoting therapeutic angiogenesis and improving hypertension without adverse effects in the vasculature. 相似文献
57.
58.
Wijeong Jang Ji Young Kim Shanyu Cui Juyeon Jo Byoung-Cheol Lee Yeonwoo Lee Ki-Sun Kwon Chul-Seung Park Changsoo Kim 《The Journal of biological chemistry》2015,290(4):2521-2528
Calcium-permeable and thermosensitive transient receptor potential (TRP) channels mediate the nociceptive transduction of noxious temperature in Drosophila nociceptors. However, the underlying molecular mechanisms are not completely understood. Here we find that Subdued, a calcium-activated chloride channel of the Drosophila anoctamin family, functions in conjunction with the thermo-TRPs in thermal nociception. Genetic analysis with deletion and the RNAi-mediated reduction of subdued show that subdued is required for thermal nociception in nociceptors. Further genetic analysis of subdued mutant and thermo-TRP mutants show that they interact functionally in thermal nociception. We find that Subdued expressed in heterologous cells mediates a strong chloride conductance in the presence of both heat and calcium ions. Therefore, our analysis suggests that Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli. 相似文献
59.
Mikalai Lapkouski Watchalee Chuenchor Min-Sung Kim Martin Gellert Wei Yang 《The Journal of biological chemistry》2015,290(23):14618-14625
Mammalian immune receptor diversity is established via a unique restricted set of site-specific DNA rearrangements in lymphoid cells, known as V(D)J recombination. The lymphoid-specific RAG1-RAG2 protein complex (RAG1/2) initiates this process by binding to two types of recombination signal sequences (RSS), 12RSS and 23RSS, and cleaving at the boundaries of RSS and V, D, or J gene segments, which are to be assembled into immunoglobulins and T-cell receptors. Here we dissect the ordered assembly of the RAG1/2 heterotetramer with 12RSS and 23RSS DNAs. We find that RAG1/2 binds only a single 12RSS or 23RSS and reserves the second DNA-binding site specifically for the complementary RSS, to form a paired complex that reflects the known 12/23 rule of V(D)J recombination. The assembled RAG1/2 paired complex is active in the presence of Mg2+, the physiologically relevant metal ion, in nicking and double-strand cleavage of both RSS DNAs to produce a signal-end complex. We report here the purification and initial crystallization of the RAG1/2 signal-end complex for atomic-resolution structure elucidation. Strict pairing of the 12RSS and 23RSS at the binding step, together with information from the crystal structure of RAG1/2, leads to a molecular explanation of the 12/23 rule. 相似文献
60.
Hyojin Park Sungwoon Lee Pravesh Shrestha Jihye Kim Jeong Ae Park Yeongrim Ko Young Ho Ban Dae-Young Park Sang-Jun Ha Gou Young Koh Victor Sukbong Hong Naoki Mochizuki Young-Myeong Kim Weontae Lee Young-Guen Kwon 《The Journal of cell biology》2015,211(3):619-637
The phosphoinositide 3-kinase–Akt signaling pathway is essential to many biological processes, including cell proliferation, survival, metabolism, and angiogenesis, under pathophysiological conditions. Although 3-phosphoinositide–dependent kinase 1 (PDK1) is a primary activator of Akt at the plasma membrane, the optimal activation mechanism remains unclear. We report that adhesion molecule with IgG-like domain 2 (AMIGO2) is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation. Loss of AMIGO2 in endothelial cells (ECs) led to apoptosis and inhibition of angiogenesis with Akt inactivation. Amino acid residues 465–474 in AMIGO2 directly bind to the PDK1 pleckstrin homology domain. A synthetic peptide containing the AMIGO2 465–474 residues abrogated the AMIGO2–PDK1 interaction and Akt activation. Moreover, it effectively suppressed pathological angiogenesis in murine tumor and oxygen-induced retinopathy models. These results demonstrate that AMIGO2 is an important regulator of the PDK1–Akt pathway in ECs and suggest that interference of the PDK1–AMIGO2 interaction might be a novel pharmaceutical target for designing an Akt pathway inhibitor. 相似文献