全文获取类型
收费全文 | 247篇 |
免费 | 19篇 |
出版年
2023年 | 1篇 |
2022年 | 2篇 |
2021年 | 3篇 |
2020年 | 5篇 |
2019年 | 3篇 |
2018年 | 1篇 |
2017年 | 7篇 |
2016年 | 7篇 |
2015年 | 7篇 |
2014年 | 6篇 |
2013年 | 26篇 |
2012年 | 30篇 |
2011年 | 19篇 |
2010年 | 16篇 |
2009年 | 8篇 |
2008年 | 23篇 |
2007年 | 20篇 |
2006年 | 10篇 |
2005年 | 6篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 7篇 |
2001年 | 1篇 |
2000年 | 5篇 |
1999年 | 1篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1971年 | 2篇 |
1970年 | 1篇 |
排序方式: 共有266条查询结果,搜索用时 15 毫秒
241.
242.
Takuji Torimura Hideki Iwamoto Toru Nakamura Hironori Koga Takato Ueno Robert S. Kerbel Michio Sata 《Translational oncology》2013,6(5):511-519
Hepatocellular carcinoma (HCC) is a hypervascular highly angiogenic tumor usually associated with liver cirrhosis. Vascular endothelial growth factor plays a critical role in vascular development in HCC. In contrast to the treatment of early-stage HCC, the treatment options for advanced HCC are limited and prognosis is often poor, which contributes to this tumor type being the third leading cause of cancer-related deaths worldwide. Metronomic chemotherapy, which was originally designed to inhibit angiogenesis, involves low-dose chemotherapeutic agents administered in a frequent regular schedule with no prolonged breaks and minimizes severe toxicities. We reviewed the potential effects and impact of metronomic chemotherapy in preclinical studies with HCC models and in patients with advanced HCC, especially when combined with a molecular targeted agent. Metronomic chemotherapy involves multiple mechanisms that include antiangiogenesis and antivasculogenesis, immune stimulation by reducing regulatory T cells and inducing dendritic cell maturation, and possibly some direct tumor cell targeting effects, including the cancer stem cell subpopulation. The total number of preclinical studies with HCC models shows impressive results using metronomic chemotherapy-based protocols, especially in conjunction with molecular targeted agents. Four clinical trials and two case reports evaluating metronomic chemotherapy for HCC indicate it to be a safe and potentially useful treatment for HCC. Several preclinical and clinical HCC studies suggest that metronomic chemotherapy may become an alternative type of chemotherapy for advanced unresectable HCC and postsurgical adjuvant treatment of HCC. 相似文献
243.
Heike M. Freese Hajnalka Dalingault J?rn Petersen Silke Pradella Karen Davenport Hazuki Teshima Amy Chen Amrita Pati Natalia Ivanova Lynne A. Goodwin Patrick Chain John C. Detter Manfred Rohde Sabine Gronow Nikos C. Kyrpides Tanja Woyke Thorsten Brinkhoff Markus G?ker J?rg Overmann Hans-Peter Klenk 《Standards in genomic sciences》2013,8(3):450-464
Phaeobacter arcticus Zhang et al. 2008 belongs to the marine Roseobacter clade whose members are phylogenetically and physiologically diverse. In contrast to the type species of this genus, Phaeobacter gallaeciensis, which is well characterized, relatively little is known about the characteristics of P. arcticus. Here, we describe the features of this organism including the annotated high-quality draft genome sequence and highlight some particular traits. The 5,049,232 bp long genome with its 4,828 protein-coding and 81 RNA genes consists of one chromosome and five extrachromosomal elements. Prophage sequences identified via PHAST constitute nearly 5% of the bacterial chromosome and included a potential Mu-like phage as well as a gene-transfer agent (GTA). In addition, the genome of strain DSM 23566T encodes all of the genes necessary for assimilatory nitrate reduction. Phylogenetic analysis and intergenomic distances indicate that the classification of the species might need to be reconsidered. 相似文献
244.
Marina Wayama Shuhei Ota Hazuki Matsuura Nobuhito Nango Aiko Hirata Shigeyuki Kawano 《PloS one》2013,8(1)
Haematococcus pluvialis is a freshwater species of green algae and is well known for its accumulation of the strong antioxidant astaxanthin, which is used in aquaculture, various pharmaceuticals, and cosmetics. High levels of astaxanthin are present in cysts, which rapidly accumulate when the environmental conditions become unfavorable for normal cell growth. It is not understood, however, how accumulation of high levels of astaxanthin, which is soluble in oil, becomes possible during encystment. Here, we performed ultrastructural 3D reconstruction based on over 350 serial sections per cell to visualize the dynamics of astaxanthin accumulation and subcellular changes during the encystment of H. pluvialis. This study showcases the marked changes in subcellular elements, such as chloroplast degeneration, in the transition from green coccoid cells to red cyst cells during encystment. In green coccoid cells, chloroplasts accounted for 41.7% of the total cell volume, whereas the relative volume of astaxanthin was very low (0.2%). In contrast, oil droplets containing astaxanthin predominated in cyst cells (52.2%), in which the total chloroplast volume was markedly decreased (9.7%). Volumetric observations also demonstrated that the relative volumes of the cell wall, starch grains, pyrenoids, mitochondria, the Golgi apparatus, and the nucleus in a cyst cell are smaller than those in green coccid cells. Our data indicated that chloroplasts are degraded, resulting in a net-like morphology, but do not completely disappear, even at the red cyst stage. 相似文献
245.
Microglial cell line established from prion protein-overexpressing mice is susceptible to various murine prion strains
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Iwamaru Y Takenouchi T Ogihara K Hoshino M Takata M Imamura M Tagawa Y Hayashi-Kato H Ushiki-Kaku Y Shimizu Y Okada H Shinagawa M Kitani H Yokoyama T 《Journal of virology》2007,81(3):1524-1527
Several lines of evidence suggest that microglia have important roles in the pathogenesis of prion diseases. Here, we establish a novel microglial cell line (MG20) from neonatal tga20 mice that overexpress murine prion protein. After exposure to Chandler scrapie, we observed the replication and accumulation of disease-associated forms of the prion protein in MG20 cells up to the 15th passage. Furthermore, MG20 cells were susceptible to ME7, Obihiro scrapie, and bovine spongiform encephalopathy agents. Thus, MG20 cell lines persistently infected with various murine prion strains provide a useful model for the study of the pathogenesis of prion diseases. 相似文献
246.
3'-Azido-2',3'-dideoxynucleoside 5'-triphosphates inhibit telomerase activity in vitro, and the corresponding nucleosides cause telomere shortening in human HL60 cells
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Liu X Takahashi H Harada Y Ogawara T Ogimura Y Mizushina Y Saneyoshi M Yamaguchi T 《Nucleic acids research》2007,35(21):7140-7149
Telomerase adds telomeric DNA repeats to the ends of linear chromosomal DNA. 3′-Azido-3′-deoxythymidine 5′-triphosphate (AZTTP) is a known telomerase inhibitor. To obtain more selective and potent inhibitors that can be employed as tools for studying telomerase, we investigated the telomerase-inhibitory effects of purine nucleosides bearing a 3′-down azido group: 3′-azido-2′,3′-dideoxyguanosine (AZddG) 5′-triphosphate (AZddGTP), 3′-azido-2′,3′-dideoxy-6-thioguanosine (AZddSG) 5′-triphosphate (AZddSGTP), 3′-azido-2′,3′-dideoxyadenosine (AZddA) 5′-triphosphate (AZddATP) and 3′-azido-2′,3′-dideoxy-2-aminoadenosine (AZddAA) 5′-triphosphate (AZddAATP). Of these, AZddGTP showed the most potent inhibitory activity against HeLa cell telomerase. AZddGTP was significantly incorporated into the 3′-terminus of DNA by partially purified telomerase. However, AZddGTP did not exhibit significant inhibitory activity against DNA polymerases α and δ, suggesting that AZddGTP is a selective inhibitor of telomerase.
We also investigated whether long-term treatment with these nucleosides could alter telomere length and growth rates of human HL60 cells in culture. Southern hybridization analysis of genomic DNA prepared from cells cultured in the presence of AZddG and AZddAA revealed reproducible telomere shortening.
相似文献247.
248.
Katsutaka Kuremoto Yuichiro Noiri Takuya Ishimoto Naomichi Yoneda Reiko Yamamoto Hazuki Maezono Takayoshi Nakano Mikako Hayashi Shigeyuki Ebisu 《Applied and environmental microbiology》2014,80(13):3804-3810
Although extraradicular biofilm formation is related to refractory periapical periodontitis, the mechanism of extraradicular biofilm development, as well as its effect on periapical lesions, is unknown. Therefore, we aimed to develop an in vivo extraradicular biofilm model in rats and to identify and quantify extraradicular biofilm-forming bacteria while investigating the effect of extraradicular biofilms on periapical lesions. Periapical lesions were induced by exposing the pulpal tissue of the mandibular first molars of male Wistar rats to their oral environment. Four weeks later, gutta-percha points were excessively inserted into the mesial root canals of the right first molars (experimental sites) but not the left first molars (control sites). After 6 and 8 weeks of pulp exposure, the presence of extraradicular biofilms was confirmed histomorphologically, and biofilm-forming bacteria were identified by using classical culture methods. The biofilms were observed in the extraradicular area of the experimental sites. Similar species were detected both inside and outside the root canals. The bacterial count, quantified by real-time PCR assays, in the extraradicular area gradually increased in the experimental sites until 20 weeks after pulp exposure. After 8 weeks of pulp exposure, the periapical lesion volume that was measured by micro-computed tomography was significantly larger in the experimental sites than in the control sites (P < 0.05 by Welch''s t test). These results suggest that we developed an extraradicular biofilm model in rats and that extraradicular biofilms affect developing periapical lesions. 相似文献
249.
Aggrecan, a large chondroitin sulfate (CS) and keratan sulfate (KS) proteoglycan, has not previously been expressed as a full-length recombinant molecule. To facilitate structure/function analysis, we have characterized recombinant bovine aggrecan (rbAgg) and link protein expressed in COS-7 cells. We demonstrate that C-terminally truncated rbAgg was not secreted. Gel filtration chromatography of rbAgg and isolated glycosaminoglycan (GAG) chains, and their susceptibility to chondroitinase ABC digestion indicate that the GAG chains are predominantly CS, which likely occupy fewer serine residues than native aggrecan. To confirm functionality, we determined that rbAgg bound hyaluronan and recombinant link protein to form proteoglycan aggregates. In addition, cleavage of rbAgg by ADAMTS-4 revealed that the p68 form of ADAMTS-4 preferentially cleaves within the CS-2 domain, whereas the p40 form only effectively cleaves within the interglobular domain (IGD). MMP-13 cleaved rbAgg within the IGD, but cleaved more rapidly at a site within the CS domains, suggesting a role in C-terminal processing of aggrecan. Our results demonstrate that recombinant aggrecan can be used for in vitro analyses of matrix protease-dependent degradation of aggrecan in the IGD and CS domains, and both recombinant aggrecan and link protein can be used to study the assembly of proteoglycan aggregates with hyaluronan. 相似文献
250.
Asami Inoue Kenichi Obayashi Yuka Sonoda Anna Nakamura Takato Ueno Satoru Kuhara Kosuke Tashiro 《Cytotechnology》2017,69(3):461-468
Hepatic stellate cells (HSCs) are key players in liver fibrosis and regeneration via collagen degradation and synthesis. These phenomena involve inflammatory cytokines released from non-parenchymal liver cells such as Kupffer cells. Although the effects of individual cytokines on many cell types have been investigated in various conditions, such as inflammation and tissue fibrosis, investigating the effect of combined cytokines would further our understanding of the regulatory mechanisms in tissue fibrosis. Here, we report the effect of multiple cytokine combinations on primary HSCs. We first examined the effect of individual cytokines and then the simultaneous exposure of different cytokines, including interleukin-6 (IL-6), IL-1 alpha (IL-1α), platelet-derived growth factor (PDGF), tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β), on matrix metalloproteinase-1 (MMP1) gene expression in primary HSCs. We observed that the combination of all five cytokines induced higher levels of MMP1 gene expression. Of these cytokines, TNF-α and IL-1α were found to be the key cytokines for not only inducing MMP1 expression, but also increasing α-smooth muscle actin gene expression. In conclusion, the combined treatment of TNF-α and IL-1α on HSCs had an enhanced effect on the expression of the fibrotic genes, MMP1 and α-smooth muscle actin, so appears to be an important regulator for tissue regeneration. This finding suggests that stimulation with combined anti-fibrotic cytokines is a potential approach in the development of a novel therapy for the recovery of liver fibrosis. 相似文献