全文获取类型
收费全文 | 1189篇 |
免费 | 68篇 |
国内免费 | 2篇 |
专业分类
1259篇 |
出版年
2023年 | 2篇 |
2022年 | 6篇 |
2021年 | 9篇 |
2020年 | 12篇 |
2019年 | 13篇 |
2018年 | 17篇 |
2017年 | 13篇 |
2016年 | 17篇 |
2015年 | 41篇 |
2014年 | 53篇 |
2013年 | 73篇 |
2012年 | 73篇 |
2011年 | 67篇 |
2010年 | 48篇 |
2009年 | 43篇 |
2008年 | 70篇 |
2007年 | 76篇 |
2006年 | 69篇 |
2005年 | 78篇 |
2004年 | 75篇 |
2003年 | 73篇 |
2002年 | 72篇 |
2001年 | 26篇 |
2000年 | 22篇 |
1999年 | 31篇 |
1998年 | 25篇 |
1997年 | 18篇 |
1996年 | 9篇 |
1995年 | 10篇 |
1994年 | 14篇 |
1993年 | 2篇 |
1992年 | 19篇 |
1991年 | 9篇 |
1990年 | 8篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1976年 | 8篇 |
1974年 | 3篇 |
排序方式: 共有1259条查询结果,搜索用时 15 毫秒
91.
Naoki Kubo Hidehiro Toh Kenjiro Shirane Takayuki Shirakawa Hisato Kobayashi Tetsuya Sato Hidetoshi Sone Yasuyuki Sato Shin-ichi Tomizawa Yoshinori Tsurusaki Hiroki Shibata Hirotomo Saitsu Yutaka Suzuki Naomichi Matsumoto Mikita Suyama Tomohiro Kono Kazuyuki Ohbo Hiroyuki Sasaki 《BMC genomics》2015,16(1)
92.
Takeichiro Aso Mioko Matsuo Hideyuki Kiyohara Kenichi Taguchi Fumihide Rikimaru Mototsugu Shimokawa Yuichi Segawa Yuichiro Higaki Hirohito Umeno Tadashi Nakashima Muneyuki Masuda 《PloS one》2015,10(3)
Background
At our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30–40 Gy concurrent chemoradiotherapy (CCRT). Patients with a favorable response (i.e., chemoradioselected; CRS) have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS). Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC) marker, CD44 variant 9 (CD44v9), with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC).Materials and Methods
Through a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies.Results
The intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008) worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9), CD44v9 positivity (HR: 3.145, 95% CI: 1.235–8.008, P = 0.0163) was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054–9.060, P = 0.0228). Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04) worse than the CD44v9-non-induced group.Conclusions
CCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of chemoradioselection and consequent organ preservation and survival. 相似文献93.
Thymidine phosphorylase suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity 总被引:7,自引:0,他引:7
Mori S Takao S Ikeda R Noma H Mataki Y Wang X Akiyama S Aikou T 《Biochemical and biophysical research communications》2002,295(2):300-305
Thymidine phosphorylase (TP) has chemotactic and angiogenic activities resulting from its enzymatic activity in vitro, and it also promotes tumor growth and inhibits apoptosis in vivo. Recently, we have reported that TP plays an important role in Fas-induced apoptosis. Caspase-8 cleavage, subsequent cytochrome c release, and caspase-3 cleavage were prevented in KB cells transfected with a TP cDNA (KB/TP cells). In this study, treatment with thymidine phosphorylase inhibitor (TPI) or thymidine did not affect cell survival of KB/TP cells during Fas-induced apoptosis. Moreover, treatment with thymine or 2-deoxy-D-ribose (degradation products of thymidine generated by TP) also did not affect cell survival of control transfectant (KB/CV) cells during Fas-induced apoptosis. These findings indicate that TP suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity. 相似文献
94.
Takabe K Mase N Matsumura H Hasegawa T Iida Y Kuribayashi H Adachi K Yoda H Ao M 《Bioorganic & medicinal chemistry letters》2002,12(17):2295-2297
Lipase-catalyzed kinetic resolution of the N,N-dialkyl-3-benzyloxymethyl-4-hydroxybutanamide 10a,b afforded the acetate 11a,b with (R) configuration, whereas the N-monoalkyl-3-benzyloxymethyl-4-hydroxybutanamide 10c-e gave the acetate 11c-e with (S) configuration. The butanamide 10 smoothly cyclized to give chiral 4-benzyloxymethyldihydrofuran-2-one 9 without racemization, which was effectively transformed into highly stereocontrolled virginiae butanolide C (VB C). 相似文献
95.
At least two polymorphic Alu insertions have been previously identified and characterized within the class I region of the
major histocompatibility complex (MHC). We have identified another two new polymorphic Alu insertions, AluyHJ and AluyHF,
located near HLA-J and HLA-F, respectively, within the a block of the MHC. Here we report on (1) the haplotypic relationships
between the Alu dimorphisms and the HLA-A locus within a panel of 51 IHW homozygous cell lines representing at least 36 HLA
class I haplotypes, (2) the Alu genotype, allele, and haplotype frequencies present in the Australian Caucasians and Japanese
populations, and (3) the frequency of association between the different Alu dimorphisms and the HLA-A alleles in 109 Australian
Caucasians and 99 Japanese. PCR was used to detect the presence or absence of insertion for AluyHJ, AluyHG, and AluyHF within
the DNA samples prepared from the cell lines and the two population groups that had been previously typed for HLA-A. In the
homozygous cell lines, all three Alu insertions were found in only one HLA class I haplotype (HLA-A1, -B57, -Cw6), no Alu
insertions were detected in six HLA class I haplotypes and one or more of the Alu insertions were found in 29 HLA class I
haplotypes. At least one of the Alu insertions was found in about 86% of the Japanese and Australian individuals, with the
AluyHJ generally related inversely to AluyHG and/or AluyHF. The gene frequency of the AluyHJ and AluyHF insertions was significantly
different (p <0.05) BETWEEN JAPANESE AND AUSTRALIANS, WHEREAS THERE WAS NO DIFFERENCE (P > 0.05) between the frequencies of
AluyHG in the two populations. The Alu haplotype frequencies were also significantly different between the Japanese and the
Australians. In the cell lines and the population groups, the AluyHJ insertion was most frequently found associated with HLA-A1
or A24, AluyHG with HLA-A2, and AluyHF with HLA-A2, -A10, or -A26. This study suggests that the three polymorphic Alu elements
have been inserted into the a block of the MHC in different progenitor groups and therefore will be useful lineage and linkage
markers in human population studies and for elucidating the evolution of HLA class I haplotypes. 相似文献
96.
Waki T Shimokawa J Watanabe S Yoshinaga T Ogawa K 《Journal of invertebrate pathology》2012,111(1):50-55
Manila clams, Ruditapes philippinarum, are widely harvested in the coastal waters in Japan. However, there have been significant decreases in the populations of Manila clams since the 1980s. It is thought that infection with the protozoan Perkinsus species has contributed to these decreases. A previous study demonstrated that high infection levels of a pure strain of Perkinsus olseni (ATCC PRA-181) were lethal to hatchery-raised small Manila clams, however, the pathogenicity of wild strain Perkinsus species to wild Manila clam is unclear. To address this, we challenged large (30-40mm in shell length) and small (3-15mm in shell length) wild Manila clams with Perkinsus species isolated from naturally infected wild Manila clams. We report high mortalities among the small clams, but not among the large ones. This is the first report to confirm the pathogenicity of wild isolate of Perkinsus species to wild Manila clams. 相似文献
97.
Masamitsu Konno Atsushi Hamabe Shinichiro Hasegawa Hisataka Ogawa Takahito Fukusumi Shimpei Nishikawa Katsuya Ohta Yoshihiro Kano Miyuki Ozaki Yuko Noguchi Daisuke Sakai Toshihiro Kudoh Koichi Kawamoto Hidetoshi Eguchi Taroh Satoh Masahiro Tanemura Hiroaki Nagano Yuichiro Doki Masaki Mori Hideshi Ishii 《Development, growth & differentiation》2013,55(3):309-318
Adipose tissue‐derived mesenchymal stem cells (ADSCs) are multipotent and can differentiate into various cell types, including osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic β‐cells, and hepatocytes. Compared with the extraction of other stem cells such as bone marrow‐derived mesenchymal stem cells (BMSCs), that of ADSCs requires minimally invasive techniques. In the field of regenerative medicine, the use of autologous cells is preferable to embryonic stem cells or induced pluripotent stem cells. Therefore, ADSCs are a useful resource for drug screening and regenerative medicine. Here we present the methods and mechanisms underlying the induction of multilineage cells from ADSCs. 相似文献
98.
Gao SY Li CY Shimokawa T Terashita T Matsuda S Yaoita E Kobayashi N 《Cell and tissue research》2007,328(2):391-400
Intercellular adhesions between renal glomerular epithelial cells (also called podocytes) are necessary for the proper function
of the glomerular filtration barrier. Although our knowledge of the molecular composition of podocyte cell-cell contact sites
has greatly progressed, the underlying molecular mechanism regulating the formation of these cell-cell contacts remains largely
unknown. We have used forskolin, an activator of adenylyl cyclase that elevates the level of intracellular cAMP, to investigate
the effect of cAMP and three Rho-family small GTPases (RhoA, Cdc42, and Rac1) on the regulation of cell-cell contact formation
in a murine podocyte cell line. Transmission electron microscopy and the immunostaining of cell adhesion molecules and actin-associated
proteins have revealed a structural change at the site of cell-cell contact following forskolin treatment. The activity of
the Rho-family small GTPases before and after forskolin treatment has been evaluated with a glutathione-S-transferase pull-down
assay. Forskolin reinforces the integrity of cell-cell contacts, resulting in the closure of an intercellular adhesion zipper,
accompanied by a redistribution of cell adhesion molecules and actin-associated proteins in a continuous linear pattern at
cell-cell contacts. The Rho-family small GTPases Rac1 and Cdc42 are activated during closure of the adhesion zipper, whereas
RhoA is suppressed. Thus, cAMP promotes the assembly of cell-cell contacts between podocytes via a mechanism that probably
involves Rho-family small GTPases.
This study was supported in part by a grant-in-aid for scientific research from the Japanese Ministry for Education, Culture,
Sports, Science, and Technology (to N. K., no. 14570015). S-Y.G. is a recipient of a grant awarded by the Japanese government
to graduate students from foreign countries. 相似文献
99.
Inoue H Iihara A Takahashi H Shimada I Ishida I Maeda Y 《Protein science : a publication of the Protein Society》2011,20(12):1971-1981
VHH is the binding domain of the IgG heavy chain. Some VHHs have an extremely long CDR3 that contributes to antigen binding. We studied the antigen binding ability of CDR3 by grafting a CDR3 from an antigen-binding VHH onto a nonbinding VHH. cAb-CA05-(1RI8), the CDR3-grafted VHH, had an antigen-binding ability. To find a human scaffold protein acceptable for VHH CDR3 grafting, we focused on the conserved structure of VHH, especially the N-terminal and C-terminal amino acid residues of the CDR3 loop and the Cys residue of CDR1. Human origin protein structures with the same orientation were searched in PDB and ubiquitin was selected. Ubi-(1RI8), the CDR3-grafted ubiquitin, had antigen-binding ability, though the affinity was relatively low compared to cAb-CA05-(1RI8). The thermodynamic parameters of Ubi-(1RI8) binding to HEWL were different from cAb-CA05-(1RI8). Hydrogen-deuterium exchange experiments showed decreased stability around the CDR3 grafting region of Ubi-(1RI8), which might explain the decreased antigen-binding ability and the differences in thermodynamic properties. We concluded that the orientation of the CDR3 sequence of Ubi-(1RI8) could not be reconstructed correctly. 相似文献
100.
Miura T Fukami TA Hasegawa K Ono N Suda A Shindo H Yoon DO Kim SJ Na YJ Aoki Y Shimma N Tsukuda T Shiratori Y 《Bioorganic & medicinal chemistry letters》2011,21(19):5778-5783
Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models. 相似文献