全文获取类型
收费全文 | 2485篇 |
免费 | 182篇 |
专业分类
2667篇 |
出版年
2021年 | 18篇 |
2019年 | 11篇 |
2018年 | 14篇 |
2017年 | 18篇 |
2016年 | 25篇 |
2015年 | 69篇 |
2014年 | 75篇 |
2013年 | 97篇 |
2012年 | 135篇 |
2011年 | 130篇 |
2010年 | 81篇 |
2009年 | 101篇 |
2008年 | 153篇 |
2007年 | 161篇 |
2006年 | 145篇 |
2005年 | 137篇 |
2004年 | 147篇 |
2003年 | 127篇 |
2002年 | 99篇 |
2001年 | 116篇 |
2000年 | 107篇 |
1999年 | 83篇 |
1998年 | 27篇 |
1997年 | 17篇 |
1996年 | 20篇 |
1995年 | 20篇 |
1994年 | 23篇 |
1993年 | 15篇 |
1992年 | 58篇 |
1991年 | 48篇 |
1990年 | 55篇 |
1989年 | 39篇 |
1988年 | 30篇 |
1987年 | 32篇 |
1986年 | 24篇 |
1985年 | 23篇 |
1984年 | 24篇 |
1983年 | 27篇 |
1982年 | 13篇 |
1981年 | 10篇 |
1980年 | 11篇 |
1979年 | 17篇 |
1978年 | 8篇 |
1977年 | 13篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1974年 | 8篇 |
1973年 | 6篇 |
1972年 | 5篇 |
1971年 | 8篇 |
排序方式: 共有2667条查询结果,搜索用时 9 毫秒
61.
62.
63.
Keisuke Iida Yamato Tsushima Yue Ma Shadi Sedghi Masoud Mai Sakuma Tomomi Yokoyama Wataru Yoshida Kazunori Ikebukuro Kazuo Nagasawa 《Bioorganic & medicinal chemistry》2019,27(8):1742-1746
G-quadruplexes (G4s) are non-B DNA structures present in guanine-rich regions of gene regulatory areas, promoters and CpG islands, but their occurrence and functions remain incompletely understood. Thus, methodology to identify G4 sequences is needed. Here, we describe the synthesis of a novel cyclic hepta-oxazole compound, L1Bio-7OTD (1), bearing a biotin affinity-tag as a tool to pull down G4 structures from mixtures of G4-forming and non G4-forming DNA sequences. We confirmed that it could pull down G4s associated with telomeres, bcl-2 gene, and c-kit gene. 相似文献
64.
Anuran (frog) tadpoles and urodeles (newts and salamanders) are the only vertebrates capable of fully regenerating amputated limbs. During the early stages of regeneration these amphibians form a "blastema", a group of mesenchymal progenitor cells that specifically directs the regrowth of the limb. We report that wnt-3a is expressed in the apical epithelium of regenerating Xenopus laevis limb buds, at the appropriate time and place to play a role during blastema formation. To test whether Wnt/beta-catenin signaling is required for limb regeneration, we created transgenic X. laevis tadpoles that express Dickkopf-1 (Dkk1), a specific inhibitor of Wnt/beta-catenin signaling, under the control of a heat-shock promoter. Heat-shock immediately before limb amputation or during early blastema formation blocked limb regeneration but did not affect the development of contralateral, un-amputated limb buds. When the transgenic tadpoles were heat-shocked following the formation of a blastema, however, they retained the ability to regenerate partial hindlimb structures. Furthermore, heat-shock induced Dkk1 blocked fgf-8 but not fgf-10 expression in the blastema. We conclude that Wnt/beta-catenin signaling has an essential role during the early stages of limb regeneration, but is not absolutely required after blastema formation. 相似文献
65.
Fujii T Yokoyama T Ninagi O Kakehashi K Obara Y Nenoi M Ishikawa T Mita K Shimada T Abe H 《Genetica》2007,130(3):267-280
In deletion-mapping of W-specific RAPD (W-RAPD) markers and putative female determinant gene (Fem), we used X-ray irradiation to break the translocation-carrying W chromosome (W
Ze
). We succeeded in obtaining a fragment of the W
Ze
chromosome designated as Ze
W, having 3 of 12 W-RAPD markers (W-Bonsai, W-Yukemuri-S, W-Yukemuri-L). Inheritance of the Ze
W fragment by males indicates that it does not include the Fem gene. On the basis of these results, we determined the relative positions of W-Yukemuri-S and W-Yukemuri-L, and we narrowed
down the region where Fem gene is located. In addition to the Ze
W fragment, the Z chromosome was also broken into a large fragment (Z1) having the +
sch
(1-21.5) and a small fragment (Z2) having the +
od
(1-49.6). Moreover, a new chromosomal fragment (Ze
WZ2) was generated by a fusion event between the Ze
W and the Z2 fragments. We analyzed the genetic behavior of the Z1 fragment and the Ze
WZ2 fragment during male (Z/Z1
Ze
WZ2) and female (Z1
Ze
WZ2/W) meiosis using phenotypic markers. It was observed that the Z1 fragment and the Z or the W chromosomes separate without fail. On the other hand, non-disjunction between the Ze
WZ2 fragment and the Z chromosome and also between the Ze
WZ2 fragment and the W chromosome occurred. Furthermore, the females (2A: Z/Ze
WZ2/W) and males (2A: Z/Z1) resulting from non-disjunction between the Ze
WZ2 fragment and the W chromosome had phenotypic defects: namely, females exhibited abnormal oogenesis and males were flapless
due to abnormal indirect flight muscle structure. These results suggest that Z2 region of the Z chromosome contains dose-sensitive gene(s), which are involved in oogenesis and indirect flight muscle development. 相似文献
66.
Prion infection correlates with hypersensitivity of P2X7 nucleotide receptor in a mouse microglial cell line 总被引:1,自引:0,他引:1
Takenouchi T Iwamaru Y Imamura M Kato N Sugama S Fujita M Hashimoto M Sato M Okada H Yokoyama T Mohri S Kitani H 《FEBS letters》2007,581(16):3019-3026
We recently established mouse microglial cells persistently infected with mouse-adapted scrapie ME7 (ScMG20/ME7) for in vitro study of prion pathogenesis. Here, we found that ScMG20/ME7 cells were hypersensitive to P2X7 receptor agonists, as demonstrated by sustained Ca(2+) influx, membrane pore formation, cell death, and interleukin-1beta release. P2X7 mRNA expression was upregulated in these cells, and also in scrapie-infected mice brains. Treatment with pentosan polysulfate eliminated the infectivity and disease-related forms of prion protein from ScMG20/ME7 cell cultures, however, hypersensitivity of P2X7 receptors remained. These results suggest that prion infections may strongly affect the P2X7 receptor system in mouse microglial cells. 相似文献
67.
Murayama K Shirouzu M Kawasaki Y Kato-Murayama M Hanawa-Suetsugu K Sakamoto A Katsura Y Suenaga A Toyama M Terada T Taiji M Akiyama T Yokoyama S 《The Journal of biological chemistry》2007,282(7):4238-4242
The Rac-specific guanine nucleotide exchange factor (GEF) Asef is activated by binding to the tumor suppressor adenomatous polyposis coli mutant, which is found in sporadic and familial colorectal tumors. This activated Asef is involved in the migration of colorectal tumor cells. The GEFs for Rho family GTPases contain the Dbl homology (DH) domain and the pleckstrin homology (PH) domain. When Asef is in the resting state, the GEF activity of the DH-PH module is intramolecularly inhibited by an unidentified mechanism. Asef has a Src homology 3 (SH3) domain in addition to the DH-PH module. In the present study, the three-dimensional structure of Asef was solved in its autoinhibited state. The crystal structure revealed that the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site. Furthermore, the RT-loop and the C-terminal region of the SH3 domain interact with the DH domain in a manner completely different from those for the canonical binding to a polyproline-peptide motif. These results demonstrate that the blocking of the Rac-binding site by the SH3 domain is essential for Asef autoinhibition. This may be a common mechanism in other proteins that possess an SH3 domain adjacent to a DH-PH module. 相似文献
68.
Curcumin has a potent anticancer effect and is a promising new therapeutic strategy. We previously demonstrated that curcumin induced non-apoptotic autophagic cell death in malignant glioma cells in vitro and in vivo. This compound inhibited the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activated the extracellular signal-regulated kinases 1/2 thereby inducing autophagy. Interestingly, activation of the first pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the latter pathway inhibited curcumin-induced autophagy and induced apoptosis, thus augmenting the cytotoxicity of curcumin. These results imply that these two autophagic pathways have opposite effects on curcumin's cytotoxicity. However, inhibition of nuclear factor kappaB, which is the main target of curcumin for its anticancer effect, was not observed in malignant glioma cells. These results suggest that autophagy but not nuclear factor kappaB plays a central role in curcumin anticancer therapy and warrant further investigation toward application in patients with malignant gliomas. Here, we discuss the therapeutic role of two autophagic pathways influenced by curcumin. 相似文献
69.
70.
In general, wild Escherichia coli strains can grow effectively under moderately acidic organic acid-rich conditions. We found that the Shiga Toxin-producing E. coli (STEC) O157:H7 NGY9 grows more quickly than a K-12 strain in Luria-Bertani (LB)-2-morpholinoethanesulphonic acid (MES) broth supplemented with acetic acid (pH 5.4). Hypothesizing that the resistance of STEC O157:H7 to acetic acid is as a result of a mechanism(s) other than those known, we screened for STEC mutants sensitive to acetic acid. NGY9 was subjected to mini-Tn5 mutagenesis and, from 50,000 colonies, five mutants that showed a clear acetic acid-sensitive phenotype were isolated. The insertion of mini-Tn5 in three mutants occurred at the fcl, wecA (rfe) and wecB (rffE) genes and caused loss of surface O-polysaccharide, loss of both O-polysaccharide and enterobacterial common antigen (ECA) and loss of ECA respectively. The other two mutants showed inactivation of the waaG (rfaG) gene but at different positions that caused a deep rough mutant with loss of the outer core oligosaccharide of lipopolysaccharide (LPS) as well as phenotypic loss of O-polysaccharide and ECA. With the introduction of plasmids carrying the fcl, wecA, wecB and waaG genes, respectively, all mutants were complemented in their production of O-polysaccharide and ECA, and normal growth was restored in organic acid-rich culture conditions. We also found that the growth of Salmonella LPS mutants Ra, Rb1, Rc, Rd1, Rd2 and Re was suppressed in the presence of acetic acid compared with that of the parents. These results suggest that the full expression of LPS (including O-polysaccharide) and ECA is indispensable to the resistance against acetic acid and other short chain fatty acids in STEC O157:H7 and Salmonella. To the best of our knowledge, this is a newly identified physiological role for O-polysaccharide and ECA as well as an acid resistance mechanism. 相似文献