全文获取类型
收费全文 | 1443篇 |
免费 | 73篇 |
专业分类
1516篇 |
出版年
2023年 | 7篇 |
2022年 | 6篇 |
2021年 | 9篇 |
2020年 | 13篇 |
2019年 | 10篇 |
2018年 | 20篇 |
2017年 | 13篇 |
2016年 | 25篇 |
2015年 | 49篇 |
2014年 | 48篇 |
2013年 | 120篇 |
2012年 | 72篇 |
2011年 | 84篇 |
2010年 | 69篇 |
2009年 | 59篇 |
2008年 | 98篇 |
2007年 | 74篇 |
2006年 | 74篇 |
2005年 | 80篇 |
2004年 | 112篇 |
2003年 | 100篇 |
2002年 | 72篇 |
2001年 | 33篇 |
2000年 | 15篇 |
1999年 | 17篇 |
1998年 | 19篇 |
1997年 | 12篇 |
1996年 | 11篇 |
1995年 | 14篇 |
1994年 | 15篇 |
1993年 | 13篇 |
1992年 | 8篇 |
1991年 | 13篇 |
1990年 | 12篇 |
1989年 | 8篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 12篇 |
1984年 | 12篇 |
1983年 | 7篇 |
1982年 | 11篇 |
1981年 | 6篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 7篇 |
1977年 | 4篇 |
1976年 | 9篇 |
1974年 | 3篇 |
1973年 | 4篇 |
排序方式: 共有1516条查询结果,搜索用时 0 毫秒
51.
Kappei Kobayashi Eriko Ohgitani Yasuyuki Tanaka Masakazu Kita Jiro Imanishi 《Microbiology and immunology》1994,38(4):321-325
The major 70 kDa heat shock protein (HSP70), which is scarcely expressed in unstressed rodent cells, was apparently induced by infection with herpes simplex virus (HSV). Infection with HSV types 1 and 2 elevated HSP70 mRNA levels within 4 hr post-infection. HSP70 synthesis and accumulation increased in HSV-infected cells. Irradiation of HSV with UV-light abolished the ability to induce HSP70 mRNA. Inhibitors of viral DNA synthesis did not affect the induction of HSP70 in infected cells. Protein synthesis within 2 hr after infection was necessary for HSP70 induction. 相似文献
52.
Hochi S Hirabayashi M Hirao M Kato M Kobayashi T Kimura K Hirasawa K Leibo SP Ueda M 《Molecular reproduction and development》2001,60(2):227-232
The objectives of this study were to examine the freezing sensitivity of pronuclear-stage rabbit zygotes and to produce transgenic rabbits using the cryopreserved zygotes. Zygotes were cryopreserved either by one of two vitrification protocols or by one of the two conventional freezing protocols. The morphological survival rates of zygotes subjected to two-step freezing in 1.5 M ethylene glycol and 0.1 M sucrose (74%) or to vitrification in 7.2 M ethylene glycol and 1.0 M sucrose (81%) were higher than those subjected to freezing in 1.5 M DMSO (46%) or to vitrification in a mixture of 2.0 M DMSO, 1.0 M acetamide, and 3.0 M propylene glycol (41%). But the in vitro development into blastocysts of zygotes cryopreserved by vitrification (17%) or to a lesser extent by freezing (52%) was impaired, when compared to that of fresh control zygotes (89%). Next, a fusion gene composed from bovine aS1-casein promoter and a human GH structural gene (2.8 kb) was microinjected into the pronucleus of rabbit zygotes frozen-thawed in ethylene glycol and sucrose. Then, the presence of exogenous DNA in the genome of newborn offspring was determined by PCR. The post-injection survival of frozen zygotes (97%) was the same as that of fresh control zygotes (96%). However, of 18 offspring derived from 414 frozen-thawed and DNA-injected zygotes, no transgenic rabbits were produced. Of 52 offspring derived from 403 DNA-injected fresh zygotes, 3 transgenic rabbits were found. Here we report the first rabbit offspring resulting from zygotes cryopreserved at the pronuclear-stage, although the cryopreservation procedure employed must be improved if zygotes are to be used for systematic production of transgenic rabbits. 相似文献
53.
Yamachika E Tsujigiwa H Matsubara M Hirata Y Kita K Takabatake K Mizukawa N Kaneda Y Nagatsuka H Iida S 《Journal of molecular histology》2012,43(2):223-233
Some progress has been made in development of methods to regenerate bone from cultured cells, however no method is put to
practical use. Here, we developed methods to isolate, purify, and expand mesenchymal stem cells (MSCs) from mouse compact
bone that may be used to regenerate bone in vivo. These cells were maintained in long-term culture and were capable of differentiating
along multiple lineages, including chondrocyte, osteocyte, and adipocyte trajectories. We used standard cell isolation and
culture methods to establish cell cultures from mouse compact bone and bone marrow. Cultures were grown in four distinct media
to determine the optimal composition of culture medium for bone-derived MSCs. Putative MSCs were subjected to flow cytometry,
alkaline phosphatase assays, immunohistochemical staining, and several differentiation assays to assess cell identity, protein
expression, and developmental potential. Finally, we used an in vivo bone formation assay to determine whether putative MSCs
were capable of regenerating bone. We found that compact bone of mice was a better source of MCSs than the bone marrow, that
growth in plastic flasks served to purify MSCs from hematopoietic cells, and that MSCs grown in basic fibroblast growth factor
(bFGF)-conditioned medium were, based on multiple criteria, superior to those grown in leukemia inhibitory factor-conditioned
medium. Moreover, we found that the MSCs isolated from compact bone and grown in bFGF-conditioned medium were capable of supporting
bone formation in vivo. The methods and results described here have implications for understanding MSC biology and for clinical
purpose. 相似文献
54.
Van Luu-The Masakazu Takahashi Fernand Labrie 《The Journal of steroid biochemistry and molecular biology》1991,40(4-6):545-548
The success in synthesis of [3H]5-androstene-3,17-dione, the intermediate product in the transformation of DHEA to 4-androstenedione by 3β-hydroxysteroid dehydrogenase/ 5-ene→4-ene isomerase (3β-HSD) offers the opportunity to determine whether or not the two activities reside in one active site or in two closely related active sites. The finding that N,N-dimethyl-4-methyl-3-oxo-4-aza-5-androstane-17β-carboxamide (4-MA) inhibits competitively and specifically the dehydrogenase activity whereas a non-competitive inhibition type with a Ki value 1000 fold higher was observed for the isomerase activity, indicated that dehydrogenase and isomerase activities belong to separate sites. Using 5-dihydro-testosterone and 5-androstane-3β,17β-diol, exclusive substrates for dehydrogenase activity, it was shown that dehydrogenase is reversible and strongly inhibited by 4-MA and that thus the irreversible step in the transformation of DHEA to 4-androstenedione is due to the isomerase activity. 相似文献
55.
Masao Ohashi Takuji Oyama Endy Widya Putranto Tsuyoshi Waku Hiromi Nobusada Ken Kataoka Kenji Matsuno Masakazu Yashiro Kosuke Morikawa Nam-ho Huh Hiroyuki Miyachi 《Bioorganic & medicinal chemistry》2013,21(8):2319-2332
In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described. 相似文献
56.
Kimura T Hosoda Y Sato Y Kitamura Y Ikeda T Horibe T Kikuchi M 《The Journal of biological chemistry》2005,280(36):31438-31441
We previously reported that the reductive activities of yeast protein-disulfide isomerase (PDI) family proteins did not completely explain their contribution to the viability of Saccharomyces cerevisiae (Kimura, T., Hosoda, Y., Kitamura, Y., Nakamura, H., Horibe, T., and Kikuchi, M. (2004) Biochem. Biophys. Res. Commun. 320, 359-365). In this study, we examined oxidative refolding activities and found that Mpd1p, Mpd2, and Eug1p exhibit activities of 13.8, 16.0, and 2.16%, respectively, compared with Pdi1p and that activity for Eps1p is undetectable. In analyses of interactions between yeast PDI proteins and endoplasmic reticulum molecular chaperones, we found that Mpd1p alone does not have chaperone activity but that it interacts with and inhibits the chaperone activity of Cne1p, a homologue of mammalian calnexin, and that Cne1p increases the reductive activity of Mpd1p. These results suggest that the interface between Mpd1p and Cne1p is near the peptide-binding site of Cne1p. In addition, Eps1p interacts with Pdi1p, Eug1p, Mpd1p, and Kar2p with dissociation constants (KD) in the range of 10(-7) to 10(-6). Interestingly, co-chaperone activities were completely suppressed in Eps1p-Pdi1p and Eps1p-Mpd1p complexes, although only Eps1p and Pdi1p have chaperone activity. The in vivo consequences of these results are discussed. 相似文献
57.
Loosli F Del Bene F Quiring R Rembold M Martinez-Morales JR Carl M Grabher C Iquel C Krone A Wittbrodt B Winkler S Sasado T Morinaga C Suwa H Niwa K Henrich T Deguchi T Hirose Y Iwanami N Kunimatsu S Osakada M Watanabe T Yasuoka A Yoda H Winkler C Elmasri H Kondoh H Furutani-Seiki M Wittbrodt J 《Mechanisms of development》2004,121(7-8):703-714
In a large scale mutagenesis screen of Medaka we identified 60 recessive zygotic mutations that affect retina development. Based on the onset and type of phenotypic abnormalities, the mutants were grouped into five categories: the first includes 11 mutants that are affected in neural plate and optic vesicle formation. The second group comprises 15 mutants that are impaired in optic vesicle growth. The third group includes 18 mutants that are affected in optic cup development. The fourth group contains 13 mutants with defects in retinal differentiation. 12 of these have smaller eyes, whereas one mutation results in enlarged eyes. The fifth group consists of three mutants with defects in retinal pigmentation. The collection of mutants will be used to address the molecular genetic mechanisms underlying vertebrate eye formation. 相似文献
58.
A wild bean weevil,Kytorhinus sharpianus Bridwell (Coleoptera: Bruchidae), has a multivoltine life cycle and enters a hibernal larval diapause at the fourth instar
under a short daylength (Shimada & Ishihara, 1991). Here, we investigated their diapause incidence under different photoperiods
at 24°C and 27°C. The critical photoperiods for diapause induction were 14.5 h at 24°C and 14 h at 27°C. The stages susceptible
to diapause-inducing stimuli were estimated by transferring larvae of various instars from long days to short days and vice
versa. Then we investigated the incidence of larval diapause. The sensitive stage was estimated to be from the third to early
fourth instar. Though larval diapause, which was induced under a short daylength, was terminated only by increasing the daylength,
the termination was more synchronized by an exposure to a low temperature followed by increasing temperature, irrespective
of photoperiod. 相似文献
59.
An aqueous acetone extract obtained from the pericarps of Mallotus japonicus (MJE) was observed to inhibit prostaglandin (PG) E(2) production in a lipopolysaccharide (LPS)-activated murine macrophage-like cell line, RAW 264.7. Six phloroglucinol derivatives isolated from MJE exhibited inhibitory activity against PGE(2) production. Among these phloroglucinol derivatives, isomallotochromanol showed the strongest inhibitory activity, with an IC(50) of 1.0 microM. MJE and its phloroglucinol derivatives did not effect the enzyme activity of either prostaglandin endoperoxide synthase (PGHS)-1 or PGHS-2. However, induction of PGHS-2 in LPS-activated macrophages was inhibited by MJE and its phloroglucinol derivatives, whereas the level of PGHS-1 protein was not affected. Moreover, RT-PCR analysis showed that MJE and its phloroglucinol derivatives significantly suppressed PGHS-2 mRNA expression. Therefore, the observed inhibition of PGHS-2 induction by MJE and its phloroglucinol derivatives was likely due to a suppression of PGHS-2 mRNA expression. These results suggest that MJE and its phloroglucinol derivatives have the pharmacological ability to suppress PGE(2) production by activated macrophages. 相似文献
60.
Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway 总被引:4,自引:0,他引:4
Senokuchi T Matsumura T Sakai M Yano M Taguchi T Matsuo T Sonoda K Kukidome D Imoto K Nishikawa T Kim-Mitsuyama S Takuwa Y Araki E 《The Journal of biological chemistry》2005,280(8):6627-6633
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) ameliorate atherosclerotic diseases. Macrophages play an important role in the development and subsequent stability of atherosclerotic plaques. We reported previously that oxidized low density lipoprotein (Ox-LDL) induced macrophage proliferation through the secretion of granulocyte/macrophage colony-stimulating factor (GM-CSF) and the consequent activation of p38 MAPK. The present study was designed to elucidate the mechanism of the inhibitory effect of statins on macrophage proliferation. Mouse peritoneal macrophages were used in our study. Cerivastatin and simvastatin each inhibited Ox-LDL-induced [(3)H]thymidine incorporation into macrophages. Statins did not inhibit Ox-LDL-induced GM-CSF production, but inhibited GM-CSF-induced p38 MAPK activation. Farnesyl transferase inhibitor and geranylgeranyl transferase inhibitor inhibited GM-CSF-induced macrophage proliferation, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the effect of statins. GM-CSF-induced p38 MAPK phosphorylation was also inhibited by farnesyl transferase inhibitor or geranylgeranyl transferase inhibitor, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the suppression of GM-CSF-induced p38 MAPK phosphorylation by statins. Furthermore, we found that statin significantly inhibited the membrane translocation of the small G protein family members Ras and Rho. GM-CSF-induced p38 MAPK activation and macrophage proliferation was partially inhibited by overexpression of dominant negative Ras and completely by that of RhoA. In conclusion, statins inhibited GM-CSF-induced Ras- or RhoA-p38 MAPK signal cascades, thereby suppressing Ox-LDL-induced macrophage proliferation. The significant inhibition of macrophage proliferation by statins may also explain, at least in part, their anti-atherogenic action. 相似文献