全文获取类型
收费全文 | 865篇 |
免费 | 51篇 |
专业分类
916篇 |
出版年
2022年 | 3篇 |
2021年 | 11篇 |
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 10篇 |
2017年 | 7篇 |
2016年 | 13篇 |
2015年 | 26篇 |
2014年 | 25篇 |
2013年 | 48篇 |
2012年 | 35篇 |
2011年 | 46篇 |
2010年 | 28篇 |
2009年 | 22篇 |
2008年 | 50篇 |
2007年 | 33篇 |
2006年 | 25篇 |
2005年 | 32篇 |
2004年 | 29篇 |
2003年 | 28篇 |
2002年 | 20篇 |
2001年 | 26篇 |
2000年 | 37篇 |
1999年 | 31篇 |
1998年 | 11篇 |
1997年 | 14篇 |
1996年 | 10篇 |
1995年 | 16篇 |
1994年 | 7篇 |
1993年 | 10篇 |
1992年 | 18篇 |
1991年 | 20篇 |
1990年 | 23篇 |
1989年 | 17篇 |
1988年 | 24篇 |
1987年 | 22篇 |
1986年 | 15篇 |
1985年 | 17篇 |
1984年 | 8篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 17篇 |
1980年 | 5篇 |
1979年 | 10篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1971年 | 3篇 |
1969年 | 2篇 |
排序方式: 共有916条查询结果,搜索用时 15 毫秒
101.
Highly polar xanthophylls of 9′-cis-neoxanthin (neoxanthin) and fucoxanthin, which have the characteristic structure of an epoxy group and an allenic bond, were
previously found to induce apoptosis in human prostate cancer cells. In the present study, we found apoptosis induction by
neoxanthin in HCT116 human colon cancer cells and examined the induction mechanism. The cells exposed to 20 μM neoxanthin
clearly showed chromatin condensation, DNA fragmentation, and an increase in hypodiploid cells. Neoxanthin treatment increased
the activities of caspase-3, -8 and -9, and the protein levels of their active subunits, except in the case of caspase-8.
The treatment also caused the loss of mitochondrial transmembrane potential at an early stage and subsequently the release
of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. The exposure of neoxanthin directly to mitochondria
isolated from the cells enhanced the release of cytochrome c and AIF in a dose-dependent manner. Approximately 50% of the
neoxanthin taken up into the HCT116 cells accumulated in the mitochondrial fraction. These results suggest that the accumulation
of neoxanthin in mitochondria causes the loss of mitochondrial transmembrane potential and thereafter releases cytochrome
c and AIF, leading to the execution of apoptosis. 相似文献
102.
Nagao K Taniyama Y Koibuchi N Morishita R 《Biochemical and biophysical research communications》2007,359(3):431-437
During heart development, various signaling cascades are tightly regulated in a stage- and region-dependent manner. Vascular endothelial growth factor (VEGF) is one of the important molecules required for both vascular development and cardiac morphogenesis. VEGF receptors are present in the embryonic heart, so we focused on heart formation in VEGF-over-expressing Xenopus embryos. Over-expression of VEGF(170) caused disorganized vessels, while the expression of an endothelial marker, Tie-2, was increased. The embryo's heart was distinctly larger than that of control, and showed abnormal morphology. Histological analysis of these embryos showed failure of heart looping. In situ hybridization with Hand-1, which controls intrinsic morphogenetic pathways, revealed that the expression level of Hand-1 was decreased in the heart region. These results suggest that increased VEGF(170) levels disturb Hand-1 expression in the region required for normal heart morphogenesis. VEGF expression level may be important in heart morphology during embryonic development. 相似文献
103.
Ikee Y Hashimoto K Nakashima M Hayashi K Sano S Shiro M Nagao Y 《Bioorganic & medicinal chemistry letters》2007,17(4):942-945
The ring-opening reactions of 1-azabicyclo[1.1.0]butane 3 with thiols 6a-f gave 3-sulfenylazetidine derivatives 7a-f in 50-92% yields. Treatment of 3 with aromatic amines 11a-e and dibenzylamine 11f in the presence of Mg(ClO(4))(2) afforded the corresponding 3-aminoazetidine derivatives 12a-f in 24-53% yields. These azetidine derivatives were introduced into the C7 position of a quinolone nucleus 8 to afford the corresponding fluoroquinolones 9a-f and 13a-f in 21-83% yields. Some of them exhibited superior antibacterial activity against quinolone-susceptible MRSA in comparison with clinically used fluoroquinolones, such as levofloxacin, ciprofloxacin, and gatifloxacin. 相似文献
104.
105.
Kazutaka Sawada Tomoya Sato Hiroshi Hamajima Lahiru Niroshan Jayakody Miyo Hirata Mikako Yamashiro Marie Tajima Susumu Mitsutake Koji Nagao Keisuke Tsuge Fumiyoshi Abe Kentaro Hanada Hiroshi Kitagaki 《Applied and environmental microbiology》2015,81(11):3688-3698
In nature, different microorganisms create communities through their physiochemical and metabolic interactions. Many fermenting microbes, such as yeasts, lactic acid bacteria, and acetic acid bacteria, secrete acidic substances and grow faster at acidic pH values. However, on the surface of cereals, the pH is neutral to alkaline. Therefore, in order to grow on cereals, microbes must adapt to the alkaline environment at the initial stage of colonization; such adaptations are also crucial for industrial fermentation. Here, we show that the yeast Saccharomyces cerevisiae, which is incapable of synthesizing glucosylceramide (GlcCer), adapted to alkaline conditions after exposure to GlcCer from koji cereal cultured with Aspergillus kawachii. We also show that various species of GlcCer derived from different plants and fungi similarly conferred alkali tolerance to yeast. Although exogenous ceramide also enhanced the alkali tolerance of yeast, no discernible degradation of GlcCer to ceramide was observed in the yeast culture, suggesting that exogenous GlcCer itself exerted the activity. Exogenous GlcCer also increased ethanol tolerance and modified the flavor profile of the yeast cells by altering the membrane properties. These results indicate that GlcCer from A. kawachii modifies the physiology of the yeast S. cerevisiae and demonstrate a new mechanism for cooperation between microbes in food fermentation. 相似文献
106.
107.
Saito T Obitsu T Kondo T Matsui T Nagao Y Kusumi K Matsumura N Ueno S Kishi A Katsumata S Kagamiishi Y Nakai H Toda M 《Bioorganic & medicinal chemistry》2011,19(18):5432-5445
To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented. 相似文献
108.
109.
Dubouzet JG Maeda S Sugano S Ohtake M Hayashi N Ichikawa T Kondou Y Kuroda H Horii Y Matsui M Oda K Hirochika H Takatsuji H Mori M 《Plant biotechnology journal》2011,9(4):466-485
Approximately 20,000 of the rice-FOX Arabidopsis transgenic lines, which overexpress 13,000 rice full-length cDNAs at random in Arabidopsis, were screened for bacterial disease resistance by dip inoculation with Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). The identities of the overexpressed genes were determined in 72 lines that showed consistent resistance after three independent screens. Pst DC3000 resistance was verified for 19 genes by characterizing other independent Arabidopsis lines for the same genes in the original rice-FOX hunting population or obtained by reintroducing the genes into ecotype Columbia by floral dip transformation. Thirteen lines of these 72 selections were also resistant to the fungal pathogen Colletotrichum higginsianum. Eight genes that conferred resistance to Pst DC3000 in Arabidopsis have been introduced into rice for overexpression, and transformants were evaluated for resistance to the rice bacterial pathogen, Xanthomonas oryzae pv. oryzae. One of the transgenic rice lines was highly resistant to Xanthomonas oryzae pv. oryzae. Interestingly, this line also showed remarkably high resistance to Magnaporthe grisea, the fungal pathogen causing rice blast, which is the most devastating rice disease in many countries. The causal rice gene, encoding a putative receptor-like cytoplasmic kinase, was therefore designated as BROAD-SPECTRUM RESISTANCE 1. Our results demonstrate the utility of the rice-FOX Arabidopsis lines as a tool for the identification of genes involved in plant defence and suggest the presence of a defence mechanism common between monocots and dicots. 相似文献
110.
The cytoplasmic tyrosine kinase Jak2 plays a crucial role in cytokine receptor signaling in hematopoietic cells. The activated Jak2-V617F mutant is present in most cases of BCR/ABL-negative myeloproliferative neoplasms and constitutively activates downstream signals from homodimeric cytokine receptors, such as the erythropoietin receptor (EpoR). Here we examine the effects of DNA damage stress on Jak2 or Jak2-V617F and on induction of apoptosis in hematopoietic cells. Etoposide or doxorubicin dose-dependently decreased the expression level of Jak2 in UT7 or 32D cells expressing EpoR in the absence of Epo and that of exogenously expressed Jak2-V617F in UT7 cells when cotreated with the Jak2 inhibitor JakI-1 or AG490. Studies with pharmacological inhibitors and genetic manipulations further showed that downregulation of the PI3K/Akt pathway leading to the activation of GSK3β may be involved in downregulation of Jak2 or Jak2-V617F as well as in synergistic induction of Bax activation and apoptosis. The downregulation of Jak2 was inhibited by the proteasome inhibitor MG132 or by expression of both of loss-of-function mutants of c-Cbl and Cbl-b, E3 ubiquitin ligases which facilitated ubiquitination of Jak2-V617F when co-expressed in 293T cells. The pan-caspase inhibitor Boc-d-fmk also inhibited the Jak2 downregulation as well as appearance of a 100-kDa fragment that contained the N-terminal portion of Jak2 in response to DNA damage. Together, these data suggest that DNA damage stress with simultaneous inhibition of the kinase activity causes degradation of Jak2 or Jak2-V617F by caspase cleavage and proteasomal degradation through GSK3β activation, which is closely involved in synergistic induction of apoptosis in hematopoietic cells. 相似文献