全文获取类型
收费全文 | 1512篇 |
免费 | 76篇 |
出版年
2022年 | 10篇 |
2021年 | 26篇 |
2020年 | 3篇 |
2019年 | 24篇 |
2018年 | 13篇 |
2017年 | 12篇 |
2016年 | 32篇 |
2015年 | 45篇 |
2014年 | 71篇 |
2013年 | 71篇 |
2012年 | 108篇 |
2011年 | 100篇 |
2010年 | 56篇 |
2009年 | 50篇 |
2008年 | 125篇 |
2007年 | 91篇 |
2006年 | 92篇 |
2005年 | 90篇 |
2004年 | 106篇 |
2003年 | 99篇 |
2002年 | 105篇 |
2001年 | 10篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 24篇 |
1997年 | 14篇 |
1996年 | 12篇 |
1995年 | 15篇 |
1994年 | 15篇 |
1993年 | 15篇 |
1992年 | 9篇 |
1991年 | 10篇 |
1990年 | 6篇 |
1989年 | 8篇 |
1988年 | 9篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1985年 | 6篇 |
1984年 | 4篇 |
1983年 | 11篇 |
1982年 | 12篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1972年 | 2篇 |
1971年 | 2篇 |
排序方式: 共有1588条查询结果,搜索用时 31 毫秒
191.
Antitumor agents. Part 214: synthesis and evaluation of curcumin analogues as cytotoxic agents 总被引:1,自引:0,他引:1
Ishida J Ohtsu H Tachibana Y Nakanishi Y Bastow KF Nagai M Wang HK Itokawa H Lee KH 《Bioorganic & medicinal chemistry》2002,10(11):3481-3487
Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and <0.63 microg/mL, respectively. 相似文献
192.
Hirano M Ogita-Nakanishi H Miyachi W Hannya N Yamamoto-Kimoto Y Sakurai K Miyoshi-Higashino M Tashiro-Yamaji J Kato R Ijiri Y Tanaka K Kanazawa A Terada T Kawata R Takenaka H Kubota T Yoshida R 《Microbiology and immunology》2012,56(6):392-405
The production of allergen-specific IgE antibodies (Abs) in allergen-sensitized patients or animals has a mutual relationship with the immunologic response leading to allergic rhinitis. We recently reported that, after an intranasal injection of cedar pollen into mice, an interleukin-4 (IL-4)-dependent increase in serum nonspecific IgE Abs was a prerequisite for the production of serum allergen-specific IgE Abs. Here, we explored which lymphoid organs were responsive to the intranasally injected allergen and how IL-4 and IgE Abs were produced in the lymphocytes. Time-dependent changes in the total cell numbers and in in vitro IgE Ab production in various lymphoid organs revealed that the submandibular lymph nodes were the main responsible organ. After treatment with allergen (for IgE production) or allergen and complete Freund's adjuvant (for IgG production), we separated submandibular lymph node cells into macrophage-, lymphocyte-, and granulocyte-rich populations by discontinuous Percoll density-gradient centrifugation. Unexpectedly, bulk cells, but not the lymphocyte- or macrophage-rich populations, produced significant amounts of IL-4, IgE, and IgG; whereas production was restored by addition of Mac-1(+) cells from the macrophage-rich to the lymphocyte-rich fraction. Furthermore, a combination of the lymphocyte-rich population (for IgG [or IgE]) production) and the macrophage-rich population (for IgE [or IgG]) production) produced a large amount of IgE (or IgG). These results indicate that, in the initiation of allergic rhinitis, macrophages in the submandibular lymph nodes are essential not only for IL-4 or immunoglobulin production, but also for class switching of immunoglobulin in lymphocytes. 相似文献
193.
Tomotsugu?AriteEmail author Hiromu?Kameoka Junko?Kyozuka 《Journal of Plant Growth Regulation》2012,31(2):165-172
Strigolactones are recently identified plant hormones that inhibit shoot branching. Pleiotropic defects in strigolactone-deficient
or -insensitive mutants indicate that strigolactones control various aspects of plant growth and development. However, our
understanding of the hormonal function of strigolactones in plants is very limited. In this study we demonstrate that rice
dwarf mutants that are strigolactone-deficient or -insensitive exhibit a short crown root phenotype. Exogenous application of GR24,
a synthetic strigolactone analog, complemented the crown root defect in strigolactone-deficient mutants but not in strigolactone-insensitive
mutants. These observations imply that strigolactones positively regulate the length of crown roots. Histological observations
revealed that the meristematic zone is shorter in dwarf mutants than in wild type, suggesting that strigolactones may exert their effect on roots via the control of cell division.
We also show that crown roots of wild type, but not dwarf mutants, become longer under phosphate starvation. 相似文献
194.
Yasutoshi Koga Nataliya Povalko Junko Nishioka Koujyu Katayama Shuichi Yatsuga Toyojiro Matsuishi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
The pathogenic mechanism of stroke-like episodes seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) has not been clarified yet. About 80% of MELAS patients have an A3243G mutation in the mitochondrial tRNALeu(UUR) gene, which is the base change at position 14 in the consensus structure of tRNALeu(UUR) gene.Scope of review
This review aims to give an overview on the actual knowledge about the pathogenic mechanism of mitochondrial cytopathy at the molecular levels, the possible pathogenic mechanism of mitochondrial angiopathy to cause stroke-like episodes at the clinical and pathophysiological levels, and the proposed site of action of l-arginine therapy on MELAS.Major conclusions
Molecular pathogenesis is mainly demonstrated using ρ0 cybrid system. The mutation creates the protein synthesis defects caused by 1) decreased life span of steady state amount of tRNALeu(UUR) molecules; 2) decreased ratio of aminoacyl-tRNALeu(UUR) versus uncharged tRNALeu(UUR) molecules; 3) the accumulation of aminoacylation with leucine without any misacylation; 4) accumulation of processing intermediates such as RNA 19, 5) wobble modification defects. All of these loss of function abnormalities are created by the threshold effects of cell or organ to the mitochondrial energy requirement when they establish the phenotype. Mitochondrial angiopathy demonstrated by muscle or brain pathology, as SSV (SDH strongly stained vessels), and by vascular physiology using FMD (flow mediated dilation). MELAS patients show decreased capacity of NO dependent vasodilation because of the low plasma levels of l-arginine and/or of respiratory chain dysfunction. Although the underlying mechanisms are not completely understood in stroke-like episodes in MELAS, l-arginine therapy improved endothelial dysfunction.General significance
Though the molecular pathogenesis of an A3243G or T3271C mutation of mitochondrial tRNALeu(UUR) gene has been clarified as a mitochondrial cytopathy, the underlying mechanisms of stroke-like episodes in MELAS are not completely understood. At this point, l-arginine therapy showed promise in treating of the stroke-like episodes in MELAS. This article is part of a Special Issue entitled Biochemistry of Mitochondria. 相似文献195.
Kageyama Y Zhang Z Roda R Fukaya M Wakabayashi J Wakabayashi N Kensler TW Reddy PH Iijima M Sesaki H 《The Journal of cell biology》2012,197(4):535-551
Mitochondria divide and fuse continuously, and the balance between these two processes regulates mitochondrial shape. Alterations in mitochondrial dynamics are associated with neurodegenerative diseases. Here we investigate the physiological and cellular functions of mitochondrial division in postmitotic neurons using in vivo and in vitro gene knockout for the mitochondrial division protein Drp1. When mouse Drp1 was deleted in postmitotic Purkinje cells in the cerebellum, mitochondrial tubules elongated due to excess fusion, became large spheres due to oxidative damage, accumulated ubiquitin and mitophagy markers, and lost respiratory function, leading to neurodegeneration. Ubiquitination of mitochondria was independent of the E3 ubiquitin ligase parkin in Purkinje cells lacking Drp1. Treatment with antioxidants rescued mitochondrial swelling and cell death in Drp1KO Purkinje cells. Moreover, hydrogen peroxide converted elongated tubules into large spheres in Drp1KO fibroblasts. Our findings suggest that mitochondrial division serves as a quality control mechanism to suppress oxidative damage and thus promote neuronal survival. 相似文献
196.
Hasegawa H Noguchi J Yamashita M Okada R Sugimoto R Furuya M Unoki T Funakoshi Y Baba T Kanaho Y 《Biology of reproduction》2012,86(5):136, 1-136,12
The lipid kinase phosphatidylinositol 4-phosphate 5-kinase (PIP5K) produces a versatile signaling phospholipid, phosphatidylinositol 4,5-bisphosphate. Three PIP5K isozymes, PIP5K1A, PIP5K1B, and PIP5K1C, have been identified in mammals so far. Although the functions of these three PIP5K isozymes have been extensively studied in vitro, the in vivo physiological roles of these PIP5K isozymes remain largely unknown. In this study, we examined the functions of PIP5K1A and PIP5K1B in spermatogenesis, using Pip5k1a-knockout (KO), Pip5k1b-KO, and Pip5k1a/Pip5k1b double (D)-KO mice. Pip5k1a-KO and D-KO males were subfertile and completely sterile, respectively. F-actin in the seminiferous epithelium was disorganized in the D-KO mice, although F-actin bundles at the apical ectoplasmic specialization was not affected. D-KO seminiferous tubules contained a greatly decreased number of elongated spermatids. Flagella of sperm from Pip5k1a-KO and D-KO mice remarkably underwent morphological change, whereas Pip5k1b-KO sperm were morphologically normal. Notably, the flagellar shape of D-KO sperm was more severely impaired than that of Pip5k1a-KO sperm. These results suggest that PIP5K1A and PIP5K1B may coordinately and/or redundantly function in the maintenance of sperm number and morphology during spermatogenesis. 相似文献
197.
Inoue K Furukawa T Kumada T Yamada J Wang T Inoue R Fukuda A 《The Journal of biological chemistry》2012,287(25):20839-20850
GABA inhibits mature neurons and conversely excites immature neurons due to lower K(+)-Cl(-) cotransporter 2 (KCC2) expression. We observed that ectopically expressed KCC2 in embryonic cerebral cortices was not active; however, KCC2 functioned in newborns. In vitro studies revealed that taurine increased KCC2 inactivation in a phosphorylation-dependent manner. When Thr-906 and Thr-1007 residues in KCC2 were substituted with Ala (KCC2T906A/T1007A), KCC2 activity was facilitated, and the inhibitory effect of taurine was not observed. Exogenous taurine activated the with-no-lysine protein kinase 1 (WNK1) and downstream STE20/SPS1-related proline/alanine-rich kinase (SPAK)/oxidative stress response 1 (OSR1), and overexpression of active WNK1 resulted in KCC2 inhibition in the absence of taurine. Phosphorylation of SPAK was consistently higher in embryonic brains compared with that of neonatal brains and down-regulated by a taurine transporter inhibitor in vivo. Furthermore, cerebral radial migration was perturbed by a taurine-insensitive form of KCC2, KCC2T906A/T1007A, which may be regulated by WNK-SPAK/OSR1 signaling. Thus, taurine and WNK-SPAK/OSR1 signaling may contribute to embryonic neuronal Cl(-) homeostasis, which is required for normal brain development. 相似文献
198.
199.
200.
Goetz R Ohnishi M Ding X Kurosu H Wang L Akiyoshi J Ma J Gai W Sidis Y Pitteloud N Kuro-O M Razzaque MS Mohammadi M 《Molecular and cellular biology》2012,32(10):1944-1954
It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to αKlotho, βKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on βKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR. 相似文献