全文获取类型
收费全文 | 1478篇 |
免费 | 197篇 |
国内免费 | 10篇 |
出版年
2022年 | 11篇 |
2021年 | 18篇 |
2020年 | 15篇 |
2019年 | 27篇 |
2018年 | 30篇 |
2017年 | 23篇 |
2016年 | 46篇 |
2015年 | 64篇 |
2014年 | 80篇 |
2013年 | 98篇 |
2012年 | 121篇 |
2011年 | 81篇 |
2010年 | 59篇 |
2009年 | 57篇 |
2008年 | 78篇 |
2007年 | 72篇 |
2006年 | 76篇 |
2005年 | 50篇 |
2004年 | 63篇 |
2003年 | 56篇 |
2002年 | 63篇 |
2001年 | 46篇 |
2000年 | 35篇 |
1999年 | 39篇 |
1998年 | 13篇 |
1997年 | 15篇 |
1996年 | 12篇 |
1995年 | 14篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 17篇 |
1991年 | 25篇 |
1990年 | 22篇 |
1989年 | 16篇 |
1988年 | 11篇 |
1987年 | 10篇 |
1986年 | 16篇 |
1985年 | 9篇 |
1984年 | 17篇 |
1983年 | 11篇 |
1982年 | 8篇 |
1980年 | 13篇 |
1979年 | 10篇 |
1978年 | 16篇 |
1977年 | 10篇 |
1975年 | 21篇 |
1974年 | 13篇 |
1973年 | 18篇 |
1972年 | 9篇 |
1965年 | 5篇 |
排序方式: 共有1685条查询结果,搜索用时 15 毫秒
121.
Dishevelled 2 is essential for cardiac outflow tract development,somite segmentation and neural tube closure 总被引:14,自引:0,他引:14
Hamblet NS Lijam N Ruiz-Lozano P Wang J Yang Y Luo Z Mei L Chien KR Sussman DJ Wynshaw-Boris A 《Development (Cambridge, England)》2002,129(24):5827-5838
The murine dishevelled 2 (Dvl2) gene is an ortholog of the Drosophila segment polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt developmental pathway. Dvl2-deficient mice were produced to determine the role of Dvl2 in mammalian development. Mice containing null mutations in Dvl2 present with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss background because of severe cardiovascular outflow tract defects, including double outlet right ventricle, transposition of the great arteries and persistent truncus arteriosis. The majority of the surviving Dvl2(-/-) mice were female, suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation. In addition, approximately 90% of Dvl2(-/-) mice have vertebral and rib malformations that affect the proximal as well as the distal parts of the ribs. These skeletal abnormalities were more pronounced in mice deficient for both Dvl1 and Dvl2. Somite differentiation markers used to analyze Dvl2(-/-) and Dvl1(-/-);Dvl2(-/-) mutant embryos revealed mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects in somite segmentation. Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail. Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes. 相似文献
122.
ErbB2 is essential in the prevention of dilated cardiomyopathy 总被引:22,自引:0,他引:22
Crone SA Zhao YY Fan L Gu Y Minamisawa S Liu Y Peterson KL Chen J Kahn R Condorelli G Ross J Chien KR Lee KF 《Nature medicine》2002,8(5):459-465
Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy. 相似文献
123.
Huang SC Hsiao LD Chien CS Wang CC Chiu CT Tsai RJ Yang CM 《Journal of biomedical science》2002,9(3):213-222
The pharmacological properties of bradykinin (BK) receptors were characterized in canine cultured corneal epithelial cells (CECs) using [(3)H]-BK as a radioligand. Analysis of binding isotherms gave an apparent equilibrium dissociation constant of 0.34 +/- 0.07 nM and a maximum receptor density of 179 +/- 23 fmol/mg protein. Neither a B(1) receptor-selective agonist (des-Arg(9)-BK) nor antagonist ([Leu(8), des-Arg(9)]-BK) significantly inhibited [(3)H]-BK binding to CECs, thus excluding the presence of B(1) receptors in canine CECs. The specific binding of [(3)H]-BK to CECs was inhibited by B(2) receptor-selective agonists (BK and kallidin) and antagonists (Hoe 140 and [D-Arg(0), Hyp(3), Thi(5,8), D-Phe(7)]-BK), with a best fit using a one-binding-site model. The order of potency for the inhibition of [(3)H]-BK binding was BK = Hoe 140 > kallidin > [D-Arg(0), Hyp(3), Thi(5,8), D-Phe(7)]-BK. Stimulation of CECs by BK produced a concentration-dependent accumulation of inositol phosphates (IP) and an initial transient peak of intracellular Ca(2+). B(2) receptor-selective antagonist ([D-Arg(0), Hyp(3), Thi(5,8), D-Phe(7)]-BK) significantly antagonized the BK-induced responses with dissociation constants of 6.0-6.1. Pretreatment of CECs with pertussis toxin (PTX) or cholera toxin did not alter the BK-induced IP accumulation. Incubation of CECs in the absence of external Ca(2+) led to a significant attenuation of the IP accumulation induced by BK. These results demonstrate that BK directly stimulates phospholipase C-mediated signal transduction through BK B(2) receptors via a PTX-insensitive G protein in canine CECs. This effect may function as the transducing mechanism for BK-mediated cellular responses. 相似文献
124.
125.
126.
127.
Boone DL Dassopoulos T Chai S Chien M Lodolce J Ma A 《American journal of physiology. Gastrointestinal and liver physiology》2003,285(2):G382-G388
IL-2 receptor alpha-deficient (IL2Ralpha-/-) mice spontaneously accumulate vast numbers of intestinal lamina propria (LP) T cells and develop bowel inflammation. The accumulation of T cells in IL2Ralpha-/- mice is thought to result, in part, from defective Fas-induced cell death. To understand the role of cell proliferation and death in regulating LP T cells in IL2Ralpha-/- mice, we have directly examined the proliferation and Fas sensitivity of wild-type, lpr/lpr, and IL2Ralpha-/- LP T cells. In wild-type mice, 5'-bromodeoxyuridine (BrdU) labeling and Fas susceptibility are greatest in CD44Hi LP T cells. Fas-deficient lpr/lpr mice have normal total numbers of LP T cells, despite an increased proportion of BrdU+ T cells. By contrast, IL2Ralpha-/- mice possess increased total numbers of LP T cells, despite normal proportions of BrdU+ LP T cells. Finally, wild-type and IL2Ralpha-/- LP T cells are equivalently Fas sensitive. These results demonstrate that LP T cells proliferate and are Fas-sensitive cells. IL2Ralpha-/- mice accumulate a large number of these Fas-sensitive LP T cells and clearly differ from Fas-deficient lpr/lpr mice in this regard. Thus our studies reveal that Fas is dispensable for LP T cell homeostasis and suggest that the intestinal inflammation observed in IL2Ralpha-/- mice is independent of defective Fas-induced cell death. 相似文献
128.
To ascertain the functional role of cysteine residue in 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP) synthase from Corynebacterium glutamicum, site-directed mutagenesis was performed to change each of the three residues to serine. Plasmids were constructed for high-level
overproduction and one-step purification of histidine-tagged DAHP synthase. Analysis of the purified wild-type and mutant
enzymes by SDS-polyacrylamide gel electrophoresis showed an apparent protein band with a molecular mass of approximately 45
kDa. Cys145Ser mutant retained about 16% of the enzyme activity, while DAHP synthase activity was abolished in Cys67Ser mutant. Kinetic analysis of Cys145Ser mutant with PEP as a substrate revealed a marked increase in K
m
with significant change in k
cat
, resulting in a 13.6-fold decrease in k
cat
/K
m
PEP. Cys334 was found to be nonessential for catalytic activity, although it is highly conserved in DAHP synthases. From these studies,
Cys67 appears important for synthase activity, while Cys145 plays a crucial role in the catalytic efficiency through affecting the mode of substrate binding.
Received: 10 October 2000 / Accepted: 17 November 2000 相似文献
129.
130.