全文获取类型
收费全文 | 2483篇 |
免费 | 240篇 |
出版年
2023年 | 16篇 |
2022年 | 35篇 |
2021年 | 80篇 |
2020年 | 41篇 |
2019年 | 55篇 |
2018年 | 55篇 |
2017年 | 59篇 |
2016年 | 83篇 |
2015年 | 157篇 |
2014年 | 153篇 |
2013年 | 148篇 |
2012年 | 235篇 |
2011年 | 181篇 |
2010年 | 105篇 |
2009年 | 91篇 |
2008年 | 155篇 |
2007年 | 111篇 |
2006年 | 120篇 |
2005年 | 123篇 |
2004年 | 84篇 |
2003年 | 78篇 |
2002年 | 76篇 |
2001年 | 23篇 |
2000年 | 29篇 |
1999年 | 32篇 |
1998年 | 14篇 |
1997年 | 16篇 |
1995年 | 11篇 |
1993年 | 11篇 |
1992年 | 17篇 |
1991年 | 17篇 |
1990年 | 16篇 |
1989年 | 20篇 |
1988年 | 23篇 |
1987年 | 16篇 |
1986年 | 14篇 |
1985年 | 14篇 |
1984年 | 14篇 |
1983年 | 12篇 |
1982年 | 7篇 |
1980年 | 11篇 |
1979年 | 10篇 |
1977年 | 7篇 |
1975年 | 8篇 |
1973年 | 12篇 |
1972年 | 10篇 |
1971年 | 19篇 |
1969年 | 8篇 |
1968年 | 8篇 |
1966年 | 10篇 |
排序方式: 共有2723条查询结果,搜索用时 46 毫秒
1.
Silvio Antoniak Erica M. Sparkenbaugh Michael Tencati Mauricio Rojas Nigel Mackman Rafal Pawlinski 《PloS one》2013,8(11)
Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro. PAR-2 also contributes to myocardial infarction and heart remodeling after ischemia/reperfusion injury. In this study, we found that PAR-2 induced hypertrophic growth of cultured rat neonatal cardiomyocytes in a MEK1/2 and p38 dependent manner. In addition, PAR-2 activation on mouse cardiomyocytes increased expression of the pro-fibrotic chemokine MCP-1. Furthermore, cardiomyocyte-specific overexpression of PAR-2 in mice induced heart hypertrophy, cardiac fibrosis, inflammation and heart failure. Finally, in a mouse model of myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, PAR-2 deficiency attenuated heart remodeling and improved heart function independently of its contribution to the size of the initial infarct. Taken together, our data indicate that PAR-2 signaling contributes to the pathogenesis of hypertrophy and heart failure. 相似文献
2.
Johnathan L Meaders Erica F Geers Belen Fernandez‐Garcia Marvin E Tanenbaum 《The EMBO journal》2012,31(21):4179-4190
The microtubule motor protein kinesin‐5 (Eg5) provides an outward force on centrosomes, which drives bipolar spindle assembly. Acute inhibition of Eg5 blocks centrosome separation and causes mitotic arrest in human cells, making Eg5 an attractive target for anti‐cancer therapy. Using in vitro directed evolution, we show that human cells treated with Eg5 inhibitors can rapidly acquire the ability to divide in the complete absence of Eg5 activity. We have used these Eg5‐independent cells to study alternative mechanisms of centrosome separation. We uncovered a pathway involving nuclear envelope (NE)‐associated dynein that drives centrosome separation in prophase. This NE‐dynein pathway is essential for bipolar spindle assembly in the absence of Eg5, but also functions in the presence of full Eg5 activity, where it pulls individual centrosomes along the NE and acts in concert with Eg5‐dependent outward pushing forces to coordinate prophase centrosome separation. Together, these results reveal how the forces are produced to drive prophase centrosome separation and identify a novel mechanism of resistance to kinesin‐5 inhibitors. 相似文献
3.
4.
5.
George B. Stefano Erica Braham Patrick Finn Edward Aiello Michael K. Leung 《Cellular and molecular neurobiology》1987,7(2):209-219
1. This report further demonstrates that etorphine influences presynaptic dopamine release, which in turn centrally modulates peripheral cilioinhibition. 2. In older animals cilioinhibition has become enhanced due to a lack of responsiveness to endogenous opioids which results in greater dopamine release, causing a higher level of cilioinhibition as demonstrated by challenging the visceral ganglia with etorphine or destroying the dopaminergic component with 6-hydroxydopamine. 3. Only the central cilioinhibitory, not the peripheral inhibitory response, mechanism appears to be altered in older animals. Thus, the alteration appears in the central integrative mechanisms involved with regulating ciliary activity. 4. The KCl-stimulated release of dopamine is unaltered in both young and old organisms, whereas the opiate inhibition of the KCl-stimulated release of dopamine is reduced in older organisms. Thus, the aging-associated alteration is associated with a specific process. 5. The reduction of opioid influence and the resulting enhanced cilioinhibitory activity may make the organisms more susceptible to environmental stress. 相似文献
6.
A K Ghoshal T H Rushmore P Buc-Calderon M Roberfroid E Farber 《Free radical biology & medicine》1990,8(1):3-7
This study was designed to explore the possible preventive effects of a novel radicophile, N-p-methoxyphenylacetyl-dehydroalanine (AD5) and three other antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD), butylated hydroxyanisole (BHA) and a water-soluble analogue of vitamin E, trolox C, on the acute effects of the liver of feeding a choline-deficient (CD) diet. It has been suggested that some of the acute effects of a CD diet are related to free radicals, the generation or metabolism of which is disturbed in this acute dietary model. AD5 was found to be very effective in preventing nuclear lipid peroxidation, DNA damage and cell death induced by a CD diet but to have little effect on triglyceride accumulation ("fatty liver"). DPPD, BHA, and trolox C were ineffective. These results add strength to the hypothesis that oxygen free radicals might be an important component in the early events during carcinogenesis induced by feeding a CD diet. 相似文献
7.
The large family of signal transducing proteins known as G proteins are heterotrimers that dissociate into an independent α-subunit and βγ-subunit complex after ligand binding or other stimulation. For Gα, at least 30 distinct sequences representing 10 different classes have been identified. On the other hand, cDNAs for only three Gβ-subunit genes have been isolated so far. All three of the Gβ genes have been chromosomally mapped in the human, but only two in the mouse. Using a human retinal cDNA for the third G protein β-subunit, we have mapped the corresponding gene, termed Gnb-3, to mouse Chromosome 6 with somatic cell hybrids and have positioned it distal to but near the marker Raf-1 by analysis of the progeny of three genetic crosses. 相似文献
8.
The gram-positive bacterium Listeria monocytogenes is an ubiquitous, intracellular pathogen which has been implicated within the past decade as the causative organism in several outbreaks of foodborne disease. Listeriosis, with a mortality rate of about 24%, is found mainly among pregnant women, their fetuses, and immunocompromised persons, with symptoms of abortion, neonatal death, septicemia, and meningitis. Epidemiological investigations can make use of strain-typing procedures such as DNA restriction enzyme analysis or electrophoretic enzyme typing. The organism has a multifactorial virulence system, with the thiol-activated hemolysin, listeriolysin O, being identified as playing a crucial role in the organism's ability to multiply within host phagocytic cells and to spread from cell to cell. The organism occurs widely in food, with the highest incidences being found in meat, poultry, and seafood products. Improved methods for detecting and enumerating the organism in foodstuffs are now available, including those based on the use of monoclonal antibodies, DNA probes, or the polymerase chain reaction. As knowledge of the molecular and applied biology of L. monocytogenes increases, progress can be made in the prevention and control of human infection. 相似文献
9.
M Danciger C A Kozak T Abe T Shinohara D B Farber 《Cytogenetics and cell genetics》1991,56(3-4):202-205
A water-soluble protein (called "33-kDa protein") that exhibits light-dependent phosphorylation has been shown to be a major protein of mammalian rod photoreceptors. Although the function of this protein is unknown, it has been implicated in the biochemical cascade mediating the rod visual response. Using a retinal cDNA from the rat and somatic cell hybrids, we have mapped the gene corresponding to this protein to mouse Chromosome 1 and, by analyzing the progeny of an intersubspecific backcross, have positioned it near Lamb2 (the beta 2 chain of laminin). We have designated the gene Rpr-1 (rod photoreceptor protein-1). 相似文献
10.
Generation of, lipid neutrophil chemoattractant activity by histamine-stimulated cultured endothelial cells 总被引:3,自引:0,他引:3
H W Farber P F Weller S Rounds D J Beer D M Center 《Journal of immunology (Baltimore, Md. : 1950)》1986,137(9):2918-2924
Endothelial cell-neutrophil interactions are an important aspect of inflammatory responses. Because vascular endothelial cells respond to the inflammatory mediator histamine, these studies determined whether histamine could induce endothelial cells to release substances that affect human neutrophil migration. Cultured bovine and human endothelial cells incubated with histamine released neutrophil chemoattractant activity within 1 min; peak levels were noted in 45 min. Cimetidine, an H2 receptor antagonist, blocked chemoattractant production, whereas diphenhydramine, an H1 receptor antagonist, did not. Cycloheximide did not inhibit release of chemoattractant activity, suggesting de novo protein synthesis was not necessary for its appearance. Extraction with acidified diethyl ether partitioned all neutrophil chemoattractant activity into the organic phase. The lipoxygenase pathway inhibitors, diethylcarbamazine and 5,8,11,14 eicosatetraynoic acid, inhibited generation of this lipophilic chemoattractant activity, whereas indomethacin, a cyclo-oxygenase inhibitor, did not. Resolution of the histamine-induced endothelial cell-derived chemoattractant activity by reverse-phase high pressure liquid chromatography yielded several peaks of chemoattractant activity, none of which co-eluted with leukotriene B4, platelet-activating factor, or two mono-hydroxyeicostetraenoic acids. These findings suggest that endothelial cells release lipid neutrophil chemoattractant activity that may play a role in inflammatory responses associated with histamine. 相似文献