全文获取类型
收费全文 | 1399篇 |
免费 | 115篇 |
出版年
2023年 | 7篇 |
2022年 | 20篇 |
2021年 | 40篇 |
2020年 | 34篇 |
2019年 | 27篇 |
2018年 | 48篇 |
2017年 | 33篇 |
2016年 | 72篇 |
2015年 | 94篇 |
2014年 | 82篇 |
2013年 | 128篇 |
2012年 | 179篇 |
2011年 | 154篇 |
2010年 | 90篇 |
2009年 | 61篇 |
2008年 | 99篇 |
2007年 | 108篇 |
2006年 | 60篇 |
2005年 | 40篇 |
2004年 | 27篇 |
2003年 | 22篇 |
2002年 | 20篇 |
2001年 | 4篇 |
2000年 | 6篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1994年 | 2篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1965年 | 1篇 |
1957年 | 1篇 |
1935年 | 2篇 |
1924年 | 1篇 |
排序方式: 共有1514条查询结果,搜索用时 234 毫秒
141.
142.
Jennifer L. Christianson Emilie Boutet Vishwajeet Puri Anil Chawla Michael P. Czech 《Journal of lipid research》2010,51(12):3455-3462
Cidea, the cell death-inducing DNA fragmentation factor-α-like effector (CIDE) domain-containing protein, is targeted to lipid droplets in mouse adipocytes, where it inhibits triglyceride hydrolysis and promotes lipid storage. In mice, Cidea may prevent lipolysis by binding and shielding lipid droplets from lipase association. Here we demonstrate that human Cidea localizes with lipid droplets in both adipocyte and nonadipocyte cell lines, and we ascribe specific functions to its protein domains. Expression of full-length Cidea in undifferentiated 3T3-L1 cells or COS-1 cells increases total cellular triglyceride and strikingly alters the morphology of lipid droplets by enhancing their size and reducing their number. Remarkably, both lipid droplet binding and increased triglyceride accumulation are also elicited by expression of only the carboxy-terminal 104 amino acids, indicating this small domain directs lipid droplet targeting and triglyceride shielding. However, unlike the full-length protein, expression of the carboxy-terminus causes clustering of small lipid droplets but not the formation of large droplets, identifying a novel function of the N terminus. Furthermore, human Cidea promotes lipid storage via lipolysis inhibition, as the expression of human Cidea in fully differentiated 3T3-L1 adipocytes causes a significant decrease in basal glycerol release. Taken together, these data indicate that the carboxy-terminal domain of Cidea directs lipid droplet targeting, lipid droplet clustering, and triglyceride accumulation, whereas the amino terminal domain is required for Cidea-mediated development of enlarged lipid droplets. 相似文献
143.
Emilie Michel-Marks Charmain T. Courcelle Justin Courcelle 《Journal of molecular biology》2010,401(4):579-589
In Escherichia coli, the recovery of replication following disruption by UV-induced DNA damage requires the RecF protein and occurs through a process that involves stabilization of replication fork DNA, resection of nascent DNA to allow the offending lesion to be repaired, and reestablishment of a productive replisome on the DNA. RecF forms a homodimer and contains an ATP binding cassette ATPase domain that is conserved among eukaryotic SMC (structural maintenance of chromosome) proteins, including cohesin, condensin, and Rad50. Here, we investigated the functions of RecF dimerization, ATP binding, and ATP hydrolysis in the progressive steps involved in recovering DNA synthesis following disruption by DNA damage. RecF point mutations with altered biochemical properties were constructed in the chromosome. We observed that protein dimerization, ATP binding, and ATP hydrolysis were essential for maintaining and processing the arrested replication fork, as well as for restoring DNA synthesis. In contrast, stabilization of the RecF protein dimer partially protected the DNA at the arrested fork from degradation, although overall processing and recovery remained severely impaired. 相似文献
144.
Tabary O Boncoeur E de Martin R Pepperkok R Clément A Schultz C Jacquot J 《Cellular signalling》2006,18(5):652-660
Dysregulation of nuclear factor kappa B (NF-(kappa)B) and increased Ca(2+) signals have been reported in airway epithelial cells of patients with cystic fibrosis (CF). The hypothesis that Ca(2+) signaling may regulate NF-(kappa)B activation was tested in a CF bronchial epithelial cell line (IB3-1, CFTR genotype DeltaF508/W1282X) and compared to the CFTR-corrected epithelial cell line S9 using fluorescence microscopy to visualized in situ NF-(kappa)B activation at the single cell level. Upon stimulation with IL-1beta,we observed a slow but prolonged [Ca(2+)](i) increase (up to 10 min) in IB3-1 cells compared to S9 cells. The IL-1beta-induced [Ca(2+)](i) response was accompanied by an activation of NF-(kappa)B in IB3-1 but not in S9 cells. Pretreatment of IB3-1 cells with the ER Ca(2+) pump inhibitor thapsigargin inhibited the IL-1beta-induced [Ca(2+)](i) response. Treatment with either the calcium chelator BAPTA or an inhibitor of I(kappa)Balpha phosphorylation (digitoxin) led to a drastic [Ca(2+)](i) decrease accompanied by an inhibition of NF-(kappa)B activation of IL-1beta-stimulated IB3-1 cells in comparison to untreated cells. In IB3-1 cells cultured at low temperature (26 degrees C) for 16 h, the IL-1beta-induced [Ca(2+)](i) response was inhibited and no significant NF-(kappa)B activation was observed. To our knowledge, this is the first report of visualization of the Ca(2+)-mediated activation of NF-(kappa)B in individual living airway epithelial cells. Our results support the concept that [Ca(2+)](i) is a key regulator of NF-(kappa)B activation in CF airway epithelial cells. 相似文献
145.
146.
Horton H Frank I Baydo R Jalbert E Penn J Wilson S McNevin JP McSweyn MD Lee D Huang Y De Rosa SC McElrath MJ 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):7406-7415
HIV-1-infected persons with HLA-B27 and -B57 alleles commonly remain healthy for decades without antiretroviral therapy. Properties of CD8+ T cells restricted by these alleles considered to confer disease protection in these individuals are elusive but important to understand and potentially elicit by vaccination. To address this, we compared CD8+ T cell function induced by HIV-1 immunogens and natural infection using polychromatic flow cytometry. HIV-1-specific CD8+ T cells from all four uninfected immunized and 21 infected subjects secreted IFN-gamma and TNF-alpha. However, CD8+ T cells induced by vaccination and primary infection, but not chronic infection, proliferated to their cognate epitopes. Notably, B27- and B57-restricted CD8+ T cells from nonprogressors exhibited greater expansion than those restricted by other alleles. Hence, CD8+ T cells restricted by certain protective alleles can resist replicative defects, which permits expansion and antiviral effector activities. Our findings suggest that the capacity to maintain CD8+ T cell proliferation, regardless of MHC-restriction, may serve as an important correlate of disease protection in the event of infection following vaccination. 相似文献
147.
Vauloup C Krzysiek R Greangeot-Keros L Wendling D Goupille P Brault R Brousse C Mariette X Emilie D 《European cytokine network》2006,17(4):290-293
BACKGROUND: Chronic hepatitis C infection is frequently associated with a mixed cryoglobulinaemia and circulating auto-antibodies, especially anti-smooth muscle cells (SMA) and anti-liver/kidney/microsome type 1 (LKM-1) anti-tissue antibodies. Treatments with TNF antagonists favour the emergence of auto-antibodies, and particularly anti-dsDNA antibodies. OBJECTIVE: To determine the impact of TNF antagonists on hepatitis C-related immune abnormalities. METHODS: We prospectively monitored for 14 weeks, six patients with actively replicating chronic hepatitis C, initiating an anti-TNF treatment for an associated rheumatoid arthritis. RESULTS: Anti-nuclear and anti-dsDNA antibodies were induced in two and three patients, respectively. Treatment had no impact on the production of antibodies against extractable nuclear antigens, and it did not induce anti-tissues antibodies in any patient. Cryoglobulinaemia appeared in 2/6 patients, and it persisted in 2 others. No patient developed any news signs of autoimmunity. HCV viraemia remained unchanged. CONCLUSIONS: Induction of auto-antibodies by TNF antagonist treatments does not involve anti-tissues antibodies, even in patients with actively replicating chronic hepatitis C prone to produce anti-SMA and anti-LKM-1 antibodies. In contrast, TNF antagonists may favour emergence of cryoglobulinaemia in such patients. 相似文献
148.
Eight-carbon volatiles in mushrooms and fungi: properties, analysis, and biosynthesis 总被引:1,自引:0,他引:1
Eight-carbon volatiles are ubiquitous among fungi and characteristic of the fungal aroma. They are the product of the oxidation
and cleavage of the fatty acid linoleic acid and are classified as oxylipins, molecules taking part in a wide range of biological
processes. Their involvement in the fungal aroma, interactions with pests and pathogens, and reproductive events are reviewed
here, as well as the enzymic systems involved in their biosynthesis. 相似文献
149.
Cuthbertson DJ Babraj J Smith K Wilkes E Fedele MJ Esser K Rennie M 《American journal of physiology. Endocrinology and metabolism》2006,290(4):E731-E738
We hypothesized a differential activation of the anabolic signaling proteins protein kinase B (PKB) and p70 S6 kinase (p70(S6K)) and subsequent differential stimulation of human muscle protein synthesis (MPS) after dynamic shortening or lengthening exercise. Eight healthy men [25 +/- 5 yr, BMI 26 +/- 3 kg/m(-2) (means +/- SD)] were studied before and after 12 min of repeated stepping up to knee height, and down again, while carrying 25% of their body weight, i.e., shortening exercise with the "up" leg and lengthening exercise with contralateral "down" leg. Quadriceps biopsies were taken before and 3, 6, and 24 h after exercise. After exercise, over 2 h before the biopsies, the subjects ingested 500 ml of water containing 45 g of essential amino acids and 135 g of sucrose. Rates of muscle protein synthesis were determined via incorporation over time of [1-(13)C]leucine (相似文献
150.