全文获取类型
收费全文 | 2029篇 |
免费 | 200篇 |
出版年
2024年 | 2篇 |
2023年 | 9篇 |
2022年 | 8篇 |
2021年 | 58篇 |
2020年 | 39篇 |
2019年 | 34篇 |
2018年 | 40篇 |
2017年 | 33篇 |
2016年 | 69篇 |
2015年 | 109篇 |
2014年 | 108篇 |
2013年 | 151篇 |
2012年 | 193篇 |
2011年 | 176篇 |
2010年 | 111篇 |
2009年 | 97篇 |
2008年 | 144篇 |
2007年 | 141篇 |
2006年 | 134篇 |
2005年 | 126篇 |
2004年 | 105篇 |
2003年 | 99篇 |
2002年 | 77篇 |
2001年 | 14篇 |
2000年 | 14篇 |
1999年 | 16篇 |
1998年 | 19篇 |
1997年 | 8篇 |
1996年 | 9篇 |
1995年 | 7篇 |
1994年 | 11篇 |
1993年 | 9篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 4篇 |
1987年 | 8篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 6篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有2229条查询结果,搜索用时 15 毫秒
41.
Altered proteolysis of amyloid precursor protein is an important determinant of pathology development in Alzheimer''s disease. Here, we describe the detection of two novel fragments of amyloid precursor protein in H4 neuroglioma cells undergoing apoptosis. Immunoreactivity of these 25–35 kDa fragments to two different amyloid precursor protein antibodies suggests that they contain the amyloid-β region and an epitope near the C-terminus of amyloid precursor protein. Generation of these fragments is associated with cleavage of caspase-3 and caspase-7, suggesting activation of these caspases. Studies in neurons undergoing DNA damage-induced apoptosis also showed similar results. Inclusion of caspase inhibitors prevented the generation of these novel fragments, suggesting that they are generated by a caspase-dependent mechanism. Molecular weight prediction and immunoreactivity of the fragments generated suggested that such fragments could not be generated by cleavage at any previously identified caspase, secretase, or calpain site on amyloid precursor protein. Bioinformatic analysis of the amino acid sequence of amyloid precursor protein revealed that fragments fitting the observed size and immunoreactivity could be generated by either cleavage at a novel, hitherto unidentified, caspase site or at a previously identified matrix metalloproteinase site in the extracellular domain. Proteolytic cleavage at any of these sites leads to a decrease in the generation of α-secretase cleaved secreted APP, which has both anti-apoptotic and neuroprotective properties, and thus may contribute to neurodegeneration in Alzheimer''s disease. 相似文献
42.
Kanjoormana Aryan Manu Muthu K. Shanmugam Tina H. Ong Aruljothi Subramaniam Kodappully Sivaraman Siveen Ekambaram Perumal Ramar Perumal Samy Pradeep Bist Lina H. K. Lim Alan Prem Kumar Kam M. Hui Gautam Sethi 《PloS one》2013,8(3)
Accumulating evidence(s) indicate that CXCL12-CXCR4 signaling cascade plays an important role in the process of invasion and metastasis that accounts for more than 80% of deaths in hepatocellular carcinoma (HCC) patients. Thus, identification of novel agents that can downregulate CXCR4 expression and its associated functions have a great potential in the treatment of metastatic HCC. In the present report, we investigated an anthraquinone derivative, emodin for its ability to affect CXCR4 expression as well as function in HCC cells. We observed that emodin downregulated the expression of CXCR4 in a dose-and time-dependent manner in HCC cells. Treatment with pharmacological proteasome and lysosomal inhibitors did not have substantial effect on emodin-induced decrease in CXCR4 expression. When investigated for the molecular mechanism(s), it was observed that the suppression of CXCR4 expression was due to downregulation of mRNA expression, inhibition of NF-κB activation, and abrogation of chromatin immunoprecipitation activity. Inhibition of CXCR4 expression by emodin further correlated with the suppression of CXCL12-induced migration and invasion in HCC cell lines. In addition, emodin treatment significantly suppressed metastasis to the lungs in an orthotopic HCC mice model and CXCR4 expression in tumor tissues. Overall, our results show that emodin exerts its anti-metastatic effect through the downregulation of CXCR4 expression and thus has the potential for the treatment of HCC. 相似文献
43.
Sujatha Srinivasan Martin T. Morgan Congzhou Liu Frederick A. Matsen Noah G. Hoffman Tina L. Fiedler Kathy J. Agnew Jeanne M. Marrazzo David N. Fredricks 《PloS one》2013,8(10)
Bacterial vaginosis (BV) is a highly prevalent condition associated with adverse health outcomes. Gram stain analysis of vaginal fluid is the standard for confirming the diagnosis of BV, wherein abundances of key bacterial morphotypes are assessed. These Lactobacillus, Gardnerella, Bacteroides, and Mobiluncus morphotypes were originally linked to particular bacterial species through cultivation studies, but no studies have systematically investigated associations between uncultivated bacteria detected by molecular methods and Gram stain findings. In this study, 16S-rRNA PCR/pyrosequencing was used to examine associations between vaginal bacteria and bacterial morphotypes in 220 women with and without BV. Species-specific quantitative PCR (qPCR) and fluorescence in Situ hybridization (FISH) methods were used to document concentrations of two bacteria with curved rod morphologies: Mobiluncus and the fastidious BV-associated bacterium-1 (BVAB1). Rank abundance of vaginal bacteria in samples with evidence of curved gram-negative rods showed that BVAB1 was dominant (26.1%), while Mobiluncus was rare (0.2% of sequence reads). BVAB1 sequence reads were associated with Mobiluncus morphotypes (p<0.001). Among women with curved rods, mean concentration of BVAB1 DNA was 2 log units greater than Mobiluncus (p<0.001) using species-specific quantitative PCR. FISH analyses revealed that mean number of BVAB1 cells was 2 log units greater than Mobiluncus cells in women with highest Nugent score (p<0.001). Prevotella and Porphyromonas spp. were significantly associated with the “Bacteroides morphotype,” whereas Bacteroides species were rare. Gram-negative rods designated Mobiluncus morphotypes on Gram stain are more likely BVAB1. These findings provide a clearer picture of the bacteria associated with morphotypes on vaginal Gram stain. 相似文献
44.
Sheridan Kevin J. Duncan Elizabeth J. Eaton-Rye Julian J. Summerfield Tina C. 《Photosynthesis research》2020,145(2):111-128
Photosynthesis Research - The psbA gene family in cyanobacteria encodes different forms of the D1 protein that is part of the Photosystem II reaction centre. We have identified a phylogenetically... 相似文献
45.
46.
Alexander Jason B. Bunce Michael White Nicole Wilkinson Shaun P. Adam Arne A. S. Berry Tina Stat Michael Thomas Luke Newman Stephen J. Dugal Laurence Richards Zoe T. 《Coral reefs (Online)》2020,39(1):159-171
Coral Reefs - Cumulative anthropogenic pressures have triggered a global decline in the health of marine ecosystems, and coral reefs, in particular, are in crisis. With climate and... 相似文献
47.
Tina Paradzik Nives Ivic Zelimira Filic Babu A. Manjasetty Paul Herron Marija Luic Dusica Vujaklija 《Nucleic acids research》2013,41(6):3659-3672
The linear chromosome of Streptomyces coelicolor contains two paralogous ssb genes, ssbA and ssbB. Following mutational analysis, we concluded that ssbA is essential, whereas ssbB plays a key role in chromosome segregation during sporulation. In the ssbB mutant, ∼30% of spores lacked DNA. The two ssb genes were expressed differently; in minimal medium, gene expression was prolonged for both genes and significantly upregulated for ssbB. The ssbA gene is transcribed as part of a polycistronic mRNA from two initiation sites, 163 bp and 75 bp upstream of the rpsF translational start codon. The ssbB gene is transcribed as a monocistronic mRNA, from an unusual promoter region, 73 bp upstream of the AUG codon. Distinctive DNA-binding affinities of single-stranded DNA-binding proteins monitored by tryptophan fluorescent quenching and electrophoretic mobility shift were observed. The crystal structure of SsbB at 1.7 Å resolution revealed a common OB-fold, lack of the clamp-like structure conserved in SsbA and previously unpublished S-S bridges between the A/B and C/D subunits. This is the first report of the determination of paralogous single-stranded DNA-binding protein structures from the same organism. Phylogenetic analysis revealed frequent duplication of ssb genes in Actinobacteria, whereas their strong retention suggests that they are involved in important cellular functions. 相似文献
48.
49.
Mircea Winter Mirjam A Moser Dominique Meunier Katharina Mattes Christina Murko Christina Humer Tina Meischel Gerald Brosch Patrick Matthias Maria Sibilia Christian Seiser 《The EMBO journal》2013,32(24):3176-3191
The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage‐dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue. Strikingly, deletion of a single Hdac2 allele in HDAC1 knockout mice results in severe epidermal defects, including alopecia, hyperkeratosis, hyperproliferation and spontaneous tumour formation. These mice display impaired Sin3A co‐repressor complex function, increased levels of c‐Myc protein, p53 expression and apoptosis in hair follicles (HFs) and misregulation of HF bulge stem cells. Surprisingly, ablation of HDAC1 but not HDAC2 in a skin tumour model leads to accelerated tumour development. Our data reveal a crucial function of HDAC1/HDAC2 in the control of lineage specificity and a novel role of HDAC1 as a tumour suppressor in the epidermis. 相似文献
50.
Dimitry N. Krementsov Tina M. Thornton Cory Teuscher Mercedes Rincon 《Molecular and cellular biology》2013,33(19):3728-3734
Multiple sclerosis (MS), the most common disabling neurologic disease of young adults, is considered a classical T cell-mediated disease and is characterized by demyelination, axonal damage, and progressive neurological dysfunction. The currently available disease-modifying therapies are limited in their efficacy, and improved understanding of new pathways contributing to disease pathogenesis could reveal additional novel therapeutic targets. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is known to be triggered by stress stimuli and to contribute to inflammatory responses. Importantly, a number of recent studies have identified this signaling pathway as a central player in MS and its principal animal model, experimental allergic encephalomyelitis. Here, we review the evidence from mouse and human studies supporting the role of p38 MAPK in regulating key immunopathogenic mechanisms underlying autoimmune inflammatory disease of the central nervous system and the potential of targeting this pathway as a disease-modifying therapy in MS. 相似文献