全文获取类型
收费全文 | 2680篇 |
免费 | 271篇 |
国内免费 | 2篇 |
专业分类
2953篇 |
出版年
2024年 | 2篇 |
2023年 | 15篇 |
2022年 | 42篇 |
2021年 | 64篇 |
2020年 | 43篇 |
2019年 | 49篇 |
2018年 | 49篇 |
2017年 | 47篇 |
2016年 | 83篇 |
2015年 | 157篇 |
2014年 | 196篇 |
2013年 | 174篇 |
2012年 | 283篇 |
2011年 | 281篇 |
2010年 | 166篇 |
2009年 | 134篇 |
2008年 | 199篇 |
2007年 | 165篇 |
2006年 | 160篇 |
2005年 | 157篇 |
2004年 | 136篇 |
2003年 | 104篇 |
2002年 | 102篇 |
2001年 | 15篇 |
2000年 | 5篇 |
1999年 | 12篇 |
1998年 | 27篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 15篇 |
1994年 | 10篇 |
1993年 | 6篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 5篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1974年 | 1篇 |
排序方式: 共有2953条查询结果,搜索用时 15 毫秒
1.
During an ultrastructural study of small-intestinal mucosa from a patient suffering from alpha-chain disease organisms were identified within the epithelial cytoplasm which showed the fine structural features of the coccidian group. Though coccidiosis is well recognized as causing a diarrhoeal and often lethal illness in animals it has been neglected as a cause of disease in man. Thus this finding may be significant and warrants further investigation into its possible role in the pathogenesis of alpha-chain disease. 相似文献
2.
Victoria Levterova Stefan Panaiotov Nadia Brankova Kristin Tankova 《Molecular biotechnology》2010,45(1):34-38
Identification of genetic markers involved in stress response to physical factors or chemical substances in organisms is a
challenging task. Typing of upregulated gene expression due to selective antibacterial pressure is a promising approach in
the search of molecular mechanisms responsible for development of resistance. cDNA-Fluorescent Amplified Fragment Length Polymorphism
(cDNA-FAFLP) strategy was developed and applied in the search of antimycotic drug resistance marker(s) in medically important
fungi as an alternative method to microarray analysis. We compared differential gene expression of two sensitive Candida albicans reference strains (ATCC 10231 and ATCC 60133) and two of their paired resistant to fluconazole and itraconazole mutants.
Resistant mutants Candida albicans
FLC-R, resistant to fluconazole (MIC > 128 μg/ml) and Candida albicans ICZ-R, resistant to itraconazole (MIC > 4 μg/ml) were obtained in subcultures with gradual increase of the antifungal in the culture
medium. cDNA-AFLP profile in both itraconazole resistant mutants showed specific spectrophotometric peaks with 5–6-fold RNA
overexpression product of 500 bp length compared to the sensitive strains. Fluconazole mutants do not reveal RNA level changes
under tested by us typing conditions. These results indicate that the cDNA-FAFLP strategy is a relatively rapid, simple, and
reliable method for simultaneous typing of both constitutive and induced differences in expression of host genes providing
insight into the biological processes involved in response to drugs in bacteria and fungi. Moreover, this methodology could
be tested for typing of the genome response of any organism to physical or chemical stress factors. 相似文献
3.
Kristin Kassler Anselm H. C. Horn Heinrich Sticht 《Journal of molecular modeling》2010,16(5):1011-1020
Converging lines of evidence suggest that soluble Aβ-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer’s
disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-Aβ-amyloid point mutants
(E22G, E22K, E22Q) and the deletion mutant E22Δ exhibit an enhanced tendency to form prefibrillar aggregates. The present
study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic
analyses. Our data shows that E22 plays a unique role in wild type Aβ, since it has a destabilising effect on the oligomer
structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged
residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is
consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid
fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important
salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers
an explanation for the experimentally observed enhanced oligomer formation and stability. 相似文献
4.
Marianne Schwartz Maria Anvret Mireille Claustres Hans Geir Eiken Kristin Eiklid Charlotte Schaedel Lisa Stolpe Lisbeth Tranebjærg 《Human genetics》1994,93(2):157-161
In a systematic screening for mutations in the gene encoding the cystic fibrosis transmembrane regulator among Danish cystic fibrosis (CF) patients, we identified a mutation in exon 3 (394delTT); this mutation was found to be relatively common in Denmark. We therefore screened for 394delTT in Sweden and Norway, where it turned out to be the second most frequent mutation, accounting for 4% of all CF mutations. It also occurs with a high frequency in Finland, but has not been found in larger surveys of mutations in the CFTR gene. Thus, 394delTT seems to be a specific Nordic CF mutation. 相似文献
5.
6.
Twelve of 21 human, hemolytic, fecal isolates ofEscherichia coli produced type 1 hemolysin (HLY1), an extracellular, heat-labile molecule (alpha-hemolysin). Although no common plasmid species was apparent, 11 of 12 HLY1 strains possessed a plasmid60 megadaltons (Mdal); 5 of 9 strains with other hemolysins possessed a plasmid of comparable molecular mass (Fisher's exact probability=0.0805). One derivative of an HLY1+strain, which contained a 125 Mdal plasmid, no longer expressed HLY1 and contained a single 102 Mdal plasmid. The presence of large plasmids of varying size and an apparent deletion mutation in HLY1 strains suggest that HLY1 determinants are located on a small, unstable genetic element. In an initial survey of 224 human fecal isolates ofE. coli, the predominant hemolytic serotype was 06:H-, and conversely most (85%) 06:H-isolates were HLY1+. Serotype appears to play an important role in HLY1 expression. 相似文献
7.
8.
Robert Chan Madaline Gilbert Kristin M. Thompson H. Nicholas Marsh David M. Epstein P. Shannon Pendergrast 《Nucleic acids research》2006,34(5):e36
The specific down-regulation of gene expression in cells is a powerful method for elucidating a gene's function. A common method for suppressing gene expression is the elimination of mRNA by RNAi or antisense. Alternatively, oligonucleotide-derived aptamers have been used as protein-directed agents for the specific knock-down of both intracellular and extracellular protein activity. Protein-directed methods offer the advantage of more closely mimicking small molecule therapeutics' mechanism of activity. Furthermore, protein-directed methods may synergize with RNA-directed methods since the two methods attack gene expression at different levels. Here we have knocked down a well-characterized intracellular protein's activity, NFκB, by expressing either aptamers or small interfering RNAs (siRNAs). Both methods can diminish NFκB's activity to similar levels (from 29 to 64%). Interestingly, expression of both aptamers and siRNAs simultaneously, suppressed NFκB activity better than either method alone (up to 90%). These results demonstrate that the expression of intracellular aptamers is a viable alternative to siRNA knock-down. Furthermore, for the first time, we show that the use of aptamers and siRNA together can be the most effective way to achieve maximal knock-down of protein activity. 相似文献
9.
Finger JN Lich JD Dare LC Cook MN Brown KK Duraiswami C Bertin J Bertin JJ Gough PJ 《The Journal of biological chemistry》2012,287(30):25030-25037
Nucleotide-binding domain leucine-rich repeat proteins (NLRs) play a key role in immunity and disease through their ability to modulate inflammation in response to pathogen-derived and endogenous danger signals. Here, we identify the requirements for activation of NLRP1, an NLR protein associated with a number of human pathologies, including vitiligo, rheumatoid arthritis, and Crohn disease. We demonstrate that NLRP1 activity is dependent upon ASC, which associates with the C-terminal CARD domain of NLRP1. In addition, we show that NLRP1 activity is dependent upon autolytic cleavage at Ser(1213) within the FIIND. Importantly, this post translational event is dependent upon the highly conserved distal residue His(1186). A disease-associated single nucleotide polymorphism near His(1186) and a naturally occurring mRNA splice variant lacking exon 14 differentially affect this autolytic processing and subsequent NLRP1 activity. These results describe key molecular pathways that regulate NLRP1 activity and offer insight on how small sequence variations in NLR genes may influence human disease pathogenesis. 相似文献
10.
Results from the analysis of copy number variations (CNVs) in human pluripotent cell-derived neuroprogenitor cell lines (hiPSC and hESC-derived NPC) are presented. Two different types of CNVs were detected: a) CNVs inherited from the original source of pluripotent cells (hESC and hiPSC) and b) CNVs detected either in the original source of pluripotent cells or in the derived NPC cell lines but not in both at the same time. Our data suggest that submicroscopic chromosomal changes happened during culture and manipulation of cells and those differentiation procedures could result in gains and losses of genomic regions in pluripotent cell-derived neuroprogenitors. Overall, the results indicate that even chromosomally stable stem cell lines would need to be analyzed in detail by high resolution methodologies before their clinical use. 相似文献