全文获取类型
收费全文 | 1052篇 |
免费 | 54篇 |
出版年
2024年 | 2篇 |
2023年 | 5篇 |
2022年 | 12篇 |
2021年 | 46篇 |
2020年 | 27篇 |
2019年 | 36篇 |
2018年 | 38篇 |
2017年 | 33篇 |
2016年 | 51篇 |
2015年 | 48篇 |
2014年 | 59篇 |
2013年 | 83篇 |
2012年 | 115篇 |
2011年 | 92篇 |
2010年 | 51篇 |
2009年 | 53篇 |
2008年 | 58篇 |
2007年 | 41篇 |
2006年 | 44篇 |
2005年 | 35篇 |
2004年 | 29篇 |
2003年 | 28篇 |
2002年 | 28篇 |
2001年 | 15篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1981年 | 4篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1960年 | 1篇 |
排序方式: 共有1106条查询结果,搜索用时 31 毫秒
91.
Crooke RM Graham MJ Lemonidis KM Whipple CP Koo S Perera RJ 《Journal of lipid research》2005,46(5):872-884
High levels of plasma apolipoprotein B-100 (apoB-100), the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide (ASO) would reduce LDL cholesterol (LDL-C). Because most of the plasma apoB is made in the liver, and antisense drugs distribute to that organ, we tested the effects of a mouse-specific apoB-100 ASO in several mouse models of hyperlipidemia, including C57BL/6 mice fed a high-fat diet, Apoe-deficient mice, and Ldlr-deficient mice. The lead apoB-100 antisense compound, ISIS 147764, reduced apoB-100 mRNA levels in the liver and serum apoB-100 levels in a dose- and time-dependent manner. Consistent with those findings, total cholesterol and LDL-C decreased by 25-55% and 40-88%, respectively. Unlike small-molecule inhibitors of microsomal triglyceride transfer protein, ISIS 147764 did not produce hepatic or intestinal steatosis and did not affect dietary fat absorption or elevate plasma transaminase levels. These findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia. 相似文献
92.
Curcumin is a natural polyphenolic compound having an antiproliferative property, which recent evidence suggests is due to its ability to induce apoptosis. However, the molecular mechanisms through which curcumin induces apoptosis are not fully understood. Here, we report that the curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome system. Exposure of curcumin to the mouse neuro 2a cells causes a dose-dependent decrease in proteasome activity and an increase in ubiquitinated proteins. Curcumin exposure also decreases the turnover of the destabilized enhanced green fluorescence protein, a model substrate for proteasome and cellular p53 protein. Like other proteasome inhibitors, curcumin targets proliferative cells more efficiently than differentiated cells and induces apoptosis via mitochondrial pathways. Addition of curcumin to neuro 2a cells induces a rapid decrease in mitochondrial membrane potential and the release of cytochrome c into cytosol, followed by activation of caspase-9 and caspase-3. 相似文献
93.
Mutualism among species is ubiquitous in natural ecosystems but its evolution is not well understood. We provided a simple lattice model to clarify the importance of spatial structure for the evolution of mutualism. We assumed reproductive rates of two species are modified through interaction between species and examine conditions where mutualists of both species, that give some benefit to the other species with their own cost, invade non-mutualists populations. When dispersal of offspring is unlimited, we verified the evolution of mutualism is impossible under any condition. On the other hand, when the dispersal is limited to neighboring lattice sites, mutualists can invade if the ratio of cost to benefit is low and the intrinsic reproductive rate is low in case where the parameter values are symmetric between species. Under the same conditions, non-mutualists cannot invade mutualist populations, that is, the latter are evolutionarily stable. In case of asymmetric parameters, mutualists tend to invade if the average value of costs to two species is low or that of benefits is high, and if the intrinsic reproductive rate is low for one of the two species. A mechanistic explanation of why mutualists increase when the dispersal is limited is given by showing that mutualist pairs of the two species at the same lattice site rapidly increase at the initial phase of the invasion. 相似文献
94.
Subcellular protein localization is a universal feature of eukaryotic cells, and the ubiquity of protein localization in prokaryotic species is now acquiring greater appreciation. Though some targeting anchors are known, the origin of polar and division-site localization remains mysterious for a large fraction of bacterial proteins. Ultimately, the molecular components responsible for such symmetry breaking must employ a high degree of self-organization. Here we propose a novel physical mechanism, based on the two-dimensional curvature of the membrane, for spontaneous lipid targeting to the poles and division site of rod-shaped bacterial cells. If one of the membrane components has a large intrinsic curvature, the geometrical constraint of the plasma membrane by the more rigid bacterial cell wall naturally leads to lipid microphase separation. We find that the resulting clusters of high-curvature lipids are large enough to spontaneously and stably localize to the two cell poles. Recent evidence of localization of the phospholipid cardiolipin to the poles of bacterial cells suggests that polar targeting of some proteins may rely on the membrane's differential lipid content. More generally, aggregates of lipids, proteins, or lipid-protein complexes may localize in response to features of cell geometry incapable of localizing individual molecules. 相似文献
95.
Lytic phages infect their bacterial hosts, use the host machinery to replicate, and finally lyse and kill their hosts, releasing progeny phages. Various mathematical models have been developed that describe these phage-host viral dynamics. The aim of this study was to determine which of these models best describes the viral dynamics of lytic RNA phage MS2 and its host Escherichia coli C-3000. Experimental data consisted of uninfected and infected bacterial cell densities, free phage density, and substrate concentration. Parameters of various models were either determined directly through other experimental techniques or estimated using regression analysis of the experimental data. The models were evaluated using a Bayesian-based model discrimination technique. Through model discrimination it was shown that phage-resistant cells inhibited the growth of phage population. It was also shown that the uninfected bacterial population was a quasispecies consisting of phage-sensitive and phage-resistant bacterial cells. When there was a phage attack the phage-sensitive cells died out and the phage-resistant cells were selected for and became the dominant strain of the bacterial population. 相似文献
96.
Andriy V. Kubarenko Satish Ranjan Anna Rautanen Tara C. Mills Sunny Wong Fredrik Vannberg Michael Neumaier Isabelle Bekeredjian-Ding Adrian V. S. Hill Parviz Ahmad-Nejad Alexander N. R. Weber 《The Journal of biological chemistry》2010,285(47):36486-36494
The innate immune system employs Toll-like receptors (TLRs) for the detection of invading microorganisms based on distinct molecular patterns. For example, TLR9 is activated by microbial DNA and also by short therapeutic CpG-containing oligonucleotides (CpG-ODN). TLR9 activation leads to the production of interferons and the priming of humoral adaptive immune responses. Unfortunately, the principles of ligand recognition by TLR9 are poorly understood, and genetic variants of TLR9, which may affect its function, have not been characterized systematically on the molecular level. We therefore sought to functionally characterize reported single nucleotide polymorphisms of TLR9 in the HEK293 model system. We discovered that two variants, P99L and M400I, are associated with altered receptor function regarding NF-κB activation and cytokine induction. Our investigations show that for the most functionally impaired variant, P99L, the ability to respond to physiological and therapeutic TLR9 ligands is severely compromised. However, CpG-ODN binding is normal. CpG-ODN recognition by TLR9 thus appears to involve two separate events, CpG-ODN binding and sensing. Our studies highlight Pro-99 as a residue important for the latter process. In genotyping studies, we confirmed that both M400I (rs41308230) and P99L (rs5743844) are relatively rare variants of TLR9. Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG-ODN-based therapies. 相似文献
97.
Bera R Dhara TK Bhadra R Majumder GC Sen PC 《Indian journal of experimental biology》2010,48(12):1194-1203
Eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) enriched polyunsaturated fatty acids (PUFA) significantly present in marine fish oil emerge as preventive agents for combating many health problems specially in chronic or metabolic disorders. The fish in the coastal area of Bay of Bengal has remained unexplored with respect to EPA/DHA enriched PUFA content in its oils, although it may be a potential source in harnessing the health benefit. In this study, seven varieties of the coastal fish were analysed for the content of EPA/DHA. The one locally known as lotte, (Harpadon nehereus) though has low content of total lipids, was found to have high EPA/DHA in its oil. The phospholipids rich fraction was extracted from the total fish oil. The EPA/DHA enriched PUFA was isolated to investigate the potential use for health benefits. EPA/DHA is found to act as protective agent against mercury poisoning studied in cell culture as well as in animal mode. It is found to be highly preventive in diabetes. The lotte is available in the coastal area of Bay of Bengal adjoining West Bengal, India in large scale and it is the first report showing EPA/DHA enriched PUFA in these fish oil that can be availed to harness in important health benefits. 相似文献
98.
In mammalian cells DNA damage activates a checkpoint that halts progression through S phase. To determine the ability of nitrating agents to induce S-phase arrest, mouse C10 cells synchronized in S phase were treated with nitrogen dioxide (NO(2)) or SIN-1, a generator of reactive nitrogen species (RNS). SIN-1 or NO(2) induced S-phase arrest in a dose- and time-dependent manner. As for the positive controls adozelesin and cisplatin, arrest was accompanied by phosphorylation of ATM kinase; dephosphorylation of pRB; decreases in RF-C, cyclin D1, Cdc25A, and Cdc6; and increases in p21. Comet assays indicated that RNS induce minimal DNA damage. Moreover, in a cell-free replication system, nuclei from cells treated with RNS were able to support control levels of DNA synthesis when incubated in cytosolic extracts from untreated cells, whereas nuclei from cells treated with cisplatin were not. Induction of phosphatase activity may represent one mechanism of RNS-induced arrest, for the PP1/PP2A phosphatase inhibitor okadaic acid inhibited dephosphorylation of pRB; prevented decreases in the levels of RF-C, cyclin D1, Cdc6, and Cdc25A; and bypassed arrest by SIN-1 or NO(2), but not cisplatin or adozelesin. Our studies suggest that RNS may induce S-phase arrest through mechanisms that differ from those elicited by classical DNA-damaging agents. 相似文献
99.
Ranjan P Boss JM 《Apoptosis : an international journal on programmed cell death》2006,11(10):1837-1849
The CCAAT enhancer binding protein-β (C/EBPβ) is a critical regulator of many cellular processes. Exposure of C/EBPβ-deficient
fibroblasts to tumor necrosis factor-α (TNF) resulted in their death due to apoptosis. While, the expression of Bad, Bcl-2,
Bcl-x, CAS, and hILP/XIAP, as well as the nuclear translocation of NF-κB was normal in C/EBPβ-deficient cells, induction of
manganous superoxide dismutase (MnSOD) gene did not occur. Ectopic expression of C/EBPβ in C/EBPβ–deficient fibroblasts prevented
TNF-induced apoptosis. C/EBPβ complemented cells were able to induce MnSOD in response to TNF, ruling out the possibilities
that C/EBPβ could render protection by regulating early apoptotic gene expression and/or NF-κB p65 expression. Moreover, C/EBPβ-deficient
cells stably transfected with an MnSOD expression vector bypassed the requirement of C/EBPβ in protection against TNF-induced
cell death, suggesting that C/EBPβ protects TNF-induced apoptotic cell death through its role in activating MnSOD expression.
Mechanistically, C/EBPβ was required for induced NF-κB p65 binding to MnSOD’s intronic TNF response element and indispensable
for histone acetylation of the element in response to TNF. These results suggest a role for C/EBPβ in MnSOD regulation through
remodeling of local chromatin structure.
This work was supported by a grant from the National Institutes of Health, CA96810. 相似文献