全文获取类型
收费全文 | 709篇 |
免费 | 44篇 |
出版年
2021年 | 5篇 |
2019年 | 5篇 |
2018年 | 7篇 |
2017年 | 7篇 |
2016年 | 7篇 |
2015年 | 22篇 |
2014年 | 18篇 |
2013年 | 19篇 |
2012年 | 25篇 |
2011年 | 30篇 |
2010年 | 28篇 |
2009年 | 29篇 |
2008年 | 34篇 |
2007年 | 21篇 |
2006年 | 27篇 |
2005年 | 29篇 |
2004年 | 18篇 |
2003年 | 18篇 |
2002年 | 23篇 |
2001年 | 19篇 |
2000年 | 20篇 |
1999年 | 25篇 |
1998年 | 13篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1993年 | 5篇 |
1992年 | 15篇 |
1991年 | 10篇 |
1990年 | 12篇 |
1989年 | 17篇 |
1988年 | 20篇 |
1987年 | 5篇 |
1986年 | 11篇 |
1985年 | 6篇 |
1984年 | 15篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1979年 | 13篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1974年 | 8篇 |
1972年 | 4篇 |
1971年 | 7篇 |
1969年 | 6篇 |
1968年 | 6篇 |
1966年 | 6篇 |
1965年 | 7篇 |
1964年 | 4篇 |
1963年 | 5篇 |
排序方式: 共有753条查询结果,搜索用时 31 毫秒
81.
Hogan C Hutchison C Marcar L Milne D Saville M Goodlad J Kernohan N Meek D 《The Journal of biological chemistry》2008,283(26):18012-18023
Mutation of the p53 gene is a common event during tumor pathogenesis. Other mechanisms, such as mdm2 amplification, provide alternative routes through which dysfunction of the p53 pathway is promoted. Here, we address the hypothesis that elevated expression of pim oncogenes might suppress p53 by regulating Mdm2. At a physiological level, we show that endogenous Pim-1 and Pim-2 interact with endogenous Mdm2. Additionally, the Pim kinases phosphorylate Mdm2 in vitro and in cultured cells at Ser(166) and Ser(186), two previously identified targets of other signaling pathways, including Akt. Surprisingly, at high levels of Pim expression, as would occur in tumors, active, but not inactive, Pim-1 or Pim-2 blocks the degradation of both p53 and Mdm2 in a manner that is independent of Mdm2 phosphorylation, leading to increased p53 levels and, proportionately, p53-dependent transactivation. Additionally, Pim-1 induces endogenous ARF, p53, Mdm2, and p21 in primary murine embryo fibroblasts and stimulates senescence-associated beta-galactosidase levels, consistent with the induction of senescence. Immunohistochemical analysis of a cohort of 33 human mantle cell lymphomas shows that elevated expression of Pim-1 occurs in 42% of cases, with elevated Pim-2 occurring in 9% of cases, all of which also express Pim-1. Notably, elevated Pim-1 correlates with elevated Mdm2 in MCL with a p value of 0.003. Taken together, our data are consistent with the idea that Pim normally interacts with the p53 pathway but, when expressed at pathological levels, behaves as a classic dominant oncogene that stimulates a protective response through induction of the p53 pathway. 相似文献
82.
Andrew A Carmen Lisa Milne Michael Grunstein 《The Journal of biological chemistry》2002,277(7):4778-4781
Heterochromatin at yeast telomeres and silent mating (HM) loci represses adjacent genes and is formed by the binding and spreading of silencing information regulators (SIR proteins) along histones. This involves the interaction between the C terminus of SIR3 and the N terminus of histone H4. Since H4 is hypoacetylated in heterochromatin we wished to determine whether acetylation is involved in regulating the contacts between SIR3 and H4. Binding of H4 peptide (residues 1-34) acetylated at lysines Lys-5, Lys-8, Lys-12, and Lys-16 to an immobilized SIR3 protein fragment (residues 510-970) was investigated using surface plasmon resonance. We find that acetylation of H4 lysines reduces binding (K(a)) of H4 to SIR3 in a cumulative manner so that the fully acetylated peptide binding is decreased approximately 50-fold relative to unacetylated peptide. Thus, by affecting SIR3-H4 binding, acetylation may regulate the formation of heterochromatin. These data help explain the hypoacetylated state of histone H4 in heterochromatin of eukaryotes. 相似文献
83.
84.
Robert Milne 《BMJ (Clinical research ed.)》1908,2(2496):1333-1334
85.
86.
Diagnosis of dermatophytoses using vinyl adhesive tape 总被引:1,自引:0,他引:1
87.
88.
Lipid peroxidation changes the expression of specific epitopes of apolipoprotein A-I 总被引:1,自引:0,他引:1
Y L Marcel D Jewer L Leblond P K Weech R W Milne 《The Journal of biological chemistry》1989,264(33):19942-19950
Incubation of human serum or high density lipoprotein (HDL) at 37 degrees C in the presence of Fe2+, Fe2+/Fe3+, or Mn2+ results in the increased immunoreactivity (up to 12-, 40-, and 80-fold, respectively) of specific apoA-I epitopes identified as 3D4 and 6B8, while Mg2+, Ca2+, or Cu2+ have minimal or nonsignificant effects. The effect of Mn2+ on the 3D4 epitope requires a specific association with lipids since it can be observed with HDL but not with apoHDL, even in the presence of other lipoproteins. The increase in immunoreactivity noted with Fe2+/Fe3+ or Mn2+ can be blocked with either EDTA or antioxidants (GSH and ascorbic acid), suggesting that it takes place during a peroxidative reaction of the lipids. The peroxidation of lipids which accompanies the increase in immunoreactivity does cross-link apoA-I both with itself and with apoA-II but does not cleave the molecule. The apoA-I-containing lipoproteins which float between 1.18 and 1.22 g/ml and have a pre B-electrophoretic migration are characterized by a very low immunoreactivity with monoclonal antibody 3D4 but are 10-fold or more responsive to Mn2+ treatment than other lipoprotein subfractions, thus demonstrating heterogeneity under oxidative conditions. Proteoliposomes containing apoA-I, cholesterol, and dilinoleyl-lecithin are sensitive to Mn2+ treatment, but not those made with dioleyl- or dimyristoyl-lecithins. However, the increase in 3D4 immunoreactivity is weak and transient and is followed by the disappearance of the epitope caused by cross-linking. We conclude that lipid peroxidation can specifically cross-link apoA-I and change its conformation and antigenicity. 相似文献
89.
End product inhibition of hepatic 25-hydroxyvitamin D production in the rat: specificity and kinetics 总被引:3,自引:0,他引:3
The role of vitamin D metabolites in the regulation of hepatic 25-hydroxyvitamin D production was investigated by examining the effects of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D on the synthesis of [25-3H]hydroxyvitamin D by rachitic rat liver homogenates. Production of [25-3H]hydroxyvitamin D was inhibited by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, but not by 24,25-dihydroxyvitamin D. 25-Hydroxyvitamin D increased the Km of the vitamin D-25-hydroxylase enzyme(s), while 1,25-dihydroxyvitamin D decreased the Vmax with a Ki of 88.7 ng/ml. Inhibition of hepatic 25-hydroxyvitamin D production by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may be another control mechanism to regulate circulating vitamin D levels. 相似文献
90.