首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   577篇
  免费   19篇
  596篇
  2024年   6篇
  2023年   4篇
  2022年   4篇
  2021年   8篇
  2020年   7篇
  2019年   4篇
  2018年   8篇
  2017年   2篇
  2016年   15篇
  2015年   23篇
  2014年   25篇
  2013年   34篇
  2012年   56篇
  2011年   38篇
  2010年   34篇
  2009年   23篇
  2008年   32篇
  2007年   34篇
  2006年   34篇
  2005年   25篇
  2004年   15篇
  2003年   14篇
  2002年   23篇
  2001年   6篇
  2000年   3篇
  1999年   7篇
  1998年   11篇
  1997年   7篇
  1995年   6篇
  1994年   5篇
  1993年   6篇
  1992年   5篇
  1991年   4篇
  1990年   3篇
  1989年   4篇
  1988年   7篇
  1987年   6篇
  1985年   4篇
  1980年   4篇
  1978年   4篇
  1977年   3篇
  1975年   4篇
  1974年   3篇
  1972年   4篇
  1964年   2篇
  1961年   4篇
  1954年   1篇
  1944年   1篇
  1943年   1篇
  1932年   1篇
排序方式: 共有596条查询结果,搜索用时 0 毫秒
1.
    
Rapid, ongoing permafrost thaw of peatlands in the discontinuous permafrost zone is exposing a globally significant store of soil carbon (C) to microbial processes. Mineralization and release of this peat C to the atmosphere as greenhouse gases is a potentially important feedback to climate change. Here we investigated the effects of permafrost thaw on peat C at a peatland complex in western Canada. We collected 15 complete peat cores (between 2.7 and 4.5 m deep) along four chronosequences, from elevated permafrost peat plateaus to saturated thermokarst bogs that thawed up to 600 years ago. The peat cores were analysed for peat C storage and peat quality, as indicated by decomposition proxies (FTIR and C/N ratios) and potential decomposability using a 200-day aerobic laboratory incubation. Our results suggest net C loss following thaw, with average total peat C stocks decreasing by ~19.3 ± 7.2 kg C m−2 over <600 years (~13% loss). Average post-thaw accumulation of new peat at the surface over the same period was ~13.1 ± 2.5 kg C m−2. We estimate ~19% (±5.8%) of deep peat (>40 cm below surface) C is lost following thaw (average 26 ± 7.9 kg C m−2 over <600 years). Our FTIR analysis shows peat below the thaw transition in thermokarst bogs is slightly more decomposed than peat of a similar type and age in permafrost plateaus, but we found no significant changes to the quality or lability of deeper peat across the chronosequences. Our incubation results also showed no increase in C mineralization of deep peat across the chronosequences. While these limited changes in peat quality in deeper peat following permafrost thaw highlight uncertainty in the exact mechanisms and processes for C loss, our analysis of peat C stocks shows large C losses following permafrost thaw in peatlands in western Canada.  相似文献   
2.
    
The O(6)-methylguanine-DNA-methyltransferase (MGMT) inactivator O(6)-benzylguanine (O(6)-beG) is currently under clinical investigation as a potential tumour-sensitising agent. In clinical trials its use has been associated with increased myelotoxicity and a reduced maximum tolerated dose (MTD) for BCNU. Thus the concept of myeloprotection by gene therapy with an O(6)-beG-insensitive mutant of MGMT is soon to be tested. Recently, an alternative inactivator has been described (O(6)-(4-bromothenyl)guanine, PaTrin-2), which shows potential advantages over O(6)-beG in terms of higher activity against wild-type MGMT and oral formulation. The use of PaTrin-2 has also been associated with increased myelotoxicity in clinical trials and thus PaTrin-2 may also be a candidate for use in conjunction with mutant MGMT gene transfer in genetic chemoprotective strategies. However, its activity against mutant MGMTs has not been reported. We show here that the P(140)K mutant of MGMT is highly resistant to inactivation by PaTrin-2. Furthermore, we show that a human haemopoietic cell line (K562) transduced with a retroviral vector encoding MGMT(P140K) is highly resistant to the cytotoxic effects of PaTrin-2 in combination with the methylating agent temozolomide, and that cells expressing MGMT(P140K) can be effectively enriched in vitro following challenge with this drug combination. Finally, we show that animals reconstituted with bone marrow expressing MGMT(P140K) exhibit haemopoietic resistance to PaTrin-2/temozolomide, which results in in vivo selection of gene-modified cells. All of these effects were comparable to those also achieved using O(6)-beG/temozolomide. Thus our data show that MGMT(P140K) is a suitable candidate for chemoprotective gene therapy where PaTrin-2 is being used in conjunction with temozolomide.  相似文献   
3.
In many mammals, the energetic costs of lactation double a female's daily energy requirements on her activity budgets, food choice and ranging behaviour–but the effects of lactation have rarely been documented. In this paper, the ecological consequences of lactation in free-ranging Red deer ( Cervus elaphus ) hinds on the lsle of Rhum is examined by comparing the feeding behaviour, habitat use and ranging behaviour of hinds that were supporting calves (milk hinds) with hinds that did not have calves (yeld hinds). In summer, milk hinds graze for approximately two hours longer per day then yeld hinds. This difference has disappeared by the latter half of the winter, when the grazing budgets of milk and yeld hinds are similar. Both in summer and winter milk hinds spend more time grazing on the most strongly selected plant communities (short, herb-rich greens) where standing crops are low but food quality is comparatively high. Inter-year variation in habitat use by milk hinds is also closely related to variation in rainfall—while this is not the case among yeld hinds. Both in summer and winter, yeld hinds range more widely than milk hinds.  相似文献   
4.
Localisation of Protein Kinase A (PKA) by A-Kinase Anchoring Proteins (AKAPs) is known to coordinate localised signalling complexes that target cAMP-mediated signalling to specific cellular sub-domains. The cAMP PKA signalling pathway is implicated in both meiotic arrest and meiotic resumption, thus spatio-temporal changes in PKA localisation during development may determine the oocytes response to changes in cAMP. In this study we aim to establish whether changes in PKA localisation occur during oocyte and early embryo development.Using fluorescently-labelled PKA constructs we show that in meiotically incompetent oocytes PKA is distributed throughout the cytoplasm and shows no punctuate localisation. As meiotic competence is acquired, PKA associates with mitochondria. Immature germinal vesicle (GV) stage oocytes show an aggregation of PKA around the GV and PKA remains co-localised with mitochondria throughout oocyte maturation. After fertilisation, the punctuate, mitochondrial distribution was lost, such that by the 2-cell stage there was no evidence of PKA localisation. RT-PCR and Western blotting revealed two candidate AKAPs that are known to be targeted to mitochondria, AKAP1 and D-AKAP2. In summary these data show a dynamic regulation of PKA localisation during oocyte and early embryo development.  相似文献   
5.
The diversity and phylogenetic relationships of fungi obtained from Antarctic soils were analysed using molecular techniques. Direct extraction of soil community DNA from two locations, Fossil Bluff (FB) and Jane Col (JC), was supplemented with isolation studies. Nucleic acids from both the community DNA and the colony extracts were PCR amplified using primers specific for the 18S rRNA gene (18S rDNA). Amplicons were separated in denaturant gels (DGGE) or following endonuclease digestion (ARDRA). Clones presenting unique ARDRA banding patterns and unique DGGE bands were sequenced. Comparison of the experimental sequences from the different techniques employed with those held online resulted in the repeated recovery of a limited range of related organisms indicating low species diversity of microfungi in these soils. A total of 102 fungal sequences were obtained from FB (37 sequences) and JC (65 sequences) that together were distributed among the Basidiomycota (48 sequences), Ascomycota (48 sequences) and Zygomycota (6 sequences). Sequences of the latter were only recovered from the JC soils. Phylogenetic comparisons of the experimental sequences with those held online have shown high rRNA gene relatedness with those obtained from other, less extreme, environments.  相似文献   
6.
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).  相似文献   
7.
8.
To investigate the possible role of basic residues in H+ translocation through vacuolar-type H+-pumping pyrophosphatases (V-PPases), conserved arginine and lysine residues predicted to reside within or close to transmembrane domains of an Arabidopsis thaliana V-PPase (AVP1) were subjected to site-directed mutagenesis. One of these mutants (K461A) exhibited a “decoupled” phenotype in which proton-pumping but not hydrolysis was inhibited. Similar results were reported previously for an E427Q mutant, resulting in the proposal that E427 might be involved in proton translocation. However, the double mutant E427K/K461E has a wild type phenotype, suggesting that E427 and K461 form a stabilising salt bridge, but that neither residue plays a critical role in proton translocation.  相似文献   
9.
10.
Back signaling by the Nrg-1 intracellular domain   总被引:4,自引:0,他引:4  
Transmembrane isoforms of neuregulin-1 (Nrg-1), ligands for erbB receptors, include an extracellular domain with an EGF-like sequence and a highly conserved intracellular domain (ICD) of unknown function. In this paper, we demonstrate that transmembrane isoforms of Nrg-1 are bidirectional signaling molecules in neurons. The stimuli for Nrg-1 back signaling include binding of erbB receptor dimers to the extracellular domain of Nrg-1 and neuronal depolarization. These stimuli elicit proteolytic release and translocation of the ICD of Nrg-1 to the nucleus. Once in the nucleus, the Nrg-1 ICD represses expression of several regulators of apoptosis, resulting in decreased neuronal cell death in vitro. Thus, regulated proteolytic processing of Nrg-1 results in retrograde signaling that appears to mediate contact and activity-dependent survival of Nrg-1-expressing neurons.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号