全文获取类型
收费全文 | 603篇 |
免费 | 71篇 |
出版年
2023年 | 5篇 |
2021年 | 12篇 |
2020年 | 9篇 |
2019年 | 7篇 |
2018年 | 13篇 |
2017年 | 7篇 |
2016年 | 16篇 |
2015年 | 15篇 |
2014年 | 29篇 |
2013年 | 36篇 |
2012年 | 30篇 |
2011年 | 35篇 |
2010年 | 26篇 |
2009年 | 20篇 |
2008年 | 28篇 |
2007年 | 33篇 |
2006年 | 28篇 |
2005年 | 17篇 |
2004年 | 22篇 |
2003年 | 31篇 |
2002年 | 21篇 |
2001年 | 14篇 |
2000年 | 21篇 |
1999年 | 19篇 |
1998年 | 7篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 12篇 |
1990年 | 8篇 |
1989年 | 6篇 |
1988年 | 8篇 |
1987年 | 6篇 |
1986年 | 13篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1976年 | 5篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1968年 | 3篇 |
1966年 | 3篇 |
1945年 | 3篇 |
1942年 | 6篇 |
排序方式: 共有674条查询结果,搜索用时 15 毫秒
71.
Salinthone S Schillace RV Tsang C Regan JW Bourdette DN Carr DW 《The Journal of nutritional biochemistry》2011,22(7):681-690
Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and anti-inflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer's disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R-LA and S-LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study, we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, such as dihydrolipoic acid (DHLA), S,S-dimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCs with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G protein-coupled receptors, including histamine and adenosine but not the β-adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases. 相似文献
72.
Nonheme iron accumulates in CNS tissue after ischemic and hemorrhagic insults and may contribute to cell loss. The source of this iron has not been precisely defined. After blood-brain barrier disruption, CNS cells may be exposed to plasma concentrations of transferrin-bound iron (TBI), which exceed that in the CSF by over 50-fold. In this study, the hypothesis that these concentrations of TBI produce cell iron accumulation and neurotoxicity was tested in primary cortical cultures. Treatment with 0.5-3 mg/ml holotransferrin for 24 h resulted in the loss of 20-40% of neurons, associated with increases in malondialdehyde, ferritin, heme oxygenase-1, and iron; transferrin receptor-1 expression was reduced by about 50%. Deferoxamine, 2,2′-bipyridyl, Trolox, and ascorbate prevented all injury, but apotransferrin was ineffective. Cell TBI accumulation was significantly reduced by deferoxamine, 2,2′-bipyridyl, and apotransferrin, but not by ascorbate or Trolox. After treatment with 55Fe-transferrin, approximately 40% of cell iron was exported within 16 h. Net export was increased by deferoxamine and 2,2′-bipyridyl, but not by apotransferrin. These results suggest that downregulation of transferrin receptor-1 expression is insufficient to prevent iron-mediated death when neurons are exposed to plasma concentrations of TBI. Chelator therapy may be beneficial for acute CNS injuries associated with loss of blood-brain barrier integrity. 相似文献
73.
Regan EA Mazur W Meoni E Toljamo T Millar J Vuopala K Bowler RP Rahman I Nicks ME Crapo JD Kinnula VL 《Free radical biology & medicine》2011,51(3):726-732
Extracellular superoxide dismutase (ECSOD) is the major superoxide-scavenging enzyme in the lung. Certain ECSOD polymorphisms are protective against COPD. We postulated that smokers and COPD subjects would have altered levels of ECSOD in the lung, airway secretions, and/or plasma. Lung tissue ECSOD was evaluated from nonsmokers, smokers, and subjects with mild to very severe COPD by Western blot, immunohistochemistry, and ELISA. ECSOD levels in plasma, bronchoalveolar lavage fluid (BALF), and induced-sputum supernatants were analyzed by ELISA and correlated with smoking history and disease status. Immunohistochemistry identified ECSOD in extracellular matrix around bronchioles, arteries, and alveolar walls, with decreases seen in the interstitium and vessels of severe COPD subjects using digital image analysis. Plasma ECSOD did not differ between COPD subjects and controls nor based on smoking status. ECSOD levels in induced sputum supernatants were elevated in current smokers and especially in COPD subjects compared to nonsmokers, whereas corresponding changes could not be seen in the BALF. ECSOD expression was reduced around vessels and bronchioles in COPD lungs. Substantial increases in sputum ECSOD in smokers and COPD is interpreted as an adaptive response to increased oxidative stress and may be a useful biomarker of disease activity in COPD. 相似文献
74.
Pierre F Stefan E Nédellec AS Chevrel MC Regan CF Siddiqui-Jain A Macalino D Streiner N Drygin D Haddach M O'Brien SE Anderes K Ryckman DM 《Bioorganic & medicinal chemistry letters》2011,21(22):6687-6692
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies. 相似文献
75.
Repeat proteins comprise tandem arrays of a small structural motif. Their structure is defined and stabilized by interactions between residues that are close in the primary sequence. Several studies have investigated whether their structural modularity translates into modular thermodynamic properties. Tetratricopeptide repeat proteins (TPRs) are a class in which the repeated unit is a 34 amino acid helix-turn-helix motif. In this work, we use differential scanning calorimetry (DSC) to study the equilibrium stability of a series of TPR proteins with different numbers of an identical consensus repeat, from 2 to 20, CTPRa2 to CTPRa20. The DSC data provides direct evidence that the folding/unfolding transition of CTPR proteins does not fit a two-state folding model. Our results confirm and expand earlier studies on TPR proteins, which showed that apparent two-state unfolding curves are better fit by linear statistical mechanics models: 1D Ising models in which each repeat is treated as an independent folding unit. 相似文献
76.
There is a current need to develop novel non-toxic antifouling materials. The mechanisms utilized by marine organisms to prevent fouling of external surfaces are of interest in this regard. Biomimicry of these mechanisms and the ability to transfer the antifouling characteristics of these surfaces to artificial surfaces are a highly attractive prospect to those developing antifouling technologies. In order to achieve this, the mechanisms responsible for any antifouling ability must be elucidated from the study of the natural organism and the critical surface parameters responsible for fouling reduction. Dermal denticles of members of the shark family have been speculated to possess some natural, as yet unidentified antifouling mechanism related to the physical presence of denticles. In this study, the dermal denticles of one particular member of the slow-swimming sharks, Scyliorhinus canicula were characterized and it was found that a significant natural variation in denticle dimensions exists in this species. The degree of denticle surface contamination was quantified on denticles at various locations and it was determined that the degree of contamination of the dorsal surface of denticles varies with the position on the shark body. In addition, we successfully produced synthetic sharkskin samples using the real skin as a template. Testing of the produced synthetic skin in field conditions resulted in significant differences in material attachment on surfaces exhibiting denticles of different dimensions. 相似文献
77.
Novel PMS1 alleles preferentially affect the repair of primer strand loops during DNA replication
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Erdeniz N Dudley S Gealy R Jinks-Robertson S Liskay RM 《Molecular and cellular biology》2005,25(21):9221-9231
Null mutations in DNA mismatch repair (MMR) genes elevate both base substitutions and insertions/deletions in simple sequence repeats. Data suggest that during replication of simple repeat sequences, polymerase slippage can generate single-strand loops on either the primer or template strand that are subsequently processed by the MMR machinery to prevent insertions and deletions, respectively. In the budding yeast Saccharomyces cerevisiae and mammalian cells, MMR appears to be more efficient at repairing mispairs comprised of loops on the template strand compared to loops on the primer strand. We identified two novel yeast pms1 alleles, pms1-G882E and pms1-H888R, which confer a strong defect in the repair of "primer strand" loops, while maintaining efficient repair of "template strand" loops. Furthermore, these alleles appear to affect equally the repair of 1-nucleotide primer strand loops during both leading- and lagging-strand replication. Interestingly, both pms1 mutants are proficient in the repair of 1-nucleotide loop mispairs in heteroduplex DNA generated during meiotic recombination. Our results suggest that the inherent inefficiency of primer strand loop repair is not simply a mismatch recognition problem but also involves Pms1 and other proteins that are presumed to function downstream of mismatch recognition, such as Mlh1. In addition, the findings reinforce the current view that during mutation avoidance, MMR is associated with the replication apparatus. 相似文献
78.
The sll1418 gene encodes a PsbP-like protein in Synechocystis sp. PCC 6803. Expression of sll1418 was similar in BG-11 and in Cl−- or Ca2+-limiting media, and inactivation of sll1418 did not prevent photoautotrophic growth in normal or nutrient-limiting conditions. Also the wild-type and ΔPsbP strains exhibited similar oxygen evolution and assembly of Photosystem II (PS II) centers. Inactivation of sll1418 in the ΔPsbO: ΔPsbP, ΔPsbQ:ΔPsbP, ΔPsbU:ΔPsbP and ΔPsbV:ΔPsbP mutants did not prevent photoautotrophy or alter PS II assembly and oxygen evolution in these strains. Moreover, the absence of PsbP did not affect the ability of alkaline pH to restore photoautotrophic growth in the ΔPsbO:ΔPsbU strain. The PsbO, PsbU and PsbV proteins are required for thermostability of PS II and thermal acclimation in Synechocystis sp. PCC 6803 [Kimura et al. (2002) Plant Cell Physiol 43: 932–938]. However, thermostability and thermal acclimation in ΔPsbP cells were similar to wild type. These results are consistent with the conclusion that PsbP is associated with ∼3 of PS II centers, and may play a regulatory role in PS II [Thornton et al. (2004) Plant Cell 16: 2164–2175]. 相似文献
79.
Flinn B Rothwell C Griffiths R Lägue M DeKoeyer D Sardana R Audy P Goyer C Li XQ Wang-Pruski G Regan S 《Plant molecular biology》2005,59(3):407-433
To help develop an understanding of the genes that govern the developmental characteristics of the potato (Solanum tuberosum), as well as the genes associated with responses to specified pathogens and storage conditions, The Canadian Potato Genome
Project (CPGP) carried out 5′ end sequencing of regular, normalized and full-length cDNA libraries of the Shepody potato cultivar,
generating over 66,600 expressed sequence tags (ESTs). Libraries sequenced represented tuber developmental stages, pathogen-challenged
tubers, as well as leaf, floral developmental stages, suspension cultured cells and roots. All libraries analysed to date
have contributed unique sequences, with the normalized libraries high on the list. In addition, a low molecular weight library
has enhanced the 3′ ends of our sequence assemblies. Using the combined assembly dataset, unique tuber developmental, cold
storage and pathogen-challenged sequences have been identified. A comparison of the ESTs specific to the pathogen-challenged
tuber and foliar libraries revealed minimal overlap between these libraries. Mixed assemblies using over 189,000 potato EST
sequences from CPGP and The Institute for Genomics Research (TIGR) has revealed common sequences, as well as CPGP- and TIGR-unique
sequences.
Electronic Supplementary Material Electronic Supplementary material is available for this article at
and accessible for authorised users. 相似文献
80.
Guo Z Wu D Zhu YF Tucci FC Regan CF Rowbottom MW Struthers RS Xie Q Reijmers S Sullivan SK Sai Y Chen C 《Bioorganic & medicinal chemistry letters》2005,15(16):3685-3690
SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM. 相似文献