全文获取类型
收费全文 | 173篇 |
免费 | 13篇 |
出版年
2023年 | 3篇 |
2022年 | 2篇 |
2021年 | 18篇 |
2020年 | 8篇 |
2019年 | 14篇 |
2018年 | 6篇 |
2017年 | 2篇 |
2016年 | 9篇 |
2015年 | 9篇 |
2014年 | 4篇 |
2013年 | 10篇 |
2012年 | 11篇 |
2011年 | 15篇 |
2010年 | 9篇 |
2009年 | 3篇 |
2008年 | 9篇 |
2007年 | 8篇 |
2006年 | 5篇 |
2005年 | 7篇 |
2004年 | 3篇 |
2003年 | 5篇 |
2002年 | 4篇 |
2001年 | 2篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 5篇 |
1979年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1969年 | 1篇 |
1968年 | 2篇 |
1964年 | 1篇 |
排序方式: 共有186条查询结果,搜索用时 187 毫秒
21.
Liao WL Heo GY Dodder NG Reem RE Mast N Huang S Dipatre PL Turko IV Pikuleva IA 《Journal of proteome research》2011,10(1):241-248
Cytochrome P450 enzymes (CYP or P450) 46A1 and 27A1 play important roles in cholesterol elimination from the brain and retina, respectively, yet they have not been quantified in human organs because of their low abundance and association with membrane. On the basis of our previous development of a multiple reaction monitoring (MRM) workflow for measurements of low-abundance membrane proteins, we quantified CYP46A1 and CYP27A1 in human brain and retina samples from four donors. These enzymes were quantified in the total membrane pellet, a fraction of the whole tissue homogenate, using 1?N-labled recombinant P450s as internal standards. The average P450 concentrations/mg of total tissue protein were 345 fmol of CYP46A1 and 110 fmol of CYP27A1 in the temporal lobe, and 60 fmol of CYP46A1 and 490 fmol of CYP27A1 in the retina. The corresponding P450 metabolites were then measured in the same tissue samples and compared to the P450 enzyme concentrations. Investigation of the enzyme-product relationships and analysis of the P450 measurements based on different signature peptides revealed a possibility of retina-specific post-translational modification of CYP27A1. The data obtained provide important insights into the mechanisms of cholesterol elimination from different neural tissues. 相似文献
22.
Oxadiazols: a new class of rationally designed anti-human immunodeficiency virus compounds targeting the nuclear localization signal of the viral matrix protein 下载免费PDF全文
Haffar O Dubrovsky L Lowe R Berro R Kashanchi F Godden J Vanpouille C Bajorath J Bukrinsky M 《Journal of virology》2005,79(20):13028-13036
Despite recent progress in anti-human immunodeficiency virus (HIV) therapy, drug toxicity and emergence of drug-resistant isolates during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the process of nuclear translocation of the HIV preintegration complex. Previously we described a class of arylene bis(methylketone) compounds that inhibit HIV-1 nuclear import by targeting the nuclear localization signal (NLS) in the matrix protein (MA). Here we report a different class of MA NLS-targeting compounds that was selected using computer-assisted drug design. The leading compound from this group, ITI-367, showed potent anti-HIV activity in cultures of T lymphocytes and macrophages and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue. The virus carrying inactivating mutations in MA NLS was resistant to ITI-367. Analysis by real-time PCR demonstrated that the compound specifically inhibited nuclear import of viral DNA, measured by two-long terminal repeat circle formation. Evidence of the existence of this mechanism was provided by immunofluorescent microscopy, using fluorescently labeled HIV-1, which demonstrated retention of the viral DNA in the cytoplasm of drug-treated macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for further development. 相似文献
23.
24.
Novel drug delivery vehicles based on the biodegradable, mucoadhesive polysaccharide chitosan covalently linked to a boronic acid protease inhibitor have been prepared and characterized. It was anticipated that these conjugates could protect a proteinaceous drug, such as salmon calcitonin, against proteolysis by serine proteases, an obstacle that prevents its oral administration. Specifically, 4-formylphenylboronic acid was linked to chitosan. Three types of conjugates were prepared. In the first, 4-formylphenylboronic acid was directly linked to chitosan. The other two conjugates employed glycylglycine and pentaglycine spacers. Enzyme-inhibition assays toward trypsin and elastase, in the presence of the enzyme chitosanase, demonstrated a strong inhibitory effect for the chitosan-pentaglycine-phenylboronic acid conjugates, while no inhibitory effect could be detected without chitosanase. The chitosan-pentaglycine-phenylboronic acid conjugate with the highest degree of substitution of 4-formylphenylboronic acid was able to decrease the salmon calcitonin degradation rate by trypsin. It is concluded that chitosan-pentaglycine-phenylboronic acid conjugates are a potential multifunctional, colon-specific vehicle for orally administered salmon calcitonin. 相似文献
25.
Young Ah Kim Ravindra K. Rawal Jakyung Yoo Ashoke Sharon Ashok K. Jha Chung K. Chu Reem H. Rais Omar N. Al Safarjalani Fardos N.M. Naguib Mahmoud H. el Kouni 《Bioorganic & medicinal chemistry》2010,18(10):3403-3412
Carbocyclic 6-benzylthioinosine analogues were synthesized and evaluated for their binding affinity against Toxoplasma gondii adenosine kinase [EC.2.7.1.20]. Various substituents on the aromatic ring of the 6-benzylthio group resulted in increased binding affinity to the enzyme as compared to the unsubstituted compound. Carbocyclic 6-(p-methylbenzylthio)inosine 9n exhibited the most potent binding affinity. Docking simulations were performed to position compound 9n into the T. gondii adenosine kinase active site to determine the probable binding mode. Experimental investigations and theoretical calculations further support that an oxygen atom of the sugar is not critical for the ligand-binding. In agreement with its binding affinity, carbocyclic 6-(p-methylbenzylthio)inosine 9n demonstrated significant anti-toxoplasma activity (IC50 = 11.9 μM) in cell culture without any apparent host-toxicity. 相似文献
26.
A draft genome sequence of Actinomyces massiliensis, an anaerobic bacterium isolated from a patient's blood culture, is described here. CRISPR-associated proteins, insertion sequences, and toxin-antitoxin loci were found on the genome. 相似文献
27.
Retroviral Gag proteins are synthesized as soluble, myristoylated precursors that traffic to the plasma membrane and promote viral particle production. The intracellular transport of human immunodeficiency virus type 1 (HIV-1) Gag to the plasma membrane remains poorly understood, and cellular motor proteins responsible for Gag movement are not known. Here we show that disrupting the function of KIF4, a kinesin family member, slowed temporal progression of Gag through its trafficking intermediates and inhibited virus-like particle production. Knockdown of KIF4 also led to increased Gag degradation, resulting in reduced intracellular Gag protein levels; this phenotype was rescued by reintroduction of KIF4. When KIF4 function was blocked, Gag transiently accumulated in discrete, perinuclear, nonendocytic clusters that colocalized with endogenous KIF4, with Ubc9, an E2 SUMO-1 conjugating enzyme, and with SUMO. These studies identify a novel transit station through which Gag traffics en route to particle assembly and highlight the importance of KIF4 in regulating HIV-1 Gag trafficking and stability. 相似文献
28.
Avital Torres Malka Hochberg Inna Pergament Reem Smoum Valerie Niddam Valery M Dembitsky Marina Temina Inka Dor Ovadia Lev Morris Srebnik Claes D Enk 《European journal of biochemistry》2004,271(4):780-784
A novel photo protective mycosporine was isolated from the lichenized ascomycete Collema cristatum. Biological activity was measured in terms of protection against UV-B induced membrane destruction and pyrimidine dimer formation in cultured human keratinocytes, and prevention of UV-B induced erythema. It was found that the pure isolated compound prevented UV-B induced cell destruction in a dose-dependent manner, that the compound partially prevented pyrimidine dimer formation and completely prevented UV-B induced erythema when applied to the skin prior to irradiation. 相似文献
29.
30.
Iman Al-Saleh Mai Abduljabbar Reem Al-Rouqi Rola Elkhatib Ammar Alshabbaheen Neptune Shinwari 《Biological trace element research》2013,153(1-3):145-154
The objective of this work was to assess exposure to mercury (Hg) and its induction of oxidative stress in 155 healthy lactating Saudi mothers and their infants. Samples of breast milk and blood were collected from the mothers, while urine was taken from both infants and mothers. Both urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured in mothers and infants as biomarkers of oxidative stress. The mean concentration of Hg in breast milk was 1.19 μg/L (range 0.012–6.44 μg/L) with only one mother having Hg >4 μg/L, the upper limit established by the US Agency for Toxic Substance and Disease Registry. However, 57.4 % had Hg ≥1 μg/L, the background level for Hg in human milk. The mean urinary Hg corrected for creatinine (Hg-C) in mothers and infants was 1.47 and 7.90 μg/g creatinine, respectively, with a significant correlation between the two (p?<?0.001). Urinary Hg levels over 5 μg/g creatinine (the background level in an unexposed population) were found in 3.3 % of mothers and 50.1 % of infants. None of the mothers had total blood Hg above the US Environmental Protection Agency’s maximum reference dose of 5.8 μg/L. No correlation was noted between urinary Hg in infants and Hg in breast milk (p?>?0.05). Hg in breast milk, though, was associated with Hg in blood (p?<?0.001), suggesting the efficient transfer of Hg from blood to milk. Hg in the breast milk of mothers and in the urine of infants affected the excretion of urinary MDA and 8-OHdG, respectively, in a dose-related manner. These findings reveal for the first time lactational exposure to Hg-induced oxidative stress in breast-fed infants, which may play a role in pathogenesis, particularly during neurodevelopment. This will also contribute to the debate over the benefits of breast milk versus the adverse effects of exposure to pollutants. Nevertheless, breastfeeding should not be discouraged, but efforts should be made to identify and eliminate the source of Hg exposure in the population. 相似文献