全文获取类型
收费全文 | 651篇 |
免费 | 28篇 |
国内免费 | 25篇 |
专业分类
704篇 |
出版年
2023年 | 12篇 |
2022年 | 21篇 |
2021年 | 12篇 |
2020年 | 21篇 |
2019年 | 9篇 |
2018年 | 14篇 |
2017年 | 12篇 |
2016年 | 17篇 |
2015年 | 11篇 |
2014年 | 24篇 |
2013年 | 50篇 |
2012年 | 12篇 |
2011年 | 30篇 |
2010年 | 14篇 |
2009年 | 28篇 |
2008年 | 29篇 |
2007年 | 25篇 |
2006年 | 33篇 |
2005年 | 25篇 |
2004年 | 23篇 |
2003年 | 28篇 |
2002年 | 26篇 |
2001年 | 13篇 |
2000年 | 14篇 |
1999年 | 13篇 |
1998年 | 15篇 |
1997年 | 9篇 |
1996年 | 13篇 |
1995年 | 8篇 |
1994年 | 14篇 |
1993年 | 7篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 5篇 |
1985年 | 10篇 |
1984年 | 21篇 |
1983年 | 9篇 |
1982年 | 21篇 |
1981年 | 12篇 |
1980年 | 6篇 |
1979年 | 11篇 |
1978年 | 1篇 |
1976年 | 3篇 |
1974年 | 1篇 |
排序方式: 共有704条查询结果,搜索用时 15 毫秒
651.
Indira Singh Chauhan G. Subba Rao Jai Shankar Lalit Kumar Singh Chauhan Govind J. Kapadia Neeloo Singh 《Parasitology international》2018,67(5):627-636
Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by DBA. This economically synthesizable simple monoketone analog of curcumin has the potential for field use against visceral leishmaniasis which is currently widespread in tropical and subtropical developing countries of the world. In conclusion, we have identified an analog of curcumin for potential applications against leishmaniasis, based on its strong antiparasitic activity and low toxicity. This curcumin analog compares favorably, at least in vitro, with the existing medication miltefosine. 相似文献
652.
S. E. Favero-Longo C. Gazzano M. Girlanda D. Castelli M. Tretiach C. Baiocchi 《Geomicrobiology journal》2013,30(8):732-744
Physicochemical deterioration processes driven by lithobiontic microcolonial fungi (MCF) and endolithic lichens (EL) are still mostly unresolved. Here, the millimetric penetration of MCF strains within silicate and carbonate lithotypes was quantified. The influence of petrographic features in determining hyphal passageways satisfies a model of physical penetration during the early stages of colonization, already described for EL. The MCF and EL secretion of iron-chelating metabolites accounts for iron mobilization in desert-varnish formation, often putatively related to fungal colonization. Increased dissolution of limestone by the model iron chelator desferrioxamine indicates the possible involvement of these MCF and EL secretes in pitting carbonates. 相似文献
653.
Guangyi Jin Christina C. N. Wu Dennis A. Carson Howard B. Cottam 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1391-1397
The synthesis of a guanosine analog in the pyrido[2,3-d]pyrimidine ring system has been accomplished by glycosylation of the preformed aromatic heterocyclic base, which was prepared in 2 steps by condensation of methyl acrylate with guanidine carbonate and methyl cyanoacetate in the presence of sodium methoxide, followed by dehydrogenation. The analog was evaluated in vitro for its ability to modulate the innate immune response by acting as an agonist or as an antagonist of Toll-like receptor (TLR) signaling by measuring cytokine induction or inhibition of induction, respectively, in mouse bone marrow-derived macrophages. Despite its structural similarity to 7-thia-8-oxoguanosine, a known TLR7 agonist, the analog was found to antagonize TLR7-induced cytokine induction in this cell-based assay. 相似文献
654.
《Nucleosides, nucleotides & nucleic acids》2013,32(8-9):1527-1529
The deoxyribonucleoside kinase of Drosophila melanogaster (Dm‐dNK) has a broad substrate specificity and a higher catalytic rate than other known deoxyribonucleoside kinases. Therefore it is a natural candidate for possible use as a suicide gene in combined gene/chemotherapy of cancer. We have performed site directed mutagenesis and tested different truncated forms of the enzyme in order to increase the affinity for ganciclovir. 相似文献
655.
Mönkkönen H Ottewell PD Kuokkanen J Mönkkönen J Auriola S Holen I 《Life sciences》2007,81(13):1066-1070
Bisphosphonates are currently the most important class of anti-resorptive drugs used for the treatment of diseases involving excess bone resorption. Recently we discovered a new mechanism of action for bisphosphonates. Previously it has been shown that nitrogen-containing bisphosphonates (N-BPs) are not metabolized. However, our studies revealed that N-BPs induce formation of a novel pro-apoptotic ATP analog (ApppI), as a consequence of the inhibition of FPP synthase in the mevalonate pathway, and the subsequent accumulation of isopentenyl pyrophosphate (IPP) in vitro. The primary aim of the current study was to determine whether zoledronic acid (a N-BP) induces IPP/ApppI formation in vivo. Mass spectrometry was used to identify whether in vivo administration of zoledronic acid-induced IPP/ApppI production by mouse peritoneal macrophages or bone marrow cells. IPP/ApppI could be detected in extracts from peritoneal macrophages isolated from zoledronic acid-treated animals. Increasing IPP/ApppI accumulation was determined up to 7 days after drug injection, indicating prolonged FPP synthase inhibition by zoledronic acid. Importantly, this is the first report of in vivo production of ApppI, supporting the biological significance of this molecule. 相似文献
656.
McKenzie KM Mee JM Rogers CJ Hixon MS Kaufmann GF Janda KD 《Journal of molecular biology》2007,365(3):722-731
Cocaine is a powerful and addictive stimulant whose abuse remains a prevalent health and societal crisis. Unfortunately, no pharmacological therapies exist and therefore alternative protein-based therapies have been examined. One such approach is immunopharmacotherapy, wherein antibodies are utilized to either bind or hydrolyze cocaine thereby blocking it from exerting its euphoric effect. Towards this end, antibodies capable of binding and hydrolyzing cocaine were identified by phage display from a biased single chain antibody library generated from the spleens of mice previously immunized with a cocaine phosphonate transition state analog hapten. Two classes of antibodies emerged based on sequence homology and mode of action. Alanine scanning mutagenesis and kinetic analysis revealed that residues H97, H99, and L96 are crucial for antibodies 3F5 and 3H9 to accelerate the hydrolysis of cocaine. Antibodies 3F1 through 3F4, which are similar to our previously identified 3A6 class of antibodies, catalyze hydrolysis through transition state stabilization by tyrosine or histidine residues H50 and L94. Mutation of either one or both tyrosine residues to histidine conferred hydrolytic activity on previously inactive antibody 3F4. Mutational analysis of residue H50 of antibody 3F3 resulted in a glutamine mutant with a rate enhancement three times greater than wild-type. A double mutant, containing glutamineH50 and lysineH52, showed a tenfold rate enhancement over wild-type. These results indicate the power of initial selection of catalytic antibodies from a biased antibody library in both rapid generation and screening of mutants for improved catalysis. 相似文献
657.
Little is known about the effect of sugars in controlling secondary metabolism. In this study, sugars alone or in combination
with their analogs were used to investigate their role in the production of the antimalarial drug, artemisinin, in Artemisia annua L. seedlings. Compared to sucrose, a 200% increase in artemisinin by glucose was observed. Different ratios of fructose to
glucose yielded artemisinin levels directly proportional to increases in relative glucose concentration. When the glucose
analog, 3-O-methylglucose, was added with glucose, artemisinin production was dramatically decreased, but hexokinase activity was significantly
increased compared to glucose alone. In contrast, neither mannose nor mannitol had any significant effect on artemisinin yield.
In comparison with 30 g/l sucrose, artemisinin levels were significantly reduced by 80% in the presence of 27 g/l sucrose + 3 g/l
palatinose, which cannot be transported into cells through the sucrose transporter. Together these results suggest that both
monosaccharide and disaccharide sugars are likely acting not only as carbon sources but also as signals to affect the downstream
production of artemisinin, and that the mechanism of these effects appears to be complex. 相似文献
658.
659.
Park HS Jun DY Han CR Kim YH 《Biochemical and biophysical research communications》2008,377(1):280-285
Phenylalanine analog, ρ-fluorophenylalanine (pFPhe)-mediated cytotoxicity and several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, Bid cleavage, degradation of PARP and PLCγ-1, and DNA fragmentation were more significant in p56lck-deficient Jurkat T cells (JCaM1.6) than in wild-type Jurkat T cells (E6.1). The susceptibility of JCaM1.6 toward apoptogenic activity of pFPhe decreased after acquisition of p56lck by transfection. The p56lck kinase activity increased 1.6-fold at 15-30 min after pFPhe treatment. The pan-caspase inhibitor (z-VAD-fmk) completely blocked the pFPhe-mediated apoptotic changes except caspase-9 activation. The caspase-8 inhibitor (z-IETD-fmk), which failed to influence pFPhe-induced caspase-9 activation, completely blocked caspase-8 activation and PLCγ-1 degradation with a marked reduction in caspase-3 activation and PARP degradation, indicating pFPhe-induced caspase-8 activation as a downstream event of mitochondria-dependent activation of caspase-9. These results indicate that the deficiency of p56lck augments pFPhe-induced mitochondrial cytochrome c release and resultant apoptotic cell death in Jurkat T cells. 相似文献
660.