全文获取类型
收费全文 | 615篇 |
免费 | 54篇 |
专业分类
669篇 |
出版年
2023年 | 4篇 |
2022年 | 16篇 |
2021年 | 27篇 |
2020年 | 15篇 |
2019年 | 16篇 |
2018年 | 11篇 |
2017年 | 22篇 |
2016年 | 20篇 |
2015年 | 23篇 |
2014年 | 34篇 |
2013年 | 51篇 |
2012年 | 50篇 |
2011年 | 48篇 |
2010年 | 23篇 |
2009年 | 31篇 |
2008年 | 37篇 |
2007年 | 25篇 |
2006年 | 36篇 |
2005年 | 39篇 |
2004年 | 34篇 |
2003年 | 22篇 |
2002年 | 20篇 |
2001年 | 11篇 |
2000年 | 14篇 |
1999年 | 5篇 |
1998年 | 1篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1985年 | 1篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有669条查询结果,搜索用时 15 毫秒
91.
92.
Choudhary AK Andrabi R Prakash SS Kumar R Choudhury SD Wig N Biswas A Hazarika A Luthra K 《Journal of microbiology (Seoul, Korea)》2012,50(1):149-154
We assessed the anti-V3 antibody content and viral neutralization potential of the plasma of 63 HIV-1-infected patients (antiretroviral naïve=39, treated=24) against four primary isolates (PIs) of clade C and a tier 1 clade B isolate SF162. Depletion and inhibition of anti-V3 antibodies in the plasma of five patients with high titers of anti-V3 antibodies led to modest change in the neutralization percentage against two PIs (range 0–21%). The plasma of antiretroviral-treated patients exhibited higher neutralization potential than that of the drug-naïve plasmas against the four PIs tested which was further evidenced by a follow-up study. 相似文献
93.
94.
M Hegde SS Karki E Thomas S Kumar K Panjamurthy SR Ranganatha KS Rangappa B Choudhary SC Raghavan 《PloS one》2012,7(9):e43632
Background
Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole).Materials and Methods
ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo.Results
We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 µM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models.Conclusion
Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent. 相似文献95.
Bacteria can coordinate community-wide behaviors through quorum sensing, that is, the secretion and sensing of autoinducer (AI) molecules. Bacterial quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, bacterial virulence, and drug resistance. Inhibitors of bacterial quorum sensing could therefore be useful therapeutics. Herein we report for the first time the discovery of several pyrogallol compounds as single digit micromolar inhibitors of bacterial quorum sensing in Vibrio harveyi. 相似文献
96.
Weiguo Xiang Shruti Choudhary Ernest Hamel Susan L. Mooberry Aleem Gangjee 《Bioorganic & medicinal chemistry》2018,26(9):2437-2451
We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4′-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC50 values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, the S-methyl analog 3 was more potent than 1 in MDA-MB-435 cells (IC50?=?4.6?nM). Incubation of 3 with human liver microsomes showed that the primary metabolite of the S-methyl moiety of 3 was the methyl sulfinyl group, as in analog 5. This metabolite was equipotent with the lead compound 1 in MDA-MB-435 cells (IC50?=?7.9?nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound 3 emerged as the lead compound for further SAR and preclinical development. 相似文献
97.
S A Shaffi Y R Manohar S L Choudhary N Ghani 《Physiological research / Academia Scientiarum Bohemoslovaca》1999,48(3):221-226
The sublethal effect of cadmium on the specific activities of lactic, malic and succinic dehydrogenases in different brain regions in Labeo rohita (HAM) was assessed with reference to acute, chronic and recovery conditions. Cadmium enhanced succinic, malic and lactic dehydrogenases to a marked extent in the cerebrum from 0 to 12 h exposure. However, a subsequent fall of the above enzymes in some regions was recorded from 12 to 24 h. In chronic studies, the greatest decrease in succinic dehydrogenase was noted in the cerebrum (0 to 15 days) and the least reduction in the cerebellum (30 to 45 days) in comparison with malic and lactic dehydrogenase. In recovery studies an optimum rise in lactic, malic and succinic dehydrogenase was found in the cerebrum (30-45 days). In general, cadmium accumulation was highest in the cerebrum (12 h and 15 days) and least in the cerebellum (24 h and 45 days). This was markedly above the safety level in acute and chronic situations. 相似文献
98.
Charlotte B. Spliid Alejandro Gomez Toledo Patience Sanderson Yang Mao Francesco Gatto Tobias Gustavsson Swati Choudhary Ana L. Saldanha Rasmus P. Vogelsang Ismail Ggenur Thor G. Theander Franklin E. Leach rd I. Jonathan Amster Jeffrey D. Esko Ali Salanti Thomas Mandel Clausen 《The Journal of biological chemistry》2021,297(6)
Placental malaria infection is mediated by the binding of the malarial VAR2CSA protein to the placental glycosaminoglycan, chondroitin sulfate. Recombinant subfragments of VAR2CSA (rVAR2) have also been shown to bind specifically and with high affinity to cancer cells and tissues, suggesting the presence of a shared type of oncofetal chondroitin sulfate (ofCS) in the placenta and in tumors. However, the exact structure of ofCS and what determines the selective tropism of VAR2CSA remains poorly understood. In this study, ofCS was purified by affinity chromatography using rVAR2 and subjected to detailed structural analysis. We found high levels of N-acetylgalactosamine 4-O-sulfation (∼80–85%) in placenta- and tumor-derived ofCS. This level of 4-O-sulfation was also found in other tissues that do not support parasite sequestration, suggesting that VAR2CSA tropism is not exclusively determined by placenta- and tumor-specific sulfation. Here, we show that both placenta and tumors contain significantly more chondroitin sulfate moieties of higher molecular weight than other tissues. In line with this, CHPF and CHPF2, which encode proteins required for chondroitin polymerization, are significantly upregulated in most cancer types. CRISPR/Cas9 targeting of CHPF and CHPF2 in tumor cells reduced the average molecular weight of cell-surface chondroitin sulfate and resulted in a marked reduction of rVAR2 binding. Finally, utilizing a cell-based glycocalyx model, we showed that rVAR2 binding correlates with the length of the chondroitin sulfate chains in the cellular glycocalyx. These data demonstrate that the total amount and cellular accessibility of chondroitin sulfate chains impact rVAR2 binding and thus malaria infection. 相似文献
99.
Vanadium plays an important role in biological systems and exhibits a variety of bioactivities. In an effort to uncover the chemistry and biochemistry of vanadium with nitrogen- and oxygen-containing ligands, we report herein the synthesis and spectroscopic characterization of vanadium(IV) complexes with hydrazide ligands. Substituents on these ligands exhibit systematic variations of electronic and steric factors. Elemental and spectral data indicate the presence of a dimeric unit with two vanadium(IV) ions coordinated with two hydrazide ligands along with two H(2)O molecules. The stability studies of these complexes over time in coordinating solvent, DMSO, indicates binding of the solvent molecules to give [V2O2L2(H2O)2(DMSO)2]2+ (L=hydrazide ligand) and then conversion of it to a monomeric intermediate species, [VOL(DMSO)3]1+. Hydrazide ligands are inactive against urease, whereas vanadium(IV) complexes of these ligands show significant inhibitory potential against this enzyme and are found to be non-competitive inhibitors. These complexes also show low phytotoxicity indicating their usefulness for soil ureases. Structure-activity relationship studies indicate that the steric and/or electronic effects that may change the geometry of the complexes play an important role in their inhibitory potential and phytotoxicity. 相似文献
100.
Mahroof-Tahir M Brezina D Fatima N Choudhary MI Atta-ur-Tahman 《Journal of inorganic biochemistry》2005,99(2):589-599
The increasing interest in vanadium coordination chemistry is based on its well-established chemical and biological functions. A beta-diketonato complex of oxovanadium(IV) is known to be having numerous catalytic applications and also exhibits promising insulin mimetic properties. In continuation of our structure activity relationship studies of metal complexes, we report herein the synthesis and characterization of the vanadium complexes of beta-diketonato ligand system with systematic variations of electronic and steric factors. Two complexes, VO(tmh)(2) (tmh = 2,2,6,6,-tetramethyl-3,5-heptanedione), and VO(hd)(2) (hd = 3,5-heptanedione) were synthesized and characterized by using different spectroscopic techniques. Elemental and mass spectral analysis supports the presence of two beta-diketonato ligands per VO(2+) unit. UV-Vis spectra in different solvents indicate coordination of coordinating solvent molecules at sixth position resulting in red shift of the band I transition. NMR and IR spectra reveal binding of coordinating solvent molecule at vacant sixth position trans to oxo group without releasing beta-diketonato ligands. Enzyme inhibition studies of these and other related oxovanadium(IV) complexes with beta-diketonato ligand system are conducted with snake venom phosphodiesterase I (SPVDE). All of these complexes showed significant inhibitory potential and were found to be non-competitive inhibitors against this enzyme. 相似文献