全文获取类型
收费全文 | 535篇 |
免费 | 51篇 |
出版年
2023年 | 3篇 |
2022年 | 8篇 |
2021年 | 25篇 |
2020年 | 7篇 |
2019年 | 9篇 |
2018年 | 18篇 |
2017年 | 13篇 |
2016年 | 15篇 |
2015年 | 26篇 |
2014年 | 34篇 |
2013年 | 42篇 |
2012年 | 33篇 |
2011年 | 42篇 |
2010年 | 27篇 |
2009年 | 27篇 |
2008年 | 32篇 |
2007年 | 24篇 |
2006年 | 25篇 |
2005年 | 10篇 |
2004年 | 17篇 |
2003年 | 13篇 |
2002年 | 9篇 |
2000年 | 5篇 |
1999年 | 7篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1992年 | 3篇 |
1991年 | 10篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1983年 | 5篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1973年 | 8篇 |
1972年 | 5篇 |
1971年 | 2篇 |
1970年 | 12篇 |
1969年 | 5篇 |
1967年 | 2篇 |
1966年 | 3篇 |
1965年 | 8篇 |
排序方式: 共有586条查询结果,搜索用时 15 毫秒
21.
Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) were administered during the last 21 days (8–28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1 mg/kg., p.o.) and fluoxetine (20 mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (p < 0.05) increased the BDNF level and inhibited the hypothalamic–pituitary–adrenocortical (HPA) axis hyperactivity, as evidenced by low serum CORT level in stressed mice. In addition, etazolate and fluoxetine also showed significant antidepressant- and anxiolytic-like effects in normal control mice. In this study no significant changes were observed in locomotor activity in actophotometer test. Moreover, we did not find any effect of etazolate and fluoxetine on CORT and BDNF levels in normal control mice. In conclusion, the results of the present study suggested compelling evidences that etazolate has more marked effect on depression-like behavior in mice, which is atleast in part may be related to their modulating effects on the HPA axis and BDNF level. 相似文献
22.
Huiguo Lai Dengfeng Dou Sridhar Aravapalli Tadahisa Teramoto Gerald H. Lushington Tom M. Mwania Kevin R. Alliston David M. Eichhorn Radhakrishnan Padmanabhan William C. Groutas 《Bioorganic & medicinal chemistry》2013,21(1):102-113
1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one—1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 μM). The IC50 values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure–activity relationship studies, in vitro screening and X-ray crystallography. 相似文献
23.
Divya Thomas Satish Sagar Thomas Caffrey Paul M. Grandgenett Prakash Radhakrishnan 《Journal of cellular and molecular medicine》2019,23(10):6885-6896
Aberrant expression of Sialyl‐Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Co re 1 s ynthase specific m olecular c haperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O‐glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial‐to‐mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re‐expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O‐glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties. 相似文献
24.
Ramaraj Sathasivam Ramalingam Radhakrishnan Abeer Hashem Elsayed F. Abd_Allah 《Saudi Journal of Biological Sciences》2019,26(4):709-722
Microalgae are one of the important components in food chains of aquatic ecosystems and have been used for human consumption as food and as medicines. The wide diversity of compounds synthesized from different metabolic pathways of fresh and marine water algae provide promising sources of fatty acids, steroids, carotenoids, polysaccharides, lectins, mycosporine-like amino acids, halogenated compounds, polyketides, toxins, agar agar, alginic acid and carrageenan. This review discusses microalgae used to produce biological substances and its economic importance in food science, the pharmaceutical industry and public health. 相似文献
25.
Coupling of fast and slow modes in the reaction pathway of the minimal hammerhead ribozyme cleavage 总被引:1,自引:0,他引:1
Radhakrishnan R 《Biophysical journal》2007,93(7):2391-2399
By employing classical molecular dynamics, correlation analysis of coupling between slow and fast dynamical modes, and free energy (umbrella) sampling using classical as well as mixed quantum mechanics molecular mechanics force fields, we uncover a possible pathway for phosphoryl transfer in the self-cleaving reaction of the minimal hammerhead ribozyme. The significance of this pathway is that it initiates from the minimal hammerhead crystal structure and describes the reaction landscape as a conformational rearrangement followed by a covalent transformation. The delineated mechanism is catalyzed by two metal (Mg(2+)) ions, proceeds via an in-line-attack by CYT 17 O2' on the scissile phosphorous (ADE 1.1 P), and is therefore consistent with the experimentally observed inversion configuration. According to the delineated mechanism, the coupling between slow modes involving the hammerhead backbone with fast modes in the cleavage site appears to be crucial for setting up the in-line nucleophilic attack. 相似文献
26.
Ansuman Panda Debashis Jena Mrinal Kanti Datta Janmejay Parhi Radhakrishnan Kizhakke Veettil Pramod Kumar Pandey 《Zeitschrift fur angewandte Ichthyologie》2019,35(6):1242-1248
The present study explains the intraspecific variation in Indian Hill trout (Barilius bendelisis) on the basis of image based truss network system and D‐loop region of mtDNA. A total of 210 samples were collected from three different rivers (Teesta, Kameng and Myntudu River) of North East India in Indo‐Burma Biodiversity Hotspot. By using the software applications (tpsDig version 2.1 and PAST), a total of 25 morphometric measurements were generated from 10 landmarks. The Analysis of Variance (ANOVA), Factor Analysis (FA) and Discriminate Function Analysis (DFA) showed, out of the total variations, factor 1 explained 46.74% while factor 2 and factor 3 explained 27.14% and 11.92%, respectively. Using these variables 83.33% of the cross‐validated specimens were classified into distinct groups. Analysis of Molecular Variance (AMOVA) and pairwise Fst value for D‐loop region of mtDNA also showed high to medium level of genetic variation among the stocks and within the stocks. We conclude that the observed discrete stocks might be the result of changing environmental conditions in different rivers of the hotspot as the rivers are present at different altitudinal labels. It is also believed that the variation might be due to the construction of barrages across the river which hinder the mixing among the stocks. 相似文献
27.
Lucas R. Struble Audrey L. Smith William E. Lutz Gabrielle Grubbs Satish Sagar Kenneth W. Bayles Prakash Radhakrishnan Surender Khurana Dalia ElGamal Gloria E. O. Borgstahl 《Protein science : a publication of the Protein Society》2022,31(5)
The COVID‐19 pandemic caused by SARS‐CoV‐2 infection has led to socio‐economic shutdowns and the loss of over 5 million lives worldwide. There is a need for the identification of therapeutic targets to treat COVID‐19. SARS‐CoV‐2 spike is a target of interest for the development of therapeutic targets. We developed a robust SARS‐CoV‐2 S spike expression and purification protocol from insect cells and studied four recombinant SARS‐CoV‐2 spike protein constructs based on the original SARS‐CoV‐2 sequence using a baculovirus expression system: a spike protein receptor‐binding domain that includes the SD1 domain (RBD) coupled to a fluorescent tag (S‐RBD‐eGFP), spike ectodomain coupled to a fluorescent tag (S‐Ecto‐eGFP), spike ectodomain with six proline mutations and a foldon domain (S‐Ecto‐HexaPro(+F)), and spike ectodomain with six proline mutations without the foldon domain (S‐Ecto‐HexaPro(‐F)). We tested the yield of purified protein expressed from the insect cell lines Spodoptera frugiperda (Sf9) and Trichoplusia ni (Tni) and compared it to previous research using mammalian cell lines to determine changes in protein yield. We demonstrated quick and inexpensive production of functional glycosylated spike protein of high purity capable of recognizing and binding to the angiotensin converting enzyme 2 (ACE2) receptor. To further confirm functionality, we demonstrate binding of eGFP fused construct of the spike ectodomain (S‐Ecto‐eGFP) to surface ACE2 receptors on lung epithelial cells by flow cytometry analysis and show that it can be decreased by means of receptor manipulation (blockade or downregulation). 相似文献
28.
Sridhar R Perumal PT Etti S Shanmugam G Ponnuswamy MN Prabavathy VR Mathivanan N 《Bioorganic & medicinal chemistry letters》2004,14(24):6035-6040
In a SAR study, we have synthesized a few 1H-pyrazole carboxylate related microbicides using Vilsmeier reagent. The anti-microbial screening results of 1H-pyrazole-3-carboxylate are reported here for the first time. The effect of 1H-pyrazole carboxylates on the mycelial growth of plant pathogenic fungi is revealed. The first X-ray structure in the family of microbicidal 1H-pyrazole-4-carboxylates is presented. 相似文献
29.
Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain 总被引:7,自引:0,他引:7
Mammalian cells control their membrane composition by regulating the vesicular transport of membrane-bound sterol regulatory element binding proteins (SREBPs) from endoplasmic reticulum (ER) to Golgi. Transport is blocked by cholesterol, which triggers SCAP, the SREBP escort protein, to bind to Insigs, which are ER retention proteins. The cholesterol trigger mechanism is unknown. Using recombinant SCAP purified in detergent, we show that cholesterol acts by binding with high affinity and specificity to the 767 amino acid octahelical membrane region of SCAP. This octahelical region contains a conserved pentahelical sterol-sensing domain found in six other polytopic membrane proteins. We show that the membrane domain of SCAP is a tetramer and that cholesterol binding is inhibited by cationic amphiphiles, raising the possibility of allosteric regulation by positively charged phospholipids. The current studies show that cells control their cholesterol content through receptor-ligand interactions and not through changes in the physical properties of the membrane. 相似文献
30.
Vijai J Kapoor A Ravishankar HM Cherian PJ Girija AS Rajendran B Rangan G Jayalakshmi S Mohandas S Radhakrishnan K Anand A 《Human genetics》2003,113(5):461-463
Juvenile myoclonic epilepsy (JME) is a common subtype of idiopathic generalized epilepsy that shows a complex pattern of inheritance. We have tested the association between JME phenotype and an intragenic marker in KCNQ3 by using the transmission disequilibrium test in 119 probands and their parents. Mutations in KCNQ3 are known to cause benign familial neonatal convulsions and are involved in the physiologically important M current in neurons. Our results provide suggestive evidence of allelic association between JME and KCNQ3 (P-value=0.008) and raise an interesting possibility of a genetic contribution to JME, viz., of a gene that causes a monogenic form of human epilepsy. 相似文献