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221.
Christopher R Brown Swati Gupta June Qin Timothy Racie Guo He Scott Lentini Ryan Malone Mikyung Yu Shigeo Matsuda Svetlana Shulga-Morskaya Anil V Nair Christopher S Theile Karyn Schmidt Azar Shahraz Varun Goel Rubina G Parmar Ivan Zlatev Mark K Schlegel Jayaprakash K Nair Muthusamy Jayaraman Muthiah Manoharan Dennis Brown Martin A Maier Vasant Jadhav 《Nucleic acids research》2020,48(21):11827
One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly generated Argonaute 2 protein complexes weeks after dosing, enabling continuous RNAi activity over time. Identical siRNAs delivered in lipid nanoparticles or as GalNAc conjugates were dose-adjusted to achieve similar knockdown, but only GalNAc–siRNAs supported an extended duration of activity, illustrating the importance of receptor-mediated siRNA trafficking in the process. Taken together, we provide several lines of evidence that acidic intracellular compartments serve as a long-term depot for GalNAc–siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo. 相似文献
222.
223.
Anton Simeonov Avanti Kulkarni Dorjbal Dorjsuren Ajit Jadhav Min Shen Daniel R. McNeill Christopher P. Austin David M. Wilson III 《PloS one》2009,4(6)
APE1 is the major nuclease for excising abasic (AP) sites and particular 3′-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC1280), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays – a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen – and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals. 相似文献
224.
Anuradha N. Kagalkar Umesh B. Jagtap Jyoti P. Jadhav Sanjay P. Govindwar Vishwas A. Bapat 《Planta》2010,232(1):271-285
In vitro culture plants of Typhonium flagelliforme were found to decolorize a variety of dyes, including Malachite Green, Red HE 8B, Methyl Orange, Reactive Red 2, Direct Red
5B (DR5B), Red HE 7B, Golden Yellow HER, Patent Blue, and Brilliant Blue R (BBR), to varying extents within 4 days. The enzymatic
analysis of plant roots of aseptically raised plantlets performed before and after degradation of the dye BBR by these plantlets
showed a significant induction in the activities of peroxidase, laccase, tyrosinase, and 2,6-dichlorophenol-indophenol reductase,
which indicated the involvement of these enzymes in the metabolism of the dye. Comparative study of the enzyme status of the
plants Typhonium flagelliforme and Blumea malcolmii during the degradation of DR5B and BBR showed marked variations in the enzyme profile with respect to the use of different
sources of the enzyme. Phytoremediation of BBR using Typhonium flagelliforme was confirmed with high performance liquid chromatography and Fourier transform infrared spectroscopy analysis performed
before and after the degradation of the dye. One of the products of the metabolism of the dye was identified as 4-(4-ethylimino-cyclohexa-2,5-dienylidinemethyl)-phenylamine
with the aid of gas chromatography–mass spectroscopy (GC–MS) analysis. Significant decrease in the American Dye Manufacturer’s
Institute, biological oxygen demand, and chemical oxygen demand values of synthetic mixture of textile dyes and industrial
effluent confirmed the decolorization and detoxification. Phytotoxicity studies also revealed the nontoxic nature of the metabolites
of BBR. 相似文献
225.
Priya Iyer Abhishek Shukla Vivek Jadhav Bikash Kumar Sahoo 《Evolution; international journal of organic evolution》2020,74(6):1018-1032
We reexamine the influential parental investment hypothesis proposed by Trivers for the causal relationship between anisogamy and widespread female-biased parental care. We build self-consistent versions of Maynard Smith's simple evolutionary game between males and females over parental care, and incorporate consequences of anisogamy for gamete production and its trade-off with parental care, and for patterns of mate limitation. As male mating opportunities are limited by females, frequency-dependent selection acts on male strategies. Assuming synchrony of matings in the population, our analytical models find either symmetric sex roles or male-biased care as an evolutionarily stable strategy (ESS), in contrast to Trivers' hypothesis. We simulate evolution in asynchronously mating populations and find that diverse parental roles, including female care, can be ESS depending on the parameters. When caring males can also remate, or when females can increase the clutch size by deserting, there is stronger selection for male-biased care. Hence, we argue that the mating-caring trade-off for males is neither a necessary consequence of anisogamy nor sufficient to select for female-biased care. Instead, the factors excluded from our models—costly competitive traits, sexual selection, and partial parentage—may be necessary for the parental investment hypothesis to work. 相似文献
226.
Low Level Lead Exposure Decreases In Vivo Release of Dopamine in the Rat Nucleus Accumbens: A Microdialysis Study 总被引:1,自引:0,他引:1
Abstract: The basal and K+ -induced release of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were measured in microdialysate samples obtained in vivo from the nucleus accumbens region of rats subchronically exposed to 50 ppm lead for 90 days. The basal and stimulus-induced release of dopamine and the metabolites were significantly reduced in the lead-exposed rats as compared with the controls. These reductions in dopamine and its metabolites are consistent with the reports of decreased dopamine availability associated with lead-induced changes in certain behavioral indices (fixed-interval performance) in rats. Furthermore, these changes were observed at blood lead levels similar to those considered to cause impairment in cognitive functions in children. 相似文献
227.
Sarah H. Felix Kedar G. Shah Vanessa M. Tolosa Heeral J. Sheth Angela C. Tooker Terri L. Delima Shantanu P. Jadhav Loren M. Frank Satinderpall S. Pannu 《Journal of visualized experiments : JoVE》2013,(79)
Microelectrode arrays for neural interface devices that are made of biocompatible thin-film polymer are expected to have extended functional lifetime because the flexible material may minimize adverse tissue response caused by micromotion. However, their flexibility prevents them from being accurately inserted into neural tissue. This article demonstrates a method to temporarily attach a flexible microelectrode probe to a rigid stiffener using biodissolvable polyethylene glycol (PEG) to facilitate precise, surgical insertion of the probe. A unique stiffener design allows for uniform distribution of the PEG adhesive along the length of the probe. Flip-chip bonding, a common tool used in microelectronics packaging, enables accurate and repeatable alignment and attachment of the probe to the stiffener. The probe and stiffener are surgically implanted together, then the PEG is allowed to dissolve so that the stiffener can be extracted leaving the probe in place. Finally, an in vitro test method is used to evaluate stiffener extraction in an agarose gel model of brain tissue. This approach to implantation has proven particularly advantageous for longer flexible probes (>3 mm). It also provides a feasible method to implant dual-sided flexible probes. To date, the technique has been used to obtain various in vivo recording data from the rat cortex. 相似文献
228.
Kamaleshwar P. Singh Amit L. Mahendra Vibha Jayaraj Pramod P. Wangikar Sameer Jadhav 《Journal of industrial microbiology & biotechnology》2013,40(2):235-244
Secondary metabolites such as antibiotics are typically produced by actinomycetes as a response to growth limiting stress conditions. Several studies have shown that secondary metabolite production is correlated with changes observed in actinomycete pellet morphology. Therefore, we investigated the correlation between the production of balhimycin and the spatio-temporal distribution of live and dead cells in pellets of Amycolatopsis balhimycina in submerged cultures. To this end, we used laser scanning confocal microscopy to analyze pellets from balhimycin producing and nonproducing media containing 0.2 and 1.0 g l?1 of potassium di-hydrogen phosphate, respectively. We observed a substantially higher fraction of live cells in pellets from cultures yielding larger amounts of balhimycin. Moreover, in media that resulted in no balhimycin production, the pellets exhibit an initial death phase which commences from the centre of the pellet and extends in the radial direction. A second growth phase was observed in these pellets, where live mycelia are seen to appear in the dead core of the pellets. This secondary growth was absent in pellets from media producing higher amounts of balhimycin. These results suggest that distribution of live and dead cells and its correlation with antibiotic production in the non-sporulating A. balhimycina differs markedly than that observed in Streptomycetes. 相似文献
229.
Suhail B. Noolkar Namdeo R. Jadhav Santosh A. Bhende Suresh G. Killedar 《AAPS PharmSciTech》2013,14(2):569-577
The effect of ternary solid dispersions of poor water-soluble NSAID meloxicam with moringa coagulant (obtained by salt extraction of moringa seeds) and polyvinylpyrrolidone on the in vitro dissolution properties has been investigated. Binary (meloxicam–moringa and meloxicam–polyvinylpyrrolidone (PVP)) and ternary (meloxicam–moringa–PVP) systems were prepared by physical kneading and ball milling and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry. The in vitro dissolution behavior of meloxicam from the different products was evaluated by means of United States Pharmacopeia type II dissolution apparatus. The results of solid-state studies indicated the presence of strong interactions between meloxicam, moringa, and PVP which were of totally amorphous nature. All ternary combinations were significantly more effective than the corresponding binary systems in improving the dissolution rate of meloxicam. The best performance in this respect was given by the ternary combination employing meloxicam–moringa–PVP ratio of [1:(3:1)] prepared by ball milling, with about six times increase in percent dissolution rate, whereas meloxicam–moringa (1:3) and meloxicam–PVP (1:4) prepared by ball milling improved dissolution of meloxicam by almost 3- and 2.5-folds, respectively. The achieved excellent dissolution enhancement of meloxicam in the ternary systems was attributed to the combined effects of impartation of hydrophilic characteristic by PVP, as well as to the synergistic interaction between moringa and PVP. 相似文献
230.
Purification and characterization of dye degrading of veratryl alcohol oxidase from Pseudomonas aeruginosa strain BCH 总被引:1,自引:0,他引:1
Phugare Swapnil S. Waghmare Shailesh R. Jadhav Jyoti P. 《World journal of microbiology & biotechnology》2011,27(10):2415-2423
In the present study we have purified the intracellular veratryl alcohol oxidase (VAO) enzyme from Pseudomonas aeruginosa strain BCH to evaluate its dye decolorizing potential. The enzyme was purified by ion exchange chromatography using DEAE
cellulose followed by gel filtration chromatography using Biogel P-100. The molecular weight of the purified enzyme was estimated
by polyacrylamide gel electrophoresis (PAGE) analysis. The VAO was purified up to 12 and 16.3-fold by ion exchange and gel
filtration chromatography respectively. VAO was estimated to be about 85 kDa by SDS–PAGE. The optimum pH and temperature for
purified VAO was 3 and 55°C respectively. The purified enzyme exerted its optimal activity with veratryl alcohol and also
oxidized various other substrates, whereas diminished activity was noted in case of tryptophan and xylidine. The metal ions
Mn++ and Hg++ were found to suppress the oxidase activity. The purified enzyme decolorized different dyes with variable decolorization
rates and efficiencies. Decolorization mechanism of Remazol Black by purified enzyme was studies in detail using various analytical
techniques like HPLC, GC–MS and FTIR. This study is useful for understanding the precise role of Pseudomonas aeruginosa strain BCH in the decolorization of textile dyes containing industrial wastewater. 相似文献