全文获取类型
收费全文 | 1170篇 |
免费 | 60篇 |
国内免费 | 2篇 |
出版年
2023年 | 15篇 |
2022年 | 19篇 |
2021年 | 54篇 |
2020年 | 25篇 |
2019年 | 34篇 |
2018年 | 53篇 |
2017年 | 33篇 |
2016年 | 62篇 |
2015年 | 79篇 |
2014年 | 73篇 |
2013年 | 94篇 |
2012年 | 99篇 |
2011年 | 109篇 |
2010年 | 47篇 |
2009年 | 45篇 |
2008年 | 74篇 |
2007年 | 48篇 |
2006年 | 43篇 |
2005年 | 26篇 |
2004年 | 27篇 |
2003年 | 25篇 |
2002年 | 17篇 |
2001年 | 19篇 |
2000年 | 6篇 |
1999年 | 10篇 |
1998年 | 2篇 |
1997年 | 4篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 8篇 |
1990年 | 3篇 |
1989年 | 7篇 |
1988年 | 5篇 |
1987年 | 8篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 4篇 |
1982年 | 4篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1972年 | 1篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1968年 | 1篇 |
排序方式: 共有1232条查询结果,搜索用时 543 毫秒
51.
52.
Xabier Agirrezabala Ekaterina Samatova Meline Macher Marija Liutkute Manisankar Maiti David GilCarton Jiri Novacek Mikel Valle Marina V Rodnina 《The EMBO journal》2022,41(4)
Cellular proteins begin to fold as they emerge from the ribosome. The folding landscape of nascent chains is not only shaped by their amino acid sequence but also by the interactions with the ribosome. Here, we combine biophysical methods with cryo‐EM structure determination to show that folding of a β‐barrel protein begins with formation of a dynamic α‐helix inside the ribosome. As the growing peptide reaches the end of the tunnel, the N‐terminal part of the nascent chain refolds to a β‐hairpin structure that remains dynamic until its release from the ribosome. Contacts with the ribosome and structure of the peptidyl transferase center depend on nascent chain conformation. These results indicate that proteins may start out as α‐helices inside the tunnel and switch into their native folds only as they emerge from the ribosome. Moreover, the correlation of nascent chain conformations with reorientation of key residues of the ribosomal peptidyl‐transferase center suggest that protein folding could modulate ribosome activity. 相似文献
53.
Rance Nault Satabdi Saha Sudin Bhattacharya Jack Dodson Samiran Sinha Tapabrata Maiti Tim Zacharewski 《Nucleic acids research》2022,50(8):e48
The application of single-cell RNA sequencing (scRNAseq) for the evaluation of chemicals, drugs, and food contaminants presents the opportunity to consider cellular heterogeneity in pharmacological and toxicological responses. Current differential gene expression analysis (DGEA) methods focus primarily on two group comparisons, not multi-group dose–response study designs used in safety assessments. To benchmark DGEA methods for dose–response scRNAseq experiments, we proposed a multiplicity corrected Bayesian testing approach and compare it against 8 other methods including two frequentist fit-for-purpose tests using simulated and experimental data. Our Bayesian test method outperformed all other tests for a broad range of accuracy metrics including control of false positive error rates. Most notable, the fit-for-purpose and standard multiple group DGEA methods were superior to the two group scRNAseq methods for dose–response study designs. Collectively, our benchmarking of DGEA methods demonstrates the importance in considering study design when determining the most appropriate test methods. 相似文献
54.
Maiti K Li JH Wang AF Acharjee S Kim WP Im WB Kwon HB Seong JY 《Molecules and cells》2003,16(2):173-179
Recently, we identified three types of non-mammalian gonadotropin-releasing hormone receptors (GnRHR) in the bullfrog (designated bfGnRHR-1-3), and a mammalian type-II GnRHR in green monkey cell lines (denoted gmGnRHR-2). All these receptors responded better to GnRH-II than GnRH-I, while mammalian type-I GnRHR showed greater sensitivity to GnRH-I than GnRH-II. In the present study, we designed new GnRH-II analogs and examined whether they activated or inhibited non-mammalian and mammalian type-II GnRHRs. [D-Ala6]GnRH-II, with D-Ala substituted for Gly6 in GnRH-II, increased inositol phosphate (IP) production in cells stably expressing non-mammalian GnRHRs more effectively than native GnRH-II. However, it exhibited lower activity for mammalian type-I GnRHR than GnRH-I itself. Trptorelix-1, a GnRH-II antagonist, inhibited GnRH-induced IP production in cells expressing non-mammalian GnRHRs more effectively than Cetrorelix, a GnRH-I antagonist. Trptorelix-1, however, had lower potency for mammalian type-I GnRHR than Cetrorelix. Ligand-receptor binding assays revealed that [D-Ala6]GnRH-II and Trptorelix-1 have higher affinities for non-mammalian GnRHRs but lower affinities for mammalian type-I GnRHR than GnRH-II and Cetrorelix, respectively. Moreover, [D-Ala6]GnRH-II and Trptorelix-1 had a higher affinity for gmGnRHR-2 than GnRH-II and Cetrorelix, respectively. These results indicate that [D-Ala6]GnRH-II and Trptorelix-1 are highly effective agonist and antagonist, respectively, for non-mammalian and type-II mammalian GnRHRs. 相似文献
55.
Maiti S Chaudhury NK Chowdhury S 《Biochemical and biophysical research communications》2003,310(2):505-512
In vitro binding of Hoechst 33258 to the promoter region of human c-myc, d(GG GGAGGG TGG GGA GGG TGG GGA AGG TGG GG) which forms G-quadruplex, both in vitro and in vivo in the presence of metal ions, was investigated by equilibrium absorption, fluorescence, and kinetic surface plasmon resonance methods. Hypochromic effect in UV absorption spectra and blue shift in fluorescence emission maxima of Hoechst in the presence of quadruplex revealed that Hoechst binds to the quadruplex. Analysis of UV and fluorescence titration data revealed that Hoechst binds to quadruplex with binding affinity of the order of 10(6). Anisotropy measurements and higher lifetime obtained from time-resolved decay experiments revealed that quadruplex-bound Hoechst is rotationally restricted in a less polar environment than the bulk buffer medium. From surface plasmon resonance studies, we obtained kinetic association (k(a)) and dissociation (k(d)) of 1.23+/-0.04 x 10(5)M(-1)s(-1) and 0.686+/-0.009 s(-1), respectively. As Hoechst is known to bind A-T-rich region of duplex DNA, here we propose the likelihood of Hoechst interacting with the AAGGT loop of the quadruplex. 相似文献
56.
Effect of green tea polyphenols on angiogenesis induced by an angiogenin-like protein 总被引:2,自引:0,他引:2
Maiti TK Chatterjee J Dasgupta S 《Biochemical and biophysical research communications》2003,308(1):64-67
Angiogenesis is a fundamental process by which new blood vessels are formed. The angiogenesis process is induced by several growth factors. Among them angiogenin is the most potent blood vessel inducer known. In this paper, we have investigated the effect of green tea polyphenols, mainly the catechins, on an angiogenin-like protein induced angiogenesis process. The angiogenin-like protein was isolated from goat serum and the effect of green tea components was tested by the chicken chorioallantoic membrane (CAM) assay. The results show that green tea components are capable of reducing the vascularization on CAM that is induced by the angiogenin-like protein. 相似文献
57.
RPE65 operates in the vertebrate visual cycle by stereospecifically binding all-trans-retinyl esters
RPE65 is a major protein of unknown function found associated with the retinyl pigment epithelial (RPE) membranes [Hamel, C. P., Tsilou, E., Pfeffer, B. A., Hooks, J. J., Detrick, B., and Redmond, T. M. (1993) J. Biol. Chem. 268, 15751-15757; Bavik, C. O., Levy, F., Hellman, U., Wernstedt, C., and Eriksson, U. (1993) J. Biol. Chem. 268, 20540-20546]. RPE65 knockouts fail to synthesize 11-cis-retinal, the chromophore of rhodopsin, and accumulate all-trans-retinyl esters in the RPE. Previous studies have also shown that RPE65 is specifically labeled with all-trans-retinyl ester based affinity labeling agents, suggesting a retinyl ester binding role for the protein. In the present work, we show that purified RPE65 binds all-trans-retinyl palmitate (tRP) with a K(D) = 20 pM. These quantitative experiments are performed by measuring the quenching of RPE65 fluorescence by added tRP. The binding for tRP is highly specific because 11-cis-retinyl palmitate binds with a K(D) = 14 nM, 11-cis-retinol binds with a K(D) = 3.8 nM, and all-trans-retinol (vitamin A) binds with a K(D) = 10.8 nM. This stereospecificity for tRP is to be compared to the binding of retinoids to BSA, where virtually no discrimination is found in the binding of the same retinoids. This work provides further evidence that RPE65 functions by binding to and mobilizing the highly hydrophobic all-trans-retinyl esters, allowing them to enter the visual cycle. 相似文献
58.
The amyloid beta peptide (Abeta(1-40)) is thermodynamically soluble at physiological concentrations 总被引:2,自引:0,他引:2
Precipitation of the 39-43-residue amyloid beta peptide (Abeta) is a crucial factor in Alzheimer's disease (AD). In normal as well as in AD-afflicted brain, the Abeta concentration is estimated to be a few nanomolar. Here we show that Abeta(1-40) precipitates in vitro only if the dissolved concentration is >14 microM. Using fluorescence correlation spectroscopy, we further show that the precipitation is complete in 1 day, after which the size distribution of Abeta monomer/oligomers in the solution phase becomes stationary in time and independent of the starting Abeta concentration. Mass spectra confirm that both the solution phase and the coexisting precipitate contain chemically identical Abeta molecules. Incubation at 68 degrees C for 1 h reduces the solubility by <12%. Together, these results show that the thermodynamic saturation concentration (C(sat)) of Abeta(1-40) in phosphate-buffered saline (PBS) at pH 7.4 has a well-defined lower limit of 15.5 +/- 1 microM. Divalent metal ions (believed to play a role in AD) at near-saturation concentrations in PBS reduce C(sat) only marginally (2 mM Mg(2+) by 6%, 2.5 microM Ca(2+) by 7%, and 4 microM Zn(2+) by 11%). Given that no precipitation is possible at concentrations below C(sat), we infer that coprecipitant(s), and not properties of Abeta(1-40) alone, are key factors in the in vivo aggregation of Abeta. 相似文献
59.
Maiti M Das S Sen A Das A Kumar GS Nandi R 《Journal of biomolecular structure & dynamics》2002,20(3):455-464
Sanguinarine exhibits pH dependent structural equilibrium between iminium form (structure I) and alkanolamine form (structure II) with a pKa of 7.4 as revealed from spectrophotometric titration. The titration data show that the compound exists almost exclusively as structure I and structure II in the pH range 1 to 6 and 8.5 to 11, respectively. The interaction of structure I and structure II to several B-form natural and synthetic double and single stranded DNAs has been studied by spectrophotometric, spectrofluorimetric and circular dichroic measurements in buffers of pH 5.2 and pH 10.4 where the physicochemical properties of DNA remain in B-form structure. The results show that structure I bind strongly to all B-form DNA structures showing typical hypochromism and bathochromism of the alkaloid's absorption maximum, quenching of steady-state fluorescence intensity and perturbations in circular dichroic spectrum. The structure II does not bind to DNA, but in presence of large amount of DNA significant population of structure I is generated, which binds to DNA and forms a structure I-DNA intercalated complex. The nature and magnitude of the spectral pattern are very much dependent on the structure as well as base composition of each DNA. The generation of the structure I from structure II is significantly affected by increasing ionic strength of the medium. The conversion of structure II to structure I in presence of high concentration of DNA in solution is explained through formation of a binding equilibrium process between structure II and structure I-DNA intercalated complex. 相似文献
60.
We previously demonstrated the presence of three distinct types of the gonadotropin-releasing hormone receptor (GnRHR) in a bullfrog (denoted bfGnRHR-1, bfGnRHR-2, and bfGnRHR-3). The bfGnRHRs exhibited differential tissue distribution and ligand selectivity. In the present study, we demonstrated the desensitization and internalization kinetics of these receptors in both transiently-transfected HEK293 cells and retrovirus-mediated stable cells. The time-course accumulation of the inositol phosphate in response to GnRH revealed that bfGnRHR-1 and -2 were rapidly desensitized, whereas bfGnRHR-3 was slowly desensitized. A comparison of the internalization kinetics revealed the most rapid rate and highest extent of internalization of bfGnRHR-2 among the three receptors. Interestingly, the mechanisms that underlie the receptor internalization appear to differ from each other. Internalization of bfGnRHR-1 was dependent on both dynamin and beta-arrestin, whereas those of bfGnRHR-2 and -3 were dependent on dynamin, but not on arrestin. These results, therefore, suggest that differential regulatory mechanisms for desensitization and internalization of the GnRHR are involved in diverse cellular and physiological responses to GnRH stimulation. 相似文献