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121.
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
122.
Madhura Pradhan Charu Suri Sinjan Choudhary Pradeep Kumar Naik 《Journal of biomolecular structure & dynamics》2018,36(1):195-208
Beta-sitosterol (β-SITO), a phytosterol present in many edible vegetables, has been reported to possess antineoplastic properties and cancer treatment potential. We have shown previously that it binds at a unique site (the ‘SITO-site’) compared to the colchicine binding site at the interface of α- and β-tubulin. In this study, we investigated the anticancer efficacy of β-SITO against invasive breast carcinoma using MCF-7 cells. Since ‘isotypes’ of β-tubulin show tissue-specific expression and many are associated with cancer drug resistance, using computer-assisted docking and atomistic molecular dynamic simulations, we also examined its binding interactions to all known isotypes of β-tubulin in αβ-tubulin dimer. β-SITO inhibited MCF-7 cell viability by up to 50%, compared to vehicle-treated control cells. Indicating its antimetastatic potential, the phytosterol strongly inhibited cell migration. Immunofluorescence imaging of β-SITO-treated MCF-7 cells exhibited disruption of the microtubules and chromosome organization. Far-UV circular dichroism spectra indicated loss of helical stability in tubulin when bound to β-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that β-SITO preferentially binds with specific β-tubulin isotypes (βII and βIII) in the αβ-tubulin dimer. Both these β-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of β-SITO, and its potential clinical utility against βII and βIII isotype-overexpressing neoplasms. 相似文献
123.
D. Choudhary M. Srivastava A. Sarma R. K. Kale 《Radiation and environmental biophysics》1998,37(3):177-185
Cellular membranes are vital elements, and their integrity is extremely essential for the viability of the cells. We studied
the effects of high linear energy transfer (LET) radiation on the membranes. Rabbit erythrocytes (1×107 cells/ml) and microsomes (0.6 mg protein/ml) prepared from liver of rats were irradiated with 7Li ions of energy 6.42 MeV/u and 16O ions of energy 4.25 MeV/u having maximum LET values of 354 keV/μm and 1130 keV/μm, respectively. 7Li- and 16O-induced microsomal lipid peroxidation was found to increase with fluence. The 16O ions were more effective than 7Li ions, which could be due to the denser energy distribution in the track and the yield of free radicals. These findings
suggested that the biological membranes could be peroxidized on exposure to high-LET radiation. Inhibition of the lipid peroxidation
was observed in the presence of a membrane-active drug, chlorpromazine (CPZ), which could be due to scavenging of free radicals
(mainly HO⋅ and ROO⋅), electron donation, and hydrogen transfer reactions. The 7Li and 16O ions also induced hemolysis in erythrocytes. The extent of hemolysis was found to be a function of time and fluence, and
showed a characteristic sigmoidal pattern. The 16O ions were more effective in the lower fluence range than 7Li ions. These results were compared with lipid peroxidation and hemolysis induced by gamma-radiation.
Received: 10 March 1998 / Accepted in revised form: 6 July 1998 相似文献
124.
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
125.
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
126.
Mohd. Quadir Siddiqui Rajan Kumar Choudhary Pankaj Thapa Neha Kulkarni Yogendra S. Rajpurohit Hari S. Misra 《Journal of biomolecular structure & dynamics》2017,35(14):3032-3042
Fanconi anemia complementation groups – I (FANCI) protein facilitates DNA ICL (Inter-Cross-link) repair and plays a crucial role in genomic integrity. FANCI is a 1328 amino acids protein which contains armadillo (ARM) repeats and EDGE motif at the C-terminus. ARM repeats are functionally diverse and evolutionarily conserved domain that plays a pivotal role in protein–protein and protein–DNA interactions. Considering the importance of ARM repeats, we have explored comprehensive in silico and in vitro approach to examine folding pattern. Size exclusion chromatography, dynamic light scattering (DLS) and glutaraldehyde crosslinking studies suggest that FANCI ARM repeat exist as monomer as well as in oligomeric forms. Circular dichroism (CD) and fluorescence spectroscopy results demonstrate that protein has predominantly α- helices and well-folded tertiary structure. DNA binding was analysed using electrophoretic mobility shift assay by autoradiography. Temperature-dependent CD, Fluorescence spectroscopy and DLS studies concluded that protein unfolds and start forming oligomer from 30°C. The existence of stable portion within FANCI ARM repeat was examined using limited proteolysis and mass spectrometry. The normal mode analysis, molecular dynamics and principal component analysis demonstrated that helix-turn-helix (HTH) motif present in ARM repeat is highly dynamic and has anti-correlated motion. Furthermore, FANCI ARM repeat has HTH structural motif which binds to double-stranded DNA. 相似文献
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129.
Summary: Accurate estimation of DNA copy numbers from arraycomparative genomic hybridization (CGH) data is important forcharacterizing the cancer genome. An important part of thisprocess is the segmentation of the log-ratios between the sampleand control DNA along the chromosome into regions of differentcopy numbers. However, multiple algorithms are available inthe literature for this procedure and the results can vary substantiallyamong these. Thus, a visualization tool that can display thesegmented profiles from a number of methods can be helpful tothe biologist or the clinician to ascertain that a feature ofinterest did not arise as an artifact of the algorithm. Sucha tool also allows the methodologist to easily contrast hismethod against others. We developed a web-based tool that applies a number of popularalgorithms to a single array CGH profile entered by the user.It generates a heatmap panel of the segmented profiles for eachmethod as well as a consensus profile. The clickable heatmapcan be moved along the chromosome and zoomed in or out. It alsodisplays the time that each algorithm took and provides numericalvalues of the segmented profiles for download. The web interfacecalls algorithms written in the statistical language R. We encouragedevelopers of new algorithms to submit their routines to beincorporated into the website. Availability: http://compbio.med.harvard.edu/CGHweb Contact: peter_park{at}harvard.edu
Associate Editor: Keith Crandall 相似文献
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