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111.
Jared Cumming Suresh Babu Ying Huang Carolyn Carrol Xia Chen Leonard Favreau William Greenlee Tao Guo Matthew Kennedy Reshma Kuvelkar Thuy Le Guoqing Li Nansie McHugh Peter Orth Lynne Ozgur Eric Parker Kurt Saionz Andrew Stamford Corey Strickland Dawit Tadesse Qi Zhang 《Bioorganic & medicinal chemistry letters》2010,20(9):2837-2842
With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ40 in transgenic mice with a single subcutaneous dose. 相似文献
112.
Xuefei Tan Richland W. Tester Gregory R. Luedtke Sarvajit Chakravarty Babu J. Mavunkel John J. Perumattam Qing Lu Imad Nashashibi Joon Jung Jie Hu Albert Liclican Ramona Almirez Jocelyn Tabora Vinh Tran Maureen Laney Daniel E. Levy Sundeep Dugar 《Bioorganic & medicinal chemistry letters》2010,20(3):828-831
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38α MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene. 相似文献
113.
T. Sreelatha A. Hymavathi J. Madhusudhana Murthy P.U. Rani J. Madhusudana Rao K. Suresh Babu 《Bioorganic & medicinal chemistry letters》2010,20(9):2974-2977
A bioassay-guided fractionation and chemical examination of chloroform extract of Plumbago capensis roots resulted in isolation and characterization of two new napthaquinone derivatives (4, 8) along with six known compounds (1–3, 5–7). Their structures were determined on the basis of extensive spectroscopic (IR, MS, 1D and 2D NMR) data analysis and by comparison with the literature data. All the compounds were tested for their mosquito larvicidal activity against fourth instar larvae of Aedes aegypti, and compared with that of rotenone. Among the tested compounds, isoshinanolone (3) and plumbagin (1) showed excellent toxicity with LC50 values of 1.26 and 5.43 μg/mL. New compound (8) displayed moderate toxicity against the tested mosquito species. 相似文献
114.
Bandamaravuri Kishore Babu S. S. Reddy Mukesh K. Yadav M. Sukumar Vijendra Mishra A. K. Saxena Dilip K. Arora 《Indian journal of microbiology》2010,50(2):199-204
Genetic diversity analysis of Macrophomina phaseolina isolates obtained from different host range and diverse geographical locations in India was carried out using RAPD fingerprinting.
Of the thirteen 10-mer random primers used, primer OPB-08 gave the maximum polymorphism and the UPGMA clustering could separate
50 isolates in to ten groups at more than 65% similarity level. The ten clusters correlated well with the geographical locations
with exceptions for isolates obtained from Eastern and Western Ghats. There was a segregation of isolates from these two geographical
locations in to two clusters thus, distributing 10 genotypes in to eight geographical locations. All the isolates M. phaseolina irrespective of their host and geographical origin, exhibited two representative monomorphic bands at 250 bp and 1 kb, presence
of these bands suggests that isolates might have evolved from a common ancestor but due to geographical isolation fallowed
by natural selection and genetic drift might have segregated in to subpopulations. Genetic similarity in the pathogenic population
reflects the dispersal of single lineage in all locations in India. 相似文献
115.
Selvaraj Michael Gomez N. Manikanda Boopathi S. Satheesh Kumar T. Ramasubramanian Zhu Chengsong P. Jeyaprakash A. Senthil R. Chandra Babu 《Acta Physiologiae Plantarum》2010,32(2):355-364
Drought is a major limitation for rice production in rainfed ecosystems. Identifying quantitative trait loci (QTLs) linked
to drought resistance provides opportunity to breed high yielding rice varieties suitable for drought-prone areas. Although
considerable efforts were made in mapping QTLs associated with drought-resistance traits in rice, most of the studies involved
indica × japonica crosses and hence, the drought-resistance alleles were contributed mostly by japonica ecotypes. It is desirable to look for genetic variation within indica ecotypes adapted to target environment (TE) as the alleles from japonica ecotype may not be expressed under lowland conditions. A subset of 250 recombinant inbred lines (RILs) of F8 generation derived from two indica rice lines (IR20 and Nootripathu) with contrasting drought-resistance traits were used to map the QTLs for morpho-physiological
and plant production traits under drought stress in the field in TE. A genetic linkage map was constructed using 101 polymorphic
PCR-based markers distributed over the 12 chromosomes covering a total length of 1,529 cM in 17 linkage groups with an average
distance of 15.1 cM. Composite interval mapping analysis identified 22 QTLs, which individually explained 4.8–32.2% of the
phenotypic variation. Consistent QTLs for drought-resistance traits were detected using locally adapted indica ecotypes, which may be useful for rainfed rice improvement. 相似文献
116.
Sudha Ananth Elangovan Gopal Babu Ellappan Vadivel Ganapathy 《Biochemical and biophysical research communications》2010,394(1):75-257
SMCT1 is a Na+-coupled monocarboxylate transporter expressed in a variety of tissues including kidney, thyroid, small intestine, colon, brain, and retina. We found recently that several non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of SMCT1. Here we evaluated the effect of diclofenac, also a NSAID, on SMCT1. SMCT1 cDNA was expressed heterologously in the human retinal pigment epithelial cell lines HRPE and ARPE-19, the human mammary epithelial cell line MCF7, and in Xenopus laevis oocytes. Transport was monitored by substrate uptake and substrate-induced currents. Na+-dependent uptake/current was considered as SMCT1 activity. The effect of diclofenac was evaluated for specificity, dose-response, and influence on transport kinetics. To study the specificity of the diclofenac effect, we evaluated the influence of this NSAID on the activity of several other cloned transporters in mammalian cells under identical conditions. In contrast to several NSAIDs that inhibited SMCT1, diclofenac stimulated SMCT1 when expressed in HRPE and ARPE-19 cells. The stimulation was marked, ranging from 2- to 5-fold depending on the concentration of diclofenac. The stimulation was associated with an increase in the maximal velocity of the transport system as well as with an increase in substrate affinity. The observed effect on SMCT1 was selective because the activity of several other cloned transporters, when expressed in HRPE cells and studied under identical conditions, was not affected by diclofenac. Interestingly, the stimulatory effect on SMCT1 observed in HRPE and ARPE-19 cells was not evident in MCF7 cells nor in the X. laevis expression system, indicating that SMCT1 was not the direct target for diclofenac. The RPE-specific effect suggests that the target of diclofenac that mediates the stimulatory effect is expressed in RPE cells but not in MCF7 cells or in X. laevis oocytes. Since SMCT1 is a concentrative transporter for metabolically important compounds such as pyruvate, lactate, β-hydroxybutyrate, and nicotinate, the stimulation of its activity by diclofenac in RPE cells has biological and clinical significance. 相似文献
117.
Mohan Babu Boggara 《Biophysical journal》2010,98(4):586-595
Using the potential of mean constrained force method, molecular dynamics simulations with atomistic details were performed to examine the partitioning and nature of interactions of two nonsteroidal antiinflammatory drugs, namely aspirin and ibuprofen, in bilayers of dipalmitoylphosphatidylcholine. Two charge states (neutral and anionic) of the drugs were simulated to understand the effect of protonation or pH on drug partitioning. Both drugs, irrespective of their charge state, were found to have high partition coefficients in the lipid bilayer from water. However, the values and trends of the free energy change and the location of the minima in the bilayer are seen to be influenced by the drug structure and charge state. In the context of the transport of the drugs through the bilayer, the charged forms were found to permeate fully hydrated in contrast to the neutral forms that permeate unhydrated. 相似文献
118.
119.
Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell 总被引:1,自引:0,他引:1
Bae J Mitsiades C Tai YT Bertheau R Shammas M Batchu RB Li C Catley L Prabhala R Anderson KC Munshi NC 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(12):7730-7737
The 90-kDa heat shock protein (Hsp90) plays an important role in conformational regulation of cellular proteins and thereby cellular signaling and function. As Hsp90 is considered a key component of immune function and its inhibition has become an important target for cancer therapy, we here evaluated the role of Hsp90 in human dendritic cell (DC) phenotype and function. Hsp90 inhibition significantly decreased cell surface expression of costimulatory (CD40, CD80, CD86), maturation (CD83), and MHC (HLA-A, B, C and HLA-DP, DQ, DR) markers in immature DC and mature DC and was associated with down-regulation of both RNA and intracellular protein expression. Importantly, Hsp90 inhibition significantly inhibited DC function. It decreased Ag uptake, processing, and presentation by immature DC, leading to reduced T cell proliferation in response to tetanus toxoid as a recall Ag. It also decreased the ability of mature DC to present Ag to T cells and secrete IL-12 as well as induce IFN-gamma secretion by allogeneic T cells. These data therefore demonstrate that Hsp90-mediated protein folding is required for DC function and, conversely, Hsp90 inhibition disrupts the DC function of significant relevance in the setting of clinical trials evaluating novel Hsp90 inhibitor therapy in cancer. 相似文献
120.
Kaur K Patel SR Patil P Jain M Khan SI Jacob MR Ganesan S Tekwani BL Jain R 《Bioorganic & medicinal chemistry》2007,15(2):915-930
We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development. 相似文献