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991.
Dong Xiao Cheng Wang Anandan Palani Hon-Chung Tsui Gregory Reichard Sunil Paliwal Neng-Yang Shih Robert Aslanian Ruth Duffy Jean Lachowicz Geoffrey Varty Cynthia Morgan Fei Liu Amin Nomeir 《Bioorganic & medicinal chemistry letters》2010,20(21):6313-6315
Modification of prototype NK1 antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK1 antagonists. 相似文献
992.
Shukla NM Mutz CA Ukani R Warshakoon HJ Moore DS David SA 《Bioorganic & medicinal chemistry letters》2010,20(22):6384-6386
Toll-like receptor (TLR)-7 agonists show prominent immunostimulatory activities. The synthesis of a TLR7-active N(1)-(4-aminomethyl)benzyl substituted imidazoquinoline 5d served as a convenient precursor for the covalent attachment of fluorophores without significant loss of activity. Fluorescence microscopy experiments show that the fluorescent analogues are internalized and distributed in the endosomal compartment. Flow cytometry experiments using whole human blood show differential partitioning into B, T, and natural killer (NK) lymphocytic subsets, which correlate with the degree of activation in these subsets. These fluorescently-labeled imidazoquinolines will likely be useful in examining the trafficking of TLR7 in immunological synapses. 相似文献
993.
Improved methods of cell culture from eye stalk, hepatopancreas, muscle, ovary, and hemocytes of shrimp (Penaeus vannamei) were established using synthetic media and shrimp muscle extract (SME). For hemocytes and ovarian cell cultures, Grace’s
insect medium supplemented with 10% (v/v) fetal bovine serum and 10% SME (v/v) showed enhanced attachment and proliferation of the cells. The hemocyte and ovarian cell cultures could be maintained for
48 and 66 days, respectively, and have been sub-cultured four and six times, respectively. Both ovary and hemocyte cell cultures
contained primarily epithelial-like cells. Cells derived from ovary tissue grew preferably between 26°C and 28°C with 5% CO2. Although the temperature preference of hemocyte cells was the same as ovarian cells, CO2 supplementation did not show any difference in the growth of hemocyte cells. When the shrimp were injected with lipopolysaccharide
(8 μg/g of shrimp) and hemolymph was drawn 24 h post-injection, the in vitro multiplicity of hemocytes dramatically improved. The growth of eye stalk, hepatopancreas, and muscle-derived cells was much
less compared to ovarian cells and hemocytes under the conditions described above. The optimal culture conditions for ovarian
cells and hemocytes were also different from that for eye stalk, hepatopancreas, and muscle cell culture. The proliferation
efficiencies of primary cultures of hepatopancreas, eyestalk, and muscle cells were about 30, 12, and <7 d, respectively.
The improved culture conditions described here, particularly for hemocytes and ovary, will be very useful for in vitro studies involving viruses infecting shrimp and in shrimp genomic studies. 相似文献
994.
Chhatre S Francis R Bracewell DG Titchener-Hooker NJ 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(30):3067-3075
The demands on the biopharmaceutical sector to expedite process development have instigated the deployment of micro-biochemical engineering techniques to acquire manufacturing insight with extremely small sample volumes. In conjunction with automated liquid handlers, this permits the simultaneous evaluation of multiple operating conditions and reduces manual intervention. For these benefits to be sustained, novel ways are now required to accelerate analysis and so prevent this becoming a throughput bottleneck. For example, although Protein G HPLC is used to quantify antibody titres in bioprocess feedstocks, it can be time-consuming owing to the serial nature of its application. Although commercial options are available that can process many samples simultaneously, these require separate, potentially expensive instruments. A more integrated approach is desirable wherein the assay is implemented directly on a robot. This article describes a high-throughput alternative to antibody HPLC analysis which uses an eight-channel liquid handler to control pipette tips packed with 40 μL of Protein G affinity matrix. The linearity, range, limit of detection, specificity and precision of the method were established, with results showing that antibody was detected reliably and specifically between 0.10 and 1.00 mg/mL. Subsequently, the technique was used to quantify the antibody titre in ovine serum, which is used as feed material by BTG PLC for manufacturing FDA-approved polyclonal bio-therapeutics. The mean concentration determined by the tips was comparable to that found by HPLC, but the tip method delivered its results in less than 40% of the time and with the potential for further, substantial time-savings possible by using higher capacity robots. 相似文献
995.
Mobashar Hussain Urf Turabe Fazil Sunil Kumar Naidu Subbarao Haushila Prasad Pandey Durg Vijai Singh 《Journal of molecular modeling》2010,16(5):1003-1009
Aeromonas hydrophila has been implicated in extra-intestinal infection and diarrhoea in humans. Targetting unique effectors of bacterial pathogens
is considered a powerful strategy for drug design against bacterial variations to drug resistance. The two-component bacterial
system involving sensor histidine kinase (SHK) and its response regulators is considered a lucrative target for drug design.
This is the first report describing a three-dimensional (3D) structure for SHK of A. hydrophila. The model was constructed by homology modelling using the X-ray structure of PleD—a response regulator—in conjunction with
cdiGMP (PDB code 1W25) and HemAT sensor domain (PDB code 1OR4)—a globin coupled sensor. A combination of homology modelling
methodology and molecular dynamics (MD) simulations was applied to obtain a reasonable structure to understand the dynamic
behaviour of SHK. Homology modelling was performed using MODELLER9v2 software. The structure was relaxed to eliminate bad
atomic contacts. The final model obtained by molecular mechanics and dynamics methods was assessed using PROCHECK and VERIFY
3D graph, which confirmed that the final refined model is reliable. Until complete biochemical and structural data of SHK
are determined by experimental means, this model can serve as a valuable reference for characterising the protein and could
be explored for drug targetting by design of suitable inhibitors. 相似文献
996.
Manju Mamtani Tomoyo Matsubara Chisato Shimizu Susumu Furukawa Teiji Akagi Yoshihiro Onouchi Akira Hata Akihiro Fujino Weijing He Sunil K. Ahuja Jane C. Burns 《PloS one》2010,5(7)
Background
The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.Methodology/Principal Findings
We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., < or > four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR) = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071).Conclusions/Significance
The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG. 相似文献997.
998.
Carole Sourbier Vladimir Valera-Romero Alessio Giubellino Youfeng Yang Sunil Sudarshan Len Neckers W Marston Linehan 《Cell cycle (Georgetown, Tex.)》2010,9(20):4183-4189
Hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated renal tumors are aggressive and tend to metastasize early. There are currently no effective forms of therapy for patients with advanced HLRCC-associated kidney cancer. We have previously shown that HLRCC cells express a high level of reactive oxygen species (ROS). In the present study we investigated the cytotoxic-effects of increasing ROS level using bortezomib in combination with cisplatin on HLRCC cells in vitro and in an in vivo xenograft model. The cytotoxic effect of several ROS inducers on FH-deficient cells was assessed by synthetic lethality. ROS inducers had a pronounced impact on the viability of FH-deficient cells. Because of its high potency, the proteasome inhibitor bortezomib was further investigated. Bortezomib induced apoptosis in vitro in HLRCC cells and inhibited HLRCC tumor growth in vivo. Bortezomib-associated cytotoxicity was highly correlated with cellular ROS level: combining bortezomib with other ROS inducers enhanced cytotoxicity, while combining bortezomib with a ROS scavenger inhibited its cytotoxic effect. Finally, HLRCC murine xenografts were treated with bortezomib and cisplatin, another ROS inducer. This regimen induced HLRCC tumor regression in vivo. These findings suggest that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors.Key words: HLRCC, bortezomib, cisplatin, ROS, kidney cancer, FH 相似文献
999.
Sunil Suchindran David Rivedal John R. Guyton Tom Milledge Xiaoyi Gao Ashlee Benjamin Jennifer Rowell Geoffrey S. Ginsburg Jeanette J. McCarthy 《PLoS genetics》2010,6(4)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass. 相似文献
1000.