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991.
Cowley PM Baker J Barn DR Buchanan KI Carlyle I Clark JK Clarkson TR Deehan M Edwards D Goodwin RR Jaap D Kiyoi Y Mort C Palin R Prosser A Walker G Ward N Wishart G Young T 《Bioorganic & medicinal chemistry letters》2011,21(1):497-501
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist. 相似文献
992.
Wang GZ Haile PA Daniel T Belot B Viet AQ Goodman KB Sha D Dowdell SE Varga N Hong X Chakravorty S Webb C Cornejo C Olzinski A Bernard R Evans C Emmons A Briand J Chung CW Quek R Lee D Gough PJ Sehon CA 《Bioorganic & medicinal chemistry letters》2011,21(24):7291-7294
A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood. 相似文献
993.
Ihmaid S Al-Rawi J Bradley C Angove MJ Robertson MN Clark RL 《Bioorganic & medicinal chemistry》2011,19(13):3983-3994
A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity. 相似文献
994.
Zhou Q Stefano JE Harrahy J Finn P Avila L Kyazike J Wei R Van Patten SM Gotschall R Zheng X Zhu Y Edmunds T Pan CQ 《Bioconjugate chemistry》2011,22(4):741-751
Engineering proteins for selective tissue targeting can improve therapeutic efficacy and reduce undesired side effects. The relatively high dose of recombinant human acid α-glucosidase (rhGAA) required for enzyme replacement therapy of Pompe disease may be attributed to less than optimal muscle uptake via the cation-independent mannose 6-phosphate receptor (CI-MPR). To improve muscle targeting, Zhu et al. (1) conjugated periodate oxidized rhGAA with bis mannose 6-phosphate bearing synthetic glycans and achieved 5-fold greater potency in a murine Pompe efficacy model. In the current study, we systematically evaluated multiple strategies for conjugation based on a structural homology model of GAA. Glycan derivatives containing succinimide, hydrazide, and aminooxy linkers targeting free cysteine, lysines, and N-linked glycosylation sites on rhGAA were prepared and evaluated in vitro and in vivo. A novel conjugation method using enzymatic oxidation was developed to eliminate side oxidation of methionine. Conjugates derived from periodate oxidized rhGAA still displayed the greatest potency in the murine Pompe model. The efficiency of conjugation and its effect on catalytic activity were consistent with predictions based on the structural model and supported its use in guiding selection of appropriate chemistries. 相似文献
995.
Our previous work suggested that treatment of cells with hyperosmotic media during 2D passaging primes cells for cartilage tissue engineering applications. Here, we used label-free proteomic profiling to evaluate the effects of control and hyperosmotic treatment environments on the phenotype of multipotent adipose-derived stem cells (ASCs) cultivated with a chondrogenic growth factor cocktail. Spectra were recorded in a data-independent fashion at alternate low (precursor) and high (product) fragmentation voltages (MS(E)). This method was supplemented with data mining of accurate mass and retention time matches in precursor ion spectra across the experiment. The results indicated a complex cellular response to osmotic treatment, with a number of proteins differentially expressed between control and treated cell groups. The roles of some of these proteins have been documented in the literature as characteristic of the physiological states studied, especially aldose reductase (osmotic stress). This protein acted as a positive control in this work, providing independent corroborative validation. Other proteins, including 5'-nucleotidase and transgelin, have been previously linked to cell differentiation state. This study demonstrates that label-free profiling can serve as a useful tool in characterizing cellular responses to chondrogenic treatment regimes, recommending its use in optimization of cell priming protocols for cartilage tissue engineering. 相似文献
996.
997.
Review of Florida Red Tide and Human Health Effects 总被引:1,自引:0,他引:1
Fleming LE Kirkpatrick B Backer LC Walsh CJ Nierenberg K Clark J Reich A Hollenbeck J Benson J Cheng YS Naar J Pierce R Bourdelais AJ Abraham WM Kirkpatrick G Zaias J Wanner A Mendes E Shalat S Hoagland P Stephan W Bean J Watkins S Clarke T Byrne M Baden DG 《Harmful algae》2011,10(2):224-233
This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue-one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The Review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people. 相似文献
998.
Michael B. Clark Paulo P. Amaral Felix J. Schlesinger Marcel E. Dinger Ryan J. Taft John L. Rinn Chris P. Ponting Peter F. Stadler Kevin V. Morris Antonin Morillon Joel S. Rozowsky Mark B. Gerstein Claes Wahlestedt Yoshihide Hayashizaki Piero Carninci Thomas R. Gingeras John S. Mattick 《PLoS biology》2011,9(7)
999.
Yanyi Liu Michael Clark Qifeng Zhang Danmei Yu Dawei Liu Jun Liu Guozhong Cao 《Liver Transplantation》2011,1(2):194-202
Nanostructured V2O5 thin films have been prepared by means of cathodic deposition from an aqueous solution made from V2O5 and H2O2 directly on fluorine‐doped tin oxide coated (FTO) glasses followed by annealing at 500°C in air, and studied as film electrodes for lithium ion batteries. XPS results show that the as‐deposited films contained 15% V4+, however after annealing all the vanadium is oxidized to V5+. The crystallinity, surface morphology, and microstructures of the films have been investigated by means of XRD, SEM, and AFM. The V2O5 thin film electrodes show excellent electrochemical properties as cathodes for lithium ion intercalation: a high initial discharge capacity of 402 mA h g?1 and 240 mA h g?1 is retained after over 200 cycles with a discharging rate of 200 mA g?1 (1.3 C). The specific energy density is calculated as 900 W h kg?1 for the 1st cycle and 723 W h kg?1 for the 180th cycle when the films are tested at 200 mA g?1 (1.3 C). When discharge/charge is carried out at a high current density of 10.5 A g?1 (70 C), the thin film electrodes retain a good discharge capacity of 120 mA h g?1, and the specific power density is over 28 kW kg?1. 相似文献
1000.
Clark MJ Chen R Lam HY Karczewski KJ Chen R Euskirchen G Butte AJ Snyder M 《Nature biotechnology》2011,29(10):908-914
Whole exome sequencing by high-throughput sequencing of target-enriched genomic DNA (exome-seq) has become common in basic and translational research as a means of interrogating the interpretable part of the human genome at relatively low cost. We present a comparison of three major commercial exome sequencing platforms from Agilent, Illumina and Nimblegen applied to the same human blood sample. Our results suggest that the Nimblegen platform, which is the only one to use high-density overlapping baits, covers fewer genomic regions than the other platforms but requires the least amount of sequencing to sensitively detect small variants. Agilent and Illumina are able to detect a greater total number of variants with additional sequencing. Illumina captures untranslated regions, which are not targeted by the Nimblegen and Agilent platforms. We also compare exome sequencing and whole genome sequencing (WGS) of the same sample, demonstrating that exome sequencing can detect additional small variants missed by WGS. 相似文献