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111.
Robichaud J Fournier JF Gagné S Gauthier JY Hamel M Han Y Hénault M Kargman S Levesque JF Mamane Y Mancini J Morin N Mulrooney E Wu J Black WC 《Bioorganic & medicinal chemistry letters》2011,21(14):4366-4368
Our series of competitive antagonists against the G-protein coupled receptor P2Y14 were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile. 相似文献
112.
113.
Tan JC Miller BA Tan A Patel JJ Cheeseman IH Anderson TJ Manske M Maslen G Kwiatkowski DP Ferdig MT 《Genome biology》2011,12(4):R35
We present an optimized probe design for copy number variation (CNV) and SNP genotyping in the Plasmodium falciparum genome. We demonstrate that variable length and isothermal probes are superior to static length probes. We show that sample
preparation and hybridization conditions mitigate the effects of host DNA contamination in field samples. The microarray and
workflow presented can be used to identify CNVs and SNPs with 95% accuracy in a single hybridization, in field samples containing
up to 92% human DNA contamination. 相似文献
114.
Phosphatidylethanolamine N-methyltransferase (PEMT) is a liver-specific enzyme that converts phosphatidylethanolamine to phosphatidylcholine (PC). Mice that lack PEMT have reduced plasma levels of PC and cholesterol in high density lipoproteins (HDL). We have investigated the mechanism responsible for this reduction with experiments designed to distinguish between a decreased formation of HDL particles by hepatocytes or an increased hepatic uptake of HDL lipids. Therefore, we analyzed lipid efflux to apoA-I and HDL lipid uptake using primary cultured hepatocytes isolated from Pemt(+/+) and Pemt(-/-) mice. Hepatic levels of the ATP-binding cassette transporter A1 are not significantly different between Pemt genotypes. Moreover, hepatocytes isolated from Pemt(-/-) mice released cholesterol and PC into the medium as efficiently as did hepatocytes from Pemt(+/+) mice. Immunoblotting of liver homogenates showed a 1.5-fold increase in the amount of the scavenger receptor, class B, type 1 (SR-BI) in Pemt(-/-) compared with Pemt(+/+) livers. In addition, there was a 1.5-fold increase in the SR-BI-interacting protein PDZK1. Lipid uptake experiments using radiolabeled HDL particles revealed a greater uptake of [(3)H]cholesteryl ethers and [(3)H]PC by hepatocytes derived from Pemt(-/-) compared with Pemt(+/+) mice. Furthermore, we observed an increased association of [(3)H]cholesteryl ethers in livers of Pemt(-/-) compared with Pemt(+/+) mice after tail vein injection of [(3)H]HDL. These results strongly suggest that PEMT is involved in the regulation of plasma HDL levels in mice, mainly via HDL lipid uptake by SR-BI. 相似文献
115.
David P. Rotella Geraldine R. McFarlane Alexander Greenfield Cristina Grosanu Albert J. Robichaud Rajiah Aldrin Denny Rolf W. Feenstra Sara Núñez-García Jan-Hendrik Reinders Martina van der Neut Andrew McCreary Chris G. Kruse Kelly Sullivan Farhana Pruthi Margaret Lai Jean Zhang Dianne M. Kowal Tikva Carrick Steven M. Grauer Rachel L. Navarra Mark H. Pausch 《Bioorganic & medicinal chemistry letters》2009,19(19):5552-5555
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays. 相似文献
116.
Michael J. Boyd Sheldon N. Crane Joël Robichaud John Scheigetz W. Cameron Black Nathalie Chauret Qingping Wang Frédéric Massé Renata M. Oballa 《Bioorganic & medicinal chemistry letters》2009,19(3):675-679
Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics. 相似文献
117.
Kevin G. Liu Jennifer R. Lo Thomas A. Comery Guo Ming Zhang Jean Y. Zhang Dianne M. Kowal Deborah L. Smith Li Di Edward H. Kerns Lee E. Schechter Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2009,19(4):1115-1117
As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT6 receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT6 ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay. 相似文献
118.
Ronald C. Bernotas Steven Lenicek Schuyler Antane Derek C. Cole Boyd L. Harrison Albert J. Robichaud Guo Ming Zhang Deborah Smith Brian Platt Qian Lin Ping Li Joseph Coupet Sharon Rosenzweig-Lipson Chad E. Beyer Lee E. Schechter 《Bioorganic & medicinal chemistry》2009,17(14):5153-5163
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a–z was prepared as novel 5-HT6 ligands. The best compounds were high affinity, full agonists at 5-HT6 receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders. 相似文献
119.
The Glutaraldehyde test (GT), a rapid and inexpensive test, has been utilized empirically for many years in bovine practice
for diagnosing inflammatory diseases. GT is used primarily to demonstrate increased serum concentrations of fibrinogen and
globulin. Glutaraldehyde binds with free amino groups in fibrinogen and immunoglobulin to create a clot in a first degree
chemical reaction. The clotting time of the GT estimates the content of proteins produced in response to inflammation. The
applicability of GT for diagnosing inflammation in the horse has never been investigated. The objective of this study was
to determine the ability of GT to distinguish between acute and chronic inflammatory disease in horses. Thirty-seven horses
with suspected inflammatory diseases were evaluated using the GT, history, complete clinical examination and routine blood
analysis. GT-times, laboratory results and clinical outcome were compared statistically. Horses that were determined to be
acutely affected (based on history, clinical examination and routine blood analysis) tended to have a negative GT (75%). Results
of the GT did not correlate with blood fibrinogen concentration. Positive GT also predicted a fatal outcome in 69% of the
clinical cases. The results of this trial indicate that GT can be a useful screening test to distinguish between acute and
chronic inflammatory disease in horses. 相似文献
120.