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31.
Molecular evolution of rodent insulins 总被引:1,自引:0,他引:1
Several trees of amino acid sequences of rodent insulins were derived with
the maximum-parsimony procedure. Possible orthologous and paralogous
relationships were investigated. Except for a recent gene duplication in
the ancestor of rat and mouse, there are no strong arguments for other
paralogous relationships. Therefore, a tree in agreement with other
biological data is the most reasonable one. According to this tree, the
capacity to form zinc-binding hexamers was lost once in the ancestor of the
hystricomorph rodents, followed by moderately increased evolutionary rates
in the lineages to African porcupine and chinchilla but highly increased
rates in at least three independent lines to other taxa of this suborder:
guinea pig, cuis, and Octodontoidea (coypu and casiragua).
相似文献
32.
Kwong CD Clark JL Fowler AT Geng F Kezar HS Roychowdhury A Reynolds RC Maddry JA Ananthan S Secrist JA Shih NY Piwinski JJ Li C Feld B Huang HC Tong X George Njoroge F Arasappan A 《Bioorganic & medicinal chemistry letters》2012,22(2):1160-1164
Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase). 相似文献
33.
VM Girijavallabhan C Alvarez F Bennett L Chen S Gavalas Y Huang SH Kim A Kosinski P Pinto R Rizvi R Rossman B Shankar L Tong F Velazquez S Venkatraman VA Verma J Kozlowski NY Shih JJ Piwinski M Maccoss CD Kwong N Bansal JL Clark AT Fowler HS Kezar J Valiyaveettil RC Reynolds JA Maddry S Ananthan JA Secrist C Li R Chase S Curry HC Huang X Tong FG Njoroge A Arasappan 《Bioorganic & medicinal chemistry letters》2012,22(17):5652-5657
Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity. 相似文献
34.
Kuang R Shue HJ Xiao L Blythin DJ Shih NY Chen X Gu D Schwerdt J Lin L Ting PC Cao J Aslanian R Piwinski JJ Prelusky D Wu P Zhang J Zhang X Celly CS Billah M Wang P 《Bioorganic & medicinal chemistry letters》2012,22(7):2594-2597
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported. 相似文献
35.
Gonsiorek W Hesk D Chen SC Kinsley D Fine JS Jackson JV Bober LA Deno G Bian H Fossetta J Lunn CA Kozlowski JA Lavey B Piwinski J Narula SK Lundell DJ Hipkin RW 《The Journal of biological chemistry》2006,281(38):28143-28151
Studies to characterize the endogenous expression and pharmacology of peripheral human cannabinoid receptor (hCB2) have been hampered by the dearth of authentic anti-hCB2 antibodies and the lack of radioligands with CB2 selectivity. We recently described a novel CB2 inverse agonist, N-[1(S)-[4-[[4-methoxy-2-[(4methoxyphenyl)sulfonyl] phenyl]sulfonyl] phenyl]ethyl]methane-sulfonamide (Sch225336), that binds hCB2 with high affinity and excellent selectivity versus hCB1. The precursor primary amine of Sch225336 was prepared and reacted directly with [(35)S]mesyl chloride (synthesized from commercially obtained [(35)S]methane sulfonic acid) to generate [(35)S]Sch225336. [(35)S]Sch225336 has high specific activity (>1,400 Ci/mmol) and affinity for hCB2 (65 pm). Using [(35)S]Sch225336, we assayed hemopoietic cells and cell lines to quantitate the expression and pharmacology of hCB2. Lastly, we used [(35)S]Sch225336 for detailed autoradiographic analysis of CB2 in lymphoid tissues. Based on these data, we conclude that [(35)S]Sch225336 represents a unique radioligand for the study of CB2 endogenously expressed in blood cells and tissues. 相似文献
36.
Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold
Vaccaro WD Sher R Berlin M Shih NY Aslanian R Schwerdt JH McCormick KD Piwinski JJ West RE Anthes JC Williams SM Wu RL She HS Rivelli MA Mutter JC Corboz MR Hey JA Favreau L 《Bioorganic & medicinal chemistry letters》2006,16(2):395-399
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker. 相似文献
37.
38.
Victor van der Meer Henk F van Stel Moira J Bakker Albert C Roldaan Willem JJ Assendelft Peter J Sterk Klaus F Rabe Jacob K Sont 《Respiratory research》2010,11(1):74
Background
Internet-based self-management has shown to improve asthma control and asthma related quality of life, but the improvements were only marginally clinically relevant for the group as a whole. We hypothesized that self-management guided by weekly monitoring of asthma control tailors pharmacological therapy to individual needs and improves asthma control for patients with partly controlled or uncontrolled asthma.Methods
In a 1-year randomised controlled trial involving 200 adults (18-50 years) with mild to moderate persistent asthma we evaluated the adherence with weekly monitoring and effect on asthma control and pharmacological treatment of a self-management algorithm based on the Asthma Control Questionnaire (ACQ). Participants were assigned either to the Internet group (n = 101) that monitored asthma control weekly with the ACQ on the Internet and adjusted treatment using a self-management algorithm supervised by an asthma nurse specialist or to the usual care group (UC) (n = 99). We analysed 3 subgroups: patients with well controlled (ACQ ≤ 0.75), partly controlled (0.75>ACQ ≤ 1.5) or uncontrolled (ACQ>1.5) asthma at baseline.Results
Overall monitoring adherence was 67% (95% CI, 60% to 74%). Improvements in ACQ score after 12 months were -0.14 (p = 0.23), -0.52 (p < 0.001) and -0.82 (p < 0.001) in the Internet group compared to usual care for patients with well, partly and uncontrolled asthma at baseline, respectively. Daily inhaled corticosteroid dose significantly increased in the Internet group compared to usual care in the first 3 months in patients with uncontrolled asthma (+278 μg, p = 0.001), but not in patients with well or partly controlled asthma. After one year there were no differences in daily inhaled corticosteroid use or long-acting β2-agonists between the Internet group and usual care.Conclusions
Weekly self-monitoring and subsequent treatment adjustment leads to improved asthma control in patients with partly and uncontrolled asthma at baseline and tailors asthma medication to individual patients'' needs.Trial registration
Current Controlled Trials ISRCTN79864465 相似文献39.
Background
The assembly and spatial organization of enzymes in naturally occurring multi-protein complexes is of paramount importance for the efficient degradation of complex polymers and biosynthesis of valuable products. The degradation of cellulose into fermentable sugars by Clostridium thermocellum is achieved by means of a multi-protein "cellulosome" complex. Assembled via dockerin-cohesin interactions, the cellulosome is associated with the cell surface during cellulose hydrolysis, forming ternary cellulose-enzyme-microbe complexes for enhanced activity and synergy. The assembly of recombinant cell surface displayed cellulosome-inspired complexes in surrogate microbes is highly desirable. The model organism Lactococcus lactis is of particular interest as it has been metabolically engineered to produce a variety of commodity chemicals including lactic acid and bioactive compounds, and can efficiently secrete an array of recombinant proteins and enzymes of varying sizes. 相似文献40.
Reichard GA Spitler J Aslanian R Mutahi Mw Shih NY Lin L Ting PC Anthes JC Piwinski JJ 《Bioorganic & medicinal chemistry letters》2002,12(5):833-836
A thorough SAR study of the oxime region of the dual NK(1)/NK(2) antagonist 1 revealed several modifications that result in potent dual antagonists. Follow up SAR studies on a second-generation scaffold demonstrate that certain polar groups on the oxime can improve the dual binding affinity to the subnanomolar range. 相似文献