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51.
Lidocaine block of cardiac sodium channels was studied in voltage-clamped rabbit purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 μM). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltage-dependent K(d). The half-blocking concentration varied from more than 300 μM, at a negative holding potential where inactivation was completely removed, to approximately 10 μM, at a depolarized holding potential where inactivation was nearly complete. Lidocaine block showed prominent use dependence with trains of depolarizing pulses from a negative holding potential. During the interval between pulses, repriming of I (Na) displayed two exponential components, a normally recovering component (τless than 0.2 s), and a lidocaine-induced, slowly recovering fraction (τ approximately 1-2 s at pH 7.0). Raising the lidocaine concentration magnified the slowly recovering fraction without changing its time course; after a long depolarization, this fraction was one-half at approximately 10 μM lidocaine, just as expected if it corresponded to drug-bound, inactivated channels. At less than or equal to 20 μM lidocaine, the slowly recovering fraction grew exponentially to a steady level as the preceding depolarization was prolonged; the time course was the same for strong or weak depolarizations, that is, with or without significant activation of I(Na). This argues that use dependence at therapeutic levels reflects block of inactivated channels, rather than block of open channels. Overall, these results provide direct evidence for the “modulated-receptor hypothesis” of Hille (1977) and Hondeghem and Katzung (1977). Unlike tetrodotoxin, lidocaine shows similar interactions with Na channels of heart, nerve, and skeletal muscle. 相似文献
52.
Lancelot Barrington-Ward Hubert Bond Edwin Bramwell Duncan C. L. Fitzwilliams Francis Fraser R. S. Frew William Goschen F. J. McCann Macmillan Arthur MacNalty Frederick Kay Menzies George Newman George Riddoch Humphry Rolleston Bertram Shires Frederick Still G. A. Sutherland James Taylor James Walton David Wilkie 《BMJ (Clinical research ed.)》1938,2(4046):195-196
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54.
Seven capsule-negative mutants of Cryptococcus neoformans were isolated. All mutations were linked (maximum map distance, 38 U); two mutations were found to be allelic. 相似文献
55.
Eric Barklis Ayna Alfadhli Carolyn McQuaw Suraj Yalamuri Amelia Still Robin Lid Barklis Ben Kukull Claudia S. López 《Journal of molecular biology》2009,387(2):376-75
During the morphogenesis of mature human immunodeficiency virus-1 cores, viral capsid proteins assemble conical or tubular shells around viral ribonucleoprotein complexes. This assembly step is mimicked in vitro through reactions in which capsid proteins oligomerize to form long tubes, and this process can be modeled as consisting of a slow nucleation period, followed by a rapid phase of tube growth. We have developed a novel fluorescence microscopy approach to monitor in vitro assembly reactions and have employed it, along with electron microscopy analysis, to characterize the assembly process. Our results indicate that temperature, salt concentration, and pH changes have differential effects on tube nucleation and growth steps. We also demonstrate that assembly can be unidirectional or bidirectional, that growth can be capped, and that proteins can assemble onto the surfaces of tubes, yielding multiwalled or nested structures. Finally, experiments show that a peptide inhibitor of in vitro assembly also can dismantle preexisting tubes, suggesting that such reagents may possess antiviral effects against both viral assembly and uncoating. Our investigations help establish a basis for understanding the mechanism of mature human immunodeficiency virus-1 core assembly and avenues for antiviral inhibition. 相似文献
56.
Penicillium stoloniferum NRRL5267 contains two electrophoretically distinct viruses (PsV-F and PsV-S). An in vivo system was developed to test whether a number of fungal metabolites had antiviral properties on PsV-F replication in O.erties on PsV-F replication in P. stoloniferum. Preliminary results indicated that the mycotoxin patulin can block mycovirus replication. Portions of 48 h mycelium were incubated in the presence of varying levels of patulin, and after an additional 48 h incubation, PsV-F content was measured in E260 units by polyacrylamide gel electrophoresis. Patulin at 11, 16 and 20 mug/mg dry wt mycelia blocked PsV-F replication 26, 61 and 71%, respectively, compared with untreated controls. At these levels, host biomass RNA and protein synthesis were minimally affected. No-proliferating fungal mycelium is capable of continued support of PsV-F replication, which is sensitive to patulin. Apparently, inhibitory doses of patulin stimulated PsV-S replication during this 48 h incubation. The preferential action of patulin may arise from metabolite binding to functional enzymes required for virus replication. 相似文献
57.
Corrine J Porter Jacqueline M Matthews Joel P Mackay Sharon E Pursglove Jason W Schmidberger Peter J Leedman Stephanie C Pero David N Krag Matthew CJ Wilce Jacqueline A Wilce 《BMC structural biology》2007,7(1):1-15
Background
Human growth factor receptor bound protein 7 (Grb7) is an adapter protein that mediates the coupling of tyrosine kinases with their downstream signaling pathways. Grb7 is frequently overexpressed in invasive and metastatic human cancers and is implicated in cancer progression via its interaction with the ErbB2 receptor and focal adhesion kinase (FAK) that play critical roles in cell proliferation and migration. It is thus a prime target for the development of novel anti-cancer therapies. Recently, an inhibitory peptide (G7-18NATE) has been developed which binds specifically to the Grb7 SH2 domain and is able to attenuate cancer cell proliferation and migration in various cancer cell lines.Results
As a first step towards understanding how Grb7 may be inhibited by G7-18NATE, we solved the crystal structure of the Grb7 SH2 domain to 2.1 Å resolution. We describe the details of the peptide binding site underlying target specificity, as well as the dimer interface of Grb 7 SH2. Dimer formation of Grb7 was determined to be in the μM range using analytical ultracentrifugation for both full-length Grb7 and the SH2 domain alone, suggesting the SH2 domain forms the basis of a physiological dimer. ITC measurements of the interaction of the G7-18NATE peptide with the Grb7 SH2 domain revealed that it binds with a binding affinity of Kd = ~35.7 μM and NMR spectroscopy titration experiments revealed that peptide binding causes perturbations to both the ligand binding surface of the Grb7 SH2 domain as well as to the dimer interface, suggesting that dimerisation of Grb7 is impacted on by peptide binding.Conclusion
Together the data allow us to propose a model of the Grb7 SH2 domain/G7-18NATE interaction and to rationalize the basis for the observed binding specificity and affinity. We propose that the current study will assist with the development of second generation Grb7 SH2 domain inhibitors, potentially leading to novel inhibitors of cancer cell migration and invasion. 相似文献58.
Gwendoline Kint David De Coster Kathleen Marchal Jos Vanderleyden Sigrid CJ De Keersmaecker 《BMC microbiology》2010,10(1):276
Background
LuxS is the synthase enzyme of the quorum sensing signal AI-2. In Salmonella Typhimurium, it was previously shown that a luxS deletion mutant is impaired in biofilm formation. However, this phenotype could not be complemented by extracellular addition of quorum sensing signal molecules. 相似文献59.
Jensen GL Silver HJ Roy MA Callahan E Still C Dupont W 《Obesity (Silver Spring, Md.)》2006,14(3):509-517
Objective : To test the a priori hypothesis that obesity is a predictor of risk for reporting homebound status. Research Methods and Procedures : A longitudinal cohort study was conducted with 21, 645 community‐dwelling men and women 65 to 97 years old. A nutrition risk screen was administered baseline between 1994 and 1999 and again 3 to 4 years later. Univariate analyses identified baseline variables associated with subsequent reporting of homebound status. Multivariable logistic regression models were created to identify baseline variables that were significant independent predictors of reporting homebound status. Results : At baseline, 24% of the cohort had BMI ≥ 30. There were 12, 834 (45% men) respondents at follow‐up (68% response). Non‐responders at follow‐up differed little from responders except for greater baseline age (72.2 ± 6.2 vs. 71.4 ± 5.6 years, p < 0.001) and reporting of any functional limitations (9.2% vs. 4.9%, p < 0.001). At follow‐up, those who reported homebound status (n = 169) were significantly (p < 0.001) older (80.3 ± 7.3 vs. 75.1 ± 5.5 years) and more likely to report functional limitations (83.4% vs. 10.8%). Univariate analyses identified 16 baseline variables that were eliminated stepwise until five significant independent predictors remained: age ≥ 75 years (2.21, 1.55 to 3.15/odds ratio, 95% confidence interval), BMI ≥ 35 (1.75, 1.04 to 2.96), poor appetite (2.50, 1.29 to 4.86), low income (1.59, 1.00 to 2.56), and any functional limitation (10.67, 7.36 to 15.46). Discussion : Obesity remained a significant independent predictor for reporting homebound status and should be considered in screening of older populations and in the planning, implementation, and evaluation of services for homebound older persons. 相似文献
60.
H-K Liu S Perrier C Lipina D Finlay H McLauchlan CJ Hastie HS Hundal C Sutherland 《BMC molecular biology》2006,7(1):14-12