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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.
53.
We consider three models of cholesterol distribution in the plane of a bilayer of DMPC. We analyse recent 2H-NMR data obtained from deuterated fluorescent probes and show that, on the characteristic time-scale of 2H-NMR, it is in accord with a random distribution of cholesterol in a fluid-like DMPC bilayer in a single phase at least for T greater than or approximately equal to 35 degrees C and for 0 less than or equal to c less than or equal to 0.42. 相似文献
54.
We have modelled the effect of integral proteins upon the permeability of a lipid bilayer membrane to small ions. Our intention is to predict the temperature-and protein concentration-dependence of the relative ionic diffusion coefficient if it is assumed that the ions diffuse entirely through the lipid regions of the membrane, and do not cross the bilayer either by moving through the protein or along its hydrophobic surface. We used models of lipid-protein bilayers that have been used successfully before, together with a modification of the (protein-free) permeability mechanism of Kanchisa, Tsong, Cruzeiro-Hansson and Mouritsen (KTCM). We used Monte Carlo techniques to simulate the thermodynamics and permeability of the membrane because such a calculation, which depends upon spatial and time correlations, cannot be done using a mean field approximation. We took the protein to be analogous to bacteriorhodopsin and calculated the relative diffusion coefficients, R, of small ions through a DMPC bilayer containing such proteins. We found that although there is only a small change in R when T > T
m
, R can change by an order of magnitude, depending upon the protein concentration, for T < T
m
. We showed that regions of largest lipid area fluctuations and, hence, compressibility occur (i) at the interfaces between regions (which may be very small and not macroscopic phases) of extended-chain and excited-chain lipids, thus showing the similarity between this model and the KTCM model, and (ii) in regions where the temperature is close to T
m
but the lipids are prevented from becoming ordered because of the proximity of proteins which try to keep them in their excited-chain states. We have plotted lipid fluctuation and ionic permeability maps to show which regions of the membrane display the largest permeability, and we show how these regions change as a function of temperature.
Offprint requests to D. A. Pink 相似文献
55.
56.
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57.
SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors 总被引:3,自引:0,他引:3
Heron NM Anderson M Blowers DP Breed J Eden JM Green S Hill GB Johnson T Jung FH McMiken HH Mortlock AA Pannifer AD Pauptit RA Pink J Roberts NJ Rowsell S 《Bioorganic & medicinal chemistry letters》2006,16(5):1320-1323
A novel series of 5-aminopyrimidinyl quinazolines has been developed from anilino-quinazoline 1, which was identified in a high throughput screen for Aurora A. Introduction of the pyrimidine ring and optimisation of the substituents both on this ring and at the C7 position of the quinazoline led to the discovery of compounds that are highly specific Aurora kinase inhibitors. Co-crystallisation of one of these inhibitors with a fragment of Aurora A shows the importance of the benzamido group in achieving selectivity. 相似文献
58.
Hunter PJ Hand P Pink D Whipps JM Bending GD 《Applied and environmental microbiology》2010,76(24):8117-8125
Morphological and chemical differences between plant genera influence phyllosphere microbial populations, but the factors driving within-species variation in phyllosphere populations are poorly understood. Twenty-six lettuce accessions were used to investigate factors controlling within-species variation in phyllosphere bacterial populations. Morphological and physiochemical characteristics of the plants were compared, and bacterial community structure and diversity were investigated using terminal restriction fragment length polymorphism (T-RFLP) profiling and 16S rRNA gene clone libraries. Plant morphology and levels of soluble carbohydrates, calcium, and phenolic compounds (which have long been associated with plant responses to biotic stress) were found to significantly influence bacterial community structure. Clone libraries from three representative accessions were found to be significantly different in terms of both sequence differences and the bacterial genera represented. All three libraries were dominated by Pseudomonas species and the Enterobacteriaceae family. Significant differences in the relative proportions of genera in the Enterobacteriaceae were detected between lettuce accessions. Two such genera (Erwinia and Enterobacter) showed significant variation between the accessions and revealed microbe-microbe interactions. We conclude that both leaf surface properties and microbial interactions are important in determining the structure and diversity of the phyllosphere bacterial community. 相似文献
59.
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60.
National Blood Service (NBS) Tissue Services (TS) operates living donor and deceased donor tissue banking programmes. The
living bone donor programme operates in collaboration with 91 orthopaedic departments across the country and collects bone
donations, in the form of surgically removed femoral heads (FHs), from over 5000 patients per annum undergoing total hip replacement.
Bone donated via the living programme constitutes approximately 55% of the total bone donated to NBS. Non-NBS tissue banks,
primarily in hospital orthopaedic departments, also bank donated bone for the UK. A survey of information received from 16
collaborating orthopaedic centres, between April 2003 and August 2004, identified 709 excluded donors. The total number of
donations banked from these sites was 1538. Donations can be excluded before collection if there are contraindications noted
in a potential donor’s medical history before their operation. Donors may also be excluded after collection of the FH, for
instance because of reactive microbiology tests for blood borne viruses, or if the donation storage conditions or related
documentation have not met stringent quality requirements. In this survey, bone or joint conditions were the major reasons
for excluding potential donors before donation (154 of 709 exclusions, 22%), followed by a current or a past history of malignancy
(139 of 709 exclusions, 20%). Local staffing and operational difficulties sometimes resulted in potential donors being missed,
or specific reasons for exclusion not being reported (117 exclusions). These out numbered exclusions due to patient refusal
(80 exclusions). A small number (< 5) appear to have been excluded erroneously. There was considerable local variation in
the reasons given for exclusion and certainly under-reporting. A survey of donations discarded after collection in the same
period highlighted that 43% were donor related; 110 of 370 did not provide a follow-up blood sample. More than 30% were due
to delays in forwarding blood samples to the microbiological laboratory for testing, resulting in deterioration of the sample
quality. Training to ensure that standards are complied with and a firm evidence base for exclusion criteria, applied uniformly,
will help focus donor identification efforts on individuals meeting rational criteria so that fewer potential donations are
lost. 相似文献