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1.
(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.  相似文献   
2.
A computer algorithm, CLIX, capable of searching a crystallographic data-base of small molecules for candidates which have both steric and chemical likelihood of binding a protein of known three-dimensional structure is presented. The algorithm is a significant advance over previous strategies which consider solely steric or chemical requirements for binding. The algorithm is shown to be capable of predicting the correct binding geometry of sialic acid to a mutant influenza-virus hemagglutinin and of proposing a number of potential new ligands to this protein.  相似文献   
3.
The actions of synthetic piperidine derivatives on the response to ionophoretically-applied acetylcholine (ACh) have been tested on the cell body membrane of the fast coxal depressor motoneurone (Ff) of the cockroach Periplaneta americana. The cis form and the cis (80%):trans (20%) mixture of 2-methyl-6-undecyl piperidine were the most effective (the half-maximal blocking action of the mixed isomers was estimated to be 6.3 × 10?5 M). Less potent was the cis (50%):trans (50%) mixture of 2-methyl-6-tridecyl piperidine. However, pure cis 2-methyl-6-tridecyl piperidine was even less effective than the mixed isomers, indicating that, in the case of the tridecyl derivative, the trans form was largely responsible for the block of the ACh response.Cis 2-Methyl-6-undecyl piperidine failed to inhibit the binding of N-[propionyl-3H] propionylated α-bungarotoxin to metathoracic ganglion homogenates at concentrations up to 1.0 × 10?4 M. Also, block of ACh-induced current by 2-methyl-6-undecyl piperidine (cis 80%:trans 20%) was largely independent of membrane potential in the range ?120 mV to ?60 mV, indicating an interaction with the closed ACh receptor/ion channel complex at a site which, in the case of the cis isomer, is separate from the binding site for α-bungarotoxin.  相似文献   
4.
Cyclic voltammetry at a micro electrode of Co(II) salen, Fe(II) salen, electrode generated Fe(II)(acac)2, Fe(II) (salicylaldehyde)2, Fe(II) (salicylaldoxime)2, Fe(II) (bipy)3, Fe(II) (bipy)2, Co(II) (bipy)3, Co(II) (benzacac)2, and electrode generated Co(acac)2 in oxygen saturated aprotic solvents show positive shift of the O2 sigmoidal wave, as well as enhancement of the limiting current in the case of the first five compounds. In the case of Co(II) (bipy)3 the slope of the sigmoidal wave due to O2 becomes more positive, while for the other two Co(II) complexes there is no change except a small decrease in the wave height. The data are used to correlate and predict the O2 binding properties of the chelates in solution. The data for the diketone complexes of Co(II) indicate absence of any direct association, which is in line with the interpretation offered in the literature on the mechanism of their catalytic role in the O2 oxidation of substrates. The mechanism of the autoxidation of dimethylformamide in the presence of Fe(III) (bipy)3 and Cu(II) (bipy)2 is elucidated by the observation that these higher valent compounds are reduced to their next lower oxidation state by DMF.  相似文献   
5.
The 1H-NMR spectrum of cucumber basic blue protein (CBP) has been recorded. Examination of the spectrum of the reduced protein suggests that one or more sidechains exist in conformations which interconvert slowly at ambient temperatures. His 39, His 84 and Met 89 are identified as copper ligands by redox titration and by amino acid sequence homology with plastocyanin and azurin. The importance of a Phe sidechain close to the Met ligand in the potential blue copper site is confirmed. Broadening of His ligand resonances at elevated temperatures reveals an exchange process at the reduced copper centre.  相似文献   
6.
Copper(II) N-salicylidene-(S)-alaninate trihydrate reacting as the S-enantiomeric parent compound with KOCN in hot diluted methanol yielded by slow crystallisation from the cooled reaction mixture (in the course of 1 day) the racemic product K[Cu{sal-(RS)-ala}(NCO)]. The parameters of the axial type EPR spectrum in X-band region and the LF band position in the electronic spectrum are typical of an axially distorted square pyramidal coordination of the Cu(II) atom in this complex. The spectral properties of the complex cuprate prepared and its basal crystallographic data are consistent with those of the earlier studied15 K2[Cu2{sal-(RS)-ala}2(μ-NCO)2] synthetized by using [Cu{sal-(RS)-ala}(H2O)].H2O as the racemic parent complex in the reaction mixture with KOCN.  相似文献   
7.
Streptavidin binds 2'-iminobiotin in a pH-dependent fashion--affinity decreases as the pH is lowered. This property makes the purification of compounds conjugated to streptavidin or immobiotin possible under mild conditions by affinity chromatography. In order to understand the molecular details of this pH-dependent binding, we analyzed the crystal structures of the complex of core streptavidin with 2'-iminobiotin at pH values 4.0 and 7.5. The two structures are very similar to each other even at their binding sites. Although the relative abundance of the protonated species of the ligand is increased more than 3,000-fold on going from pH 7.5 to pH 4.0, both structures contain only the nonprotonated from of the ligand. Streptavidin selects the nonprotonated form, which, at pH 4.0, is one part in 7.9 x 10(7).  相似文献   
8.
Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL play critical roles in bone re-modeling, immune function, vascular disease and mammary gland development. To study the interaction of RANK and RANKL, we have expressed both extracellular domain of RANK and ectodomain of RANKL using Escherichia coli expression system. RANK was expressed as an inclusion body first which properly refolded later, while RANKL was initially produced as a GST fusion protein, after which the GST was removed by enzyme digestion. Soluble RANK existed as a monomer while RANKL was seen as a trimer in solution, demonstrated by gel filtration chromatography and cross-linking experiment. The recombinant RANK and RANKL could bind to each other and the binding affinity of RANKL for RANK was measured with surface plasmon resonance technology and KD value is about 1.09 × 10−10 M.  相似文献   
9.
Induction of tumoricidal activity is one of the major functions of activated macrophages. Our previous study demonstrated that P388D1 murine macrophage-like cells secreted a plasmacytoma cytotoxic factor (PCF) that selectively killed certain tumor cell lines including MOPC-315 plasmacytoma in vitro. Our subsequent studies demonstrated that PCF killed MOPC-315 cells by induction of apoptosis. In this report, the involvement of Fas and Fas ligand (FasL) in PCF-induced apoptosis was investigated. Results suggest that expression of Fas mRNA time-dependently increased in PCF-treated cells and reached an optimal level after 36 h of treatment. The augmented effect of PCF on Fas mRNA expression was significantly reduced by the addition of CB7.C2, an anti-PCF monoclonal antibody. The expression of FasL mRNA was also induced by PCF and reached an optimal level at 24 h, but sharply decreased after 36 h of treatment. Caspase-3 is one of the proteolytic enzymes that can be activated by the Fas-FasL interaction. In our studies, the enzymatic activity of caspase-3 was significantly induced by PCF after 6 h of treatment and reached an optimal level at 12 h. The augmented effect of PCF on caspase activity was significantly reduced by the addition of CB7.C2 and the caspase-3-specific inhibitor, DEVD-fmk. Therefore, PCF-treated plasmacytoma cells might undergo apoptosis via interaction between Fas and FasL.  相似文献   
10.
Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).  相似文献   
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