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排序方式: 共有266条查询结果,搜索用时 15 毫秒
41.
Bromée T Kukkonen JP Andersson P Conlon JM Larhammar D 《British journal of pharmacology》2005,144(1):11-16
Ligand interactions of a piscine bradykinin (BK) receptor expressed in vitro have been characterized for the first time by measuring inositol phosphate accumulation.The ligands were analogues of zebrafish BK with serial substitutions by D-amino acids or alanine. Substitutions at residues Arg(1), Gly(4), Ser(6), Pro(7), Leu(8) and Arg(9) caused greatly reduced potency and maximum response. The Pro(3) --> Ala analogue had higher potency but lower maximum response.The peptide HOE140 was a weak partial agonist although it is an antagonist at the human B2 receptor and a potent agonist at chicken B2.Thus, cloned zebrafish BK receptor reveals a ligand-interaction profile that is distinct from mammalian B1 and B2 receptors and from the previously characterized BK receptor in trout stomach, but similar to the receptor in cod intestine. These results increase our understanding of the evolution of BK receptors and the functions of the kallikrein-kinin system. 相似文献
42.
Background
Bariatric surgery has shown to be safe for patients over 60 years with good results especially considering resolving of comorbidities. Sleeve gastrectomy is considered to be safer than gastric bypass (GBP) and more effective than gastric banding with less adverse symptoms. Weight loss may be more modest than after GBP, but the effect on vitamins may also be milder. 相似文献43.
The binding sites for agonists and antagonist of orexin receptors are not know, hampering progressive drug design approaches. In the current study, we utilized chimaeric orexin receptor approach to map the receptor areas contributing to the selectivity of the classical antagonist, SB-334867, for OX1 receptors. Altogether ten chimaeras between OX1 and OX2 orexin receptors were utilized. The receptors were transiently expressed in HEK-293 cells. The ability (KB) of SB-334867 to inhibit orexin-A-induced inositol phosphate release (phospholipase C activity) was measured. The results, in synthesis, suggest that there are several possible interactions contributing to the high affinity binding, all of which are not required simultaneously. This is indicated by the fact that most of the chimaeras display affinity (at least somewhat) higher than OX2. As previously shown for the agonist distinction, the second quarter of the receptor, from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 seems to be most central also for SB-334867 binding, but also the third quarter, from the transmembrane helix 4 to the transmembrane helix 6 is able to contribute (and compensate for loss of other sites). A previous study has suggested that amino acids conserved between OX1 and OX2 receptors would somehow confer selectivity for subtype-selective antagonists. In contrast to previous findings, our results indicate that the amino acids distinct between the receptor subtypes are in key position. 相似文献
44.
45.
Langel K Engblom C Pehrsson A Gunnar T Ariniemi K Lillsunde P 《Journal of analytical toxicology》2008,32(6):393-401
Nine different oral fluid (OF) collection devices were studied to evaluate their suitability for collecting samples for drug analysis. The devices were Greiner Bio-One, Orasure Intercept, Immunalysis Quantisal, StatSure Saliva.Sampler, Cozart, Sarstedt Salivette, Malvern Medical OraCol, Acro Biotech Salicule, and Varian OraTube. For comparison, OF was also collected into plastic tubes. The volume of collected OF was quantified for samples collected both in vitro and from volunteers. Drug recovery was studied by collecting OF fortified at 1000 ng/mL with amphetamine, 3,4-methylenedioxymethamphetamine, cocaine, Delta(9)-tetrahydrocannabinol, morphine, codeine, diazepam, and alprazolam with the devices in vitro and analyzing the samples with gas chromatography-mass spectrometry. Recovery of ethanol was measured from 0.2% in OF by headspace gas chromatography-flame-ionization detection. The stability of drugs in the samples was studied by analyzing the samples after 0, 14, and 28 days storage. The study shows that there are substantial differences between the OF collection devices on the market. Some are well suited for collecting samples for toxicological analysis, but some give quite poor results. 相似文献
46.
Pauliina Taimisto Marko Tainio Niko Karvosenoja Kaarle Kupiainen Petri Porvari Ari Karppinen Leena Kangas Jaakko Kukkonen Jouni T. Tuomisto 《Air quality, atmosphere, & health》2011,4(3-4):199-209
Domestic wood combustion and traffic are the two most significant primary fine particulate matter (PM2.5) emission source categories in Finland. We estimated emission–exposure relationships for primary PM2.5 emissions from these source categories using intake fractions (iF), which describes the fraction of an emission that is ultimately inhaled by a target population. The iFs were calculated for four different emission source subcategories in Finland in 2000: (1) domestic wood combustion in residential buildings, (2) domestic wood combustion in recreational buildings, (3) traffic exhaust and wear emissions, and (4) traffic resuspension emissions. The iFs were estimated for both total population and for subpopulations with different gender, age, and educational status. Primary PM2.5 emissions were based on the Finnish Regional Emission Scenario model and the dispersion of particles was calculated using the Urban Dispersion Modeling system of Finnish Meteorological Institute. Both emissions and dispersion were estimated on a 1 km spatial resolution. The iFs for primary PM2.5 emissions from (1) residential and (2) recreational buildings were 3.4 and 0.6 per million, respectively. The corresponding iF for (3) traffic exhaust and wear and (4) traffic resuspension emissions were 9.7 and 9.5 per million, respectively. The differences in population-weighted outdoor concentrations were significant between subpopulations with different educational status so that people with higher education were exposed more to traffic-related PM2.5. 相似文献
47.
48.
We showed previously that OX(1) orexin receptor stimulation produced a strong (3)H overflow response from [(3)H]arachidonic acid (AA)-labeled cells. Here we addressed this issue with a novel set of tools and methods, to distinguish the enzyme pathways responsible for this response. CHO-K1 cells heterologously expressing human OX(1) receptors were used as a model system. By using selective pharmacological inhibitors, we showed that, in orexin-A-stimulated cells, the AA-derived radioactivity was released as two distinct components, i.e., free AA and the endocannabinoid 2-arachidonoyl glycerol (2-AG). Two orexin-activated enzymatic cascades are responsible for this response: cytosolic phospholipase A(2) (cPLA(2)) and diacylglycerol lipase; the former cascade is responsible for part of the AA release, whereas the latter is responsible for all of the 2-AG release and part of the AA release. Essentially only diacylglycerol released by phospholipase C but not by phospholipase D was implicated as a substrate for 2-AG production, although both phospholipases were strongly activated. The 2-AG released acted as a potent paracrine messenger through cannabinoid CB(1) receptors in an artificial cell-cell communication assay that was developed. The cPLA(2) cascade, in contrast, was involved in the activation of orexin receptor-operated Ca(2+) influx. 2-AG was also released upon OX(1) receptor stimulation in recombinant HEK-293 and neuro-2a cells. The results directly show, for the first time, that orexin receptors are able to generate potent endocannabinoid signals in addition to arachidonic acid signals, which may explain the proposed orexin-cannabinoid interactions (e.g., in neurons). 相似文献
49.
Putkonen N Kukkonen JP Mudo G Putula J Belluardo N Lindholm D Korhonen L 《The European journal of neuroscience》2011,34(8):1212-1221
Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin‐dependent kinase‐5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)‐induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA‐mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post‐synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N ′,N′‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM) and glycol‐bis (2‐aminoethylether)‐N,N,N ′,N ′‐tetra‐acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant‐negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant‐negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA‐mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases. 相似文献
50.
Pesonen S Diaconu I Kangasniemi L Ranki T Kanerva A Pesonen SK Gerdemann U Leen AM Kairemo K Oksanen M Haavisto E Holm SL Karioja-Kallio A Kauppinen S Partanen KP Laasonen L Joensuu T Alanko T Cerullo V Hemminki A 《Cancer research》2012,72(7):1621-1631
The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n = 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-γ ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type-specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401. 相似文献