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991.
Nika Adham Laurence A. Borden Lee E. Schechter Eric L. Gustafson Tamara L. Cochran Pierrre J.-J. Vaysse Richard L. Weinshank Theresa A. Branchek 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(6):566-575
We recently described the cloning of a fifth member of the 5-hydroxytryptamine (5-HT)1 (serotonin1) receptor class that inhibits adenylyl cyclase, namely the human 5-HT1F receptor (Adham et al. 1993 a). In the present study we have examined in greater detail the functional coupling of the 5-HT1F receptor in two different cell lines, NIH-3T3 and LM(tk–) fibroblasts (receptor densities of 1.7 and 4.4 pmol/mg protein, respectively). The maximal inhibitory response elicited by 5-HT was significantly greater in NIH-3T3 as compared to LM(tk–) cells, whereas the EC50 values were comparable.To investigate the relationship between receptor occupancy and inhibition of cAMP accumulation mediated by 5-HT1F receptors in NIH-3T3 cells (and hence the degree of receptor reserve), we used the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The half-maximal response required only about 10% receptor occupancy, consistent with a receptor reserve of 90% (88±2.1%, n = 4) for 5-HT-induced inhibition of FSCA. Despite the presence of such a high degree of receptor reserve, a range of intrinsic activities was displayed by structurally diverse classes of compounds. For example, sumatriptan and lysergol were as efficacious as 5-HT itself and thus acted as full agonists, whereas metergoline and 1-NP behaved as partial agonists and as shown previously (Adham et al. 1993a), methiothepin was a silent antagonist (Kb = 438 nM).We have also investigated activation of additional signal transduction pathways by the 5-HT1F receptor and found that the responses differ in the two cell lines with respect to stimulation of phospholipase C. For example, in NIH-3T3 cells no elevation of inositol phosphates (IP) of [Ca2+]i was observed even at very high agonist concentrations (100 M). In contrast, in LM(tk–) cells concentrations of 5-HT as low as 10 nM induced stimulation of IP and a rapid increase of [Ca2+]i. The 5-HT1F receptor failed to alter arachidonic acid release in either cell line.The maximal increase in IP accumulation in LM(tk–) cells was modest, averaging about 100% above basal. The increases of IP and [Ca2+]i required 5-HT concentrations less than one order of magnitude greater than those inhibiting FSCA (EC50 = 17, 55 and 8 nM, respectively), and both responses were blocked by 100 M methiothepin. All three responses (cAMP, IP, and [Ca2+]i) were sensitive to pertussis toxin pre-treatment, suggesting the involvement of Gi/Go protein(s) in these signal transduction pathways. [Ca2+]i was also elevated by sumatriptan, which may provide a mechanism by which this drug causes constriction of the vasculature. In conclusion, these data indicate that the human 5-HT1F receptor can couple to multiple effectors, and that this coupling is cell-type dependent.Abbreviations FSCA
forskolin-stimulated cAMP accumulation
- [Ca2+]
intracellular free calcium concentration
- AA
arachidonic acid
- EEDQ
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
- CHO
chinese hamster ovary cell
- LM(tk–)
mouse fibroblast cell
- Bmax
maximal binding site density
- Ki
apparent dissociation constant obtained from competition binding studies
- G protein
guanine nucleotide-binding protein
- HBS
HEPES-buffered saline
- IP
inositol phosphates
- IP3
inositol 1,4,5 trisphosphate
- PLC
phospholipase C
- Kb
antagonist dissociation constant
- Kd
equilibrium dissociation constant
- N-1F-6
stable NIH-3T3 cells expressing the cloned 5-HT1F receptor
- L-1F-3
stable LM(tk–) cells expressing the cloned 5-HT1F receptor
- PTX
pertussis toxin
- BSA
bovine serum albumin
- METH
methiothepin
- SUMA
sumatriptan
- 5-MeO-DMT
5-methoxy-N,N-dimethyltryptamine
- 1-NP
1-(1-napthyl)piperazine
- 5-CT
5-carboxyamidotryptamine
Correspondence to: N. Adham at the above address 相似文献
992.
Boveri J Parry R Ruffin W Gustafson M Lee K He W Donahoe P 《International journal of oncology》1993,2(2):135-143
Mullerian Inhibiting Substance (MIS), a gonadal growth factor important in sexual differentiation, has antiproliferative activity against several human carcinoma cell lines. In this study, we examine the effect of MIS-transfection on the growth characteristics of Chinese hamster ovary (CHO) and human ocular melanoma (OM431) cells, compared to wild-type lines and a CHO line transfected with a noncleavable, inactive MIS mutant. MIS-transfection inhibited proliferation of CHO cells in double-layer agarose, tumor spheroid, and murine subrenal capsule assays, as well as growth of CHO and OM431 cells in pulmonary metastasis studies. These results anticipate further study of targeted gene therapy of certain human tumors with MIS gene constructs. 相似文献
993.
Kyo E Yokozaki H Yanagihara K Yasui W Ito M Sano T Lee P Saya H Tahara E 《International journal of oncology》1993,3(2):265-271
Wild-type or mutant human p53 gene was transfected into a human gastric carcinoma cell line MKN-1 which shares a mutant p53 allele. Transfected wild-type p53 reduced the colony forming efficiency and tumorigenicity of MKN-1 cells. However, no difference in expression of cell adhesion molecule, oncogenes and growth factors was observed among parent, wild-type p53 and mutant p53 transfectants. In motility assay, the wild-type p53 transfectants relative to the parental or mutant p53 transfectants exhibited a decreased motility, and HGF had a greater effect on the motility of the mutant p53 transfectants, but very little effect on the motility of either the parental or wild-type transfectants. In invasion assay, mutant p53 transfectants revealed the increased invasion ability into collagen gel. These results suggest that allele loss and point mutation of p53 gene may play a critical role not only in growth but also in invasion of gastric carcinoma cells. 相似文献
994.
995.
996.
Patrick A. Boudewyns Lee Hyer Marilyn G. Woods William R. Harrison Edward McCranie 《Journal of traumatic stress》1990,3(3):359-368
Vietnam combat veteran inpatients were evaluated after being treated in a PTSD special treatment unit. Selected pretreatment measures that included mental and physical problems, combat variables, PTSD symptoms, and the standard MMPI scales found no clinically meaningful differences between a group that was found to be successes and another group found to be failures, based on predetermined cutoff scores on the VETS scale, a reliable outcome measure for veteran patients. At 3 months post-therapy, a significantly greater number of subjects treated with Direct Therapeutic Exposure (DTE) (flooding therapy) as compared to another group treated with a more conventional individual therapy, were identified as successes as opposed to failures, based on the VETs scale. Also, the number of failures was greater for those treated with the more conventional therapy and the number of successess was greater for those treated with DTE, when compared to all other subjects in the sample. These preliminary results were interpreted as indicating that DTE, when offered as part of an inpatient milieu, shows promise as an effective treatment for chronic/severe combat veteran PTSD sufferers. 相似文献
997.
Y K Lee 《Singapore medical journal》1990,31(6):599-613
This article traces the history of Kandang Kerbau Hospital ("the hospital beside the Bukit Timah Canal") and the maternity and infant welfare services of Singapore from 1858 to the present. This includes the development of teaching of Obstetrics and Gynaecology to medical undergraduates and postgraduates, and the training and registration of midwives, and the resulting saving of maternal and infant lives. Why was Kandang Kerbau Hospital converted into a Maternity Hospital in 1924? 相似文献
998.
999.
The Effects of Permeation Enhancers on the Surface Morphology of the Rat Nasal Mucosa: A Scanning Electron Microscopy Study 总被引:2,自引:0,他引:2
A rat model has been developed to compare relative morphological changes in the nasal mucosa after exposure to potential membrane permeation enhancers. Scanning electron microscopy was used to characterize gross structural and specific cellular changes following exposure. Micrographs of the rat nasal mucosa were scored in four categories: (1) mucosal surface integrity, (2) ciliary morphology, (3) mucus/extracellular debris, and (4) presence of red blood cells. The order of increasing morphological damage resulting from a 5-min exposure to each surfactant was 0.5% Solulan C-24 0.5% Solulan C-24/0.5% sodium tauro-24,25-dihydrofusidate (STDHF) < 0.5% STDHF < 1.0% STDHF 1.0% Laureth-9 < 1.0% sodium taurodeoxycholate 1.0% sodium deoxycholate. The changes observed in the mucosal morphology after exposure to the various surfactants are in general agreement with data in the literature. This model is able to compare rapidly the relative morphological effects on the mucosal membrane of different nasal formulations. 相似文献
1000.