全文获取类型
收费全文 | 14556篇 |
免费 | 1081篇 |
国内免费 | 51篇 |
专业分类
耳鼻咽喉 | 132篇 |
儿科学 | 353篇 |
妇产科学 | 325篇 |
基础医学 | 2595篇 |
口腔科学 | 178篇 |
临床医学 | 1548篇 |
内科学 | 3052篇 |
皮肤病学 | 260篇 |
神经病学 | 1012篇 |
特种医学 | 564篇 |
外科学 | 2212篇 |
综合类 | 114篇 |
现状与发展 | 1篇 |
一般理论 | 2篇 |
预防医学 | 910篇 |
眼科学 | 237篇 |
药学 | 1234篇 |
中国医学 | 14篇 |
肿瘤学 | 945篇 |
出版年
2023年 | 78篇 |
2022年 | 84篇 |
2021年 | 244篇 |
2020年 | 186篇 |
2019年 | 274篇 |
2018年 | 337篇 |
2017年 | 294篇 |
2016年 | 288篇 |
2015年 | 351篇 |
2014年 | 446篇 |
2013年 | 609篇 |
2012年 | 862篇 |
2011年 | 801篇 |
2010年 | 448篇 |
2009年 | 465篇 |
2008年 | 727篇 |
2007年 | 724篇 |
2006年 | 652篇 |
2005年 | 644篇 |
2004年 | 596篇 |
2003年 | 520篇 |
2002年 | 508篇 |
2001年 | 349篇 |
2000年 | 349篇 |
1999年 | 331篇 |
1998年 | 171篇 |
1997年 | 118篇 |
1996年 | 125篇 |
1995年 | 104篇 |
1994年 | 131篇 |
1993年 | 107篇 |
1992年 | 257篇 |
1991年 | 241篇 |
1990年 | 281篇 |
1989年 | 285篇 |
1988年 | 262篇 |
1987年 | 225篇 |
1986年 | 240篇 |
1985年 | 243篇 |
1984年 | 184篇 |
1983年 | 166篇 |
1982年 | 100篇 |
1981年 | 87篇 |
1979年 | 121篇 |
1978年 | 87篇 |
1977年 | 69篇 |
1975年 | 79篇 |
1974年 | 107篇 |
1973年 | 99篇 |
1972年 | 77篇 |
排序方式: 共有10000条查询结果,搜索用时 687 毫秒
991.
Tagmose TM Schou SC Mogensen JP Nielsen FE Arkhammar PO Wahl P Hansen BS Worsaae A Boonen HC Antoine MH Lebrun P Hansen JB 《Journal of medicinal chemistry》2004,47(12):3202-3211
Phenylcyanoguanidines substituted with lipophilic electron-withdrawing functional groups, e.g. N-cyano-N'-[3,5-bis-(trifluoromethyl)phenyl]-N' '-(cyclopentyl)guanidine (10) and N-cyano-N'-(3,5-dichlorophenyl)-N' '-(3-methylbutyl)guanidine (12) were synthesized and investigated for their ability to inhibit insulin release from beta cells, to repolarize beta cell membrane potential, and to relax precontracted rat aorta rings. Structural modifications gave compounds, which selectively inhibit insulin release from betaTC6 cells (e.g. compound 10: IC(50) = 5.45 +/- 1.9 microM) and which repolarize betaTC3 beta cells (10: IC(50) = 4.7 +/- 0.5 microM) without relaxation of precontracted aorta rings (10: IC(50) > 300 microM). Inhibition of insulin release from rat islets was observed in the same concentration level as for betaTC6 cells (10: IC(50) = 1.24 +/- 0.1 microM, 12: IC(50) = 3.8 +/- 0.4 microM). Compound 10 (10 microM) inhibits calcium outflow and insulin release from perifused rat pancreatic islets. The mechanisms of action of 10 and 12 were further investigated. The compounds depolarize mitochondrial membrane from smooth muscle cells and beta cell and stimulate glucose utilization and mitochondrial respiration in isolated liver cells. Furthermore, 10 was studied in a patch clamp experiment and was found to activate Kir6.2/SUR1 and inhibit Kir6.2/SUR2B type of K(ATP) channels. These studies indicate that the observed effects of the compounds on beta cells result from activation of K(ATP) channels of the cell membrane in combination with a depolarization of mitochondrial membranes. It also highlights that small structural changes can dramatically shift the efficacy of the cyanoguanidine type of selective activators of Kir6.2/SUR2 potassium channels. 相似文献
992.
Våbenø J Lejon T Nielsen CU Steffansen B Chen W Ouyang H Borchardt RT Luthman K 《Journal of medicinal chemistry》2004,47(4):1060-1069
A series of five Phe-Gly dipeptidomimetics containing different amide bond replacements have been synthesized in a facile way from the readily available unsaturated ketoester 1, and their affinities for the di-/tripeptide transporters hPEPT1 (Caco-2 cells) and rPEPT2 (SKPT cells) were tested. The compounds contained the amide bond isosteres ketomethylene (2a), (R)- and (S)-hydroxyethylidene (3a and 4a), and (R)- and (S)-hydroxyethylene (5a and 6a) to provide information on the conformational and stereochemical requirements for hPEPT1 and rPEPT2 affinity. The affinity studies showed that for rPEPT2 there is no significant difference in affinity between the ketomethylene isostere 2a and the natural substrate Phe-Gly (K(i) values of 18.8 and 14.6 microM, respectively). Also the affinities for hPEPT1 are in the same range (K(i) values of 0.40 and 0.20 mM, respectively). This corroborates earlier findings that the amide bond as such is not essential for binding to PEPTX, but the results also reveal possible differences in the binding of ketomethylene isosteres to hPEPT1 and rPEPT2. The trans-hydroxyethylidene and hydroxyethylene isosteres proved to be poor substrates for PEPTX. These results provide new information about the importance of flexibility and of the stereochemistry at the C(4)-position for this class of compounds. Furthermore, the intracellular uptake of 2a-4a in Caco-2 cells was investigated, showing a 3-fold reduction of the uptake of 2a in the presence of the competetive inhibitor Gly-Pro, indicating contribution from an active transport component. No active uptake of 3a and 4a was observed. Transepithelial transport studies also indicated active transport of 2a across Caco-2 monolayers. 相似文献
993.
Almholt DL Loechel F Nielsen SJ Krog-Jensen C Terry R Bjørn SP Pedersen HC Praestegaard M Møller S Heide M Pagliaro L Mason AJ Butcher S Dahl SW 《Assay and drug development technologies》2004,2(1):7-20
Redistribution (BioImage) A/S, S?borg, Denmark) is a novel high-throughput screening technology that monitors translocation of specific protein components of intracellular signaling pathways within intact mammalian cells, using green fluorescent protein as a tag. A single Redistribution assay can be used to identify multiple classes of compounds that act at, or upstream of, the level of the protein target used in the primary screening assay. Such compounds may include both conventional and allosteric enzyme inhibitors, as well as protein-protein interaction modulators. We have developed a series of Redistribution assays to discover and characterize compounds that inhibit tumor necrosis factor-alpha biosynthesis via modulation of the p38 mitogen-activated protein kinase (MAPK) pathway. A primary assay was designed to identify low-molecular-weight compounds that inhibit the activation-dependent nuclear export of the p38 kinase substrate MAPK-activated protein kinase 2 (MK2). Hits from the primary screen were categorized, using secondary assays, either as direct inhibitors of MK2 nuclear export, or as inhibitors of the upstream p38 MAPK pathway. Activity profiles are presented for a nuclear export inhibitor, and a compound that structurally and functionally resembles a known p38 kinase inhibitor. These results demonstrate the utility of Redistribution technology as a pathway screening method for the identification of diverse and novel compounds that are active within therapeutically important signaling pathways. 相似文献
994.
New adjuvant therapies are needed for the treatment of stage III colon cancer. The essential fatty acids, linoleic and arachidonic acid enhance tumorigenesis through the cyclooxygenase and lipoxygenase pathways. Leukotriene B4 (LTB4) is a product of 5-lipoxygenase (5-LOX) which has tumor-promoting effects. The LTB4 receptor antagonist, LY293111 inhibited tumor growth and induced apoptosis in vitro. The effectiveness of LY293111, alone and in combination with gemcitabine was investigated in a heterotopic xenograft model in athymic mice using HT29 and LoVo human colonic cancer cells. The combined therapy markedly inhibited tumor growth and could warrant consideration as a new therapeutic option. 相似文献
995.
Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles 总被引:10,自引:0,他引:10
Subramanian S West RB Corless CL Ou W Rubin BP Chu KM Leung SY Yuen ST Zhu S Hernandez-Boussard T Montgomery K Nielsen TO Patel RM Goldblum JR Heinrich MC Fletcher JA van de Rijn M 《Oncogene》2004,23(47):7780-7790
Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated. 相似文献
996.
997.
Drøjdahl N Fenger C Nielsen HH Owens T Finsen B 《Journal of neuroscience research》2004,75(2):203-217
The inflammatory cytokine tumour necrosis factor (TNF) can both induce oligodendrocyte and myelin pathology and promote proliferation of oligodendrocyte progenitor cells and remyelination. We have compared the response of the oligodendrocyte lineage to anterograde axonal (Wallerian) and terminal degeneration and lesion-induced axonal sprouting in the hippocampal dentate gyrus in TNF-transgenic mice with the response in genetically normal mice. Transectioning of the entorhino-dentate perforant path axonal projection increased hippocampal TNF mRNA expression in both types of mice, but to significantly larger levels in the TNF-transgenics. At 5 days after axonal transection, numbers of oligodendrocytes and myelin basic protein (MBP) mRNA expression in the denervated dentate gyrus in TNF-transgenic mice had increased to the same extent as in nontransgenic littermates. At this time, transgenics showed a tendency towards a greater increase in the number of juxtaposed, potentially proliferating oligodendrocytes. Noteworthy, at day 5 we also observed upregulation of MBP mRNA expression in adjacent hippocampal subregions with lesion-induced axonal sprouting, which were devoid of axonal degeneration, raising the possibility that sprouting axons provide trophic stimuli to the oligodendrocyte lineage. Twenty-eight days after lesioning, oligodendrocyte numbers and MBP mRNA expression were reduced to near normal levels. However, oligodendrocyte densities in the TNF-transgenic mice were significantly lower than in nontransgenics. We conclude that the early response of the oligodendrocyte lineage to axonal lesioning and lesion-induced axonal sprouting appears unaffected by the supranormal TNF levels in the TNF-transgenic mice. TNF may, however, have long-term inhibitory effects on the oligodendrocyte response to axonal lesioning. 相似文献
998.
Community psychiatry in Denmark has been criticized because of drop-outs of the patients with severe mental illness. In order to deal with these problems, the first Assertive Community Treatment (ACT) project in Denmark was started in the T?nder region on 1 May 2001. Before starting the clinical study, an epidemiological analysis of severe mental illness was performed. Severe mental illness was defined from register data on the basis of psychosis and high use of psychiatric services. Data concerning drop-out (inactive during a period), death and address were obtained. The point prevalence rate of severe mental illness on 31 December 2000 in S?nderjylland (SJ) county was 1.31/1000. The rate of inactive patients was 0.28/1000. The rates were distributed inhomogeneously between regions. In a 4-year cohort, half of the patients were inactive at least once. The T?nder and Aabenraa regions had homogeneous patterns. In conclusion, the register diagnosis is a target group for ACT. The register diagnosis and the status active/inactive may be used as an unbiased effect parameter. 相似文献
999.
Functional mapping of GABA A receptor subtypes in the amygdala 总被引:2,自引:0,他引:2
The physiological significance of the large diversity of GABA A receptors is poorly understood. Using mice, which carry a point mutation that renders specific subtypes of GABA A receptors diazepam insensitive, it was recently discovered that particular types of GABA A receptors are involved in specific, behaviorally relevant signaling pathways. We have used these mice to study inhibitory synaptic transmission in the amygdala. GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) per se were not affected by the point mutations. Their modulation by diazepam, however, was altered depending on the genotype of the mice studied. Based on the different responses to diazepam, we found that IPSCs in the lateral/basolateral amygdala were mediated by both alpha2- and alpha1-subunit-containing GABA A receptors whereas those in the central amygdala were mediated only by alpha2-subunit-containing GABA A receptors. Immunohistochemical staining corroborated these findings at a morphological level. To investigate a possible link between interneuron and receptor diversity, we selectively depressed release from the subset of GABAergic terminals carrying type 1 cannabinoid receptors. These receptors are known to modulate amygdala-mediated behavior. Application of a type 1 cannabinoid receptor agonist resulted in a selective reduction of inhibitory current mediated by alpha1-subunit-containing GABA A receptors. Mice with specific diazepam-insensitive GABA A receptor subtypes therefore provide a novel tool to investigate GABA A receptor distribution and the organization of inhibitory circuits at a functional level. The crucial role of the amygdala for the mediation of anxiety is in agreement with the part that alpha2-subunit-containing GABA A receptors play in anxiolysis and their important function in this area of the brain. 相似文献
1000.