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81.
82.
Mai A Artico M Valente S Sbardella G Turini P Befani O Vedova LD Agostinelli E 《Medicinal chemistry (Shāriqah (United Arab Emirates))》2005,1(2):117-124
A novel series of 5-substituted-3-(1H-pyrrol-2-yl)-2-oxazolidinones 2a-s has been described as pyrrole analogues of toloxatone and befloxatone, two phenyl-oxazolidinones active as anti-MAO agents and used in antidepressant therapy. Tested against MAO-A and MAO-B enzymes, the majority of 2a-s show highly potent inhibitory effect against the A isoform of the enzyme, with Ki values in the range 0.52-0.004 microM, whilst their anti-MAO-B activity is considerably lower (Ki = >100-0.5 microM). Structurally, 2a-s differs for the substituent inserted at the C5 position of the 2-oxazolidinone ring (hydroxymethyl (2a-d), methoxymethyl (2e-h), azidomethyl (2i-l), methylaminomethyl (2m-p), and aminomethyl (2q-s)), and the size of the alkyl chain at the pyrrole N1 position (methyl, ethyl, allyl, or benzyl). As a rule, apart from the C5 substitution, the bulkier is the alkyl group at the pyrrole-N1, the lower is the anti-MAO-A activity of the compounds, being the N1-methyl derivatives 2a, 2e, 2i, and 2q among the most potent (K(iMAO-A) = 0.087-0.004 microM) and A-selective (A-selectivity ratio: >11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (K(iMAO-A) = 0.009 microM) and the N1-allylpyrrole 2o (K(iMAO-A) = 0.04 microM). In comparison with the reference drugs, these highly active derivatives are more potent than toloxatone, slightly less potent than befloxatone, and several times more A-selective than both the references. Such results indicate that 2a-s may represent a new promising series of antidepressant agents. 相似文献
83.
CpG motifs of DNA vaccines induce the expression of chemokines and MHC class II molecules on myocytes 总被引:5,自引:0,他引:5
Determining how an immune response is initiated after in vivo transfection of myocytes with plasmids encoding foreign antigens is essential to understand the mechanisms of intramuscular (i. m.) genetic immunization. Since myocytes are facultative antigen-presenting cells lacking MHC class II and co-stimulatory molecules, it was assumed that their unique role upon DNA vaccination is to synthesize and secrete the protein encoded by the plasmid. Here we describe that i. m. injection of unmethylated CpG motifs induced the expression of chemokines (monocyte chemotactic protein-1) and MHC class II molecules on myocytes. Our results indicate that immunostimulatory DNA sequences (CpG motifs) of DNA vaccines augment synthesis of chemokine by myocytes with subsequent recruitment of inflammatory cells secreting IFN-gamma, a potent cytokine that up-regulates the expression of MHC class II molecules on myocytes. A myoblast cell line triple transfected with plasmids encoding MHC class II molecules and an immunodominant CD4 T cell epitope of influenza virus presented the endogenously synthesized peptide and activated specific T cells. These findings suggest that one mechanism for the immunogenicity of DNA vaccines consists in the presentation of peptides to CD4 T cells by in vivo plasmid-transfected myocytes. 相似文献
84.
Enrico M Trecarichi Mario Tumbarello de Gaetano Katleen Donati Enrica Tamburrini Roberto Cauda Christina Brahe Francesco D Tiziano 《AIDS research and therapy》2006,3(1):22-4
Despite multiple sexual exposure to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN). The
mechanisms underlying this resistance remain still unclear, although a multifactorial pathogenesis can be hypothesised. Although
several genetic factors have been related to HIV-1 resistance, the homozigosity for a mutation in CCR5 gene (the 32 bp deletion, i.e. CCR5-Delta32 allele) is presently considered the most relevant one. In the present study we
analysed the genotype at CCR5 locus of 30 Italian ESN individuals (case group) who referred multiple unprotected heterosexual intercourse with HIV-1 seropositive
partner(s), for at least two years. One hundred and twenty HIV-1 infected patients and 120 individuals representative of the
general population were included as control groups. Twenty percent of ESN individuals had heterozygous CCR5-Delta 32 genotype,
compared to 7.5% of HIV-1 seropositive and 10% of individuals from the general population, respectively. None of the analysed
individuals had CCR5-Delta 32 homozygous genotype. Sequence analysis of the entire open reading frame of CCR5 was performed in all ESN subjects and no polymorphisms or mutations were identified. Moreover, we determined the distribution
of C77G variant in CD45 gene, which has been previously related to HIV-1 infection susceptibility. The frequency of the C77G
variant showed no significant difference between ESN subjects and the two control groups. 相似文献
85.
Coiera E 《International journal of medical informatics》2003,69(2-3):205-222
OBJECTIVE: This paper presents a framework for the design of interactions between human and computational agents working in organisations, mediation by technological systems. DESIGN: The design of interactions within an organisation is viewed from the point of view, not of the technology mediating the new interaction, but of the human and computational agents who interact with each other. RESULTS: Understanding the limits to individual agent resources permits an analysis of the impact that a new interaction will have in a given setting. When we look beyond simple interaction settings, we can use the notion of interaction equilibria to predict the impact of new information and communication technologies within an organisation. Economic supply and demand curves, for example, may allow us to make both qualitative and quantitative predictions about technological adoption of communication systems. CONCLUSION: Rather than focusing solely on characteristics of individual technologies, or psychological and social issues, these can be combined to explain the overall decisions that individuals make when using technologies. Without necessarily understanding all the local decision criteria used by any individual, we can make robust predictions about how a group as a whole will interact. 相似文献
86.
Antonio Marchetti Fiamma Buttitta Salvatore Girlando Paolo Dalla Palma Silvia Pellegrini Paolo Fina Claudio Doglioni Generoso Bevilacqua Mattia Barbareschi 《The Journal of pathology》1995,175(1):31-38
This study investigates the mdm2 gene status and expression in 66 surgically resected human breast carcinomas, with correlations with clinico-pathological and biological data (histological type, grading, steroid receptor status, p53 expression, proliferative activity). Four (7.7 per cent) out of 52 informative cases bear mdm2 gene amplification (four- to ten-fold) and 8 (15.4 per cent) of 52 cases showed borderline amplification (three-fold). Nine (13.6 per cent) out of 66 cases showed strong mdm2 nuclear immunoreactivity. Twenty-seven (40.9 per cent) cases showed isolated mdm2 reactive nuclei. All cases with clear amplification showed a high percentage of mdm2 immunoreactive nuclei. The relationship between gene amplification and mdm2 protein expression is highly significant (P<0.0001). No association was observed between mdm2 gene amplification and any of the considered clinico-pathological and biological parameters, while mdm2 immunoreactivity showed a significant association only with oestrogen receptor immunoreactivity (P=0.009). p53 expression was associated neither with mdm2 gene amplification nor with mdm2 immunoreactivity. It could be tempting to hypothesize that the evaluation of the combined mdm2/p53 immunohistochemical phenotype in human breast carcinoma could give us better prognostic information than the evaluation of the expression of the p53 protein alone. 相似文献
87.
88.
89.
Dick Jaarsma Maria R Dino Hitoshi Ohishi Ryuichi Shigemoto Enrico Mugnaini 《Journal of neurocytology》1998,27(5):303-327
Unipolar brush cells (UBCs) are a class of small neurons that are densely concentrated in the granular layers of the vestibulocerebellar cortex and dorsal cochlear nucleus. The UBCs form giant synapses with individual mossy fibre rosettes on the dendrioles which make up their brush formations and are provided with numerous, unusual non-synaptic appendages. In accord with the glutamatergic nature of mossy fibres, our previous post-embedding immunocytochemical studies indicated that various ionotropic glutamate receptor subunits are localized at the post-synaptic densities of the giant synapses, whereas the non-synaptic appendages are immunonegative. On the contrary, the metabotropic glutamate receptors mGluR1 and mGluR2/3 are situated at the non-synaptic appendages and are lacking at the post-synaptic densities. Other authors, however, have shown that antibodies to these metabotropic receptors stain both appendages and post-synaptic densities. In the present study, we have re-evaluated the distribution of metabotropic glutamate receptors in the UBCs of the cerebellum and the cochlear nuclear complex by light and electron microscopic pre-embedding immunocytochemistry with subtype-specific antibodies. We confirm that UBCs dendritic brushes are densely immunostained by antibody to mGluR1 particularly in the cerebellum and that antibody to mGluR2/3 labels at least a percentage of the UBC brushes in both the cerebellum and cochlear nuclei. At the ultrastructural level, it appears that mGluR1 and mGluR2/3 immunoreactivities are not associated with the post-synaptic densities of the giant mossy fibre–UBC synapses, but instead are concentrated on the non-synaptic appendages of the cerebellar UBCs. The non-synaptic appendages, therefore, may be an important avenue for regulating the excitability of UBCs and mediating glutamate effects on their still unknown intracellular signal transduction cascades. We also show that the pre-synaptic densities of UBC dendrodendritic junctions are mGluR2/3 positive. As previously demonstrated, antibodies to mGluR1 and mGluR2/3 label subsets of Golgi cells. Antibody to mGluR5 does not stain UBCs in the cerebellum and cochlear nucleus and reveals the somatodendritic compartment of Golgi cells situated in the core of the cerebellar granular layer, whilst cochlear nucleus Golgi cells are mGluR5 negative. 相似文献
90.
9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene 总被引:5,自引:2,他引:5
Carbonara Caterina; Longa Lucia; Grosso Enrico; Borrone Carla; Garre Maria Grazia; Brisigotti Massimo; Migone Nicola 《Human molecular genetics》1994,3(10):1829-1832
Tuberous sclerosis is an autosomal dominant disease whose characteristicfeature is the development of multiple hamartomas in a varietyof organs and tissues. Two major loci have been identified sofar: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3.Loss of heterozygosity at 16p13.3-associated markers has beenrecently observed in hamartomatous lesions of some tuberoussclerosis patients. Here we report the first evidence of lossof heterozygosity at the TSC1 critical region in a giant cellastrocytoma of a familial tuberous sclerosis case. Segregationanalysis showed that the 9q34 haplotype lost carried the putativenormal TSC1 gene. These data support the hypothesis of botha germline and somatic loss-of-function mutation for the developmentof tuberous sclerosis hamartomas and suggest a tumor-suppressor-likeactivity also for the TSC1 gene product. Finally, the possiblesignificance of a second small region of loss of heterozygosityat 9p21, found in the same astrocytoma, is discussed. 相似文献