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1.
Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas. 相似文献
2.
The main features of central 5-HT1 receptors 总被引:1,自引:0,他引:1
M Hamon L Lanfumey S el Mestikawy C Boni M C Miquel F Bola?os L Schechter H Gozlan 《Neuropsychopharmacology》1990,3(5-6):349-360
The 5-HT1 receptor family comprises five different pharmacologic subtypes, designated 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1E, whose common property is to bind 5-HT with nanomolar affinity. Recent investigations with molecular biology approaches led to the cloning and sequencing of 5-HT1A receptors in the rat and in the human, and of the 5-HT1C receptor in the rat. Although the 5-HT1A and 5-HT1C protein binding subunits exhibit the same structure with seven hydrophobic transmembrane domains, an extracellular N terminal and an intracellular C tail, their respective amino-acid sequences are markedly different. Indeed, a higher degree of sequence homology is found between the 5-HT1C and 5-HT2 receptors than between the former and 5-HT1A receptors, suggesting that the 5-HT1C subtype in fact belongs to the 5-HT2 class of central 5-HT receptors. All other 5-HT1 receptor subtypes are negatively coupled to adenylyl cyclase, whereas the 5-HT1C subtype, like 5-HT2 receptors, is positively coupled to phospholipase C. The respective regional distributions and regulatory properties, as well as pending questions regarding the ultrastructural localization, synthesis, mutual interactions, and axonal flow of 5-HT1 receptor subtypes, are also discussed. 相似文献
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4.
Bola Lukman Solanke Semiu Adebayo Rahman Peter Olasupo Ogunjuyigbe 《Health & social care in the community》2021,29(4):992-1000
Existing studies have established several individual drivers of health facility delivery in many developing countries. However, the community characteristics that drive health facility delivery have been less studied across developing countries. This study thus examines the extent to which community characteristics drives health facility delivery among women who had recent live births in Nigeria based on data from the 2018 Nigeria Demographic and Health Survey (NDHS). A weighted sample size of 7,342 women was analysed. The outcome variable was health facility delivery. The explanatory variables were selected individual and community characteristics. Results show 39.7% prevalence of health facility delivery among the women. Findings further reveals that the community characteristics have significant effects on the variations in health facility delivery across the communities. Community characteristics significantly drive health facility delivery in Nigeria. More community-based priority actions are required to improve demand for health facility delivery in the country. 相似文献
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6.
It is currently very rare to find mammary involvement in cases of tuberculosis, in either primary or secondary form. Diagnosis
is classically clinical and microbiological, and the basic techniques used in imaging diagnosis are mammography and ultrasound.
Computed tomography may define the involvement of the thoracic wall in those cases which present as mammary masses adhering
to deep levels, and is also able to evaluate accompanying pulmonary disease, if it is present. Traditionally, treatment has
consisted of quadrantectomy and specific antibiotic therapy. We present a case of tuberculous mammary abscess secondary to
pulmonary disease, which was treated by percutaneous drainage controlled by CT and specific antibiotic therapy. We revise
the diagnosis, differential diagnosis and treatment of mammary tuberculosis.
Received: 27 July 1998; Revision received: 2 February 1999; Accepted: 20 April 1999 相似文献
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P Lasso D Mesa N Bolaños A Cuellar F Guzman Z Cucunuba F Rosas V Velasco MC Thomas MC Lopez JM Gonzalez CJ Puerta 《BMC infectious diseases》2012,12(1):198
ABSTRACT: BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas' disease, is an obligate intracellular parasite which induces a CD8+ T cell immune response with secretion of cytokines and release of cytotoxic granules. Although an immune-suppressive effect of T. cruzi on the acute phase of the disease has been described, little is known about the capacity of CD8+ T cell from chronic chagasic patients to respond to a non-T. cruzi microbial antigen.Methods and resultsIn the present paper, the frequency, phenotype and the functional activity of the CD8+ T cells specific from Flu-MP*, an influenza virus epitope, were determined in 13 chagasic patients and 5 healthy donors. The results show that Flu-MP* peptide specific CD8+ T cells were found with similar frequencies in both groups. In addition, Flu-MP* specific CD8+ T cells were distributed in the early or intermediate/late differentiation stages without showing enrichment of a specific sub-population. The mentioned Flu-MP* specific CD8+ T cells from chagasic patients were predominately TEM (CCR7- CD62L-), producing IL-2, IFNgamma, CD107a/b and perforin, and did not present significant differences when compared with those from healthy donors. CONCLUSIONS: Our results support the hypothesis that there is no CD8+ T cell nonspecific immune-suppression during chronic Chagas disease infection. Nonetheless, other viral antigens must be studied in order to confirm our findings. 相似文献
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10.
Guzmán RE Bolaños P Delgado A Rojas H DiPolo R Caputo C Jaffe EH 《Pflügers Archiv : European journal of physiology》2007,454(1):131-141
Cytoskeletal F-actin associated with synaptic vesicles and granules plays an important role during Ca2+-mediated exocytosis. In the present work, we have used amperometry and confocal fluorescence to study the role of internal
Ca2+ in the rearrangement of F-actin (visualised with phalloidin-Alexa 546) during exocytosis in rat mast cells. The F-actin-depolymerising
drug, latrunculin A, and the ryanodine receptor agonists ryanodine and caffeine that, per se did not induce exocytosis, enhanced
the exocytotic responses elicited by compound 48/80 (C48/80). They also induced cortical actin depolymerisation in the presence
or absence of external Ca2+. Degranulation induced by C48/80 was accompanied by the formation of a cytoplasmic F-actin network. Depletion of internal
Ca2+ with cyclopiazonic acid inhibited latrunculin potentiation of C48/80-stimulated exocytosis and completely blocked the formation
of the cytoplasmic F-actin network. This indicates that the mobilisation of Ca2+ from ryanodine-sensitive intracellular stores plays an important role in the depolymerisation of the cortical F-actin barrier
and possibly in the formation of the internal F-actin network during exocytotic activation of peritoneal mast cells. 相似文献