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81.
Brendel C Belakhov V Werner H Wegener E Gärtner J Nudelman I Baasov T Huppke P 《Journal of molecular medicine (Berlin, Germany)》2011,89(4):389-398
Thirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown in transfected HeLa cells that readthrough of nonsense mutations in the MECP2 gene can be achieved by treatment with gentamicin and geneticin. This study was performed to test if readthrough can also
be achieved in cells endogenously expressing mutant MeCP2 and to evaluate potentially more effective readthrough compounds.
A mouse model was generated carrying the R168X mutation in the MECP2 gene. Transfected HeLa cells expressing mutated MeCP2 fusion proteins and mouse ear fibroblasts isolated from the new mouse
model were treated with gentamicin and the novel aminoglycosides NB30, NB54, and NB84. The localization of the readthrough
product was tested by immunofluorescence. Readthrough of the R168X mutation in mouse ear fibroblasts using gentamicin was
detected but at lower level than in HeLa cells. As expected, the readthrough product, full-length Mecp2 protein, was located
in the nucleus. NB54 and NB84 induced readthrough more effectively than gentamicin, while NB30 was less effective. Readthrough
of nonsense mutations can be achieved not only in transfected HeLa cells but also in fibroblasts of the newly generated Mecp2
R168X
mouse model. NB54 and NB84 were more effective than gentamicin and are therefore promising candidates for readthrough therapy
in Rett syndrome patients. 相似文献
82.
Rowe SM Sloane P Tang LP Backer K Mazur M Buckley-Lanier J Nudelman I Belakhov V Bebok Z Schwiebert E Baasov T Bedwell DM 《Journal of molecular medicine (Berlin, Germany)》2011,89(11):1149-1161
Certain aminoglycosides are capable of inducing "translational readthrough" of premature termination codons (PTCs). However, toxicity and relative lack of efficacy deter treatment with clinically available aminoglycosides for genetic diseases caused by PTCs, including cystic fibrosis (CF). Using a structure-based approach, the novel aminoglycoside NB54 was developed that exhibits reduced toxicity and enhanced suppression of PTCs in cell-based reporter assays relative to gentamicin. We examined whether NB54 administration rescued CFTR protein and function in clinically relevant CF models. In a fluorescence-based halide efflux assay, NB54 partially restored halide efflux in a CF bronchial epithelial cell line (CFTR genotype W1282X/F508del), but not in a CF epithelial cell line lacking a PTC (F508del/F508del). In polarized airway epithelial cells expressing either a CFTR-W1282X or -G542X cDNA, treatment with NB54 increased stimulated short-circuit current (I (SC)) with greater efficiency than gentamicin. NB54 and gentamicin induced comparable increases in forskolin-stimulated I (SC) in primary airway epithelial cells derived from a G542X/F508del CF donor. Systemic administration of NB54 to Cftr-/- mice expressing a human CFTR-G542X transgene restored 15-17% of the average stimulated transepithelial chloride currents observed in wild-type (Cftr+/+) mice, comparable to gentamicin. NB54 exhibited reduced cellular toxicity in vitro and was tolerated at higher concentrations than gentamicin in vivo. These results provide evidence that synthetic aminoglycosides are capable of PTC suppression in relevant human CF cells and a CF animal model and support further development of these compounds as a treatment modality for genetic diseases caused by PTCs. 相似文献
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85.
Thong MS Mols F Lemmens VE Creemers GJ Slooter GD van de Poll-Franse LV 《European journal of cancer (Oxford, England : 1990)》2011,47(12):1798-1807
Background
This population-based study assessed the impact of chemotherapy on general and disease-specific health status of resected colon cancer survivors up to 10 years post-diagnosis.Patients and methods
Colon cancer survivors diagnosed between 1998 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC colorectal module (EORTC-QLQ-CR38). Comparisons to a normative population were conducted. Multiple linear regression analyses investigated the association between treatment and health status.Results
Eight hundred and forty eight survivors were evaluated: 29% had chemotherapy (CT); 71% without chemotherapy (nCT). Survivors had similar SF-36 scores and scored better than the normative population on several domains. On the EORTC-QLQ-CR38, male nCT survivors had more sexual problems than CT survivors (p = 0.01). Among the sexually active respondents, the survivors reported sex to be less enjoyable than the normative population (p = 0.02). In multivariate analyses, CT predicted better physical function, and less male sexual dysfunction and weight loss problems than nCT.Conclusions
Overall, CT survivors have general health status scores comparable to nCT survivors and the normative population up to 10 years since initial diagnosis. Sex-related problems among survivors suggest more attention on this often sensitive issue is required in clinical management. 相似文献86.
Protein phosphorylation and dephosphorylation are important regulators of cellular and extracellular events. The purpose of this study was to define how these events regulate cartilage matrix calcification in a cell culture system that mimics endochondral ossification. The presence of casein kinase II (CK2), an enzyme known to phosphorylate matrix proteins, was confirmed by immunohistochemistry. The importance of phosphoprotein phosphorylation and dephosphorylation was examined by comparing effects of inhibiting CK2 or phosphoprotein phosphatases on mineral accretion relative to untreated mineralizing controls. Specific inhibitors were added to differentiating chick limb-bud mesenchymal cell micromass cultures during the development of a mineralized matrix at the times of cell differentiation, proliferation, formation of the mineralized matrix, or proliferation of the mineral crystals. The mineralizing media for these cultures contained 4 mM inorganic phosphate and no organic-phosphate esters; control cultures had 1 mM inorganic phosphate. Mineralization was monitored based on (45)Ca uptake and infrared characterization of the mineral; cell viability was assessed by three independent methods. Treatments that caused cell toxicity were excluded from the analysis. Inhibition of CK2 activity with apigenin or CK2 inhibitor II reduced the rate of mineral deposition, but did not block mineral accretion. Effects were greatest during the time of mineralized matrix formation. Inhibition of phosphoprotein phosphatase activities with okadaic acid, calyculin A, and microcystin-LR, at early time points also markedly inhibited mineral accretion. Inhibition after mineralization had commenced increased the mineral yield. Levamisole, an alkaline phosphatase inhibitor, had no effect on mineral accretion in this system, suggesting the involvement of other phosphatases. Adding additional inorganic phosphate to the inhibited cultures after mineralization had started, but not earlier, reversed the inhibition indicating that the phosphatases were, in part, providing a source of inorganic phosphate. To characterize the roles of specific phosphoproteins blocking studies were performed. Blocking with anti-osteopontin antibody confirmed osteopontin's previously reported role as a mineralization inhibitor. Blocking antibodies to bone sialoprotein added from day 9 or on days 9 and 11 retarded mineralization, supporting its role as a mineralization nucleator. Antibodies to osteonectin slightly stimulated early mineralization, but had no effect after the time that initial mineral deposition occurs. Taken together, the results of this study demonstrate the importance of the phosphorylation state of extracellular matrix proteins in regulating mineralization in this culture system. 相似文献
87.
Peña R Marquina D Serrano A Elfakih Y de Baptista EA Carrizo E Fernández V Valery L Teneud L Baptista T 《Schizophrenia Research》2008,106(2-3):315-319
BACKGROUND: Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine. METHODS: This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229). RESULTS: None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration. CONCLUSIONS: Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures. 相似文献
88.
Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion 总被引:8,自引:0,他引:8 下载免费PDF全文
Scehnet JS Jiang W Kumar SR Krasnoperov V Trindade A Benedito R Djokovic D Borges C Ley EJ Duarte A Gill PS 《Blood》2007,109(11):4753-4760
Vascular development is dependent on various growth factors and certain modifiers critical for providing arterial or venous identity, interaction with the surrounding stroma and tissues, hierarchic network formation, and recruitment of pericytes. Notch receptors and ligands (Jagged and Delta-like) play a critical role in this process in addition to VEGF. Dll4 is one of the Notch ligands that regulates arterial specification and maturation events. In the current study, we have shown that loss of function by either targeted allele deletion or use of a soluble form of Dll4 extracellular domain leads to inhibition of Notch signaling, resulting in increased vascular proliferation but defective maturation. Newly forming vessels have thin caliber, a markedly reduced vessel lumen, markedly reduced pericyte recruitment, and deficient vascular perfusion. sDll4 similarly induced defective vascular response in tumor implants leading to reduced tumor growth. Interference with Dll4-Notch signaling may be particularly desirable in tumors that have highly induced Dll4-Notch pathway. 相似文献
89.
de Vries M van Weert JC Jansen J Lemmens VE Maas HA 《European journal of cancer (Oxford, England : 1990)》2007,43(15):2170-2178
Medical and nursing staff in oncology for older cancer patients are confronted with a range of problems including co-morbidity, poly-pharmacy, cognitive impairments, emotional problems, functional limitations, sensory impairment and a lack of social support. Comprehensive geriatric assessment identifies many of the existing problems and can be used to estimate life expectancy and tolerance of treatment. However, health care providers have to interpret and apply the medical and nursing information and must deal with specific problems and care needs throughout the continuum of cancer care. Imperfect interdisciplinary communication, cooperation and patient-provider communication may further complicate the care actually delivered. A clinical care pathway aims to improve continuity, increase multidisciplinary tuning and deliver appropriate patient education, treatment and care for vulnerable older cancer patients. This paper gives an overview of common problems in older cancer patients and addresses communication barriers through the development of clinical care pathways in geriatric oncology. 相似文献
90.