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101.
Bozhkov PV Suarez MF Filonova LH Daniel G Zamyatnin AA Rodriguez-Nieto S Zhivotovsky B Smertenko A 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(40):14463-14468
Programmed cell death (PCD) is indispensable for eukaryotic development. In animals, PCD is executed by the caspase family of cysteine proteases. Plants do not have close homologues of caspases but possess a phylogenetically distant family of cysteine proteases named metacaspases. The cellular function of metacaspases in PCD is unknown. Here we show that during plant embryogenesis, metacaspase mcII-Pa translocates from the cytoplasm to nuclei in terminally differentiated cells that are destined for elimination, where it colocalizes with the nuclear pore complex and chromatin, causing nuclear envelope disassembly and DNA fragmentation. The cell-death function of mcII-Pa relies on its cysteine-dependent arginine-specific proteolytic activity. Accordingly, mutation of catalytic cysteine abrogates the proteolytic activity of mcII-Pa and blocks nuclear degradation. These results establish metacaspase as an executioner of PCD during embryo patterning and provide a functional link between PCD and embryogenesis in plants. Although mcII-Pa and metazoan caspases have different substrate specificity, they serve a common function during development, demonstrating the evolutionary parallelism of PCD pathways in plants and animals. 相似文献
102.
Ze-Jun Wang Boris Tabakoff Simon R Levinson Thomas Heinbockel 《Acta pharmacologica Sinica》2015,36(7):791-799
Aim:
Methyl eugenol is a major active component extracted from the Chinese herb Asari Radix et Rhizoma, which has been used to treat toothache and other pain. Previous in vivo studies have shown that methyl eugenol has anesthetic and antinociceptive effects. The aim of this study was to determine the possible mechanism underlying its effect on nervous system disorders.Methods:
The direct interaction of methyl eugenol with Na+ channels was explored and characterized using electrophysiological recordings from Nav1.7-transfected CHO cells.Results:
In whole-cell patch clamp mode, methyl eugenol tonically inhibited peripheral nerve Nav1.7 currents in a concentration- and voltage-dependent manner, with an IC50 of 295 μmol/L at a −100 mV holding potential. Functionally, methyl eugenol preferentially bound to Nav1.7 channels in the inactivated and/or open state, with weaker binding to channels in the resting state. Thus, in the presence of methyl eugenol, Nav1.7 channels exhibited reduced availability for activation in a steady-state inactivation protocol, strong use-dependent inhibition, enhanced binding kinetics, and slow recovery from inactivation compared to untreated channels. An estimation of the affinity of methyl eugenol for the resting and inactivated states of the channel also demonstrated that methyl eugenol preferentially binds to inactivated channels, with a 6.4 times greater affinity compared to channels in the resting state. The failure of inactivated channels to completely recover to control levels at higher concentrations of methyl eugenol implies that the drug may drive more drug-bound, fast-inactivated channels into drug-bound, slow-inactivated channels.Conclusion:
Methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. The antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral Na+ channels. 相似文献103.
104.
Alice Chan Marc D. Breton Boris P. Kovatchev 《Journal of diabetes science and technology》2008,2(5):844-852
Background
Most insulin pumps used for the treatment of diabetes perform subcutaneous insulin injections by pulses. The purpose of this work is to analyze the effects of pulsatile injections of modern insulins on plasma insulin levels compared with a continuous insulin infusion.Method
We simulate pulsatile implementations of a basal rate profile over a day on a type 1 diabetes mellitus patient using insulin lispro. Pulse periods were varied between 1 and 60 min, and random pump errors were included, modeled as white noise, 1/f noise, or 1/f2 noise with relative standard deviations up to 10% of the pump output.Results
Oscillations in plasma insulin caused by the pulsatile injections were not significant with respect to the global variations for pulse periods below 15 min. This cutoff period was found to be robust to random pump errors with standard deviations up to 10% of the pump output and hence solely determined by the insulin kinetics. Additionally, we showed that the pulse period achieving the best implementation of a continuous profile is an increasing function of the error variance for a given type of noise.Conclusions
Our findings support that continuous insulin infusion can be implemented by a pulsatile injection of insulin as infrequent as a pulse every 15 min without significant effects on plasma insulin levels. If clinically confirmed, this result would have important consequences on the design and in silico testing of automated insulin treatment strategies, as increased delivery intervals imply higher accuracy of insulin delivery and facilitated implementations of closed-loop control algorithms. 相似文献105.
High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis 总被引:1,自引:0,他引:1
Shevchenko YL Novik AA Kuznetsov AN Afanasiev BV Lisukov IA Kozlov VA Rykavicin OA Ionova TI Melnichenko VY Fedorenko DA Kulagin AD Shamanski SV Ivanov RA Gorodokin G 《Experimental hematology》2008,36(8):922-928
High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes. 相似文献
106.
James Sutphen M.D. Ph.D. Stephen Borowitz M.D. William Ling Ph.D. Daniel J. Cox Ph.D. Boris Kovatchev Ph.D. 《Diseases of the colon and rectum》1997,40(9):1051-1055
PURPOSE: We have investigated the use of anorectal manometry to distinguish encopretic-constipated children (n=88) from sibling controls (n=16) and nonsibling controls (n=11). METHODS: Study variables included manometrically determined resting and maximum voluntary anal sphincter pressure, depth and speed of rectoanal inhibitory reflex, minimum rectal volume sensation, critical distending volume for fecal urgency, rectal and anal pressure responses during attempted defecation, and ability to defecate a water-filled balloon. RESULTS: Change in anal sphincter pressure during attempted defecation (P=0.03), gradient between rectal and sphincter pressure during attempted defecation (P=0.02), critical distending volume for fecal urgency (P=0.02), and ability to defecate a water-filled balloon (P=0.05) distinguished encopretic-constipated from control children. The change in rectal pressure associated with the rectoanal inhibitory reflex just escaped significance at P=0.07. CONCLUSIONS: Anal sphincter spasm and megacolon are pathophysiologic abnormalities associated with pediatric constipation-encopresis. 相似文献
107.
Systemic and local expression of perforin in lymphocyte subsets in acute and chronic rheumatoid arthritis 总被引:2,自引:0,他引:2
Gulan G Ravlic-Gulan J Strbo N Sotosek V Nemec B Matovinovic D Rubinic D Podack ER Rukavina D 《The Journal of rheumatology》2003,30(4):660-670
OBJECTIVE: To investigate the role of the cytolytic action mediated by perforin in the course of rheumatoid arthritis (RA), we studied the immunophenotypic characteristics of lymphocytes containing perforin in peripheral blood (systemic level), in synovial fluid (SF), and in the synovial membrane (local level) in patients during the acute or chronic phase of RA. Cells from patients with osteoarthritis were used as controls. METHODS: Flow cytometry was used for simultaneous detection of intracellular (perforin) and cell surface antigens. Mean fluorescence intensity (MFI) was a measure of the mean perforin content per cell. Immunocytochemical staining was used to visualize perforin in the cytoplasmic compartment of cells. RESULTS: In acute RA highly significant changes in perforin expression were found in all compartments (peripheral blood, SF, and synovial membrane): (1) increase of percentage of total perforin positive cells; (2) increase of both subsets of cytolytic cells, T (CD8+P+) and NK (CD56+P+) cells; (3) increase in the frequency of perforin positive cells in CD8+ and CD56+ cell populations; and (4) the highest content of perforin/cell (MFI values) in all compartments, except in the synovial membrane. CONCLUSION: Perforin positive cells may participate in the acute phase of RA by maintaining and perpetuating inflammation and contributing to tissue destruction. 相似文献
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