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71.
Michael L. Nickerson Allen D. Bosley Jayne S. Weiss Brittany N. Kostiha Yoshihisa Hirota Wolfgang Brandt Dominic Esposito Shigeru Kinoshita Ludger Wessjohann Scott G. Morham Thorkell Andresson Howard S. Kruth Toshio Okano Michael Dean 《Human mutation》2013,34(2):317-329
Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone‐4 (MK‐4, vitamin K2), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK‐4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177‐mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two‐hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate‐binding cleft and substrate‐binding overlaps with GGPP binding, an MK‐4 substrate, suggesting potential competition between these metabolites. Impaired MK‐4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK‐4 in maintaining cornea health and visual acuity. 相似文献
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74.
Ivonne Regel Susanne Raulefs Simone Benitz Charlotte Mihaljevic Simon Rieder Georg Leinenkugel Katja Steiger Anna Melissa Schlitter Irene Esposito Julia Mayerle Bo Kong Jörg Kleeff Christoph W. Michalski 《Pancreatology》2019,19(1):149-157
Background
Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown.Methods
To uncover the role of TLR3 signaling in acute pancreatitis, we induced a cerulein-mediated pancreatitis in Tlr3 and Ticam1 knockout (KO) mice and in wildtype animals. The exocrine damage was determined by blood serum analysis and histological examination. Immunohistochemistry, gene expression and immunoblot analysis were conducted to study TLR3 function.Results
After the induction of an acute pancreatitis, wildtype mice showed a high endosomal TLR3 expression in acinar cells. In comparison to wildtype and Ticam1 KO mice, Tlr3 KO mice exhibited the highest severity of pancreatitis with an increased NF-κB activation and elevated expression of the pro-inflammatory cytokines Il6 and Tnf, although the amount of infiltrating immune cells was unaffected. Additionally, we detected a strong elevation of acinar cell necrosis and reduced levels of cleaved caspase 8 in Tlr3 and Ticam1 KO mice.Conclusions
TLR3 and its downstream adaptor TICAM1 are important mediators of acinar cell damage in acute pancreatitis. They possess a critical role in programmed cell death and our data suggest that TLR3 signaling controls the onset and severity of acute pancreatitis. 相似文献75.
Transforming growth factor beta 1 inhibits gonadotropin action in cultured porcine Sertoli cells. 总被引:3,自引:0,他引:3
A M Morera G Esposito C Ghiglieri M A Chauvin D J Hartmann M Benahmed 《Endocrinology》1992,130(2):831-836
In the present study, we have tested the effects of transforming growth factor beta 1 (TGF beta 1) on FSH action toward aromatase activity and lactate production in cultured Sertoli cells isolated from immature porcine testes. Whereas treatment of Sertoli cells with FSH resulted in a dose-dependent increase (about 7-fold) in aromatase activity (conversion of testosterone into estradiol) (ED50 = 80 ng/ml FSH), the addition of TGF beta 1 reduced this gonadotropin action. The inhibitory effect of TGF beta 1 on FSH aromatase activity was dose dependent (ED50 = 0.1 ng/ml, 4 pM TGF beta 1) with a maximal decrease (about 40%) observed after a long term (48-h) treatment. TGF beta 1 exerted its inhibitory effect on FSH action at the level(s) of cAMP accumulation, exerting no apparent effect on the gonadotropin receptor or at a site(s) related to cAMP action. TGF beta 1 (2 ng/ml) significantly (P less than 0.002) reduced (52% decrease) FSH-stimulated cAMP levels in cultured porcine Sertoli cells. However, such an inhibitory effect of the growth factor was no longer observed when stimulation of cAMP accumulation with FSH occurred in the presence of methyl isobutyl xanthine (0.5 mM), an inhibitor of cAMP-phosphodiesterase activity. This observation suggests that TGF beta 1 decreased cAMP levels by increasing catabolism of the cyclic nucleotide through an enhancement of cAMP-phosphodiesterase activity. The inhibitory effect of TGF beta 1 was not limited to the action of FSH on aromatase activity but also extended to the gonadotropin action (mediated by cAMP) on lactate production. As for the inhibitory effect of TGF beta 1 on FSH-induced aromatase activity, the inhibitory effect of the growth factor on FSH-stimulated lactate production was dose and time dependent with a maximal decrease (about 30%) observed in the picomolar range (1 ng/ml, 40 pM) after 48 h treatment with TGF beta 1. In conclusion, the present study demonstrates that TGF beta 1 attenuates FSH action on Sertoli cell activity and that such inhibitory action is potentially exerted through a decrease in cAMP levels. Because of the local production of TGF beta 1, it is suggested that the effects of the growth factor reported here might be exerted in the context of the testicular paracrine mechanisms. 相似文献
76.
Shiva K. Annamalai Michele L. Esposito Lena Jorde Theodore Schreiber Shelley A. Hall William W. ONeill Navin K. Kapur 《Journal of cardiac failure》2018,24(10):706-710
Background
Myocarditis complicated by cardiogenic shock remains a complex problem. The use of acute mechanical circulatory support devices for cardiogenic shock is growing. We explored the utility of Impella transvalvular microaxial flow catheters in the setting of myocarditis with cardiogenic shock.Methods and Results
We retrospectively analyzed data from 21 sites within the cVAD registry, an ongoing multicenter voluntary registry at sites in North America and Europe that have used Impella in patients with myocarditis. Myocarditis was defined by endomyocardial biopsy (n?=?11) or by clinical history without angiographic evidence of coronary disease (n?=?23). A total of 34 patients received an Impella 2.5, CP, 5.0, or RP device for cardiogenic shock complicating myocarditis. Baseline characteristics included age 42 ± 17 years, left ventricular ejection fraction (LVEF) 18% ± 10%, cardiac index 1.82 ± 0.46 L·min?1·m?2, pulmonary capillary wedge pressure 25 ± 7 mm Hg, and lactate 27 ± 31 mg/dL. Before Impella placement, 32% (n?=?11) of patients required intra-aortic balloon pump. Mean duration of Impella support was 91 ± 74 hours; 21 of 34 patients (62%) survived the index hospitalization and were discharged with an improved mean LVEF of 37.32% ± 20.31% (P?=?.001); 15 patients recovered with successful support, 5 patients were transferred to another hospital on initial Impella support, 1 patient underwent orthotopic heart transplantation. Ten patients required transition to another mechanical circulatory support device.Conclusions
This is the largest analysis of Impella-supported myocarditis cases to date. The use of Impella appears to be safe and effective in the settings of myocarditis complicated by cardiogenic shock. 相似文献77.
78.
Cdric Farges Olivier Cointault Marlne Murris Laurence Lavayssiere Shrazade Lakhdar‐Ghazal Arnaud Del Bello Anne‐Laure Hebral Laure Esposito Marie‐Batrice Nogier Federico Sallusto Xavier Iriart Elena Charpentier Joelle Guitard Fabrice Muscari Camille Dambrin Lydie Porte Nassim Kamar Sophie Cassaing Stanislas Faguer 《Transplant infectious disease》2020,22(1)
79.
Anna Esposito Eliana De Gregorio Maria De Fenza Daniele D'Alonzo Anil Satawani Annalisa Guaragna 《RSC advances》2019,9(37):21519
The synthesis of deflazacort (DFZ) and a preliminary evaluation of its microbial activity against the human pathogens Acinetobacter baumannii and Staphylococcus aureus is herein reported. While DFZ is inactive, one of its synthetic precursors showed a strong antibacterial activity against both Gram-negative and -positive bacteria.Synthesis of deflazacort: unexpected antibacterial activity of its epoxide synthetic precursor. 相似文献
80.