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排序方式: 共有3365条查询结果,搜索用时 31 毫秒
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Lurong Lian Aae Suzuki Vincent Hayes Sougata Saha Xuemei Han Tao Xu John R Yates III Mortimer Poncz Anna Kashina Charles S. Abrams 《Haematologica》2014,99(3):554-560
Protein arginylation by arginyl–transfer RNA protein transferase (ATE1) is emerging as a regulator protein function that is reminiscent of phosphorylation. For example, arginylation of β-actin has been found to regulate lamellipodial formation at the leading edge in fibroblasts. This finding suggests that similar functions of β-actin in other cell types may also require arginylation. Here, we have tested the hypothesis that ATE1 regulates the cytoskeletal dynamics essential for in vivo platelet adhesion and thrombus formation. To test this hypothesis, we generated conditional knockout mice specifically lacking ATE1 in their platelets and in their megakaryocytes and analyzed the role of arginylation during platelet activation. Surprisingly, rather than finding an impairment of the actin cytoskeleton structure and its rearrangement during platelet activation, we observed that the platelet-specific ATE1 knockout led to enhanced clot retraction and in vivo thrombus formation. This effect might be regulated by myosin II contractility since it was accompanied by enhanced phosphorylation of the myosin regulatory light chain on Ser19, which is an event that activates myosin in vivo. Furthermore, ATE1 and myosin co-immunoprecipitate from platelet lysates. This finding suggests that these proteins directly interact within platelets. These results provide the first evidence that arginylation is involved in phosphorylation-dependent protein regulation, and that arginylation affects myosin function in platelets during clot retraction. 相似文献
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Purpose: To review literature specific to the use of AAC with adults who have severe aphasia. Method: The authors reviewed studies involving AAC interventions for adults with severe aphasia. Results: Published data support the use of aided and unaided AAC with adults with severe aphasia in controlled treatment contexts. Reported gains in communication typically have not generalized to everyday settings. Conclusions: The application of AAC with persons with severe aphasia must address factors potentially limiting treatment success outside of training environments. 相似文献
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AndrewJ. Stott Michel C. Maillard Vahri Beaumont David Allcock Omar Aziz Alexander H. Borchers Wesley Blackaby Perla Breccia Gillian Creighton-Gutteridge Alan F. Haughan Rebecca E. Jarvis Christopher A. Luckhurst Kim L. Matthews George McAllister Scott Pollack Elizabeth Saville-Stones Amanda J. Van de Poël Huw D. Vater Julie Vann Rachel Williams Dawn Yates Ignacio Muoz-Sanjun Celia Dominguez 《ACS medicinal chemistry letters》2021,12(3):380
Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC50, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease. 相似文献
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T.R. Rudd A. Hughes J. Holman E. de Oliveira Ferreira R.M. Cavalcante Pilotto Domingues E.A. Yates 《Brazilian journal of medical and biological research》2012,45(5):386-391
Heparan sulphate (HS) and the related polysaccharide, heparin, exhibit conformational and charge arrangement properties, which provide a degree of redundancy allowing several seemingly distinct sequences to exhibit the same activity. This can also be mimicked by other sulphated polysaccharides, both in overall effect and in the details of interactions and structural consequences of interactions with proteins. Together, these provide a source of active compounds suitable for further development as potential drugs. These polysaccharides also possess considerable size, which bestows upon them an additional useful property: the capability of disrupting processes comprising many individual interactions, such as those characterising the attachment of microbial pathogens to host cells. The range of involvement of HS in microbial attachment is reviewed and examples, which include viral, bacterial and parasitic infections and which, in many cases, are now being investigated as potential targets for intervention, are identified. 相似文献
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Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy 总被引:3,自引:0,他引:3
Kwok S Selby PL McElduff P Laing I Mackness B Mackness MI Prais H Morgan J Yates AP Durrington PN Sci FM 《Clinical endocrinology》2004,61(6):760-767
OBJECTIVE: Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. DESIGN AND MEASUREMENTS: Thirty-four women were treated with conjugated equine oestrogens (CEE) 0.625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 microg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. RESULTS: The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P < 0.01) and fibrinogen (P < 0.001). CEE raised serum triglyceride (P < 0.001) and CRP (P < 0.01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0.05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP. CONCLUSION: Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision. 相似文献