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71.
Dong Guo Suzanne N Venhorst Arnault Massink Jacobus P D van Veldhoven Georges Vauquelin Adriaan P IJzerman Laura H Heitman 《British journal of pharmacology》2014,171(23):5295-5312
Background and Purpose
Many GPCRs can be allosterically modulated by small-molecule ligands. This modulation is best understood in terms of the kinetics of the ligand–receptor interaction. However, many current kinetic assays require at least the (radio)labelling of the orthosteric ligand, which is impractical for studying a range of ligands. Here, we describe the application of a so-called competition association assay at the adenosine A1 receptor for this purpose.Experimental Approach
We used a competition association assay to examine the binding kinetics of several unlabelled orthosteric agonists of the A1 receptor in the absence or presence of two allosteric modulators. We also tested three bitopic ligands, in which an orthosteric and an allosteric pharmacophore were covalently linked with different spacer lengths. The relevance of the competition association assay for the binding kinetics of the bitopic ligands was also explored by analysing simulated data.Key Results
The binding kinetics of an unlabelled orthosteric ligand were affected by the addition of an allosteric modulator and such effects were probe- and concentration-dependent. Covalently linking the orthosteric and allosteric pharmacophores into one bitopic molecule had a substantial effect on the overall on- or off-rate.Conclusion and Implications
The competition association assay is a useful tool for exploring the allosteric modulation of the human adenosine A1 receptor. This assay may have general applicability to study allosteric modulation at other GPCRs as well.Table of LinksTARGETS | LIGANDS | |
---|---|---|
Adenosine A1 receptor | CCPA | DPCPX |
CPA | NECA |
72.
Miriam C. Peeters Qilan Li Rachel Elands Gerard J.P. van Westen Eelke B. Lenselink Christa E. Müller Adriaan P. IJzerman 《Biochemical pharmacology》2014
G protein-coupled receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Most, if not all, GPCRs also display a basal level of biological response in the absence of such a stimulus. This level of so-called constitutive activity results from a delicate energy equilibrium that exists between the active and the inactive state of the receptor and is the first determinant in the GPCR activation mechanism. Here we describe new insights in specific regions of the adenosine A2B receptor that are essential in activation and inactivation. We developed a new screening method using the MMY24 S. Cerevisiae strain by which we were able to screen for constitutively inactive mutants receptors (CIMs). We applied this screening method on a mutagenic library of the adenosine A2B receptor, where random mutations were introduced in transmembrane domains four and five (TM4 and TM5) linked by extracellular loop 2 (EL2). The screen resulted in the identification of 22 single and double mutant receptors, all showing a decrease in constitutive activity as well as in agonist potency. By comparing these results with a previous screen of the same mutagenic library for constitutively active mutant receptors (CAMs), we discovered specific regions in this G protein-coupled receptor involved in either inactivation or activation or both. The results suggest the activation mechanism of GPCRs to be much less restricted to sites of high conservation or direct interaction with the ligand or G protein and illustrate how dynamic the activation process of GPCRs is. 相似文献
73.
Dludla Phiwayinkosi V. Nyambuya Tawanda M. Johnson Rabia Silvestri Sonia Orlando Patrick Mazibuko-Mbeje Sithandiwe E. Gabuza Kwazi B. Mxinwa Vuyolwethu Mokgalaboni Kabelo Tiano Luca Muller Christo J. F. Louw Johan Nkambule Bongani B. 《Heart failure reviews》2021,26(6):1437-1445
Heart Failure Reviews - Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure–related outcomes... 相似文献
74.
Avivit Cahn MD Stephen D. Wiviott MD Ofri Mosenzon MD Sabina A. Murphy MPH Erica L. Goodrich MS Ilan Yanuv MSc Aliza Rozenberg MA John P. H. Wilding MD Lawrence A. Leiter MD Deepak L. Bhatt MD Darren K. McGuire MD Leon Litwak MD Adriaan Kooy MD Ingrid A. M. Gause-Nilsson MD Martin Fredriksson MD Anna Maria Langkilde MD Marc S. Sabatine MD Itamar Raz MD 《Diabetes, obesity & metabolism》2021,23(1):29-38
75.
Genetic variation in the 22q11 locus and susceptibility to schizophrenia 总被引:10,自引:0,他引:10
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Liu H Abecasis GR Heath SC Knowles A Demars S Chen YJ Roos JL Rapoport JL Gogos JA Karayiorgou M 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(26):16859-16864
An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes. 相似文献
76.
Aetiology,timing and clinical predictors of early vs. late readmission following index hospitalization for acute heart failure: insights from ASCEND‐HF
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Marat Fudim Christopher M. O'Connor Allison Dunning Andrew P. Ambrosy Paul W. Armstrong Adrian Coles Justin A. Ezekowitz Stephen J. Greene Marco Metra Randall C. Starling Adriaan A. Voors Adrian F. Hernandez G. Michael Felker Robert J. Mentz 《European journal of heart failure》2018,20(2):304-314
Aims
Patients hospitalized for heart failure (HF) are at high risk for 30‐day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization.Methods and results
Timing and cause of readmission in the ASCEND‐HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0–7 days and 8–30 days post‐discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post‐randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180‐day outcomes. Of the 6584 patients (92%) in the ASCEND‐HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non‐HF causes. The median time to rehospitalization was 11 days (interquartile range: 6–18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180‐day all‐cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93–2.94; P < 0.001]. Risk for 180‐day all‐cause death did not differ according to early vs. late readmission (HR 0.99, 95% CI 0.67–1.45; P = 0.94).Conclusions
In this hospitalized HF trial population, a significant majority of 30‐day readmissions were for non‐HF causes and one‐third of readmissions occurred in the first 7 days. Early and late readmissions within the 30‐day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission.77.
Dr. K. Jaskiewicz MD PhD J. A. Louw MD I. N. Marks MD 《Digestive diseases and sciences》1993,38(5):937-943
Thirty-six patients with nonhealing or recurrent duodenal ulcers (DU) were treated with omeprazole; 20 mg/day for one month followed by triple therapies (metronidazole, 400 mg three times a day, tetracyclin, 500 mg four times a day with either colloidal bismuth, 120 mg four times a day or sucralfate 1 g four times a day. At least two gastric mucosal samples were collected from the antral portion of the stomach and from the duodenum before and immediately after omeprazole therapy and four weeks after completion of triple therapies. Samples were fixed in buffered formaldehyde and glutaraldehyde and examined histologically and histochemically for inflammation, density ofH. pylori colonization, and immunohistochemically for the density of gastrin-secreting cells, immunoglobulins (IgA, IgG, IgM), kappa and lambda light chains and T-lymphocyte population.H. pylori colonization of the antral mucosa before treatment was noted in 100% and active gastritis in 86% of patients. The histologically assessed clearance rate after omeprazole treatment was 47.3%, and after triple therapies, 69.5%. The prevalence of gastritis was observed in 63.9% and 33.3% respectively. All therapies were associated with an accumulation of serous fluid, increased population of lymphocytes and plasma cells, and secretion of immunoglobulins, particularly IgG and IgM in the upper part of the lamina propria. These changes, together with increased numbers of T lymphocytes within the crypt epithelium and the lamina propria, were associated with the presence ofH. pylori organisms. Increased cellular response of the lamina propria and accumulation of immunoglobulins in the upper part of mucosa-even with histologically assessed clearance-may indicate a lack of complete eradication ofH. pylori and predict relapse of DU. Omeprazole-treated patients had hyperplasia of gastrin-secreting cells in the antrum, irrespective of the presence or absence ofH. pylori.This study was supported by the SA Medical Research Council. 相似文献
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80.
Tze J. Lam Adriaan A. van Bodegraven Richelle J. F. Felt-Bersma 《International journal of colorectal disease》2014,29(8):923-929