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The recent years have seen a drastic increase in the amount of available genomic sequences. Alongside this explosion, hundreds of computational tools were developed to assess the impact of observed genetic variation. Critical Assessment of Genome Interpretation (CAGI) provides a platform to evaluate the performance of these tools in experimentally relevant contexts. In the CAGI‐5 challenge assessing the 38 missense variants affecting the human Pericentriolar material 1 protein (PCM1), our SNAP‐based submission was the top performer, although it did worse than expected from other evaluations. Here, we compare the CAGI‐5 submissions, and 24 additional commonly used variant effect predictors, to analyze the reasons for this observation. We identified per residue conservation, structural, and functional PCM1 characteristics, which may be responsible. As expected, predictors had a hard time distinguishing effect variants in nonconserved positions. They were also better able to call effect variants in a structurally rich region than in a less‐structured one; in the latter, they more often correctly identified benign than effect variants. Curiously, most of the protein was predicted to be functionally robust to mutation—a feature that likely makes it a harder problem for generalized variant effect predictors. 相似文献
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BACKGROUND: Clinical guidelines have the potential to ensure that a research knowledge base underpins practice. Their development nationally and locally has increased dramatically in recent years. The challenge lies in implementing them. This literature review of guideline implementation was conducted to inform the development of implementation strategies for the Royal College of Nursing national clinical guidelines. CONCLUSION: The evidence base for guideline implementation is still developing and many ideas and strategies require further testing. Although strategies can be developed around some core principles, as yet there is no single definitive strategy. This selective literature review offers some insight into successful implementation strategies. 相似文献
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Bozena Novotna Karolina Turnovcova Pavel Veverka Pavel Rössner Jr Yana Bagryantseva Vit Herynek 《Nanotoxicology》2016,10(6):662-670
Nanomaterials are currently the subject of intense research due to their wide variety of potential applications in the biomedical, optical and electronic fields. We prepared and tested cobalt zinc ferrite nanoparticles (Co0.5Zn0.5Fe2O4+γ [CZF-NPs]) encapsulated by amorphous silica in order to find a safe contrast agent and magnetic label for tracking transplanted cells within an organism using magnetic resonance imaging (MRI). Rat mesenchymal stem cells (rMSCs) were labeled for 48?h with a low, medium or high dose of CZF-NPs (0.05; 0.11 or 0.55?mM); silica NPs (Si-NPs; 0.11?mM) served as a positive control. The internalization of NPs into cells was verified by transmission electron microscopy. Biological effects were analyzed at the end of exposure and after an additional 72?h of cell growth without NPs. Compared to untreated cells, Annexin V/Propidium Iodide labeling revealed no significant cytotoxicity for any group of treated cells and only a high dose of CZF-NPs slowed down cell proliferation and induced DNA damage, manifested as a significant increase of DNA-strand breaks and oxidized DNA bases. This was accompanied by high concentrations of 15-F2t-isoprostane and carbonyl groups, demonstrating oxidative injury to lipids and proteins, respectively. No harmful effects were detected in cells exposed to the low dose of CZF-NPs. Nevertheless, the labeled cells still exhibited an adequate relaxation rate for MRI in repeated experiments and ICP-MS confirmed sufficient magnetic label concentrations inside the cells. The results suggest that the silica-coated CZF-NPs, when applied at a non-toxic dose, represent a promising contrast agent for cell labeling. 相似文献
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Yana Bromberg Peter C. Kahn Burkhard Rost 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(35):14255-14260
Large-scale computational analyses of the growing wealth of genome-variation data consistently tell two distinct stories. The first is expected: coding variants reported in disease-related databases significantly alter the function of affected proteins. The second is surprising: the genomes of healthy individuals appear to carry many variants that are predicted to have some effect on function. As long as the complete experimental analysis of all human genome variants remains impossible, computational methods, such as PolyPhen, SNAP, and SIFT, might provide important insights. These methods capture the effects of particular variants very well and can highlight trends in populations of variants. Diseases are, arguably, extreme phenotypic variations and are often attributable to one or a few severely functionally disruptive variants. Our findings suggest a genomic basis of the different nondisease phenotypes. Prediction methods indicate that variants in seemingly healthy individuals tend to be neutral or weakly disruptive for protein molecular function. These variant effects are predicted to be largely either experimentally undetectable or are not deemed significant enough to be published. This may suggest that nondisease phenotypes arise through combinations of many variants whose effects are weakly nonneutral (damaging or enhancing) to the molecular protein function but fall within the wild-type range of overall physiological function. 相似文献
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Rosalind Raine Martin Cartwright Yana Richens Zuhura Mahamed Debbie Smith 《Maternal and child health journal》2010,14(4):590-599
To identify key features of communication across antenatal (prenatal) care that are evaluated positively or negatively by
service users. Focus groups and semi-structured interviews were used to explore communication experiences of thirty pregnant
women from diverse social and ethnic backgrounds affiliated to a large London hospital. Data were analysed using thematic
analysis. Women reported a wide diversity of experiences. From the users’ perspective, constructive communication on the part
of health care providers was characterised by an empathic conversational style, openness to questions, allowing sufficient
time to talk through any concerns, and pro-active contact by providers (e.g. text message appointment reminders). These features
created reassurance, facilitated information exchange, improved appointment attendance and fostered tolerance in stressful
situations. Salient features of poor communication were a lack of information provision, especially about the overall arrangement
and the purpose of antenatal care, insufficient discussion about possible problems with the pregnancy and discourteous styles
of interaction. Poor communication led some women to become assertive to address their needs; others became reluctant to actively
engage with providers. General Practitioners need to be better integrated into antenatal care, more information should be
provided about the pattern and purpose of the care women receive during pregnancy, and new technologies should be used to
facilitate interactions between women and their healthcare providers. Providers require communications training to encourage
empathic interactions that promote constructive provider–user relationships and encourage women to engage effectively and
access the care they need. 相似文献