全文获取类型
收费全文 | 488篇 |
免费 | 31篇 |
专业分类
519篇 |
出版年
2023年 | 3篇 |
2022年 | 11篇 |
2021年 | 14篇 |
2020年 | 10篇 |
2019年 | 13篇 |
2018年 | 10篇 |
2017年 | 13篇 |
2016年 | 14篇 |
2015年 | 28篇 |
2014年 | 30篇 |
2013年 | 40篇 |
2012年 | 44篇 |
2011年 | 49篇 |
2010年 | 32篇 |
2009年 | 27篇 |
2008年 | 24篇 |
2007年 | 23篇 |
2006年 | 18篇 |
2005年 | 18篇 |
2004年 | 8篇 |
2003年 | 19篇 |
2002年 | 14篇 |
2001年 | 5篇 |
2000年 | 13篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1997年 | 1篇 |
1996年 | 5篇 |
1995年 | 2篇 |
1993年 | 5篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1988年 | 2篇 |
1986年 | 6篇 |
1984年 | 2篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1943年 | 2篇 |
排序方式: 共有519条查询结果,搜索用时 0 毫秒
1.
A R Gamble J A Bell J E Ronan D Pearson I O Ellis 《BMJ (Clinical research ed.)》1993,306(6873):295-298
OBJECTIVES--To determine whether variations in the expression of tumour related antigens can predict the origin of tumours. DESIGN--Immunohistological study of tumour marker expression in primary adenocarcinomas and respective metastatic deposits. Antibodies to the following tumour markers were used: polymorphic epithelial mucin (NCRC-11 and SM3), carcinoembryonic antigen, carcinoembryonic antigen with non-specific antigen co-specificity, CA125, CA19.9, prostate specific antigens, and thyroglobulin. SETTING--Histopathology department of teaching hospital. SUBJECTS--100 pathology sections of metastatic adenocarcinoma and their related primary tumours. MAIN OUTCOME MEASURES--Concordance of reactivity between primary and metastatic tumours. Reactivity profiles of tumour sites. RESULTS--The correct primary site of origin was predicted in 70% (33/47) of tumours in men and 54% (27/43) tumours in women with antibodies SM3, 288, CA19.9, CA125, and PSA (men only). Specificities ranged from 68% for breast tumour to 98% for prostate tumour. CONCLUSION--Use of tumour markers in patients presenting with metastatic adenocarcinoma of unknown origin can help localise the probable primary sites and reduce the need for extensive and expensive imaging techniques. 相似文献
2.
Alice J L Zheng Aikaterini Thermou Chrysoula Daskalogianni Laurence Malbert-Colas Konstantinos Karakostis Ronan Le
Snchal Van Trang
Dinh Maria C Tovar
Fernandez Sbastien Apcher Sa Chen Marc Blondel Robin Fahraeus 《Nucleic acids research》2022,50(17):10110
Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine–alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence. 相似文献
3.
4.
5.
Aline Awad Sokhavuth Sar Ronan Barré Clotilde Cariven Mickael Marin Jean Pierre Salles Christophe Erneux Didier Samuel Ama Gassama-Diagne 《Molecular biology of the cell》2013,24(14):2171-2185
The main targets of hepatitis C virus (HCV) are hepatocytes, the highly polarized cells of the liver, and all the steps of its life cycle are tightly dependent on host lipid metabolism. The interplay between polarity and lipid metabolism in HCV infection has been poorly investigated. Signaling lipids, such as phosphoinositides (PIs), play a vital role in polarity, which depends on the distribution and expression of PI kinases and PI phosphatases. In this study, we report that HCV core protein, expressed in Huh7 and Madin–Darby canine kidney (MDCK) cells, disrupts apicobasal polarity. This is associated with decreased expression of the polarity protein Dlg1 and the PI phosphatase SHIP2, which converts phosphatidylinositol 3,4,5-trisphosphate into phosphatidylinositol 4,5-bisphosphate (PtdIns(3,4)P2). SHIP2 is mainly localized at the basolateral membrane of polarized MDCK cells. In addition, PtdIns(3,4)P2 is able to bind to Dlg1. SHIP2 small interfering RNA or its catalytically dead mutant disrupts apicobasal polarity, similar to HCV core. In core-expressing cells, RhoA activity is inhibited, whereas Rac1 is activated. Of interest, SHIP2 expression rescues polarity, RhoA activation, and restricted core level in MDCK cells. We conclude that SHIP2 is an important regulator of polarity, which is subverted by HCV in epithelial cells. It is suggested that SHIP2 could be a promising target for anti-HCV treatment. 相似文献
6.
7.
Navin Kumar Verma Kieran Crosbie-Staunton Amro Satti Shane Gallagher Katie B Ryan Timothy Doody Colm McAtamney Ronan MacLoughlin Paul Galvin Conor S Burke Yuri Volkov Yurii K Gun’ko 《Journal of nanobiotechnology》2013,11(1):1-12
Background
Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe3O4 magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated.Results
Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting.Conclusion
We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route. 相似文献8.
Voahangy Andrianaivoarimanana Katharina Kreppel Nohal Elissa Jean-Marc Duplantier Elisabeth Carniel Minoarisoa Rajerison Ronan Jambou 《PLoS neglected tropical diseases》2013,7(11)
Plague, a zoonosis caused by Yersinia pestis, is still found in Africa, Asia, and the Americas. Madagascar reports almost one third of the cases worldwide. Y. pestis can be encountered in three very different types of foci: urban, rural, and sylvatic. Flea vector and wild rodent host population dynamics are tightly correlated with modulation of climatic conditions, an association that could be crucial for both the maintenance of foci and human plague epidemics. The black rat Rattus rattus, the main host of Y. pestis in Madagascar, is found to exhibit high resistance to plague in endemic areas, opposing the concept of high mortality rates among rats exposed to the infection. Also, endemic fleas could play an essential role in maintenance of the foci. This review discusses recent advances in the understanding of the role of these factors as well as human behavior in the persistence of plague in Madagascar. 相似文献
9.
Zhemin Zhou Angela McCann Eva Litrup Ronan Murphy Martin Cormican Seamus Fanning Derek Brown David S. Guttman Sylvain Brisse Mark Achtman 《PLoS genetics》2013,9(4)
Salmonella enterica serovar Agona has caused multiple food-borne outbreaks of gastroenteritis since it was first isolated in 1952. We analyzed the genomes of 73 isolates from global sources, comparing five distinct outbreaks with sporadic infections as well as food contamination and the environment. Agona consists of three lineages with minimal mutational diversity: only 846 single nucleotide polymorphisms (SNPs) have accumulated in the non-repetitive, core genome since Agona evolved in 1932 and subsequently underwent a major population expansion in the 1960s. Homologous recombination with other serovars of S. enterica imported 42 recombinational tracts (360 kb) in 5/143 nodes within the genealogy, which resulted in 3,164 additional SNPs. In contrast to this paucity of genetic diversity, Agona is highly diverse according to pulsed-field gel electrophoresis (PFGE), which is used to assign isolates to outbreaks. PFGE diversity reflects a highly dynamic accessory genome associated with the gain or loss (indels) of 51 bacteriophages, 10 plasmids, and 6 integrative conjugational elements (ICE/IMEs), but did not correlate uniquely with outbreaks. Unlike the core genome, indels occurred repeatedly in independent nodes (homoplasies), resulting in inaccurate PFGE genealogies. The accessory genome contained only few cargo genes relevant to infection, other than antibiotic resistance. Thus, most of the genetic diversity within this recently emerged pathogen reflects changes in the accessory genome, or is due to recombination, but these changes seemed to reflect neutral processes rather than Darwinian selection. Each outbreak was caused by an independent clade, without universal, outbreak-associated genomic features, and none of the variable genes in the pan-genome seemed to be associated with an ability to cause outbreaks. 相似文献
10.