全文获取类型
收费全文 | 1091篇 |
免费 | 89篇 |
国内免费 | 3篇 |
出版年
2023年 | 10篇 |
2022年 | 3篇 |
2021年 | 29篇 |
2020年 | 15篇 |
2019年 | 17篇 |
2018年 | 27篇 |
2017年 | 28篇 |
2016年 | 44篇 |
2015年 | 74篇 |
2014年 | 69篇 |
2013年 | 84篇 |
2012年 | 120篇 |
2011年 | 111篇 |
2010年 | 73篇 |
2009年 | 51篇 |
2008年 | 82篇 |
2007年 | 69篇 |
2006年 | 52篇 |
2005年 | 40篇 |
2004年 | 48篇 |
2003年 | 35篇 |
2002年 | 27篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 6篇 |
1997年 | 6篇 |
1996年 | 1篇 |
1995年 | 4篇 |
1994年 | 1篇 |
1993年 | 6篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 5篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1937年 | 1篇 |
排序方式: 共有1183条查询结果,搜索用时 31 毫秒
71.
Maja?von der Hagen Julia?B.?Hennermann Horst?von Bernuth Birgit?Spors Angela?M.?KaindlEmail author 《Medizinische Genetik》2016,28(1):1-14
Microcephaly affects 2–3?% of the population and is often associated with intellectual disability. The underlying reduction in brain volume can result from various exogenous factors or genetic causes. Microcephaly remains a poorly defined condition lacking both uniform diagnostic approaches and classification. A definite etiological diagnosis is the key to predict the prognosis, identify co-morbidities and offer genetic counseling. In addition, the identification of the underlying cause increases our knowledge of brain development and the clinical spectrum of microcephaly. We propose a diagnostic approach for children with microcephaly from a pediatric neurologist point of view. 相似文献
72.
Christoph Heier Ulrike Taschler Maja Radulovic Philip Aschauer Thomas O. Eichmann Susanne Grond Heimo Wolinski Monika Oberer Rudolf Zechner Sepp D. Kohlwein Robert Zimmermann 《The Journal of biological chemistry》2016,291(22):11865-11875
Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Δ mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites. 相似文献
73.
74.
Ana V. Banko Ivana B. Lazarevic Miljan M. Folic Vojko B. Djukic Andja M. Cirkovic Danijela Z. Karalic Maja D. Cupic Tanja P. Jovanovic 《PloS one》2016,11(4)
Epstein-Barr virus (EBV) infection is a significant factor in the pathogenesis of nasopharyngeal carcinoma, especially in the undifferentiated carcinoma of nasopharyngeal type (UCNT, World Health Organization type III), which is the dominant histopathological type in high-risk areas. The major EBV oncogene is latent membrane protein 1 (LMP1). LMP1 gene shows variability with different tumorigenic and immunogenic potentials. EBV nuclear antigen 1 (EBNA1) regulates progression of EBV-related tumors; however, the influence of EBNA1 sequence variability on tumor pathogenesis is controversial. The aims of this study were to characterize polymorphisms of EBV genes in non-endemic nasopharyngeal carcinoma biopsies and to investigate potential sequence patterns that correlate with the clinical presentation of nasopharyngeal carcinoma. In total, 116 tumor biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), collected from 2008 to 2014, were evaluated in this study. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. The presence of EBV DNA was significantly distributed between TNM stages. LMP1 variability showed six variants, with the detection of the first China1 and North Carolina variants in European nasopharyngeal carcinoma biopsies. Newly discovered variants Srb1 and Srb2 were UCNT-specific LMP1 polymorphisms. The B95-8 and North Carolina variants are possible predictors for favorable TNM stages. In contrast, deletions in LMP1 are possible risk factors for the most disfavorable TNM stage, independent of EBNA2 or EBNA1 variability. A newly discovered EBNA1 subvariant, P-thr-sv-5, could be a potential diagnostic marker, as it represented a UCNT-specific EBNA1 subvariant. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, type 1/Med/P-thr was identified as a possible risk factor for TNM stage IVB or progression to the N3 stage. 相似文献
75.
Wendy W. J. de Leng Christa G. Gadellaa-van Hooijdonk Fran?oise A. S. Barendregt-Smouter Marco J. Koudijs Ies Nijman John W. J. Hinrichs Edwin Cuppen Stef van Lieshout Robert D. Loberg Maja de Jonge Emile E. Voest Roel A. de Weger Neeltje Steeghs Marlies H. G. Langenberg Stefan Sleijfer Stefan M. Willems Martijn P. Lolkema 《PloS one》2016,11(2)
Background
Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.g. formalin fixed paraffin embedded (FFPE) versus fresh frozen (FF) tissue) on NGS derived results. Moreover, this study aimed to explore a standardized analysis pipeline to support consistent clinical decision-making.Method
We used the Ion Torrent PGM sequencing platform in combination with the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence frequently mutated regions in 50 cancer related genes, and validated the NGS detected variants in 250 FFPE samples using standard diagnostic assays. Next, 386 tumour samples were sequenced to explore the effect of input material on variant detection variables. For variant calling, Ion Torrent analysis software was supplemented with additional variant annotation and filtering.Results
Both FFPE and FF tissue could be sequenced reliably with a sensitivity of 99.1%. Validation showed a 98.5% concordance between NGS and conventional sequencing techniques, where NGS provided both the advantage of low input DNA concentration and the detection of low-frequency variants. The reliability of mutation analysis could be further improved with manual inspection of sequence data.Conclusion
Targeted NGS can be reliably implemented in cancer diagnostics using both FFPE and FF tissue when using appropriate analysis settings, even with low input DNA. 相似文献76.
Ariana Barbera Betancourt Juliet L. Emery Asha Recino F. Susan Wong Anne Cooke Klaus Okkenhaug Maja Wallberg 《PloS one》2016,11(1)
Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig. 相似文献
77.
Promoter optimisation of lentiviral vectors for efficient insulin gene expression in canine mesenchymal stromal cells: potential surrogate beta cells 下载免费PDF全文
78.
Chronic Helicobacter pylori Infection Does Not Significantly Alter the Microbiota of the Murine Stomach 总被引:1,自引:0,他引:1 下载免费PDF全文
Mai Ping Tan Maria Kaparakis Maja Galic John Pedersen Martin Pearse Odilia L. C. Wijburg Peter H. Janssen Richard A. Strugnell 《Applied microbiology》2007,73(3):1010-1013
We examined the impact of Helicobacter pylori infection on the murine gastric microbiota by culture and terminal-restriction fragment length polymorphism and found that neither acute nor chronic H. pylori infection substantially affected the gastric microbial composition. Interestingly, the total H. pylori burden detected by real-time PCR was significantly higher than that revealed by viable counts, suggesting that the antigenic load sustaining H. pylori-induced gastritis could be considerably higher than previously believed. 相似文献
79.
Biological availability of selenosugars in rats 总被引:1,自引:0,他引:1
Juresa D Blanusa M Francesconi KA Kienzl N Kuehnelt D 《Chemico-biological interactions》2007,168(3):203-210
The biological availability and metabolism of two selenosugars orally administered to rats were investigated. Two other selenium species, selenite and trimethylselenonium ion (TMSe) were included in the study as positive and negative controls, respectively. Male Wistar strain rats (three per group) at 8 weeks of age were exposed to sodium selenite, TMSe, selenosugar 1 (methyl-2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside) or selenosugar 2 (methyl-2-acetamido-2-deoxy-1-seleno-beta-D-glucopyranoside) through drinking water for 48 h. Total selenium concentrations (ICPMS) and selenium species concentrations (HPLC/ICPMS) were determined in urine samples collected in two 24h periods during the exposure, and total selenium concentrations in liver, kidney, small intestine and blood were determined at the end of the experiment. The major species found in background urine were selenosugar 1 (major metabolite) and TMSe (minor metabolite). Rats exposed to selenite excreted large quantities of selenosugars and TMSe consistent with efficient uptake and biotransformation of selenite, whereas TMSe-exposed rats excreted large quantities of TMSe, but there was no significant increase of other selenium metabolites, consistent with TMSe being taken up and excreted unchanged. Rats exposed to selenosugars, however, excreted significant quantities of TMSe suggesting that the sugars were at least partly biologically available and biotransformed. Rats exposed to selenite accumulated selenium in the liver, kidney, small intestine and blood, whereas no accumulation was observed for the other samples except for small increases in selenium concentrations of small intestine from the two selenosugar-exposed groups. 相似文献
80.
Marković BB Bergovec M Reiner Z Sertić J Vincelj J Marković M 《Collegium antropologicum》2007,31(1):179-183
Controversy exists as to whether the deletion/deletion (DD) genotype of angiotensin l-converting enzyme (ACE) gene polymorphism is associated with coronary heart disease (CHD). There are only a few studies dealing with this issue in the elderly, also with controversial results. The aim of this study was the assessment of correlation between genetic markers and the risk of CHD in the elderly. The results indicated DD genotype importance for CHD in the elderly as proven by discriminant analysis (chi2 = 25.77; df = 16; p = 0.0620). However, the use of univariate method demonstrated no correlation between DD genotype of ACE gene polymorphism and coronary artery disease. D allele of ACE gene was associated with higher activities of ACE plasma. A weak, but increased risk of MI is associated with high frequency of DD genotype in the elderly. Strong correlation between ACE polymorphism and ACE plasma activities was demonstrated. 相似文献