全文获取类型
收费全文 | 3204篇 |
免费 | 220篇 |
国内免费 | 1篇 |
出版年
2023年 | 11篇 |
2022年 | 29篇 |
2021年 | 54篇 |
2020年 | 35篇 |
2019年 | 47篇 |
2018年 | 71篇 |
2017年 | 54篇 |
2016年 | 98篇 |
2015年 | 175篇 |
2014年 | 179篇 |
2013年 | 205篇 |
2012年 | 277篇 |
2011年 | 243篇 |
2010年 | 151篇 |
2009年 | 144篇 |
2008年 | 203篇 |
2007年 | 190篇 |
2006年 | 151篇 |
2005年 | 147篇 |
2004年 | 157篇 |
2003年 | 146篇 |
2002年 | 86篇 |
2001年 | 70篇 |
2000年 | 74篇 |
1999年 | 59篇 |
1998年 | 16篇 |
1997年 | 21篇 |
1996年 | 24篇 |
1995年 | 15篇 |
1994年 | 9篇 |
1993年 | 12篇 |
1992年 | 23篇 |
1991年 | 16篇 |
1990年 | 15篇 |
1989年 | 13篇 |
1988年 | 15篇 |
1987年 | 16篇 |
1986年 | 16篇 |
1985年 | 13篇 |
1984年 | 13篇 |
1983年 | 13篇 |
1982年 | 10篇 |
1981年 | 10篇 |
1980年 | 10篇 |
1979年 | 8篇 |
1978年 | 6篇 |
1975年 | 11篇 |
1974年 | 8篇 |
1972年 | 6篇 |
1971年 | 6篇 |
排序方式: 共有3425条查询结果,搜索用时 15 毫秒
991.
Meegun Hong Seung Woo Kim Sang Hak Han Dong Joon Kim Ki Tae Suk Yeon Soo Kim Myong Jo Kim Moon Young Kim Soon Koo Baik Young Lim Ham 《PloS one》2015,10(2)
ObjectiveThe role of lipopolysaccharide (LPS) and toll-like receptor 4 (TLR 4) in the pathogenesis of alcoholic liver disease (ALD) has been widely established. We evaluated the biological effects of probiotics (Lactobacillus rhamnosus R0011 and acidophilus R0052), KRG (Korea red ginseng), and urushiol (Rhus verniciflua Stokes) on ALD, including their effects on normal and high-fat diet in mice.MethodsOne hundred C57BL/6 mice were classified into normal (N) and high-fat diet (H) groups. Each group was divided into 5 sub-groups: control, alcohol, alcohol+probiotics, alcohol+KRG, and alcohol+urushiol. A liver function test, histology, electron-microscopy, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-10, and TLR 4 were evaluated and compared.ResultsIn the N group, probiotics, KRG, and urushiol significantly reduced levels of TNF-α (12.3±5.1, 13.4±3.9, and 12.1±4.3 vs. 27.9±15.2 pg/mL) and IL-1β (108.4±39.4, 75.0±51.0, and 101.1±26.8 vs. 162.4±37.5 pg/mL), which were increased by alcohol. Alcohol-induced TLR 4 expression was reduced by probiotics and urushiol (0.7±0.2, and 0.8±0.1 vs. 1.0±0.3, p<0.001). In the H group, IL-10 was significantly increased by probiotics and KRG, compared with alcohol (25.3±15.6 and 20.4±6.2 vs. 7.6±5.6 pg/mL) and TLR 4 expression was reduced by probiotics (0.8±0.2 vs. 1.0±0.3, p = 0.007).ConclusionsAlcohol-induced TLR 4 expression was down-regulated by probiotics in the normal and high-fat diet groups. Probiotics, KRG, and urushiol might be effective in the treatment of ALD by regulating the gut-liver axis. 相似文献
992.
Yi Yang So-Yeon Park Thanh Thi Nguyen Young Hyun Yu Tru Van Nguyen Eun Gene Sun Jayalal Udeni Min-Hye Jeong Iris Pereira Cheol Moon Hyung-Ho Ha Kyung Keun Kim Jae-Seoun Hur Hangun Kim 《PloS one》2015,10(9)
Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3’-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action. 相似文献
993.
Ki Yeon Kim Gwanghee Lee Minsang Yoon Eun Hye Cho Chan-Sik Park Moon Gyo Kim 《Molecules and cells》2015,38(6):548-561
By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the CD31+ endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-1+ fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation. 相似文献
994.
Young-Su Seo Jae Yun Lim Jungwook Park Sunyoung Kim Hyun-Hee Lee Hoon Cheong Sang-Mok Kim Jae Sun Moon Ingyu Hwang 《BMC genomics》2015,16(1)
Background
In addition to human and animal diseases, bacteria of the genus Burkholderia can cause plant diseases. The representative species of rice-pathogenic Burkholderia are Burkholderia glumae, B. gladioli, and B. plantarii, which primarily cause grain rot, sheath rot, and seedling blight, respectively, resulting in severe reductions in rice production. Though Burkholderia rice pathogens cause problems in rice-growing countries, comprehensive studies of these rice-pathogenic species aiming to control Burkholderia-mediated diseases are only in the early stages.Results
We first sequenced the complete genome of B. plantarii ATCC 43733T. Second, we conducted comparative analysis of the newly sequenced B. plantarii ATCC 43733T genome with eleven complete or draft genomes of B. glumae and B. gladioli strains. Furthermore, we compared the genome of three rice Burkholderia pathogens with those of other Burkholderia species such as those found in environmental habitats and those known as animal/human pathogens. These B. glumae, B. gladioli, and B. plantarii strains have unique genes involved in toxoflavin or tropolone toxin production and the clustered regularly interspaced short palindromic repeats (CRISPR)-mediated bacterial immune system. Although the genome of B. plantarii ATCC 43733T has many common features with those of B. glumae and B. gladioli, this B. plantarii strain has several unique features, including quorum sensing and CRISPR/CRISPR-associated protein (Cas) systems.Conclusions
The complete genome sequence of B. plantarii ATCC 43733T and publicly available genomes of B. glumae BGR1 and B. gladioli BSR3 enabled comprehensive comparative genome analyses among three rice-pathogenic Burkholderia species responsible for tissue rotting and seedling blight. Our results suggest that B. glumae has evolved rapidly, or has undergone rapid genome rearrangements or deletions, in response to the hosts. It also, clarifies the unique features of rice pathogenic Burkholderia species relative to other animal and human Burkholderia species.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1558-5) contains supplementary material, which is available to authorized users. 相似文献995.
Jung Youn Park Yong-Rock An Naohisa Kanda Chul-Min An Hye Suck An Jung-Ha Kang Eun Mi Kim Du-Hae An Hojin Jung Myunghee Joung Myung Hum Park Sook Hee Yoon Bo-Young Lee Taeheon Lee Kyu-Won Kim Won Cheoul Park Dong Hyun Shin Young Sub Lee Jaemin Kim Woori Kwak Hyeon Jeong Kim Young-Jun Kwon Sunjin Moon Yuseob Kim David W Burt Seoae Cho Heebal Kim 《BMC genomics》2015,16(1)
Background
Whales have captivated the human imagination for millennia. These incredible cetaceans are the only mammals that have adapted to life in the open oceans and have been a source of human food, fuel and tools around the globe. The transition from land to water has led to various aquatic specializations related to hairless skin and ability to regulate their body temperature in cold water.Results
We present four common minke whale (Balaenoptera acutorostrata) genomes with depth of ×13 ~ ×17 coverage and perform resequencing technology without a reference sequence. Our results indicated the time to the most recent common ancestors of common minke whales to be about 2.3574 (95% HPD, 1.1521 – 3.9212) million years ago. Further, we found that genes associated with epilation and tooth-development showed signatures of positive selection, supporting the morphological uniqueness of whales.Conclusions
This whole-genome sequencing offers a chance to better understand the evolutionary journey of one of the largest mammals on earth.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1213-1) contains supplementary material, which is available to authorized users. 相似文献996.
Kyoung Su Sung Jin-Kyoung Shim Ji-Hyun Lee Se Hoon Kim Sohee Park Tae-Hoon Roh Ju Hyung Moon Eui-Hyun Kim Sun Ho Kim Su Jae Lee Yong Min Huh Seok-Gu Kang Jong Hee Chang 《Cancer cell international》2015,16(1):75
Background
A trend of stage-by-stage increase in tumorsphere (TS) formation from glioma samples has been reported. Despite this trend, not all surgical specimens give rise to TSs, even World Health Organization (WHO) grade IV gliomas. Furthermore, it has been reported that differences in overall survival of primary glioblastoma patients depends on the propensity of their tumors to form TSs. However, the weights of fresh specimens vary from one surgical isolate to the next.Methods
Accordingly, we evaluated the relationship between the weights of surgical specimens in WHO grade IV gliomas with the capacity to isolate TSs. Thirty-five fresh WHO grade IV glioma specimens were separated into two groups, based on whether they were positive or negative for TS isolation, and the relationship between TS isolation and weight of surgical specimens was assessed.Results
We observed no significant difference in the weights of surgical samples in the two groups, and found that the optimal weight of specimens for TSs isolation was 500 mg.Conclusion
Thus, contrary to our expectations, the ability to isolate TSs from WHO grade IV glioma specimens was not related to the weight of fresh specimens.997.
Tai Young Kim Priscila F. Siesser Kent L. Rossman Dennis Goldfarb Kathryn Mackinnon Feng Yan XianHua Yi Michael J. MacCoss Randall T. Moon Channing J. Der Michael B. Major 《Molecular and cellular biology》2015,35(1):167-181
Defining the full complement of substrates for each ubiquitin ligase remains an important challenge. Improvements in mass spectrometry instrumentation and computation and in protein biochemistry methods have resulted in several new methods for ubiquitin ligase substrate identification. Here we used the parallel adapter capture (PAC) proteomics approach to study βTrCP2/FBXW11, a substrate adaptor for the SKP1–CUL1–F-box (SCF) E3 ubiquitin ligase complex. The processivity of the ubiquitylation reaction necessitates transient physical interactions between FBXW11 and its substrates, thus making biochemical purification of FBXW11-bound substrates difficult. Using the PAC-based approach, we inhibited the proteasome to “trap” ubiquitylated substrates on the SCFFBXW11 E3 complex. Comparative mass spectrometry analysis of immunopurified FBXW11 protein complexes before and after proteasome inhibition revealed 21 known and 23 putatively novel substrates. In focused studies, we found that SCFFBXW11 bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1. High RAPGEF2 protein levels promoted cell-cell fusion and, consequently, multinucleation. Surprisingly, this occurred independently of the guanine nucleotide exchange factor (GEF) catalytic activity and of the presence of RAP1. Our data establish new functions for RAPGEF2 that may contribute to aneuploidy in cancer. More broadly, this report supports the continued use of substrate trapping proteomics to comprehensively define targets for E3 ubiquitin ligases. All proteomic data are available via ProteomeXchange with identifier PXD001062. 相似文献
998.
Tatenda Shopera William R. Henson Andrew Ng Young Je Lee Kenneth Ng Tae Seok Moon 《Nucleic acids research》2015,43(18):9086-9094
Natural regulatory networks contain many interacting components that allow for fine-tuning of switching and memory properties. Building simple bistable switches, synthetic biologists have learned the design principles of complex natural regulatory networks. However, most switches constructed so far are so simple (e.g. comprising two regulators) that they are functional only within a limited parameter range. Here, we report the construction of robust, tunable bistable switches in Escherichia coli using three heterologous protein regulators (ExsADC) that are sequestered into an inactive complex through a partner swapping mechanism. On the basis of mathematical modeling, we accurately predict and experimentally verify that the hysteretic region can be fine-tuned by controlling the interactions of the ExsADC regulatory cascade using the third member ExsC as a tuning knob. Additionally, we confirm that a dual-positive feedback switch can markedly increase the hysteretic region, compared to its single-positive feedback counterpart. The dual-positive feedback switch displays bistability over a 106-fold range of inducer concentrations, to our knowledge, the largest range reported so far. This work demonstrates the successful interlocking of sequestration-based ultrasensitivity and positive feedback, a design principle that can be applied to the construction of robust, tunable, and predictable genetic programs to achieve increasingly sophisticated biological behaviors. 相似文献
999.
Evaluation of four methods of assigning species and genus to medically important bacteria using 16S rRNA gene sequence analysis
下载免费PDF全文
![点击此处可从《Microbiology and immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Geon Park Won‐Young Jin Sook‐Jin Jang Joong‐Ki Kook Ji Ae Choi Gyun Cheol Park Min‐Jung Lee Soon‐Nang Park Xue Min Li Seong‐Sig Cho Chul Ho Jang Seong‐Ho Kang Dae‐Soo Moon 《Microbiology and immunology》2015,59(5):285-298
The four methods for assigning bacterial species are the Clinical and Laboratory Standards Institute (CLSI), modified CLSI (mCLSI), phylogenetic analysis (PA) and closest match (CM) methods, these are used to identify the genus and species using 16S rRNA gene sequence results. In this study, the results of identification by these four methods of 37 aerobic reference strains, 30 anaerobic reference strains, 15 Acinetobacter reference strains and 167 Acinetobacter clinical strains were compared. The rates of accurate identification to the species level using the CLSI, mCLSI, PA and CM methods were as follows: 24.3, 86.5, 86.5 and 89.2%, respectively, for the 37 aerobic reference strains; 73.3%, 96.7%, 90.0% and 93.3%, respectively, for the 30 anaerobic reference strains; 40.0%, 93.3%, 100% and 93.3%, respectively, for the 15 Acinetobacter reference strains; and 53.9%, 90.4%, 95.8% and 90.4%, respectively, for the 167 Acinetobacter clinical strains. The rates of accurate identification to the genus level using the CLSI, mCLSI, PA, and CM methods were as follows: 91.9%, 91.9%, 94.6% and 91.9%, respectively, for the 37 aerobic reference strains; 100%, 100%, 100% and 100%, respectively, for all of the 30 anaerobic reference strains, 15 Acinetobacter reference strains and the 167 Acinetobacter clinical strains. The mCLSI is the most practical and pragmatic method for identification of species based on 16S rRNA sequences for hospital, research or industry laboratories because it performs well and involves a simple procedure. 相似文献
1000.
Cheol Young Choi Hyun Suk Shin Na Na Kim Sang-Geun Yang Bong-Seok Kim Young Moon Yu 《Biological Rhythm Research》2015,46(5):671-682
In this study, we examined differences among the gonadotropin-inhibitory hormone (GnIH), kisspeptin 1 (Kiss1), Kiss 1 receptor (G-protein-coupled receptor 54; GPR54), melatonin receptor 1 (MT1), and melatonin levels in brain cells of goldfish Carassius auratus exposed to white fluorescent light and three light-emitting diode (LED) wavelength and melatonin treatments in the culture medium. In the green and blue LED treatment groups, GnIH and MT1 mRNA expression levels were significantly lower than in the other groups; conversely, levels significantly increased in the melatonin treatment groups. Additionally, expression levels of Kiss1 and its receptor, GPR54, in the white fluorescent and red LED light groups were significantly lower than the other groups, but levels also significantly decreased in the melatonin treatment groups. These results suggest that white fluorescent and red wavelengths downregulate the production of neurohormones in the brains of C. auratus and thus may inhibit sexual maturation in goldfish. 相似文献