全文获取类型
收费全文 | 539篇 |
免费 | 54篇 |
国内免费 | 41篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 34篇 |
2020年 | 14篇 |
2019年 | 12篇 |
2018年 | 10篇 |
2017年 | 7篇 |
2016年 | 19篇 |
2015年 | 42篇 |
2014年 | 44篇 |
2013年 | 40篇 |
2012年 | 47篇 |
2011年 | 43篇 |
2010年 | 40篇 |
2009年 | 27篇 |
2008年 | 33篇 |
2007年 | 24篇 |
2006年 | 38篇 |
2005年 | 22篇 |
2004年 | 14篇 |
2003年 | 11篇 |
2002年 | 6篇 |
2001年 | 3篇 |
2000年 | 3篇 |
1999年 | 7篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 8篇 |
1993年 | 1篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有634条查询结果,搜索用时 31 毫秒
71.
Wang J Pitarque M Ingelman-Sundberg M 《Biochemical and biophysical research communications》2006,340(2):491-497
Cytochrome P450 2A6 (CYP2A6) is the major nicotine C-oxidase in human and participates in the metabolism of drugs and precarcinogens. The CYP2A6 gene is highly polymorphic and more than 22 different alleles have been described. We here focused on the polymorphism in the 3'-UTR region, in particular the common CYP2A6*1B allele, carrying an unequal crossover element from the pseudogene CYP2A7. Analysis of CYP2A6 expression in a human liver bank (n=46) revealed that the protein level and catalytic activity using coumarin as a substrate were all higher, following a linear gene-dose relationship, in livers carrying one or two copies of CYP2A6*1B, as compared to other CYP2A6 allelic variants. Different variants of the CYP2A6 3'-UTR were cloned into a modified pGL3 plasmid downstream of the luciferase reporter gene. The plasmids, having the proximal promoter of CYP2A6 gene, were transfected into HeLa cells or injected into the tail veins of male CD1 mice. In both systems, the 3'-UTR CYP2A6*1B constructs caused higher reporter gene activity and the CYP2A7 3'-UTR construct lower activity, compared to the CYP2A6*1 3'-UTR constructs. Two SNPs differentiating the 3'-UTR between CYP2A7 and CYP2A6*1B were found to be of importance for the expression in both systems. Analysis of reporter enzyme degradation in HeLa cells showed that luciferase-3'-UTR-CYP2A6*1A had a half-life of approximately 4.9h as compared to 6.3h for luciferase-3'-UTR-CYP2A6*1B. In conclusion, we identified polymorphic motifs in the CYP2A6 3'-UTR of importance for CYP2A6 mRNA stabilization and enzyme expression. Such polymorphism has been described to influence the in vivo rate of nicotine elimination and possibly the cigarette consumption and risk of smoking induced lung cancer. 相似文献
72.
Eui-Ju Hong Se-Hyung Park Kyung-Chul Choi Peter CK Leung Eui-Bae Jeung 《Reproductive biology and endocrinology : RB&E》2006,4(1):49-12
Environmental estrogenic compounds which bind to the estrogen receptor (ER) can block or alter endogenous functions of estrogen
in reproductive and developmental stages. A microarray technology is a very valuable method for the prediction of hormone-responsive
activities in various gene expressions. Thus, we investigated the altered gene expression by estrogen and endocrine disruptors
(EDs) using microarray technology in the uterus of immature rats. In this study, the expression levels of only 555 genes (7.42%)
among the 7636 genes spotted on microarray chips were enhanced by more than two-fold following treatment with estradiol (E2),
suggesting that direct or rapid response to E2 is widespread at the mRNA levels in these genes. In addition, elevated expression
levels of the genes (over 2-fold) were observed by diethylstilbestrol (DES; 9.01%), octyl-phenol (OP; 8.81%), nonyl-phenol
(NP; 9.51%), bisphenol-A (BPA; 8.26%) or genistein (9.97%) in the uterus of immature rats. The expression levels of representative
genes, i.e., calbindin-D9k (CaBP-9k; vitamin D-dependent calcium-binding protein), oxytocin, adipocyte complement related
protein (MW 30 kDa), lactate dehydrogenase A and calcium binding protein A6 (S100a6; calcyclin), were confirmed in these tissues
by real-time PCR. In addition, the mRNA levels of these genes by real-time PCR were increased at follicular phase when E2
level was elevated during estrous cycle of adult female rats. In conclusion, these results indicate distinct altered expression
of responsive genes following exposure to E2 and estrogenic compounds, and implicate distinct effects of endogenous E2 and
environmental endocrine disrupting chemicals in the uterus of immature rats. 相似文献
73.
74.
The antitumor activity of intracellular polysaccharides from submerged fermentation of Ganoderma lucidum was investigated focusing on the inhibition on human liver cancer cells. The polysaccharides inhibited human hepatocarcinoma cell HepG2 during earlier phase with lower dosage but obviously became less functional in later phase regardless of the dosage applied. However, apoptosis of the drugged HepG2 cells appeared in later incubation phase with high dosage, and the apoptosis could be enhanced by supplemental dose of the intracellular polysaccharides. Nevertheless, the intracellular polysaccharides inhibited other human hepatocarcinoma cells such as BEL-7402 and Huh-7 but luckily stimulated human normal liver cell L02 only in a positive dose- and time-dependent manner; so did the sulfated extracellular polysaccharides when it inhibited HepG2 and L02 cells. However, the toxicity of sulfated extracellular polysaccharides to L02 cells can be eliminated by the intracellular polysaccharides. 相似文献
75.
CAROLINE BETTO‐COLLIARD MATTHIAS STÖCK 《Biological journal of the Linnean Society. Linnean Society of London》2012,105(3):584-590
In vertebrates, genome size has been shown to correlate with nuclear and cell sizes, and influences phenotypic features, such as brain complexity. In three different anuran families, advertisement calls of polyploids exhibit longer notes and intervals than diploids, and difference in cellular dimensions have been hypothesized to cause these modifications. We investigated this phenomenon in green toads (Bufo viridis subgroup) of three ploidy levels, in a different call type (release calls) that may evolve independently from advertisement calls, examining 1205 calls, from ten species, subspecies, and hybrid forms. Significant differences between pulse rates of six diploid and four polyploid (3n, 4n) green toad forms across a range of temperatures from 7 to 27 °C were found. Laboratory data supported differences in pulse rates of triploids vs. tetraploids, but failed to reach significance when including field recordings. This study supports the idea that genome size, irrespective of call type, phylogenetic context, and geographical background, might affect call properties in anurans and suggests a common principle governing this relationship. The nuclear‐cell size ratio, affected by genome size, seems the most plausible explanation. However, we cannot rule out hypotheses under which call‐influencing genes from an unexamined diploid ancestral species might also affect call properties in the hybrid‐origin polyploids. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, 105 , 584–590. 相似文献
76.
77.
The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform PrPSc 1. PrPC is detergent-soluble and sensitive to proteinase K (PK)-digestion, whereas PrPSc forms detergent-insoluble aggregates and is partially resistant to PK2-6. The conversion of PrPC to PrPSc is known to involve a conformational transition of α-helical to β-sheet structures of the protein. However, the in vivo pathway is still poorly understood. A tentative endogenous PrPSc, intermediate PrP* or "silent prion", has yet to be identified in the uninfected brain7.Using a combination of biophysical and biochemical approaches, we identified insoluble PrPC aggregates (designated iPrPC) from uninfected mammalian brains and cultured neuronal cells8, 9. Here, we describe detailed procedures of these methods, including ultracentrifugation in detergent buffer, sucrose step gradient sedimentation, size exclusion chromatography, iPrP enrichment by gene 5 protein (g5p) that specifically bind to structurally altered PrP forms10, and PK-treatment. The combination of these approaches isolates not only insoluble PrPSc and PrPC aggregates but also soluble PrPC oligomers from the normal human brain. Since the protocols described here have been used to isolate both PrPSc from infected brains and iPrPC from uninfected brains, they provide us with an opportunity to compare differences in physicochemical features, neurotoxicity, and infectivity between the two isoforms. Such a study will greatly improve our understanding of the infectious proteinaceous pathogens. The physiology and pathophysiology of iPrPC are unclear at present. Notably, in a newly-identified human prion disease termed variably protease-sensitive prionopathy, we found a new PrPSc that shares the immunoreactive behavior and fragmentation with iPrPC 11, 12. Moreover, we recently demonstrated that iPrPC is the main species that interacts with amyloid-β protein in Alzheimer disease13. In the same study, these methods were used to isolate Abeta aggregates and oligomers in Alzheimer''s disease13, suggesting their application to non-prion protein aggregates involved in other neurodegenerative disorders. 相似文献
78.
79.
Negative Affect Mediates Effects of Psychological Stress on Disordered Eating in Young Chinese Women
Jue Chen Zhen Wang Boliang Guo Jon Arcelus Haiyin Zhang Xiuzhen Jia Yong Xu Jianyin Qiu Zeping Xiao Min Yang 《PloS one》2012,7(10)
Background
The bi-relationships between psychological stress, negative affect and disordered eating has been well studied in western culture, while tri-relationship among them, i.e. how some of those factors influence these bi-relationships, has rarely been studied. However, there has been little related study in the different Chinese culture. This study was conducted to investigate the bi-relationships and tri-relationship between psychological stress, negative affect, and disordered eating attitudes and behaviors in young Chinese women.Methodology
A total of 245 young Chinese policewomen employed to carry out health and safety checks at the 2010 Shanghai World Expo were recruited in this study. The Chinese version of the Perceived Stress Scale (PSS-10), Beck Depression Inventory Revised (BDI-II), Beck Anxiety Inventory (BAI), and Eating Attitude Test (EAT-26) were administered to all participants.Principal Findings
The total scores of PSS-10, BDI-II and BAI were all highly correlated with that of EAT-26. The PSS-10 score significantly correlated with both BDI-II and BAI scores. There was no statistically significant direct effect from perceived stress to disordered eating (–0.012, 95%CI: –.038∼0.006, p = 0.357), however, the indirect effects from PSS-10 via affect factors were statistically significant, e.g. the estimated mediation effects from PSS to EAT-26 via depression and anxiety were 0.036 (95%CI: 0.022∼0.044, p<0.001) and 0.015 (95%CI: 0.005∼0.023, p<0.01), respectively.Conclusions
Perceived stress and negative affects of depression and anxiety were demonstrated to be strongly associated with disordered eating. Negative affect mediated the relationship between perceived stress and disordered eating. The findings suggest that effective interventions and preventative programmes for disordered eating should pay more attention to depression and anxiety among the young Chinese female population. 相似文献80.
A novel recombinant hirudin, RGD-hirudin, inhibits the activity of thrombin and the aggregation of platelets. Here, we successfully expressed (15)N, (13)C-labeled RGD-hirudin in Pichia pastoris in a fermenter. The protein was subsequently purified to yield sufficient quantities for structural and functional studies. The purified protein was characterized by HPLC and MALDI-TOF mass spectroscopy. Analysis revealed that the protein was pure and uniformly labeled with (15)N and (13)C. A bioassay showed that the anti-thrombin activity and the anti-platelet aggregation ability of the labeled protein were the same as those of unlabeled RGD-hirudin. Multidimensional heteronuclear NMR spectroscopy has been used to determine almost complete backbone (15)N, (13)C and (1)H resonance assignments of the r-RGD-Hirudin. The (15)N-(1)H HSQC spectrum of uniformly (15)N, (13)C-labeled RGD-hirudin allowed successful assignment of the signals. Examples of the quality of the data are provided for the (15)N-(l)H correlation spectrum, and by selected planes of the CBCA(CO)NH, CBCANH, and HNCO experiments. These results provide a basis for further studies on the structure-function relationship of RGD-hirudin with thrombin and platelets. 相似文献