全文获取类型
收费全文 | 1126篇 |
免费 | 121篇 |
国内免费 | 57篇 |
专业分类
1304篇 |
出版年
2024年 | 5篇 |
2023年 | 17篇 |
2022年 | 35篇 |
2021年 | 51篇 |
2020年 | 42篇 |
2019年 | 51篇 |
2018年 | 67篇 |
2017年 | 34篇 |
2016年 | 61篇 |
2015年 | 72篇 |
2014年 | 74篇 |
2013年 | 81篇 |
2012年 | 97篇 |
2011年 | 95篇 |
2010年 | 57篇 |
2009年 | 57篇 |
2008年 | 51篇 |
2007年 | 50篇 |
2006年 | 46篇 |
2005年 | 23篇 |
2004年 | 22篇 |
2003年 | 28篇 |
2002年 | 26篇 |
2001年 | 26篇 |
2000年 | 12篇 |
1999年 | 9篇 |
1998年 | 11篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 13篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1977年 | 1篇 |
1976年 | 4篇 |
1975年 | 1篇 |
1974年 | 3篇 |
排序方式: 共有1304条查询结果,搜索用时 15 毫秒
91.
R Feng X Zhou PM Or JY Ma XS Tan J Fu C Ma JG Shi CT Che Y Wang JH Yeung 《Phytomedicine》2012,19(12):1125-1133
Halenia elliptica D. Don is a Tibetan herb and medicinal preparations containing Halenia elliptica have been commonly used for the treatment of hepatitis B virus infection in China. The metabolism of 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1) to its metabolites is mediated through cytochrome P450 enzymes. This study aimed to investigate the herb-drug interaction potential of HM-1 by studying its effects on the metabolism of model probe substrates of five major CYP450 isoforms in human liver microsomes. HM-1 showed moderate inhibitory effects on CYP1A2 (IC(50)=1.06μM) and CYP2C9 (IC(50)=3.89μM), minimal inhibition on CYP3A4 (IC(20)=11.94μM), but no inhibition on model CYP2D6 (dextromethorphan) and CYP2E1 (chlorzoxazone) probe substrates. Inhibition kinetic studies showed that the K(i) values of HM-1 on CYP1A2, CYP2C9 and CYP3A4 were 5.12μM, 2.00μM and 95.03μM, respectively. HM-1 competitively inhibited testosterone 6β-hydroxylation (CYP3A4) but displayed mixed type inhibitions for phenacetin O-deethylation (CYP1A2) and tolbutamide 4-hydroxylation (CYP2C9). Molecular docking study confirmed the inhibition modes of HM-1 on these human CYP isoforms. 相似文献
92.
93.
Background
The development of collections of quantitatively characterized standard biological parts should facilitate the engineering of increasingly complex and novel biological systems. The existing enzymatic and fluorescent reporters that are used to characterize biological part functions exhibit strengths and limitations. Combining both enzymatic and fluorescence activities within a single reporter protein would provide a useful tool for biological part characterization.Methodology/Principal Findings
Here, we describe the construction and quantitative characterization of Gemini, a fusion between the β-galactosidase (β-gal) α-fragment and the N-terminus of full-length green fluorescent protein (GFP). We show that Gemini exhibits functional β-gal activity, which we assay with plates and fluorometry, and functional GFP activity, which we assay with fluorometry and microscopy. We show that the protein fusion increases the sensitivity of β-gal activity and decreases the sensitivity of GFP.Conclusions/Significance
Gemini is therefore a bifunctional reporter with a wider dynamic range than the β-gal α-fragment or GFP alone. Gemini enables the characterization of gene expression, screening assays via enzymatic activity, and quantitative single-cell microscopy or FACS via fluorescence activity. The analytical flexibility afforded by Gemini will likely increase the efficiency of research, particularly for screening and characterization of libraries of standard biological parts. 相似文献94.
The gene cluster composed of varicella-zoster virus (VZV) open reading frame 9 (ORF9) to ORF12 encodes four putative tegument proteins and is highly conserved in most alphaherpesviruses. In these experiments, the genes within this cluster were deleted from the VZV parent Oka (POKA) individually or in combination, and the consequences for VZV replication were evaluated with cultured cells in vitro and with human skin xenografts in SCID mice in vivo. As has been reported for ORF10, ORF11 and ORF12 were dispensable for VZV replication in melanoma and human embryonic fibroblast cells. In contrast, deletion of ORF9 was incompatible with the recovery of infectious virus. ORF9 localized to the virion tegument and formed complexes with glycoprotein E, which is an essential protein, in VZV-infected cells. Recombinants lacking ORF10 and ORF11 (POKADelta10/11), ORF11 and ORF12 (POKADelta11/12), or ORF10, ORF11 and ORF12 (POKADelta10/11/12) were viable in cultured cells. Their growth kinetics did not differ from those of POKA, and nucleocapsid formation and virion assembly were not disrupted. In addition, these deletion mutants showed no differences compared to POKA in infectivity levels for primary human tonsil T cells. Deletion of ORF12 had no effect on skin infection, whereas replication of POKADelta11, POKADelta10/11, and POKADelta11/12 was severely reduced, and no virus was recovered from skin xenografts inoculated with POKADelta10/11/12. These results indicate that with the exception of ORF9, the individual genes within the ORF9-to-ORF12 gene cluster are dispensable and can be deleted simultaneously without any apparent effect on VZV replication in vitro but that the ORF10-to-ORF12 cluster is essential for VZV virulence in skin in vivo. 相似文献
95.
目的:研究吗啡对胎动、心率、孵化率、孵化时间、雏鸡体重等的影响。方法:以气室给药的方式给鸡胚注射吗啡,记录胎动、心率、孵化率、孵化时间、雏鸡体重。结果:吗啡可以缩短雏鸡的孵化时间,降低雏鸡的孵化率,并导致雏鸡出现运动障碍;20mg/kg吗啡剂量和12—16胚龄的给药时间,鸡胚孵化率最高,残疾率最低;吗啡导致胚胎心率加快,胎动减少(P〈0.05)。结论:吗啡对胚胎发育有损伤作用,损伤程度与吗啡剂量和给药时间有关。 相似文献
96.
Teresa Żołądek Anna Chełstowska Rosine Labbe-Bois Joanna Rytka 《Molecular genetics and genomics : MGG》1995,247(4):471-481
Uroporphyrinogen decarboxylase (Uro-d; EC 4.1.1.37), the fifth enzyme in the heme biosynthetic pathway, which catalyzes the sequential decarboxylation of uroporphyrinogen to coproporphyrinogen, is encoded by the HEM12 gene in Saccharomyces cerevisiae. The HEM12 gene is transcribed into a major short mRNA and a minor longer one, approximately 1.35 and 1.55 kb, respectively, in size, and that differ in the 5′ untranslated region. “Uroporphyric” mutants, which have no mutations in the HEM12 gene but accumulate uroporphyrinogen, a phenotype chracteristic of partial Uro-d deficiency, were investigated. Genetic analysis showed that the mutant phenotype depends on the combined action of two unlinked mutations, udt1 and either ipa1, ipa2, or ipa3. ipa1 is tightly linked to HEM12 The mutation udt1 apparently acts specifically on the HEM12 gene, and causes a six to tenfold decrease in the levels of the short HEM12 mRNA, in the β-galactosidase activity of a HEM12-lacZ fusion, in immunodetectable protein and enzyme activity. But heme synthesis is normal and porphyrin accumulation was modest. The mutations ipa1, ipa2, and ipa3 had no phenotype on their own, but they caused an increase in porphyrin accumulation in a udt1 background. This multiplicity of genetic factors leading to uroporphyric yeast cells closely resembles the situation in human porphyria cutanea tarda. 相似文献
97.
Inhibition of yes‐associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model 下载免费PDF全文
Ping‐Chih Hsu Jinbai Miao Zhen Huang Yi‐Lin Yang Zhidong Xu Joanna You Yuyuan Dai Che‐Chung Yeh Geraldine Chan Shu Liu Anatoly Urisman Cheng‐Ta Yang David M. Jablons Liang You 《Journal of cellular and molecular medicine》2018,22(6):3073-3085
Yes‐associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030‐BrM3(K‐rasG12C mutation) and PC9‐BrM3 (EGFRΔexon19 mutation) had a significantly decreased p‐YAP(S127)/YAP ratio compared to parental H2030 (K‐rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030‐BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030‐BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030‐BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA‐transfected H2030‐BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030‐BrM3 cell brain metastasis in a murine model. 相似文献
98.
Dickkopf‐1‐promoted vasculogenic mimicry in non‐small cell lung cancer is associated with EMT and development of a cancer stem‐like cell phenotype 下载免费PDF全文
Baocun Sun Yanrong Liu Qiang Gu Yanhui Zhang Xueming Zhao Na Che Yanjun Zheng Fang Liu Yong Wang Jie Meng 《Journal of cellular and molecular medicine》2016,20(9):1673-1685
To characterize the contributions of Dickkopf‐1 (DKK1) towards the induction of vasculogenic mimicry (VM) in non‐small cell lung cancer (NSCLC), we evaluated cohorts of primary tumours, performed in vitro functional studies and generated xenograft mouse models. Vasculogenic mimicry was observed in 28 of 205 NSCLC tumours, while DKK1 was detected in 133 cases. Notably, DKK1 was positively associated with VM. Statistical analysis showed that VM and DKK1 were both related to aggressive clinical course and thus were indicators of a poor prognosis. Moreover, expression of epithelial‐mesenchymal transition (EMT)‐related proteins (vimentin, Slug, and Twist), cancer stem‐like cell (CSC)‐related proteins (nestin and CD44), VM‐related proteins (MMP2, MMP9, and vascular endothelial‐cadherin), and β‐catenin‐nu were all elevated in VM‐positive and DKK1‐positive tumours, whereas the epithelial marker (E‐cadherin) was reduced in the VM‐positive and DKK1‐positive groups. Non‐small cell lung cancer cell lines with overexpressed or silenced DKK1 highlighted its role in the restoration of mesenchymal phenotypes and development of CSC characteristics. Moreover, DKK1 significantly promotes NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that DKK1 enhances the growth of transplanted human tumours cells, as well as increased VM formation, mesenthymal phenotypes and CSC properties. Our results suggest that DKK1 can promote VM formation via induction of the expression of EMT and CSC‐related proteins. As such, we feel that DKK1 may represent a novel target of NSCLC therapy. 相似文献
99.
100.
Phylogenetic relationships among representative species of the family Rhacophoridae were investigated based on 2904bp of sequences from both mitochondrial (12S rRNA, 16S rRNA, the complete t-RNA for valine), and nuclear (tyrosinase, rhodopsin) genes. Maximum parsimony, maximum likelihood, and Bayesian analyses were employed to reconstruct the phylogenetic trees. This analysis, combined with previous phylogenetic studies, serves as a framework for future work in rhacophorid systematics. The monophyly of Rhacophorus is strongly confirmed except for the species R.hainanus, which is the sister taxon to A.odontotarsus. The non-monophyly of the newly designated genus Aquixalus by Delorme et al. [Delorme, M., Dubois, A., Grosjean, S., Ohler, A., 2005. Une nouvelle classification générique et subgénérique de la tribu des Philautini (Amphibia, Anura, Ranidae, Rhacophorinae). Bull. Mens. Soc. Linn. Lyon 74, 165-171] is further confirmed. Aquixalus (Aquixalus) forms a well-supported monophyletic group within Kurixalus, whereas, Aquixalus (Gracixalus) is more closely related to species of Rhacophorus, Polypedates, and Chiromantis. Philautus as currently understood, does not form a monophyletic group. Philautus (Kirtixalus) is the sister group to the clade comprising Kurixalus and Aquixalus (Aquixalus), and more remotely related to Philautus (Philautus). Chiromantisromeri does not cluster with species of Chiromantis, and forms a basal clade to all rhacophorids save Buergeria. We propose some taxonomic changes that reflect these findings, but further revision should await more detailed studies, which include combined morphological and molecular analyses, with greater species sampling. 相似文献