全文获取类型
收费全文 | 2094篇 |
免费 | 135篇 |
国内免费 | 125篇 |
出版年
2023年 | 28篇 |
2022年 | 29篇 |
2021年 | 125篇 |
2020年 | 78篇 |
2019年 | 79篇 |
2018年 | 78篇 |
2017年 | 49篇 |
2016年 | 89篇 |
2015年 | 124篇 |
2014年 | 164篇 |
2013年 | 170篇 |
2012年 | 205篇 |
2011年 | 167篇 |
2010年 | 89篇 |
2009年 | 78篇 |
2008年 | 99篇 |
2007年 | 101篇 |
2006年 | 93篇 |
2005年 | 80篇 |
2004年 | 38篇 |
2003年 | 50篇 |
2002年 | 44篇 |
2001年 | 21篇 |
2000年 | 34篇 |
1999年 | 33篇 |
1998年 | 25篇 |
1997年 | 16篇 |
1996年 | 16篇 |
1995年 | 18篇 |
1994年 | 12篇 |
1993年 | 13篇 |
1992年 | 19篇 |
1991年 | 14篇 |
1990年 | 9篇 |
1989年 | 11篇 |
1988年 | 9篇 |
1987年 | 8篇 |
1986年 | 9篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1971年 | 2篇 |
1968年 | 1篇 |
1966年 | 2篇 |
排序方式: 共有2354条查询结果,搜索用时 15 毫秒
991.
Weiwei Chen Peixin Liu Yedong Wang Weimin Nie Zhiwei Li Wen Xu Fengyi Li Zhiping Zhou Min Zhao Henggui Liu 《PloS one》2013,8(10)
B7-H3 is a recently discovered member of the B7 superfamily molecules and has been found to play a negative role in T cell responses. In this study, we identified a new B7-H3 isoform that is produced by alternative splicing from the forth intron of B7-H3 and encodes the sB7-H3 protein. Protein sequence analysis showed that sB7-H3 contains an additional four amino acids, encoded by the intron sequence, at the C-terminus compared to the ectodomain of 2Ig-B7-H3. We further found that this spliced sB7-H3 plays a negative regulatory role in T cell responses and serum sB7-H3 is higher in patients with hepatocellular carcinoma (HCC) than in healthy donors. Furthermore, we found that the expression of the spliced sb7-h3 gene is higher in carcinoma and peritumor tissues than in PBMCs of both healthy controls and patients, indicating that the high level of serum sB7-H3 in patients with HCC is caused by the increased expression of this newly discovered spliced sB7-H3 isoform in carcinoma and peritumor tissues. 相似文献
992.
Learning gene expression programs directly from a set of observations is challenging due to the complexity of gene regulation, high noise of experimental measurements, and insufficient number of experimental measurements. Imposing additional constraints with strong and biologically motivated regularizations is critical in developing reliable and effective algorithms for inferring gene expression programs. Here we propose a new form of regulation that constrains the number of independent connectivity patterns between regulators and targets, motivated by the modular design of gene regulatory programs and the belief that the total number of independent regulatory modules should be small. We formulate a multi-target linear regression framework to incorporate this type of regulation, in which the number of independent connectivity patterns is expressed as the rank of the connectivity matrix between regulators and targets. We then generalize the linear framework to nonlinear cases, and prove that the generalized low-rank regularization model is still convex. Efficient algorithms are derived to solve both the linear and nonlinear low-rank regularized problems. Finally, we test the algorithms on three gene expression datasets, and show that the low-rank regularization improves the accuracy of gene expression prediction in these three datasets. 相似文献
993.
Yanhong Gao Sergey Yechikov Ana E. Vázquez Dongyang Chen Liping Nie 《Journal of cellular and molecular medicine》2013,17(7):889-900
KCNQ4, a voltage‐gated potassium channel, plays an important role in maintaining cochlear ion homoeostasis and regulating hair cell membrane potential, both essential for normal auditory function. Mutations in the KCNQ4 gene lead to DFNA2, a subtype of autosomal dominant non‐syndromic deafness that is characterized by progressive sensorineural hearing loss across all frequencies. Despite recent advances in the identification of pathogenic KCNQ4 mutations, the molecular aetiology of DFNA2 remains unknown. We report here that decreased cell surface expression and impaired conductance of the KCNQ4 channel are two mechanisms underlying hearing loss in DFNA2. In HEK293T cells, a dramatic decrease in cell surface expression was detected by immunofluorescent microscopy and confirmed by Western blot for the pathogenic KCNQ4 mutants L274H, W276S, L281S, G285C, G285S, G296S and G321S, while their overall cellular levels remained normal. In addition, none of these mutations affected tetrameric assembly of KCNQ4 channels. Consistent with these results, all mutants showed strong dominant‐negative effects on the wild‐type (WT) channel function. Most importantly, overexpression of HSP90β, a key component of the molecular chaperone network that controls the KCNQ4 biogenesis, significantly increased cell surface expression of the KCNQ4 mutants L281S, G296S and G321S. KCNQ4 surface expression was restored or considerably improved in HEK293T cells mimicking the heterozygous condition of these mutations in DFNA2 patients. Finally, our electrophysiological studies demonstrated that these mutations directly compromise the conductance of the KCNQ4 channel, since no significant change in KCNQ4 current was observed after KCNQ4 surface expression was restored or improved. 相似文献
994.
Yan Liu Zheng-lian Xue Zhi-ming Zheng Guo-hong Gong Peng Wang Guang-jun Nie 《Annals of microbiology》2013,63(2):641-647
In an attempt to obtain a microbial strain with higher yield of folate for industrial applications, we mutated the wild strain Candida utilis Y1.0 using a novel mutagenic process, i.e., irradiation by a helium–neon (He-Ne) laser with an output power of 20 mW and an exposure time of 20 min. The yield of folate in the mutated cells reached 1,102 ng/mL, which was 20.4-fold that of the wild strain. The mutant strain Y3.636 was relatively stable in terms of folate production through eight successive transfers of cultures and batch fermentation in a 3.7-L stirred-tank fermenter. Optimization further increased the yield of the mutant by 110 %, i.e., to 2,314?±?13 ng/mL. The optimal culture conditions for folate production were: cultivation in fermentation culture medium composed of 62.5 g/L glucose, 15 g/L corn liquor, 3 g/L (NH4)2SO4, 3 g/L MgSO4, and 1 g/L glutamic acid; inoculum size of 9 %; incubation at 28 °C and 196 rpm for 36 h. A time-course study of cell growth and folate production by mutant strain Y3.636 strongly suggested that folate production in C. utilis is growth-associated. 相似文献
995.
996.
Background
The associations between the interleukin-4 receptor α chain (IL4RA) I50V and Q551R polymorphisms and asthma risk remained controversial.Methods
We searched the Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases for studies published before February 2013. The strengths of the associations were calculated using odds ratios (ORs) with 95% confidence intervals (CIs).Results
A total of 50 studies were included in this meta-analysis. There was a significant association between the IL4RA I50V polymorphism and asthma risk in a dominant genetic model (OR = 1.13, 95% CI 1.04–1.23, P = 0.005). The IL4RA Q551R polymorphism was associated with a significantly elevated asthma risk in a recessive genetic model (OR = 1.46, 95% CI 1.22–1.75, P<0.0001). Subgroup analyses found that the IL4RA I50V polymorphism was significantly associated with asthma risk in Asians (OR = 1.72, 95% CI 1.31–2.25, P<0.0001), pediatric asthma risk (OR = 1.50, 95% CI 1.13–1.99, P = 0.005), and atopic asthma risk (OR = 1.88, 95% CI 1.27–2.79, P = 0.002).Conclusions
The results of this meta-analysis suggested that the IL4RA I50V and Q551R polymorphisms may be risk factors for developing asthma. 相似文献997.
Hao Zhang Wenchen Nie Xu Zhang Gentang Zhang Zhiqiang Li Huaibing Wu Qiong Shi Yong Chen Zhijun Ding Xiuping Zhou Rutong Yu 《PloS one》2013,8(12)
Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro. 相似文献
998.
Yuqi Cheng Jian Xu Binbin Nie Chunrong Luo Tao Yang Haijun Li Jin Lu Lin Xu Baoci Shan Xiufeng Xu 《PloS one》2013,8(6)
Background
Obsessive-compulsive disorder (OCD) is a mental illness characterized by the loss of control. Because the cingulate cortex is believed to be important in executive functions, such as inhibition, we used functional magnetic resonance imaging (fMRI) techniques to examine whether and how activity and functional connectivity (FC) of the cingulate cortex were altered in drug-naïve OCD patients.Methods
Twenty-three medication-naïve OCD patients and 23 well-matched healthy controls received fMRI scans in a resting state. Functional connectivities of the anterior cingulate (ACC) and the posterior cingulate (PCC) to the whole brain were analyzed using correlation analyses based on regions of interest (ROI) identified by the fractional amplitude of low-frequency fluctuation (fALFF). Independent Component Analysis (ICA) was used to identify the resting-state sub-networks.Results
fALFF analysis found that regional activity was increased in the ACC and decreased in the PCC in OCD patients when compared to controls. FC of the ACC and the PCC also showed different patterns. The ACC and the PCC were found to belong to different resting-state sub-networks in ICA analysis and showed abnormal FC, as well as contrasting correlations with the severity of OCD symptoms.Conclusions
Activity of the ACC and the PCC were increased and decreased, respectively, in the medication-naïve OCD patients compared to controls. Different patterns in FC were also found between the ACC and the PCC with respect to these two groups. These findings implied that the cardinal feature of OCD, the loss of control, may be attributed to abnormal activities and FC of the ACC and the PCC. 相似文献999.
Chen Zhang Ying Liu Brian Z. Ring Kai Nie Mengjie Yang Miao Wang Hongwei Shen Xiyang Wu Xuejun Ma 《PloS one》2013,8(4)
Background
The tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) is a fast and economical means of assaying SNP''s, requiring only PCR amplification and subsequent electrophoresis for the determination of genotypes. To improve the throughput and efficiency of T-ARMS-PCR, we combined T-ARMS-PCR with a chimeric primer-based temperature switch PCR (TSP) strategy, and used capillary electrophoresis (CE) for amplicon separation and identification. We assessed this process in the simultaneous genotyping of four breast cancer–and two cervical cancer risk–related SNPs.Methods
A total of 24 T-ARMS-PCR primers, each 5′-tagged with a universal sequence and a pair of universal primers, were pooled together to amplify the 12 target alleles of 6 SNPs in 186 control female blood samples. Direct sequencing of all samples was also performed to assess the accuracy of this method.Results
Of the 186 samples, as many as 11 amplicons can be produced in one single PCR and separated by CE. Genotyping results of the multiplex T-ARMS-PCR were in complete agreement with direct sequencing of all samples.Conclusions
This novel multiplex T-ARMS-PCR method is the first reported method allowing one to genotype six SNPs in a single reaction with no post-PCR treatment other than electrophoresis. This method is reliable, fast, and easy to perform. 相似文献1000.
Zhongwu Li Jinquan Huang Guangming Zeng Xiaodong Nie Wenming Ma Wei Yu Wang Guo Jiachao Zhang 《PloS one》2013,8(10)
The effects of water erosion (including long-term historical erosion and single erosion event) on soil properties and productivity in different farming systems were investigated. A typical sloping cropland with homogeneous soil properties was designed in 2009 and then protected from other external disturbances except natural water erosion. In 2012, this cropland was divided in three equally sized blocks. Three treatments were performed on these blocks with different simulated rainfall intensities and farming methods: (1) high rainfall intensity (1.5 - 1.7 mm min−1), no-tillage operation; (2) low rainfall intensity (0.5 - 0.7 mm min−1), no-tillage operation; and (3) low rainfall intensity, tillage operation. All of the blocks were divided in five equally sized subplots along the slope to characterize the three-year effects of historical erosion quantitatively. Redundancy analysis showed that the effects of long-term historical erosion significantly caused most of the variations in soil productivity in no-tillage and low rainfall erosion intensity systems. The intensities of the simulated rainfall did not exhibit significant effects on soil productivity in no-tillage systems. By contrast, different farming operations induced a statistical difference in soil productivity at the same single erosion intensity. Soil organic carbon (SOC) was the major limiting variable that influenced soil productivity. Most explanations of long-term historical erosion for the variation in soil productivity arose from its sharing with SOC. SOC, total nitrogen, and total phosphorus were found as the regressors of soil productivity because of tillage operation. In general, this study provided strong evidence that single erosion event could also impose significant constraints on soil productivity by integrating with tillage operation, although single erosion is not the dominant effect relative to the long-term historical erosion. Our study demonstrated that an effective management of organic carbon pool should be the preferred option to maintain soil productivity in subtropical red soil hilly region. 相似文献