全文获取类型
收费全文 | 2345篇 |
免费 | 189篇 |
国内免费 | 1篇 |
专业分类
2535篇 |
出版年
2023年 | 10篇 |
2022年 | 30篇 |
2021年 | 33篇 |
2020年 | 19篇 |
2019年 | 29篇 |
2018年 | 28篇 |
2017年 | 22篇 |
2016年 | 53篇 |
2015年 | 129篇 |
2014年 | 158篇 |
2013年 | 179篇 |
2012年 | 195篇 |
2011年 | 194篇 |
2010年 | 110篇 |
2009年 | 109篇 |
2008年 | 130篇 |
2007年 | 121篇 |
2006年 | 109篇 |
2005年 | 108篇 |
2004年 | 102篇 |
2003年 | 72篇 |
2002年 | 70篇 |
2001年 | 66篇 |
2000年 | 56篇 |
1999年 | 46篇 |
1998年 | 28篇 |
1997年 | 16篇 |
1996年 | 13篇 |
1995年 | 11篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 26篇 |
1991年 | 40篇 |
1990年 | 24篇 |
1989年 | 17篇 |
1988年 | 19篇 |
1987年 | 14篇 |
1986年 | 13篇 |
1985年 | 13篇 |
1983年 | 6篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1979年 | 8篇 |
1978年 | 11篇 |
1977年 | 11篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 8篇 |
1971年 | 4篇 |
1969年 | 5篇 |
排序方式: 共有2535条查询结果,搜索用时 15 毫秒
61.
62.
Chuen-Mao Yang Hsi-Lung Hsieh Chih-Chung Lin Ruey-Horng Shih Pei-Ling Chi Shin-Ei Cheng Li-Der Hsiao 《Molecular neurobiology》2013,47(3):1020-1033
Bradykinin (BK) has been shown to induce the expression of several inflammatory mediators, including reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), in brain astrocytes. These mediators may contribute to neuronal dysfunction and death in various neurological disorders. However, the effects of multiple inflammatory mediators released from BK-challenged astrocytes on neuronal cells remain unclear. Here, we found that multiple factors were released from brain astrocytes (RBA-1) exposed to BK in the conditioned culture media (BK-CM), including ROS, MMP-9, and heme oxygenase-1 (HO-1)/carbon monoxide (CO), leading to neuronal cell (SK-N-SH) death. Exposure of SK-N-SH cells to BK-CM or H2O2 reduced cell viability and induced cell apoptosis which were attenuated by N-acetyl cysteine, indicating a role of ROS in these responses. The effect of BK-CM on cell viability and cell apoptosis was also reversed by immunoprecipitation of BK-CM with anti-MMP-9 antibody (MMP-9-IP-CM) or MMP2/9 inhibitor, suggesting the involvement of MMP-9 in BK-CM-mediated responses. Astroglial HO-1/CO in BK-CM induced cell apoptosis and reduced cell viability which was reversed by hemoglobin. Consistently, the involvement of CO in these cellular responses was revealed by incubation with a CO donor CO-RM2 which was reversed by hemoglobin. The role of HO-1 in BK-CM-induced responses was confirmed by overexpression of HO-1 in SK-N-SH infected with Adv-HO-1. BK-CM-induced cell apoptosis was due to the activation of caspase-3 and cleavage of PARP. Together, we demonstrate that BK-induced several neurotoxic factors, including ROS, MMP-9, and CO released from astrocytes, may induce neuronal death through a caspase-3-dependent apoptotic pathway. 相似文献
63.
64.
Ya-Lan Chang Chin-Lin Hsieh Yao-Moan Huang Wen-Liang Chiou Yueh-Hsiung Kuo Mei-Hwei Tseng 《Analytical biochemistry》2013
A wide variety of sulfur metabolites play important roles in plant functions. We have developed a precise and sensitive method for the simultaneous measurement of several sulfur metabolites based on liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) and 34S metabolic labeling of sulfur-containing metabolites in Arabidopsis thaliana seedlings. However, some sulfur metabolites were unstable during the extraction procedure. Our proposed method does not allow for the detection of the important sulfur metabolite homocysteine because of its instability during sample extraction. Stable isotope-labeled sulfur metabolites of A. thaliana shoot were extracted and utilized as internal standards for quantification of sulfur metabolites with LC–MS/MS using S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), glutathione (GSH), and glutathione disulfide (GSSG) as example metabolites. These metabolites were detected using electrospray ionization in positive mode. Standard curves were linear (r2 > 0.99) over a range of concentrations (SAM 0.01–2.0 μM, SAH 0.002–0.10 μM, Met 0.05–4.0 μM, GSH 0.17–20.0 μM, GSSG 0.07–20.0 μM), with limits of detection for SAM, SAH, Met, GSH, and GSSG of 0.83, 0.67, 10, 0.56, and 1.1 nM, respectively; and the within-run and between-run coefficients of variation based on quality control samples were less than 8%. 相似文献
65.
Neuropeptide Y (NPY) and nuclear factor-kappa B (NF-κB) are involved in regulating anorexia elicited by phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether NPY Y1 receptor (Y1R) is involved in this process, and a potential role for the proopiomelanocortin system was identified. Rats were given PPA once a day for 4 days. Changes in the hypothalamic expression of the NPY, Y1R, NF-κB, and melanocortin receptor 4 (MC4R) levels were assessed and compared. The results indicated that food intake and NPY expression decreased, with the largest reductions observed on Day 2 (approximately 50% and 45%, respectively), whereas NF-κB, MC4R, and Y1R increased, achieving maximums on Day 2 (160%, 200%, and 280%, respectively). To determine the role of Y1R, rats were pretreated with Y1R antisense or a Y1R antagonist via intracerebroventricular injection 1 h before the daily PPA dose. Y1R knockdown and inhibition reduced PPA anorexia and partially restored the normal expression of NPY, MC4R, and NF-κB. The data suggest that hypothalamic Y1R participates in the appetite-suppression from PPA by regulating MC4R and NF-κB. The results of this study increase our understanding of the molecular mechanisms in PPA-induced anorexia. 相似文献
66.
Y Li Y Kong Z Zhou H Chen Z Wang Y-C Hsieh D Zhao X Zhi J Huang J Zhang H Li C Chen 《Cell death & disease》2013,4(11):e935
Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival. 相似文献
67.
Chih-Hsiung Lai Shiang-Fu Huang Chun-Ta Liao I-How Chen Hung-Ming Wang Ling-Ling Hsieh 《PloS one》2013,8(6)
Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients'' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15–2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06–2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient''s response to radiotherapy/chemo-radiotherapy. 相似文献
68.
Theories and empirical evidence suggest that random dispersal of organisms promotes species coexistence in spatially structured environments. However, directed dispersal, where movement is adjusted with fitness-related cues, is less explored in studies of dispersal-mediated coexistence. Here, we present a metacommunity model of two consumers exhibiting directed dispersal and competing for a single resource. Our results indicated that directed dispersal promotes coexistence through two distinct mechanisms, depending on the adaptiveness of dispersal. Maladaptive directed dispersal may promote coexistence similar to random dispersal. More importantly, directed dispersal is adaptive when dispersers track patches of increased resources in fluctuating environments. Coexistence is promoted under increased adaptive dispersal ability of the inferior competitor relative to the superior competitor. This newly described dispersal-mediated coexistence mechanism is likely favored by natural selection under the trade-off between competitive and adaptive dispersal abilities. 相似文献
69.
Su Chia-Ying Lin Chun-Han Shih Pei-Ying Hsieh Chieh Yao Yu-Feng Tu Charng-Gan Chen Hao-Tsung Chen Horng-Shyang Kiang Yean-Woei Yang C. C. 《Plasmonics (Norwell, Mass.)》2016,11(3):931-939
Plasmonics - Surface plasmon (SP) coupling behaviors of an InGaN/GaN quantum well (QW) with surface plasmon polariton (SPP) induced on a smooth Ag-film/GaN interface and localized surface plasmon... 相似文献
70.
Hsueh-Tzu Shih Wei-Yu Chen Kwei-Yan Liu Zong-Siou Shih Yi-Jyun Chen Paul-Chen Hsieh Kuan-Lin Kuo Kuo-How Huang Pang-Hung Hsu Ya-Wen Liu Shih-Peng Chan Hsiu-Hsiang Lee Yu-Chen Tsai June-Tai Wu 《PLoS genetics》2016,12(9)
To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations. 相似文献