全文获取类型
收费全文 | 67411篇 |
免费 | 5138篇 |
国内免费 | 2149篇 |
出版年
2023年 | 868篇 |
2022年 | 1081篇 |
2021年 | 1782篇 |
2020年 | 2116篇 |
2019年 | 2831篇 |
2018年 | 2602篇 |
2017年 | 1812篇 |
2016年 | 1880篇 |
2015年 | 2172篇 |
2014年 | 4046篇 |
2013年 | 4798篇 |
2012年 | 2917篇 |
2011年 | 3986篇 |
2010年 | 2995篇 |
2009年 | 3302篇 |
2008年 | 3665篇 |
2007年 | 3538篇 |
2006年 | 3110篇 |
2005年 | 2800篇 |
2004年 | 2535篇 |
2003年 | 2132篇 |
2002年 | 1950篇 |
2001年 | 1299篇 |
2000年 | 1071篇 |
1999年 | 1125篇 |
1998年 | 1082篇 |
1997年 | 919篇 |
1996年 | 831篇 |
1995年 | 839篇 |
1994年 | 806篇 |
1993年 | 646篇 |
1992年 | 567篇 |
1991年 | 513篇 |
1990年 | 407篇 |
1989年 | 365篇 |
1988年 | 315篇 |
1987年 | 324篇 |
1986年 | 251篇 |
1985年 | 402篇 |
1984年 | 557篇 |
1983年 | 491篇 |
1982年 | 501篇 |
1981年 | 402篇 |
1980年 | 403篇 |
1979年 | 314篇 |
1978年 | 235篇 |
1977年 | 223篇 |
1976年 | 215篇 |
1975年 | 180篇 |
1974年 | 166篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
941.
【目的】多重耐药菌的出现对公共卫生安全构成严重威胁,本研究分离多重耐药大肠杆菌噬菌体,研究其生物学特性和基因组特征,为耐药菌的噬菌体疗法提供理论依据。【方法】使用双层平板法从污水样本中分离纯化大肠杆菌噬菌体;磷钨酸染色后通过透射电镜观察形态;测定其宿主范围,测定温度和pH稳定性、一步生长曲线和体外抑菌效果等生物学特性;体内抑菌试验评估噬菌体对多重耐药大肠杆菌N1203-1Af感染的大蜡螟幼虫的保护作用;基于全基因组测序对其基因组特点进行分析。【结果】本研究分离共得到5株大肠杆菌噬菌体,分别命名为pEC-S163-2.1、pEC-S163-2.2、pEC-M1167-5Ar.1、pEC-m1291-2Dr.1和pEC-N1203-2Af.1;电镜结果显示噬菌体pEC-N1203-2Af.1属于短尾噬菌体中罕见的C3形态型,头部较长,长是宽的2–3倍;pEC-N1203-2Af.1可裂解受试15株大肠杆菌中的3株;感染10 min后进入指数增长期,–20-50℃、pH值为4.0–10.0的环境下均能够保持稳定活性;大蜡螟幼虫感染大肠杆菌N1203-2Af后噬菌体pEC-N1203-2Af.... 相似文献
942.
943.
Ankur Srivastava Gargi Mishra Kshitij RB Singh Jay Singh Rampal Pandey Mrituanjay D. Pandey 《Luminescence》2023,38(7):1347-1357
Rare earth metals play a conspicuous role in magnetic resonance imaging (MRI) for detecting cancerous cells. The alkali metal potassium is a neurotransmitter in the sodium–potassium pump in biomedical sciences. This unique property of rare earth metals and potassium drew our attention to carry forward this study. Therefore, in this work, previously synthesized potassium (K) complexes formed by the reflux of 4-N,N-dimethylaminobenzoic acid (DBA) and potassium hydroxide in methanol, and named [(μ2–4-N,N-dimethylaminobenzoate-κO)(μ2–4-N,N-dimethylaminobenzoic acid-κO)(4-N,N-dimethylaminobenzoic acid-κO) potassium(I) coordination polymer)] were treated hydrothermally with La2O3 nanomaterials to obtain a nanohybrid La2O3/K-complex. After that, the K-complex was analyzed using single-crystal X-ray diffraction and 1H and 13C NMR spectroscopy. In addition, the structural and morphological properties of the as-prepared nanostructured La2O3/K-complex were also characterized, which involved an investigation using X-ray diffraction (XRD)spectroscopy, Fourier transform infrared (FTIR) spectroscopy, atomic force spectroscopy (AFM), transmission electron microscopy (TEM), and energy dispersive X-ray (EDX) analysis. After this, the electrochemical redox behaviour of the synthesized nanohybrid material was studied using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Therefore, the results from these studies revealed that the as-prepared material was a La2O3/K-complex that has a promising future role in sensing various analytes, as it showed effective electrocatalytic behaviour. 相似文献
944.
Hui Wang Lingling Wang Meihua Wu Minghao Fang Zhaohui Huang Xin Min 《Luminescence》2023,38(2):208-215
This paper reports a sequence of a Ca3YAl3B4O15:xEu3+ red phosphor prepared using a high-temperature solid-state reaction. At the excitation of 396 nm, the samples emitted intense red emission centred at ~623 nm, which could be attributed to the 5D0→7F2 transition of the Eu3+ ion. The results showed that the optimum Eu3+ doping concentration of Ca3YAl3B4O15:Eu3+ phosphor was x = 80 mol%, and the concentration quenching mechanism of Ca3YAl3B4O15:Eu3+ red phosphor belonged to the exchange coupling between Eu3+ ions. The Commission Internationale de l'éclairage (CIE) coordinates and colour purity of Ca3Y0.2Al3B4O15:0.8Eu3+ were calculated as (0.6375, 0.3476) and 95.5%, respectively. Moreover, the red emission of the obtained phosphor Ca3YAl3B4O15:0.8Eu3+ exhibited a low thermal quenching behaviour with an intensity retention rate of 92.85% at 150°C. The above results manifest that the Eu3+-activated Ca3YAl3B4O15 phosphor is predicted to be a promising red luminescent component for white light-emitting diodes. 相似文献
945.
Xiaoyu Yi Chao Zhang Baojie Liu Guojun Gao Yaqi Tang Yongzheng Lu Zhifang Pan Guohui Wang Weiguo Feng 《Journal of cellular and molecular medicine》2023,27(3):403-411
Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22-like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy. 相似文献
946.
Xiaohe Li Xiaoyang Ma Yang Miao Jianwei Zhang Buri Xi Wenqi Li Qianyi Zhang Li Chen Yue Yang Hongli Li Luqing Wei Honggang Zhou Cheng Yang 《Journal of cellular and molecular medicine》2023,27(3):422-434
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis. 相似文献
947.
Nan Tang Kai Zhu Cheng Jiang Zhiyong Xiong Qiangping Wang Junjun Li Weiming Xu 《Journal of cellular and molecular medicine》2023,27(2):277-286
RNF7 has been reported to play critical roles in various cancers. However, the underlying mechanisms of RNF7 in glioma development remain largely unknown. Herein, the expression level of RNF7 was examined in tissues by quantitative real-time PCR, Western blotting and immunohistochemistry. The effect of RNF7 on glioma progression was measured by performing CCK-8 and apoptosis assays, cell cycle-related experiments and animal experiments. The effect of RNF7 on PI3K/AKT signalling pathway was tested by Western blotting. First, we found that RNF7 was upregulated in tumour tissue compared with normal brain tissue, especially in high-grade glioma, and the high expression of RNF7 was significantly related to tumour size, Karnofsky Performance Scale score and a poor prognosis. Second, RNF7 overexpression facilitated tumour cell cycle progression and cell proliferation and suppressed apoptosis. Conversely, RNF7 knockdown suppressed tumour cell cycle progression and cell proliferation and facilitated apoptosis. Furthermore, follow-up mechanistic studies indicated that RNF7 could facilitate glioma cell proliferation and cell cycle progression and inhibit apoptosis by activating the PI3K/AKT signalling pathway. This study shows that RNF7 can clearly promote glioma cell proliferation by facilitating cell cycle progression and inhibiting apoptosis by activating the PI3K/AKT signalling pathway. Targeting the RNF7/PI3K/AKT axis may provide a new perspective on the prevention or treatment of glioma. 相似文献
948.
Zehra Degirmenci Sena Unver Turker Kilic Timucin Avsar 《Journal of cellular and molecular medicine》2023,27(17):2603-2613
Aberrant expression of MEG3 has been shown in various cancers. The purpose of this study is to evaluate the effect of MEG3 on glioma cells and the use of potential chemotherapeutics in glioma by modulating MEG3 expression. Cell viability, migration and chemosensitivity were assayed. Cell death was evaluated in MEG3 overexpressing and MEG3 suppressed cells. MEG3 expression was compared in patient-derived glioma cells concerning IDH1 mutation and WHO grades. Silencing of MEG3 inhibited cell proliferation and reduced cell migration while overexpression of MEG3 promoted proliferation in glioma cells. MEG3 inhibition improved the chemosensitivity of glioma cells to 5-fluorouracil (5FU) but not to navitoclax. On the other hand, there is no significant effect of MEG3 expression on temozolamide (TMZ) treatment which is a standard chemotherapeutic agent in glioma. Suppression of the MEG3 gene in patient-derived oligodendroglioma cells also showed the same effect whereas glioblastoma cell proliferation and chemosensitivity were not affected by MEG3 inhibition. Further, as a possible cell death mechanism of action apoptosis was investigated. Although MEG3 is a widely known tumour suppressor gene and its loss is associated with several cancer types, here we reported that MEG3 inhibition can be used for improving the efficiency of known chemotherapeutic drug sensitivity. We propose that the level of MEG3 should be evaluated in the treatment of different glioma subtypes that are resistant to effective drugs to increase the potential effective drug applications. 相似文献
949.
Tong Wu Qi Tian Ruiji Liu Ke Xu Shanshan Shi Xiudi Zhang Liming Gao Xiaobo Yin Shufeng Xu Ping Wang 《Journal of cellular and molecular medicine》2023,27(22):3526-3538
Exosomal microRNA (miRNA) exerts potential roles in non-small-cell lung cancer (NSCLC). The current study elucidated the role of miR-30b-5p shuttled by bone marrow mesenchymal stem cells (BMSCs)-derived exosomes in treating NSCLC. Bioinformatics analysis was performed with NSCLC-related miRNA microarray GSE169587 and mRNA data GSE74706 obtained for collection of the differentially expressed miRNAs and mRNAs. The relationship between miR-30b-5p and EZH2 was predicted and confirmed. Exosomes were isolated from BMSCs and identified. BMSCs-derived exosomes overexpressing miR-30b-5p were used to establish subcutaneous tumorigenesis models to study the effects of miR-30b-5p, EZH2 and PI3K/AKT signalling pathway on tumour growth. A total of 86 BMSC-exo-miRNAs were differentially expressed in NSCLC. Bioinfomatics analysis found that BMSC-exo-miR-30b-5p could regulate NSCLC progression by targeting EZH2, which was verified by in vitro cell experiments. Besides, the target genes of miR-30b-5p were enriched in PI3K/AKT signalling pathway. Animal experiments validated that BMSC-exo-miR-30b-5p promoted NSCLC cell apoptosis and prevented tumorigenesis in nude mice via EZH2/PI3K/AKT axis. Collectively, the inhibitory role of BMSC-derived exosomes-loaded miR-30b-5p in NSCLC was achieved through blocking the EZH2/PI3K/AKT axis. 相似文献
950.
Structural engineering of the HIV-1 protease molecule with a beta-turn mimic of fixed geometry. 总被引:2,自引:1,他引:1 下载免费PDF全文
M. Baca P. F. Alewood S. B. Kent 《Protein science : a publication of the Protein Society》1993,2(7):1085-1091
An important goal in the de novo design of enzymes is the control of molecular geometry. To this end, an analog of the protease from human immunodeficiency virus 1 (HIV-1 protease) was prepared by total chemical synthesis, containing a constrained, nonpeptidic type II' beta-turn mimic of predetermined three-dimensional structure. The mimic beta-turn replaced residues Gly16,17 in each subunit of the homodimeric molecule. These residues constitute the central amino acids of two symmetry-related type I' beta-turns in the native, unliganded enzyme. The beta-turn mimic-containing enzyme analog was fully active, possessed the same substrate specificity as the Gly16,17-containing enzyme, and showed enhanced resistance to thermal inactivation. These results indicate that the precise geometry of the beta-turn at residues 15-18 in each subunit is not critical for activity, and that replacement of the native sequence with a rigid beta-turn mimic can lead to enhanced protein stability. Finally, the successful incorporation of a fixed element of secondary structure illustrates the potential of a "molecular kit set" approach to protein design and synthesis. 相似文献