全文获取类型
收费全文 | 2549篇 |
免费 | 122篇 |
国内免费 | 52篇 |
出版年
2023年 | 37篇 |
2022年 | 51篇 |
2021年 | 59篇 |
2020年 | 75篇 |
2019年 | 85篇 |
2018年 | 91篇 |
2017年 | 61篇 |
2016年 | 45篇 |
2015年 | 44篇 |
2014年 | 134篇 |
2013年 | 211篇 |
2012年 | 89篇 |
2011年 | 155篇 |
2010年 | 99篇 |
2009年 | 106篇 |
2008年 | 107篇 |
2007年 | 113篇 |
2006年 | 104篇 |
2005年 | 105篇 |
2004年 | 56篇 |
2003年 | 72篇 |
2002年 | 59篇 |
2001年 | 38篇 |
2000年 | 47篇 |
1999年 | 36篇 |
1998年 | 44篇 |
1997年 | 37篇 |
1996年 | 27篇 |
1995年 | 35篇 |
1994年 | 27篇 |
1993年 | 36篇 |
1992年 | 33篇 |
1991年 | 41篇 |
1990年 | 32篇 |
1989年 | 19篇 |
1988年 | 27篇 |
1987年 | 15篇 |
1986年 | 5篇 |
1985年 | 36篇 |
1984年 | 36篇 |
1983年 | 20篇 |
1982年 | 33篇 |
1981年 | 33篇 |
1980年 | 22篇 |
1979年 | 18篇 |
1978年 | 11篇 |
1977年 | 12篇 |
1976年 | 16篇 |
1975年 | 10篇 |
1974年 | 8篇 |
排序方式: 共有2723条查询结果,搜索用时 15 毫秒
111.
Saied Ghadimi Ali Asghar Ebrahimi Valmoozi Mehrdad Pourayoubi Keyvan Asad Samani 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):556-561
Phosphoramido acid esters (CH3)2NP(O)X(p-OC6H4-CH3) (containing P-Cl (1), P-O (2), P-F (3), P-CN (5), and P-N (4,6) bonds, X for 2, 4 and 6 is OCH3, (C2H5)2N and morpholin) have been synthesized to investigate the structure-activity study of AChE enzyme inhibition, through the parameters logP, δ31P and IC50. After their characterization by 31P, 31P{1H}, 13C, 1H NMR, IR and mass spectroscopy, the parameters logP and δ31P (31P chemical shift in NMR) were used to evaluated the lipophilicity and electronical properties. The ability of compounds to inhibit human AChE was predicted by PASS software (version 1.193), and experimentally evaluated by a modified Ellman's assay. 相似文献
112.
β-amino acids are widely used in drug research, and S-3-amino-3-phenylpropionic acid (S-APA) is an important pharmaceutical intermediate of S-dapoxetine, which has been approved for the treatment of premature ejaculation. Chiral catalysis is an excellent method for the preparation of enantiopure compounds. In this study, we used (±)-ethyl-3-amino-3-phenylpropanoate (EAP) as the sole carbon source. Three hundred thirty one microorganisms were isolated from 30 soil samples, and 17 strains could produce S-APA. After three rounds of cultivation and identification, the strain Y1-6 exhibiting the highest enantioselective activity of S-APA was identified as Methylobacterium oryzae. The optimal medium composition contained methanol (2.5 g/L), 1,2-propanediol (7.5 g/L), soluble starch (2.5 g/L), and peptone (10 g/L); it was shaken at 220 rpm for 4–5 days at 30 °C. The optimum condition for biotransformation of EAP involved cultivation at 37 °C for 48 h with 120 mg of wet cells and 0.64 mg of EAP in 1 ml of transfer solution. Under this condition, substrate ee was 92.1% and yield was 48.6%. We then attempted to use Methylobacterium Y1-6 to catalyze the hydrolytic reaction with substrates containing 3-amino-3-phenyl-propanoate ester, N-substituted-β-ethyl-3-amino-3-phenyl-propanoate, and γ-lactam. It was found that 5 compounds with ester bonds could be stereoselectively hydrolyzed to S-acid, and 2 compounds with γ-lactam bonds could be stereoselectively hydrolyzed to (-)-γ-lactam. 相似文献
113.
Stephanie Schwalm Josef Pfeilschifter Andrea Huwiler 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(1):239-250
Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that acts either on G protein-coupled S1P receptors on the cell surface or via intracellular target sites. In addition to the well established effects of S1P in angiogenesis, carcinogenesis and immunity, evidence is now continuously accumulating which demonstrates that S1P is an important regulator of fibrosis. The contribution of S1P to fibrosis is of a Janus-faced nature as S1P exhibits both pro- and anti-fibrotic effects depending on its site of action. Extracellular S1P promotes fibrotic processes in a S1P receptor-dependent manner, whereas intracellular S1P has an opposite effect and dampens a fibrotic reaction by yet unidentified mechanisms. Fibrosis is a result of chronic irritation by various factors and is defined by an excess production of extracellular matrix leading to tissue scarring and organ dysfunction. In this review, we highlight the general effects of extracellular and intracellular S1P on the multistep cascade of pathological fibrogenesis including tissue injury, inflammation and the action of pro-fibrotic cytokines that stimulate ECM production and deposition. In a second part we summarize the current knowledge about the involvement of S1P signaling in the development of organ fibrosis of the lung, kidney, liver, heart and skin. Altogether, it is becoming clear that targeting the sphingosine kinase-1/S1P signaling pathway offers therapeutic potential in the treatment of various fibrotic processes. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. 相似文献
114.
Seongah Han Lauretta LeVoci Paul Fischer Sheng-Ping Wang Karen Gagen Ying Chen Dan Xie Timothy Fisher Anka G. Ehrhardt Andrea M. Peier Douglas G. Johns 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(4):825-833
Cholesteryl ester transfer protein (CETP) is a target of therapeutic intervention for coronary heart disease. Anacetrapib, a potent inhibitor of CETP, has been shown to reduce LDL-cholesterol by 40% and increase HDL-cholesterol by 140% in patients, and is currently being evaluated in a phase III cardiovascular outcomes trial. HDL is known to possess anti-inflammatory properties, however with such large increases in HDL-cholesterol, it is unclear whether CETP inhibition perturbs HDL functionality such as anti-inflammatory effects on endothelial cells. The purpose of the present study was to determine whether CETP inhibition by anacetrapib affects the anti-inflammatory properties of HDL. HDL was isolated from either hamsters treated with vehicle or anacetrapib for 2 weeks, or from normal human subjects treated either placebo, 20 mg, or 150 mg anacetrapib daily for 2 weeks. Anacetrapib treatment increased plasma HDL cholesterol levels by 65% and between 48 and 82% in hamsters and humans, respectively. Pre-incubation of human aortic endothelial cells with HDL isolated from both control and anacetrapib treated hamsters suppressed TNFα induced expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Similar results were obtained with human HDL samples pre and post treatment with placebo or anacetrapib. Further, HDL inhibited TNFα-induced MCP-1 secretion, monocyte adhesion and NF-κB activation in endothelial cells, and the inhibition was similar between control and anacetrapib treated groups. These studies demonstrate that anacetrapib treatment does not impair the ability of HDL to suppress an inflammatory response in endothelial cells. 相似文献
115.
《Cell communication & adhesion》2013,20(3-4):55-62
The establishment of an elaborate gap junctional intercellular communication network, especially between hepatocytes, is important for normal liver development. In fact, the production of the gap junction building blocks, the connexins, undergoes several well-defined changes throughout the hepatic differentiation process. This ultimately results in the acquisition of an adult connexin expression pattern which is critical for maintaining the fully differentiated hepatocyte-specific phenotype. Abnormalities of connexin production are observed in a number of pathological conditions, such as during liver cancer. This article provides an overview of these processes with emphasis on the underlying molecular mechanisms. 相似文献
116.
117.
Mohammad Foad Abazari Fatemeh Soleimanifar Seyed Ehsan Enderami Navid Nasiri Fatemeh Nejati Seyed Ahmad Mousavi Masoud Soleimani Jafar Kiani Pegah Ghoraeian Mousa Kehtari 《Journal of cellular biochemistry》2020,121(2):1169-1181
Human-induced pluripotent stem cells-derived hepatocyte-like cells (hiPSCs-HLCs) holds considerable promise for future clinical personalized therapy of liver disease. However, the low engraftment of these cells in the damaged liver microenvironment is still an obstacle for potential application. In this study, we explored the effectiveness of decellularized amniotic membrane (dAM) matrices for culturing of iPSCs and promoting their differentiation into HLCs. The DNA content assay and histological evaluation indicated that cellular and nuclear residues were efficiently eliminated and the AM extracellular matrix component was maintained during decelluarization. DAM matrices were developed as three-dimensional scaffolds and hiPSCs were seeded into these scaffolds in defined induction media. In dAM scaffolds, hiPSCs-HLCs gradually took a typical shape of hepatocytes (polygonal morphology). HiPSCs-HLCs that were cultured into dAM scaffolds showed a higher level of hepatic markers than those cultured in tissue culture plates (TCPs). Moreover, functional activities in term of albumin and urea synthesis and CYP3A activity were significantly higher in dAM scaffolds than TCPs over the same differentiation period. Thus, based on our results, dAM scaffold might have a considerable potential in liver tissue engineering, because it can improve hepatic differentiation of hiPSCs which exhibited higher level of the hepatic marker and more stable metabolic functions. 相似文献
118.
Zahra Farzaneh Saeed Abbasalizadeh Mohammad-Hassan Asghari-Vostikolaee Mehdi Alikhani Joaquim M. S. Cabral Hossein Baharvand 《Biotechnology and bioengineering》2020,117(12):3739-3756
Developing technologies for scalable production of human organoids has gained increased attention for “organoid medicine” and drug discovery. We developed a scalable and integrated differentiation process for generation of hepatic organoid from human pluripotent stem cells (hPSCs) in a fully controlled stirred tank bioreactor with 150 ml working volume by application of physiological oxygen concentrations in different liver tissue zones. We found that the 20–40% dissolved oxygen concentration [DO] (corresponded to 30–60 mmHg pO2 within the liver tissue) significantly influences the process outcome via regulating the differentiation fate of hPSC aggregates by enhancing mesoderm induction. Regulation of the [DO] at 30% DO resulted in efficient generation of human fetal-like hepatic organoids that had a uniform size distribution and were comprised of red blood cells and functional hepatocytes, which exhibited improved liver-specific marker gene expressions, key liver metabolic functions, and, more important, higher inducible cytochrome P450 activity compared to the other trials. These hepatic organoids were successfully engrafted in an acute liver injury mouse model and produced albumin after implantation. These results demonstrated the significant impact of the dissolved oxygen concentration on hPSC hepatic differentiation fate and differentiation efficacy that should be considered ascritical translational aspect of established scalable liver organoid generation protocols for potential clinical and drug discovery applications. 相似文献
119.
Dola Das Ehsan Fayazzadeh Xin Li Nischal Koirala Akshay Wadera Min Lang Maximilian Zernic Catherine Panick Pete Nesbitt Gordon McLennan 《Journal of cellular physiology》2020,235(9):6167-6182
Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A-HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A-HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A-HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A-HSCs in cancer generation and investigated the therapeutic potential of A-HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q-HSCs) in cancer growth or arrest. Here we report that Q-HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q-HSCs (Q-HSCCM) induces cancer cell death through a caspase-independent mechanism that involves an increase in apoptosis-inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q-HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy. 相似文献
120.
Biochemical modifications of gliadins induced by microbial transglutaminase on wheat flour 总被引:1,自引:0,他引:1
Maria F. Mazzeo Roberta BonavitaFrancesco Maurano Paolo BergamoRosa A. Siciliano Mauro Rossi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013