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51.
Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects
Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects. 相似文献
52.
Ryuzaburo Yuki Mari Hagino Sachi Ueno Takahisa Kuga Youhei Saito Yasunori Fukumoto Noritaka Yamaguchi Naoto Yamaguchi Yuji Nakayama 《Journal of cellular and molecular medicine》2021,25(3):1677-1687
v-Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v-Src-mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities-mediated chromosome instability. v-Src directly phosphorylates Tyr-15 of cyclin-dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v-Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v-Src restores cancer cell viability reduced by various microtubule-targeting agents (MTAs), although v-Src does not alter cytotoxicity of DNA-damaging anticancer drugs. v-Src causes mitotic slippage of MTAs-treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v-Src also restores cell viability reduced by a polo-like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v-Src. These results suggest that the v-Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src-induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs. 相似文献
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分析2015年至2019年辽宁省人民医院血培养分离菌的科室分布及耐药情况,为临床提供数据参考。利用Whonet5.6软件对2015年至2019年辽宁省人民医院血培养临床数据进行分析。血培养阳性率为12.3%,共分离病原菌1 266株,其中革兰阴性菌546株、革兰阳性菌649株、真菌71株;革兰阴性菌主要为大肠埃希菌(Escherichia coli, Eco)占19.1%(234/1 226)和肺炎克雷伯菌(Klebsiella pneumoniae, Kpn)占12.6%(155/1 226);革兰阳性菌主要为人葡萄球菌(Staphylococcushomini, Sho)占13.3%(98/1 226)和表皮葡萄球菌(Staphylococcus epidermidis)占9.7%(82/1 226)。血培养阳性率较高的科室分别为重症医学科、普外科、呼吸内科。耐甲氧西林的金黄色葡萄球菌(Staphylococcus aureus,Sau)的检出率为40%、未检出对万古霉素耐药的金黄色葡萄球菌和肠球菌(Enterococcus)。肠杆菌科对碳青霉烯类抗生素的耐药率低于25%。鲍曼不动杆菌(Acinetobacter baumannii, Aba)对碳青霉烯类抗生素的耐药率达到80%以上。临床应重视血培养标本的送检和细菌耐药监测,合理使用抗生素,早期控制血流感染,降低患者的病死率。 相似文献
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Developing a safe and effective antiviral treatment takes a decade, however, when it comes to the coronavirus disease (COVID-19), time is a sensitive matter to slow the spread of the pandemic. Screening approved antiviral drugs against COVID-19 would speed the process of finding therapeutic treatment. The current study examines commercially approved drugs to repurpose them against COVID-19 virus main protease using structure-based in-silico screening. The main protease of the coronavirus is essential in the viral replication and is involved in polyprotein cleavage and immune regulation, making it an effective target when developing the treatment. A Number of approved antiviral drugs were tested against COVID-19 virus using molecular docking analysis by calculating the free natural affinity of the binding ligand to the active site pocket and the catalytic residues without forcing the docking of the ligand to active site. COVID-19 virus protease solved structure (PDB ID: 6LU7) is targeted by repurposed drugs. The molecular docking analysis results have shown that the binding of Remdesivir and Mycophenolic acid acyl glucuronide with the protein drug target has optimal binding features supporting that Remdesivir and Mycophenolic acid acyl glucuronide can be used as potential anti-viral treatment against COVID-19 disease. 相似文献
57.
大量肿瘤细胞的有关研究表明,H+、Na+、Ca2+等细胞离子的动态对肿瘤发生起着关键作用.然而,单个离子作为代谢基础的作用是多方面的,其涉癌效果很不一致,有时还是相反的.因此,以控制单个离子动态作为抗癌药物的靶标,其效果并不理想.迄今对细胞离子的致癌作用的研究虽然是大量的,但均散见各章,缺少综合考虑.为此,本文简要介绍了上述离子的致癌作用,并探讨了以控制离子动态为药标,设计抗癌药物时应考虑的综合效应,供癌药物学研究者参考. 相似文献
58.
《Journal of receptor and signal transduction research》2013,33(3):207-239
A cationic protonatable amine moiety on dopaminergic ligands forms a high affinity reinforced ionic bond with an anionic aspartic acid at position 3.32 of dopamine receptors. When present, catechol hydroxyls of the ligands form hydrogen bonds with serines at position 5.42, 5.43, and 5.46, and this network of hydrogen bonds serves to orient ligands in the binding-site crevice and increase their binding affinity. A steric clash between aromatic moieties of the ligands and aromatic amino acids of the receptor (e.g., H6.55, F6.52 or F6.51 and W6.48) is likely to be propagated in domino-like fashion along the length of TM6, which is believed to trigger activation of the receptor. Specifically, it is the change in the conformation of W6.48 from an orientation perpendicular to the plane of the lipid membrane to one that is parallel that is believed to result in activation. Molecular determinants that mediate the D4/D2-selectivity of many extremely D4-selective 1,4-DAP ligands, include a nonconserved cluster of bulky amino acids at the TM2/TM3 interface (positions 2.61, 3.28 and 3.29). 相似文献
59.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):773-778
The CHCl3-soluble fraction of the whole plant of Duranta repens showed anti-plasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum, with IC50 values of 8.5?±?0.9 and 10.2?±?1.5?μg/mL, respectively. From this fraction, two new flavonoid glycosides, 7-O-α-d-glucopyranosyl-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (1) and 7-O-α-d-glucopyranosyl(6′′′-p-hydroxcinnamoyl)-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (2), along with five known flavonoids, 3,7,4′-trihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (3), 3,7-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6,4′-trimethoxyflavone (4), 5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (5), 3,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-buten-yl)-5,6,4′-trimethoxyflavone (6), and 7-O-α-d-glucopyranosyl-3,5-dihydroxy-3′-(4′′-acetoxy-3′′-methylbutyl)-6,4′-dimethoxyflavone (7), have been isolated as anti-plasmodial principles. Their structures were deduced by spectroscopic analysis including 1D and 2D NMR techniques. The compounds (1–7) showed potent anti-plasmodial activities against D6 and W2 strains of Plasmodium falciparum, with IC50 values in the range of 5.2–13.5?μM and 5.9–13.1?μM, respectively. 相似文献
60.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):18-23
The effects of ketotifen, meloxicam, phenyramidol–HCl and gadopentetic acid on the enzyme activity of GR were studied using human erythrocyte glutathione reductase (GR) enzymes in vitro. The enzyme was purified 209-fold from human erythrocytes in a yield of 19% with 0.31?U/mg. The purification procedure involved the preparation of haemolysate, ammonium sulphate precipitation, 2′′,5′-ADP Sepharose 4B affinity chromatography and Sephadex G-200 gel filtration chromatography. Purified enzyme was used in the in vitro studies. In the in vitro studies, IC50 values and Ki constants were 0.012?mM and 0.0008?±?0.00021?mM for ketotifen; 0.029?mM and 0.0061?±?0.00127?mM for meloxicam; 0.99?mM and 0.4340?±?0.0890?mM for phenyramidol–HCl; 138?mM and 28.84?±?4.69?mM for gadopentetic acid, respectively, showing the inhibition effects on the purified enzyme. Phenyramidol–HCl showed competitive inhibition, whereas the others showed non-competitive inhibition. 相似文献