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91.
Michela Silacci Nadja Baenziger-Tobler Wibke Lembke Wenjuan Zha Sarah Batey Julian Bertschinger Dragan Grabulovski 《The Journal of biological chemistry》2014,289(20):14392-14398
Fynomers are small binding proteins derived from the human Fyn SH3 domain. Using phage display technology, Fynomers were generated inhibiting the activity of the proinflammatory cytokine interleukin-17A (IL-17A). One specific Fynomer called 2C1 inhibited human IL-17A in vitro with an IC50 value of 2.2 nm. Interestingly, when 2C1 was genetically fused to the Fc part of a human antibody via four different amino acid linkers to yield bivalent IL-17A binding proteins (each linker differed in length), the 2C1-Fc fusion protein with the longest linker displayed the most potent inhibitory activity. It blocked homodimeric IL-17A with an IC50 value of 21 pm, which corresponds to a hundredfold improved IC50 value as compared to the value obtained with monovalent Fynomer 2C1. In contrast, the 2C1-Fc fusion with the shortest linker showed only an ∼8-fold improved IC50 value of 260 pm. Furthermore, in a mouse model of acute inflammation, we have shown that the most potent 2C1-Fc fusion protein is able to efficiently inhibit IL-17A in vivo. With their suitable biophysical properties, Fynomer-Fc fusion proteins represent new drug candidates for the treatment of IL-17A mediated inflammatory conditions such as psoriasis, psoriatic arthritis, or rheumatoid arthritis. 相似文献
92.
Weibin Zha Matthew L. Edin Kimberly C. Vendrov Robert N. Schuck Fred B. Lih Jawahar Lal Jat J. Alyce Bradbury Laura M. DeGraff Kunjie Hua Kenneth B. Tomer John R. Falck Darryl C. Zeldin Craig R. Lee 《Journal of lipid research》2014,55(10):2124-2136
Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. 相似文献
93.
人肝细胞癌中抑癌基因PTEN/MMAC1/TEP1的突变分析 总被引:8,自引:0,他引:8
PTEN/MMAC1/TEP1 is a tumor suppressor gene. Its mutation has been found in several different types of human cancers. 34 primary human hepatocellular carcinomas have been examined for mutations in exon 5 and exon 8 of the PTEN gene. Exon 5 and exon 8 were amplified by polymerase chain reaction (PCR) with intronic primers and subjected to single strand conformation polymorphism (SSCP) analysis. SSCPs were found in 4 of the 34 hepatocellular carcinomas analyzed. Direct sequencing of the PCR products identified single base-pair substitutions in the four tumor DNA samples, two in intron 4 and two in exon 8. One of the base-pair substitution in exon 8 is a missense mutation, which changed codon 304 of PTEN protein from Cys to Gly. These data suggest that PTEN may be involved in the carcinogenesis and development of hepatocellular carcinoma. 相似文献
94.
95.
Fuxun Yu Ferdinard Adungo Samson Limbaso Konongoi Shingo Inoue Rosemary Sang Salame Ashur Allan ole Kwallah Leo Uchida Corazon C Buerano Matilu Mwau Yan Zha Yingjie Nie Kouichi Morita 《Virology journal》2018,15(1):178
Background
Rift Valley Fever (RVF) is a mosquito-borne viral zoonosis. To detect RVF virus (RVFV) infection, indirect immunoglobulin G (IgG) and immunoglobulin M (IgM) enzyme linked immunosorbent assays (ELISAs) which utilize recombinant RVFV nucleocapsid (RVFV-N) protein as assay antigen, have reportedly been used, however, there is still a need to develop more sensitive and specific methods of detection.Methods
RVFV-N protein was expressed in Escherichia coli (E. coli) and purified by histidine-tag based affinity chromatography. This recombinant RVFV-N (rRVFV-N) protein was then used as antigen to develop an IgG sandwich ELISA and IgM capture ELISAs for human sera. Ninety six serum samples collected from healthy volunteers during the RVF surveillance programme in Kenya in 2013, and 93 serum samples collected from RVF-suspected patients during the 2006–2007 RVF outbreak in Kenya were used respectively, to evaluate the newly established rRVFV-N protein-based IgG sandwich ELISA and IgM capture ELISA systems in comparison with the inactivated virus-based ELISA systems.Results
rRVFV-N protein-based-IgG sandwich ELISA and IgM capture ELISA for human sera were established. Both the new ELISA systems were in 100% concordance with the inactivated virus-based ELISA systems, with a sensitivity and specificity of 100%.Conclusions
Recombinant RVFV-N is a safe and affordable antigen for RVF diagnosis. Our rRVFV-N-based ELISA systems are safe and reliable tools for diagnosis of RVFV infection in humans and especially useful in large-scale epidemiological investigation and for application in developing countries.96.
Yong Zhou Jie Zha Zhijuan Lin Zhihong Fang Hanyan Zeng Jintao Zhao Yiming Luo Zhifeng Li Bing Xu 《Experimental cell research》2018,362(2):287-292
Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4+ T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19+ cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19+ cells than patients who did not show recurrence. Examining cytotoxic CD4+ T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4+ T cells. Also, frequency of cytotoxic CD4+ T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4+ T cells against autologous CD19+ cells was investigated. We found that the cytotoxic potential of CD4+ T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19+ cells presented a significant reduction after longer incubation with cytotoxic CD4+ T cells, suggesting that cytotoxic CD4+ T cells preferentially eliminated MHC II-expressing CD19+ cells. Blocking MHC II on CD19+ cells significantly reduced the cytolytic capacity of CD4+ T cells. Despite these discoveries, the frequency of cytotoxic CD4+ T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4+ T cells presented an MHC II-dependent cytotoxic potential against autologous CD19+ cells and could potentially represent a future treatment option for DLBCL. 相似文献
97.
Fangxia Zou Stefan Pusch Jie Hua Tianfang Ma Lijun Yang Qihua Zhu Yungen Xu Yueqing Gu Andreas von Deimling Xiaoming Zha 《Bioorganic & medicinal chemistry letters》2018,28(3):388-393
IDH1 mutation (mIDH1) occurs in 20–30% of gliomas and is a promising target for the cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers. 相似文献
98.
Siyuan Xu Chen Zhou Rongfeng Liu Qihua Zhu Yungen Xu Fei Lan Xiaoming Zha 《Bioorganic & medicinal chemistry》2018,26(17):4871-4880
Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 12a exhibited reversible and potent inhibition (IC50?=?0.41?μM) and high selectivity over the MAO-A and MAO-B. Notably, 12a strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4). Our findings indicate that 5-arylidene barbiturate may represent a new skeleton of LSD1 inhibitors and 12a deserve as a promising agent for the further research. 相似文献
99.
应用能阻断糖蛋白N-糖链合成的衣霉素(TM),研究了N-糖链缺失对HT1080细胞分泌纤连蛋白(Fn)以及纤连蛋白受体(FnR)与配体结合的影响。结果发现,1μg/ml的TM可抑制N-糖链的合成(此时,3H-甘露糖掺入下降63%),但细胞分泌Fn的量仅下降33%,这主要是由于蛋白合成受TM抑制(25%)而引起,因而,N-糖链缺失可能并不影响Fn的分泌。而在同样条件下,单个细胞结合125I-Fn的量显著下降,显示N-糖链的缺失可能导致了膜上FnR总量或其与配体结合的亲和力的改变。TM处理组的FnR的内吞率与对照组相比较无明显差异,提示受体分子中的N-糖链缺失不影响其内吞过程. 相似文献
100.
Khai Tran Xiliang Zha Monroe Chan Patrick C. Choy 《Molecular and cellular biochemistry》1995,151(1):69-76
The hydrolysis of phospholipids in vasopressin-stimulated baby hamster kidney (BHK)-21 and H9c2 myoblastic cells was investigated. Phosphatidylcholine and phosphatidylethanolamine in these cells were pulse labelled with [3H]glycerol, [3H]myristate, [3H]choline or [3H]ethanolamine, and chased with the non-labelled precursor until linear turnover rates were obtained. When cells labelled with [3H]glycerol or [3H]myristate were stimulated by vasopressin, no significant decrease in the labelling of phosphatidylcholine was detected, but the labelling of phosphatidic acid was elevated. However, the labellings of phosphatidylethanolamine and its hydrolytic product were not affected by vasopressin stimulation. When the cells were pulse labelled with [3H]-choline, vasopressin stimulation caused a decrease in the labelled phosphatidylcholine with a corresponding increase in the labelled choline. The apparent discrepancy between the two types of labelling might be explained by the recycling of labelled phosphatidic acid back into phosphatidylcholine, thus masking the reduction in the labelled phospholipid during vasopressin stimulation. Alternatively, the labelled choline produced by vasopressin stimulation was released into the medium, thus reducing the recycling of label precursor back into the phospholipid and making the decrease in the labelling of phosphatidylcholine readily detectable. Further studies revealed that vasopressin treatment caused an enhancement of phospholipase D activity in these cells. The presence of substrate-specific phospholipase D isoforms in mammalian tissues led us to postulate that the differential stimulation of phospholipid hydrolysis by vasopressin was caused by the enhancement of a phosphatidylcholine-specific phospholipase D in both BHK-21 and the H9c2 cells.Abbreviations BHK-21 cells
baby hamster kidney-21 cells 相似文献