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医院中子照射器I型堆 5

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Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma

《医学前沿（英文）》 2023年第17卷第2期页码 290-303 doi: 10.1007/s11684-022-0956-8

摘要： Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

关键词： benzydamine cyclin-dependent kinase 2 patient-derived xenograft esophageal squamous cell carcinoma

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The role of CDK1 siRNA interference in cell cycle and cell apoptosis

Hui XIAO PhD, Ming TIAN MM, Junna GE MM, Xin Wei MD, Zhaoming LI MM, Xiaolan LI MS, Deding TAO PhD, Junbo HU MD, Jianping GONG MD,

《医学前沿（英文）》 2009年第3卷第4期页码 384-389 doi: 10.1007/s11684-009-0070-1

摘要： In the present report, cyclin-dependent kinase1 (CDK1) siRNA was transfected into cells to silence the CDK1 gene expression and study its role in the cell cycle and cell apoptosis. The siRNA targeting CDK1 gene was chemically synthesized and transfected into Hela cells by lipofectamine 2000. The expression levels of CDK1 gene and protein were examined by real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. The cell cycle was analyzed by using DNA content analysis by flow cytometry. Cell apoptosis was detected by the Annexin V/PI method. The morphological changes of transfected cells were examined under the microscopy by Wright-Giemsa stain. CDK1 gene was successfully silenced by its siRNA, and the CDK1 protein expression level was decreased significantly, especially from 48thh to 60thh after transfection. The DNA content analysis showed that transfection of CDK1 siRNA led to cells accumulating in G/M phase. There was no significant difference in the apoptotic rate between transfected cells and the control cells after transfection of CDK1 siRNA for 48 or 60h. More double nucleus or multinucleus cells could be seen under the microscopy among the transfected cells. The decreased CDK1 expression by siRNA silencing gave rise to cell cycle arrest in G/M phase but did not induce apoptosis.

关键词： cyclin-dependent kinase1 siRNA interference cell cycle apoptosis

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Lentivector-mediated RNAi efficiently downregulates expression of murine cdk4 gene

Feng JIANG PhD , Xuezhen WANG PhD , Zheng XUE MD , Suming ZHANG PhD , Siyu FANG BM , Min ZHANG MD, PhD ,

《医学前沿（英文）》 2009年第3卷第3期页码 287-291 doi: 10.1007/s11684-009-0050-5

摘要： In order to explore the role of cyclin-dependent kinase 4 (cdk4) in neurodegenerative diseases, lentiviral-delivered RNA interference (RNAi) was used to silence the expression of the murine cdk4 gene . Three cdk4-shRNAs of mouse and a negative sequence were designed. After synthesis and annealing, double strand oligonucleotides were cloned into a linearized pSIH1-H1-copGFP shRNA vector. It was confirmed by polymerase chain reaction (PCR) and sequencing that three pairs of cdk4-shRNAs and a negative shRNA were correctly inserted into the pSIH1-H1-copGFP vector. The above recombinants were transfected by lipofectamine into BV-2 cells. The gene silencing efficacy rates of the 3 targets were compared by Western blotting. The cdk4-siRNA2 was the most effective in silencing cdk4. The optimized pSIH1-cdk4-siRNA2 and pSIH-negative-siRNA were co-transfected into 293T cells with the lentiviral packaging plasmids respectively. The culture supernatant was harvested and condensed at the 24th and 48thh after transfection. Interference efficiency of the lentivirus expressing cdk4-siRNA was determined by reverse transcriptase-PCR (RT-PCR) and Western blotting in BV-2 cells. Lentivector-mediated RNAi could efficiently down-regulate the expression of the murine cdk4 gene , which provides a potential tool for studying and treating cdk4-related diseases.

关键词： cyclin-dependent kinase 4 RNA interference plasmid lentiviral vector

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Loss of liver kinase B1 causes planar polarity defects in cochlear hair cells in mice

null

《医学前沿（英文）》 2016年第10卷第4期页码 481-489 doi: 10.1007/s11684-016-0494-3

摘要：

The tumor suppressor gene liver kinase B1 (LKB1), also called STK11, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice (LKB1^Pax2 CKO mice) were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1^Pax2 CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1^Pax2 CKO mice were clustered and misoriented, respectively. Moreover, ectopic distribution of kinocilium bundles resulting from abnormal migration of kinocilium was observed in the mutant mice. The orientation of stereociliary bundles and the migration of kinocilia are critical indicators of planar cell polarity (PCP) of hair cells. LKB1 deficiency in LKB1^Pax2 CKO mice thus disrupted hair cell planar polarity during embryonic development. Our results suggest that LKB1 is required in PCP formation in cochlear hair cells in mice.

关键词： LKB1 stereociliary bundles kinocilium planar cell polarity hearing mice

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PAK1 is a novel cardiac protective signaling molecule

null

《医学前沿（英文）》 2014年第8卷第4期页码 399-403 doi: 10.1007/s11684-014-0380-9

摘要：

We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates. We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca²⁺ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.

关键词： p21-activated kinase 1 (PAK1) heart

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Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma

null

《医学前沿（英文）》 2016年第10卷第1期页码 52-60 doi: 10.1007/s11684-016-0433-3

摘要：

Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P= 0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCC-specific overall survival (HR, 2.799; 95% CI, 1.346–5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

关键词： PPM1D hepatocellular carcinoma prognosis target therapy

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breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinasecancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

Andrew Best,Katherine James,Gerald Hysenaj,Alison Tyson-Capper,David J. Elliott

《化学科学与工程前沿（英文）》 2016年第10卷第2期页码 186-195 doi: 10.1007/s11705-015-1540-4

摘要： Increased expression levels of the RNA splicing regulator Transformer2 (abbreviated Tra2 ) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2 and the highly similar Tra2 protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2 reduces splicing inclusion of a poison exon in the mRNA encoding Tra2 , thereby up-regulating Tra2 protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2 alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

关键词： RNA splicing gene expression breast cancer DNA damage CHK1

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Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5

Hui Jiang, Shan Zeng, Wenli Ni, Yan Chen, Wenyan Li

《医学前沿（英文）》 2019年第13卷第6期页码 705-712 doi: 10.1007/s11684-019-0703-y

摘要： Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells (HCs) and supporting cells during mouse inner ear development; however, the relationship between the two signaling pathways in the mouse cochlea remains largely unknown. Here, we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5 progenitors during different cochlear development stages. We found that the downregulation of Notch1 in Lgr5 cells from embryonic day (E) 14.5 to E18.5 can drive the quiescent Lgr5 cells to re-enter the cell cycle and differentiate into extra HCs, whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells. No effect was observed on the upregulation or downregulation of Notch1 in Lgr5 cells from E10.5 to E14.5. We concluded that the roles of Notch1 in Wnt-responsive Lgr5 cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5 progenitor activation during cochlear differentiation. Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

关键词： inner ear cochlear Wnt Notch Lgr5 auditory system

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庞明慧1,2,朱秋明1,2,林志鹏1,柏菲1,田越1,李茁3,陈小敏1

《信息与电子工程前沿（英文）》 2022年第23卷第9期页码 1378-1389 doi: 10.1631/FITEE.2200041

摘要：视距（line-of-sight, LoS）概率预测对于无线通信系统的性能优化至关重要。然而，由于无人机等飞行器飞行高度从十几米到数千米不等，空地（air-to-ground, A2G）通信的LoS概率预测具有挑战性。本文针对A2G场景，提出一种高度相关的经验性LoS概率模型。在模型参数估计之前，设计了一种基于K近邻（K-nearest neighbors, KNN）的策略对LoS和非视距（none-line-of-sight, NLoS）路径进行分类。然后，开发了一种基于双层反向传播神经网络（back propagation neural network, BPNN）的参数估计方法来建立每个模型参数与无人机高度之间的关系。仿真表明该模型获得的结果与射线追踪（ray trancing, RT）数据、实测数据和标准模型结果具有良好一致性。该模型还可提供比其他LoS概率模型更广泛的适用高度，能够应用于各种A2G场景下的不同通信高度。

关键词：视距概率模型；空地信道；机器学习；射线跟踪

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基于异步切换和可容许边依赖平均驻留时间方法的切换线性系统镇定研究 Research Article

侯林林1,马萱1,孙海滨2

《信息与电子工程前沿（英文）》 2022年第23卷第5期页码 810-822 doi: 10.1631/FITEE.2000698

摘要：本文研究异步切换条件下切换线性系统的镇定问题。采用可容许边依赖平均驻留时间方法，设计包含慢可容许边依赖平均驻留时间和快可容许边依赖平均驻留时间的切换信号。这种切换信号设计方法消除了异步切换最大延迟事先已知的限制。构造的李雅普诺夫函数与系统模态和控制器模态均相关。给出了获取控制器增益和设计切换信号的稳定性准则及相应算法。最后，通过两个算例验证了所提结果的有效性。

关键词：异步切换；可容许边依赖平均驻留时间；多李雅普诺夫函数

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Discovery of small molecule degraders for modulating cell cycle

《医学前沿（英文）》页码 823-854 doi: 10.1007/s11684-023-1027-5

摘要： The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

关键词： PROTAC molecular glue degrader cell cycle CDK cyclin

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The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

null

《医学前沿（英文）》 2011年第5卷第1期页码 70-76 doi: 10.1007/s11684-011-0119-9

摘要：

Protein kinase C epsilon (PKC ?) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC ? in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC ? functions in vivo, and PKC ? has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC ? on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC ? could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC ? signal pathway in the developing brain.

关键词： protein kinase C ? signal transduction neurogenic disease

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Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

《医学前沿（英文）》 2016年第10卷第4期页码 383-388 doi: 10.1007/s11684-016-0488-1

摘要：

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

关键词： EGFR tyrosine kinase inhibitor AZD9291 EAI045

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Data-driven approach to solve vertical drain under time-dependent loading

《结构与土木工程前沿（英文）》 2021年第15卷第3期页码 696-711 doi: 10.1007/s11709-021-0727-7

摘要： Currently, the vertical drain consolidation problem is solved by numerous analytical solutions, such as time-dependent solutions and linear or parabolic radial drainage in the smear zone, and no artificial intelligence (AI) approach has been applied. Thus, in this study, a new hybrid model based on deep neural networks (DNNs), particle swarm optimization (PSO), and genetic algorithms (GAs) is proposed to solve this problem. The DNN can effectively simulate any sophisticated equation, and the PSO and GA can optimize the selected DNN and improve the performance of the prediction model. In the present study, analytical solutions to vertical drains in the literature are incorporated into the DNN–PSO and DNN–GA prediction models with three different radial drainage patterns in the smear zone under time-dependent loading. The verification performed with analytical solutions and measurements from three full-scale embankment tests revealed promising applications of the proposed approach.

关键词： vertical drain artificial neural network time-dependent loading deep learning network genetic algorithm particle swarm optimization

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Effect of inhibiting tyrosine kinase Src expression on protein phosphatase 2A and tau phosphorylation

LIU Rong, ZENG Ji, ZHOU Xinwen, WANG Jianzhi, PEI Jinjing

《医学前沿（英文）》 2008年第2卷第3期页码 235-238 doi: 10.1007/s11684-008-0044-8

摘要： The aim of this study is to investigate the effect of tyrosine kinase Src on Tyrosine 307(Y307) phosphorylation, protein phosphatase 2A (PP2A) activity, and on tau phosphorylation. Specific Src siRNA was transfected into cultured mouse neuroblastoma N2a cells to inhibit the expression of Src protein, and the phosphorylation levels of PP2A Y307 and tau at different sites, as well as PP2A activity were detected at different time points after siRNA transfection. Twelve hours after siRNA transfection, the protein level of Src was dramatically decreased, with decreased PP2A Y307 phosphorylation. However, the total PP2A protein level was also decreased, together with a decreased PP2A activity. Tau was hyperphosphorylated at the Ser198/199/202 sites. Multiple factors may be involved in the cellular regulation of PP2A activity. Inhibiting Src expression could induce inactivation of PP2A and tau hyperphosphorylation.

关键词： hyperphosphorylation PP2A activity cellular regulation siRNA siRNA transfection