The messenger RNA 3'-untranslated region(3'UTR)plays an important role in regulation of gene expres-sion on the posttranscriptional level. The 3'UTR con-trols gene expression via orchestrated interactionbe...The messenger RNA 3'-untranslated region(3'UTR)plays an important role in regulation of gene expres-sion on the posttranscriptional level. The 3'UTR con-trols gene expression via orchestrated interactionbetween the structural components of mRNAs(cis-ele-ment) and the specific trans-acting factors(RNA bind-ing proteins and non-coding RNAs). The crosstalk ofthese factors is based on the binding sequences and/or direct protein-protein interaction, or just functionalinteraction. Much new evidence that has accumulatedsupports the idea that several RNA binding factors canbind to common mRNA targets: to the non-overlappingbinding sites or to common sites in a competitive fash-ion. Various factors capable of binding to the sameRNA can cooperate or be antagonistic in their actions.The outcome of the collective function of all factorsbound to the same mRNA 3'UTR depends on manycircumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3'UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological condi-tions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these altera-tions and their impact on 3'UTR-directed posttran-scriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer di-agnostics and therapy based on 3'UTR binding factors and approaches to improve them.展开更多
Three-degree of freedom（3-DOF） translational parallel manipulators（TPMs） have been widely studied both in industry and academia in the past decades. However, most architectures of 3-DOF TPMs are created mainly on ...Three-degree of freedom（3-DOF） translational parallel manipulators（TPMs） have been widely studied both in industry and academia in the past decades. However, most architectures of 3-DOF TPMs are created mainly on designers＇ intuition, empirical knowledge, or associative reasoning and the topology synthesis researches of 3-DOF TPMs are still limited. In order to find out the atlas of designs for 3-DOF TPMs, a topology search is presented for enumeration of 3-DOF TPMs whose limbs can be modeled as 5-DOF serial chains. The proposed topology search of 3-DOF TPMs is aimed to overcome the sensitivities of the design solution of a 3-DOF TPM for a LARM leg mechanism in a biped robot. The topology search, which is based on the concept of generation and specialization in graph theory, is reported as a step-by-step procedure with desired specifications, principle and rules of generalization, design requirements and constraints, and algorithm of number synthesis. In order to obtain new feasible designs for a chosen example and to limit the search domain under general considerations, one topological generalized kinematic chain is chosen to be specialized. An atlas of new feasible designs is obtained and analyzed for a specific solution as leg mechanisms. The proposed methodology provides a topology search for 3-DOF TPMs for leg mechanisms, but it can be also expanded for other applications and tasks.展开更多
OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast c...OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast cancer tissues followed by association analysis of e IF3a expression with patient′s response to chemotherapy.Ectopic overexpression and RNA interference knockdown of e IF3a were carried out in NIH3T3and H1299 cell lines,respectively,to determine the effect of altered e IF3a expression on cellular response to chemotherapeutic drugs by using MTT assay.The DNA repair capacity of these cells was evaluated by using host-cell reactivation,NHEJ and HR assay.Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of e IF3a on the DNA repair genes by using cells with altered e IF3a expression.RESULTS e IF3a expression associates with response of lung and breast cancer patients to platinum and anthracycline.e IF3a knockdown or overexpression,respectively,increased and decreased the cellular resistance to cisplatin and anthracycline anticancer drugs,DNA repair activity,and expression of NER and NHEJ DNA repair proteins.CONCLUSION e IF3a plays an important role in regulating the expression of NER and NHEJ DNA repair proteins which,in turn,contributes to cellular response to DNA-damaging anticancer drugs and patients′response to platinum and anthracycline chemotherapy.展开更多
Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section ar...Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section area of workspace, are defined; The expressions of two other indices, i.e. the global dexterity and global force transfer ratio are revised based on the main section of workspace. Using these indices, performance changes versus the varieties of dimensional parameters of mechanism are investigated in detail and the graphic descriptions of change tendencies of the performance indices are illustrated. By means of these obtained graphic descriptions, kinematic parameters for the 3-PUU pure translational parallel mechanism with better characteristics can be directly acquired.展开更多
The 3D cancer models fill the discovery gap of 2D cancer models and play an important role in cancer research.In addition to cancer cells,a range of other factors include the stroma,density and composition of extracel...The 3D cancer models fill the discovery gap of 2D cancer models and play an important role in cancer research.In addition to cancer cells,a range of other factors include the stroma,density and composition of extracellular matrix,cancer-associated immune cells(e.g.,cancer-associated fibroblasts cancer cell-stroma interactions and subsequent interactions,and a number of other factors(e.g.,tumor vasculature and tumor-like microenvironment in vivo)has been widely ignored in the 2D concept of culture.Despite this knowledge,the continued use of monolayer cell culture methods has led to the failure of a series of clinical trials.This review discusses the immense importance of tumor microenvironment(TME)recapitulation in cancer research,prioritizing the individual roles of TME elements in cancer histopathology.The TME provided by the 3D model fulfills the requirements of in vivo spatiotemporal arrangement,components,and is helpful in analyzing various different aspects of drug sensitivity in preclinical and clinical trials,some of which are discussed here.Furthermore,it discusses models for the co-assembly of different TME elements in vitro and focuses on their synergistic function and responsiveness as tumors.Furthermore,this review broadly describes of a handful of recently developed 3D models whose main focus is limited to drug development and their screening and/or the impact of this approach in preclinical and translational research.展开更多
Viruses are representative of a global threat to agricultural production. Genetic resistance is the preferred strategy for the control of viral infection and against loss of crop yield. Viral protein synthesis require...Viruses are representative of a global threat to agricultural production. Genetic resistance is the preferred strategy for the control of viral infection and against loss of crop yield. Viral protein synthesis requires host cellular factors for translating their viral RNAs, and for regulating their replication and cell to cell systemic movement. Therefore, the viruses are dependent on cellular translation factors. Mutations in the gene encoding eIF4E and eIF4G or their isoforms, eIFiso4 E, eIFiso4 G and eIF2Bβ have been mapped as a source of plant potyvirus while other genus of plant virus recessive resistance genes in many species are originated from these loci. Some of other plant translation factors, such as eIF3,eIF4 A-like helicases, eEF1A and eEF1B, which are required in interacting with viral RNAs and regulating various aspects of the infection cycle,have also been identified. Here, we summarized the mechanisms utilized by RNA viruses of eukaryotic plants and the essential roles of e IFs in virus infection. Moreover, we discussed the potential of e IFs as a target gene in the development of genetic resistance to viruses for crop improvement. This review highlighted newly revealed examples of abnormal translational strategies and provided insights into natural host resistance mechanisms that have been linked to 3 cap-independent translational enhancer activity.展开更多
Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladde...Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladder cancer patients.AT-rich interaction domain 1A(ARID1A)gene mutation occurs frequently in bladder cancer;however,the role of CDDP sensitivity in BC has not been studied.Methods We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology.IC50 determination,flow cytometry analysis of apoptosis,and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A.qRT-PCR,Western blotting,RNA interference,bioinformatic analysis,and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.Results It was found that ARID1A inactivation was associated with CDDP resistance in BC cells.Mechanically,loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3(EIF4A3)through epigenetic regulation.Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399(circ0008399),a novel circular RNA(circRNA)identified in our previous study,which,to some extent,showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells.Importantly,EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.Conclusion Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.展开更多
文摘The messenger RNA 3'-untranslated region(3'UTR)plays an important role in regulation of gene expres-sion on the posttranscriptional level. The 3'UTR con-trols gene expression via orchestrated interactionbetween the structural components of mRNAs(cis-ele-ment) and the specific trans-acting factors(RNA bind-ing proteins and non-coding RNAs). The crosstalk ofthese factors is based on the binding sequences and/or direct protein-protein interaction, or just functionalinteraction. Much new evidence that has accumulatedsupports the idea that several RNA binding factors canbind to common mRNA targets: to the non-overlappingbinding sites or to common sites in a competitive fash-ion. Various factors capable of binding to the sameRNA can cooperate or be antagonistic in their actions.The outcome of the collective function of all factorsbound to the same mRNA 3'UTR depends on manycircumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3'UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological condi-tions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these altera-tions and their impact on 3'UTR-directed posttran-scriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer di-agnostics and therapy based on 3'UTR binding factors and approaches to improve them.
基金supported by the Chinese Scholarship Council(CSC)for his Ph D study and research at LARM in the University of Cassino and South Latium,Italy,during 2013-2015
文摘Three-degree of freedom（3-DOF） translational parallel manipulators（TPMs） have been widely studied both in industry and academia in the past decades. However, most architectures of 3-DOF TPMs are created mainly on designers＇ intuition, empirical knowledge, or associative reasoning and the topology synthesis researches of 3-DOF TPMs are still limited. In order to find out the atlas of designs for 3-DOF TPMs, a topology search is presented for enumeration of 3-DOF TPMs whose limbs can be modeled as 5-DOF serial chains. The proposed topology search of 3-DOF TPMs is aimed to overcome the sensitivities of the design solution of a 3-DOF TPM for a LARM leg mechanism in a biped robot. The topology search, which is based on the concept of generation and specialization in graph theory, is reported as a step-by-step procedure with desired specifications, principle and rules of generalization, design requirements and constraints, and algorithm of number synthesis. In order to obtain new feasible designs for a chosen example and to limit the search domain under general considerations, one topological generalized kinematic chain is chosen to be specialized. An atlas of new feasible designs is obtained and analyzed for a specific solution as leg mechanisms. The proposed methodology provides a topology search for 3-DOF TPMs for leg mechanisms, but it can be also expanded for other applications and tasks.
基金The project supported by National High-tech R&D Program of China 863 Program Grant(2009AA022704)National Natural Science Foundation of China(81573463,81173129,81202595 and NIH Grant CA 94961)
文摘OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast cancer tissues followed by association analysis of e IF3a expression with patient′s response to chemotherapy.Ectopic overexpression and RNA interference knockdown of e IF3a were carried out in NIH3T3and H1299 cell lines,respectively,to determine the effect of altered e IF3a expression on cellular response to chemotherapeutic drugs by using MTT assay.The DNA repair capacity of these cells was evaluated by using host-cell reactivation,NHEJ and HR assay.Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of e IF3a on the DNA repair genes by using cells with altered e IF3a expression.RESULTS e IF3a expression associates with response of lung and breast cancer patients to platinum and anthracycline.e IF3a knockdown or overexpression,respectively,increased and decreased the cellular resistance to cisplatin and anthracycline anticancer drugs,DNA repair activity,and expression of NER and NHEJ DNA repair proteins.CONCLUSION e IF3a plays an important role in regulating the expression of NER and NHEJ DNA repair proteins which,in turn,contributes to cellular response to DNA-damaging anticancer drugs and patients′response to platinum and anthracycline chemotherapy.
基金This project is supported by National Natural Science Foundation of China (No.60275031)Municipal Key Lab Open Fund of Beijing, China (No.KP01-072200384).
文摘Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section area of workspace, are defined; The expressions of two other indices, i.e. the global dexterity and global force transfer ratio are revised based on the main section of workspace. Using these indices, performance changes versus the varieties of dimensional parameters of mechanism are investigated in detail and the graphic descriptions of change tendencies of the performance indices are illustrated. By means of these obtained graphic descriptions, kinematic parameters for the 3-PUU pure translational parallel mechanism with better characteristics can be directly acquired.
基金MHRD,Grant/Award Number:MHRD IMPRINT(4291)SERB,Grant/Award Number:CRG/2020/005069+1 种基金Indian Institute of Technology,Hyderabad,Grant/Award Number:IITH/BME/SOCH3Ministry of Education,Grant/Award Number:MoE-STARS/2023/0640。
文摘The 3D cancer models fill the discovery gap of 2D cancer models and play an important role in cancer research.In addition to cancer cells,a range of other factors include the stroma,density and composition of extracellular matrix,cancer-associated immune cells(e.g.,cancer-associated fibroblasts cancer cell-stroma interactions and subsequent interactions,and a number of other factors(e.g.,tumor vasculature and tumor-like microenvironment in vivo)has been widely ignored in the 2D concept of culture.Despite this knowledge,the continued use of monolayer cell culture methods has led to the failure of a series of clinical trials.This review discusses the immense importance of tumor microenvironment(TME)recapitulation in cancer research,prioritizing the individual roles of TME elements in cancer histopathology.The TME provided by the 3D model fulfills the requirements of in vivo spatiotemporal arrangement,components,and is helpful in analyzing various different aspects of drug sensitivity in preclinical and clinical trials,some of which are discussed here.Furthermore,it discusses models for the co-assembly of different TME elements in vitro and focuses on their synergistic function and responsiveness as tumors.Furthermore,this review broadly describes of a handful of recently developed 3D models whose main focus is limited to drug development and their screening and/or the impact of this approach in preclinical and translational research.
基金The authors thank Mr.Tomas Maher from the Department of Biology at the Pennsylvania State University for language editing.This work is supported by the National Natural Science Foundation of Zhejiang Province(Grant No.LZ20C150002)and the National Natural Science Foundation of China(Grant No.31872095).
文摘Viruses are representative of a global threat to agricultural production. Genetic resistance is the preferred strategy for the control of viral infection and against loss of crop yield. Viral protein synthesis requires host cellular factors for translating their viral RNAs, and for regulating their replication and cell to cell systemic movement. Therefore, the viruses are dependent on cellular translation factors. Mutations in the gene encoding eIF4E and eIF4G or their isoforms, eIFiso4 E, eIFiso4 G and eIF2Bβ have been mapped as a source of plant potyvirus while other genus of plant virus recessive resistance genes in many species are originated from these loci. Some of other plant translation factors, such as eIF3,eIF4 A-like helicases, eEF1A and eEF1B, which are required in interacting with viral RNAs and regulating various aspects of the infection cycle,have also been identified. Here, we summarized the mechanisms utilized by RNA viruses of eukaryotic plants and the essential roles of e IFs in virus infection. Moreover, we discussed the potential of e IFs as a target gene in the development of genetic resistance to viruses for crop improvement. This review highlighted newly revealed examples of abnormal translational strategies and provided insights into natural host resistance mechanisms that have been linked to 3 cap-independent translational enhancer activity.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81974396,No.81874091,No.82072840,and No.82102734)the Natural Science Foundation of Hubei Province(No.2020CFB829)the Health Commission of Hubei Province Scientific Research Project(No.WJ2021F081).
文摘Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladder cancer patients.AT-rich interaction domain 1A(ARID1A)gene mutation occurs frequently in bladder cancer;however,the role of CDDP sensitivity in BC has not been studied.Methods We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology.IC50 determination,flow cytometry analysis of apoptosis,and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A.qRT-PCR,Western blotting,RNA interference,bioinformatic analysis,and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.Results It was found that ARID1A inactivation was associated with CDDP resistance in BC cells.Mechanically,loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3(EIF4A3)through epigenetic regulation.Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399(circ0008399),a novel circular RNA(circRNA)identified in our previous study,which,to some extent,showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells.Importantly,EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.Conclusion Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.
