The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate...The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.展开更多
在新工科背景下,培养学生面向工程问题的创新设计能力是机械专业人才培养的关键。文中以“CDIO(Conceive-Design-Implement-Operate)创新设计”项目式实践课程为依托,将TRIZ(Theroy of Inventive Problem Solvling)创新方法和设计流程...在新工科背景下,培养学生面向工程问题的创新设计能力是机械专业人才培养的关键。文中以“CDIO(Conceive-Design-Implement-Operate)创新设计”项目式实践课程为依托,将TRIZ(Theroy of Inventive Problem Solvling)创新方法和设计流程引入到大学生机械创新设计实训教学环节中。学生通过对TRIZ理论的基本原理和设计流程的学习,以具体项目为依托,运用TRIZ理论开展项目问题分析,解决设计过程中存在的技术冲突与矛盾问题,使学生在创新设计过程中有章可循,为本科生机械创新设计能力的提升提供借鉴思路。展开更多
在机器阅读理解任务中,如何在包含不可回答问题的情况下提高答案的准确性是自然语言处理领域的一项重要挑战.虽然基于深度学习的机器阅读理解模型展现出很好的性能,但是这些模型仍然存在抽取特征冗余、语义信息不全面、问题分类任务和...在机器阅读理解任务中,如何在包含不可回答问题的情况下提高答案的准确性是自然语言处理领域的一项重要挑战.虽然基于深度学习的机器阅读理解模型展现出很好的性能,但是这些模型仍然存在抽取特征冗余、语义信息不全面、问题分类任务和答案抽取任务耦合性不强的问题.为了解决以上问题,本文提出一种结合门控机制和多级残差结构的多任务联合训练模型GMRT(Gated Mechanism and Multi-level Residual Structure for Multi-task Joint Training),以提升机器阅读理解任务中答案预测的准确性.GMRT构建门控机制来筛选交互后的关联特征,从而控制信息的流动.采用多级残差结构分别连接注意力机制和门控机制,保证每个阶段都保留原始语义信息.同时,通过边缘损失函数对问题分类任务和答案抽取任务联合训练,确保预测答案过程中任务之间的强耦合性.在SQuAD2.0数据集上的实验结果表明,GMRT模型的EM值和F1值均优于对比模型.展开更多
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11904036 and 12175081)Fundamental Research Funds for the Central Universities(Grant No.CCNU22QNOO4)。
文摘The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.
文摘在新工科背景下,培养学生面向工程问题的创新设计能力是机械专业人才培养的关键。文中以“CDIO(Conceive-Design-Implement-Operate)创新设计”项目式实践课程为依托,将TRIZ(Theroy of Inventive Problem Solvling)创新方法和设计流程引入到大学生机械创新设计实训教学环节中。学生通过对TRIZ理论的基本原理和设计流程的学习,以具体项目为依托,运用TRIZ理论开展项目问题分析,解决设计过程中存在的技术冲突与矛盾问题,使学生在创新设计过程中有章可循,为本科生机械创新设计能力的提升提供借鉴思路。
文摘在机器阅读理解任务中,如何在包含不可回答问题的情况下提高答案的准确性是自然语言处理领域的一项重要挑战.虽然基于深度学习的机器阅读理解模型展现出很好的性能,但是这些模型仍然存在抽取特征冗余、语义信息不全面、问题分类任务和答案抽取任务耦合性不强的问题.为了解决以上问题,本文提出一种结合门控机制和多级残差结构的多任务联合训练模型GMRT(Gated Mechanism and Multi-level Residual Structure for Multi-task Joint Training),以提升机器阅读理解任务中答案预测的准确性.GMRT构建门控机制来筛选交互后的关联特征,从而控制信息的流动.采用多级残差结构分别连接注意力机制和门控机制,保证每个阶段都保留原始语义信息.同时,通过边缘损失函数对问题分类任务和答案抽取任务联合训练,确保预测答案过程中任务之间的强耦合性.在SQuAD2.0数据集上的实验结果表明,GMRT模型的EM值和F1值均优于对比模型.
