Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin...Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.展开更多
Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous ass...Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous assembly factors.Our previous study showed that the Arabidopsis thaliana protein arginine methyltransferase AtPRMT3 regulates pre-rRNA processing;however,the underlying molecular mechanism remains unknown.Here,we report that AtPRMT3 interacts with Ribosomal Protein S2(RPS2),facilitating processing of the 90S/Small Subunit(SSU)processome and repressing nucleolar stress.We isolated an intragenic suppressor of atprmt3-2,which rescues the developmental defects of atprmt3-2 while produces a putative truncated AtPRMT3 protein bearing the entire N-terminus but lacking an intact enzymatic activity domain We further identified RPS2 as an interacting partner of AtPRMT3,and found that loss-of-function rps2a2b mutants were phenotypically reminiscent of atprmt3,showing pleiotropic developmental defects and aberrant pre-rRNA processing.RPS2B binds directly to pre-rRNAs in the nucleus,and such binding is enhanced in atprmt3-2.Consistently,multiple components of the 90S/SSU processome were more enriched by RPS2B in atprmt3-2,which accounts for early pre-rRNA processing defects and results in nucleolar stress.Collectively,our study uncovered a novel mechanism by which AtPRMT3 cooperates with RPS2B to facilitate the dynamic assembly/disassembly of the 90S/SSU processome during ribosome biogenesis and repress nucleolar stress.展开更多
API RP 7G-2标准、NS-2标准是钻探设备制造和检验中常用的两个标准,它们各自具有不同的特点和应用范围,了解这些差异对于确保钻探设备的安全性和可靠性至关重要。通过对二者的深入分析,识别其在钻柱常用构件方面的差异,探讨这些不同对...API RP 7G-2标准、NS-2标准是钻探设备制造和检验中常用的两个标准,它们各自具有不同的特点和应用范围,了解这些差异对于确保钻探设备的安全性和可靠性至关重要。通过对二者的深入分析,识别其在钻柱常用构件方面的差异,探讨这些不同对钻具作业整体表现的潜在影响,为同领域的技术进步与创新提供方向。展开更多
Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfor...Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfortunately their inverse kinematics have not yet been resolved.This paper discovers that the unknown kinematic parameters of middle platform are responsible for the unresolvable of inverse kinematics,meanwhile the unknown kinematic parameters of middle platform also have huge coupling relationships.Therefore,to break through this challenges,the huge coupling relationships are decoupled layer by layer,the kinematic parameters of middle platform are solved by combining Sylvester's elimination method,and the inverse displacements of 2(3RPS)and 2(3SPR)S-PMs are obtained subsequently.This paper not only solves the inverse kinematics of classical 2(3RPS)and 2(3SPR)S-PMs,but also reveals the essence of the inverse kinematics of general(3-DOF)+(3-DOF)6-DOF S-PMs and proposes a corresponding solution.展开更多
针对工业界实现的无线抄表路由协议WM2RP(Wireless Meter Reading Routing Protocol),提出将CBMC有界模型检测工具运用到该协议实现的验证方法。WM2RP协议实现是嵌入式C程序,CBMC工具主要针对嵌入式软件的验证,运用CBMC对WM2RP进行验证...针对工业界实现的无线抄表路由协议WM2RP(Wireless Meter Reading Routing Protocol),提出将CBMC有界模型检测工具运用到该协议实现的验证方法。WM2RP协议实现是嵌入式C程序,CBMC工具主要针对嵌入式软件的验证,运用CBMC对WM2RP进行验证十分适用。CBMC能够直接对C/C++源码进行验证,这样不仅省去了传统模型检测技术需要对代码抽象建模的工作,而且不用担心模型和代码之间可能存在的不一致性问题。首先利用CBMC系统自生成断言验证技术,找到WM2RP协议实现中可能存在的漏洞,并对实现协议的公司给予反馈。然后进一步借助CBMC提供的用户自定义断言技术,通过自定义断言的插入以及对实现代码的适当处理,验证了WM2RP协议的网络层接收函数实现与协议规范的相符性。展开更多
Recently,deep learning(DL)became one of the essential tools in bioinformatics.A modified convolutional neural network(CNN)is employed in this paper for building an integratedmodel for deoxyribonucleic acid(DNA)classif...Recently,deep learning(DL)became one of the essential tools in bioinformatics.A modified convolutional neural network(CNN)is employed in this paper for building an integratedmodel for deoxyribonucleic acid(DNA)classification.In any CNN model,convolutional layers are used to extract features followed by max-pooling layers to reduce the dimensionality of features.A novel method based on downsampling and CNNs is introduced for feature reduction.The downsampling is an improved form of the existing pooling layer to obtain better classification accuracy.The two-dimensional discrete transform(2D DT)and two-dimensional random projection(2D RP)methods are applied for downsampling.They convert the high-dimensional data to low-dimensional data and transform the data to the most significant feature vectors.However,there are parameters which directly affect how a CNN model is trained.In this paper,some issues concerned with the training of CNNs have been handled.The CNNs are examined by changing some hyperparameters such as the learning rate,size of minibatch,and the number of epochs.Training and assessment of the performance of CNNs are carried out on 16S rRNA bacterial sequences.Simulation results indicate that the utilization of a CNN based on wavelet subsampling yields the best trade-off between processing time and accuracy with a learning rate equal to 0.0001,a size of minibatch equal to 64,and a number of epochs equal to 20.展开更多
基金supported by grants from the National Natural Science Foundation of China(82074067)Natural Science Foundation of Jiangsu Province China(BK20181419,China)Natural Foundation of Jiangsu Higher Education Institutions of China(19KJA310006)。
文摘Although NPM1 mutations are frequently found in acute myeloid leukemia patients,therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy.Here we demonstrated that heliangin,a natural sesquiterpene lactone,exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells,with no apparent toxicity to normal hematogenous cells,by inhibiting their proliferation,inducing apoptosis,causing cell cycle arrest,and promoting differentiation.In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2(RPS2)is the main target of heliangin in treating NPM1 mutant AML.Upon covalent binding to the C222 site of RPS2,the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes,leading to nucleolar stress,which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53.Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation,leading to a poor prognosis.We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target.Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients,especially those with NPM1 mutations.
基金This work was supported by grants from the National Natural Science Foundation of China(31788103 and 91540203 to X.Cao,31770874 to C.L.,31900932 to R.H.,and 31701096 to J.S.),Chinathe Strategic Priority Research Program of Chinese Academy of Sciences(XDB27030201 to X.Cao),China+1 种基金the Key Research Program of Frontier Sciences of Chinese Academy of Sciences(QYZDY-SSW-SMC022 to X.Cao),Chinathe State Key Laboratory of Plant Genomics,China.
文摘Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous assembly factors.Our previous study showed that the Arabidopsis thaliana protein arginine methyltransferase AtPRMT3 regulates pre-rRNA processing;however,the underlying molecular mechanism remains unknown.Here,we report that AtPRMT3 interacts with Ribosomal Protein S2(RPS2),facilitating processing of the 90S/Small Subunit(SSU)processome and repressing nucleolar stress.We isolated an intragenic suppressor of atprmt3-2,which rescues the developmental defects of atprmt3-2 while produces a putative truncated AtPRMT3 protein bearing the entire N-terminus but lacking an intact enzymatic activity domain We further identified RPS2 as an interacting partner of AtPRMT3,and found that loss-of-function rps2a2b mutants were phenotypically reminiscent of atprmt3,showing pleiotropic developmental defects and aberrant pre-rRNA processing.RPS2B binds directly to pre-rRNAs in the nucleus,and such binding is enhanced in atprmt3-2.Consistently,multiple components of the 90S/SSU processome were more enriched by RPS2B in atprmt3-2,which accounts for early pre-rRNA processing defects and results in nucleolar stress.Collectively,our study uncovered a novel mechanism by which AtPRMT3 cooperates with RPS2B to facilitate the dynamic assembly/disassembly of the 90S/SSU processome during ribosome biogenesis and repress nucleolar stress.
基金Supported by National Natural Science Foundation of China(Grant No.52275033)National Natural Science Youth Foundation of China(Grant No.52205033)Hebei Provincial Natural Science Foundation of China(Grant No.E2021203019)。
文摘Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfortunately their inverse kinematics have not yet been resolved.This paper discovers that the unknown kinematic parameters of middle platform are responsible for the unresolvable of inverse kinematics,meanwhile the unknown kinematic parameters of middle platform also have huge coupling relationships.Therefore,to break through this challenges,the huge coupling relationships are decoupled layer by layer,the kinematic parameters of middle platform are solved by combining Sylvester's elimination method,and the inverse displacements of 2(3RPS)and 2(3SPR)S-PMs are obtained subsequently.This paper not only solves the inverse kinematics of classical 2(3RPS)and 2(3SPR)S-PMs,but also reveals the essence of the inverse kinematics of general(3-DOF)+(3-DOF)6-DOF S-PMs and proposes a corresponding solution.
文摘针对工业界实现的无线抄表路由协议WM2RP(Wireless Meter Reading Routing Protocol),提出将CBMC有界模型检测工具运用到该协议实现的验证方法。WM2RP协议实现是嵌入式C程序,CBMC工具主要针对嵌入式软件的验证,运用CBMC对WM2RP进行验证十分适用。CBMC能够直接对C/C++源码进行验证,这样不仅省去了传统模型检测技术需要对代码抽象建模的工作,而且不用担心模型和代码之间可能存在的不一致性问题。首先利用CBMC系统自生成断言验证技术,找到WM2RP协议实现中可能存在的漏洞,并对实现协议的公司给予反馈。然后进一步借助CBMC提供的用户自定义断言技术,通过自定义断言的插入以及对实现代码的适当处理,验证了WM2RP协议的网络层接收函数实现与协议规范的相符性。
基金This research was funded by the Deanship of Scientific Research at Princess Nourah Bint Abdulrahman University through the Fast-track Research Funding Program.
文摘Recently,deep learning(DL)became one of the essential tools in bioinformatics.A modified convolutional neural network(CNN)is employed in this paper for building an integratedmodel for deoxyribonucleic acid(DNA)classification.In any CNN model,convolutional layers are used to extract features followed by max-pooling layers to reduce the dimensionality of features.A novel method based on downsampling and CNNs is introduced for feature reduction.The downsampling is an improved form of the existing pooling layer to obtain better classification accuracy.The two-dimensional discrete transform(2D DT)and two-dimensional random projection(2D RP)methods are applied for downsampling.They convert the high-dimensional data to low-dimensional data and transform the data to the most significant feature vectors.However,there are parameters which directly affect how a CNN model is trained.In this paper,some issues concerned with the training of CNNs have been handled.The CNNs are examined by changing some hyperparameters such as the learning rate,size of minibatch,and the number of epochs.Training and assessment of the performance of CNNs are carried out on 16S rRNA bacterial sequences.Simulation results indicate that the utilization of a CNN based on wavelet subsampling yields the best trade-off between processing time and accuracy with a learning rate equal to 0.0001,a size of minibatch equal to 64,and a number of epochs equal to 20.
