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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

《医学前沿（英文）》 2022年第16卷第3期页码 442-458 doi: 10.1007/s11684-021-0877-y

摘要： T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia HDAC inhibitor chidamide NOTCH1 MYC ubiquitination

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Parametric equations for notch stress concentration factors of rib–deck welds under bending loading

《结构与土木工程前沿（英文）》 2021年第15卷第3期页码 595-608 doi: 10.1007/s11709-021-0720-1

摘要： The effective notch stress approach for evaluating the fatigue strength of rib–deck welds requires notch stress concentration factors obtained from complex finite element analysis. To improve the efficiency of the approach, the notch stress concentration factors for three typical fatigue-cracking modes (i.e., root–toe, root–deck, and toe–deck cracking modes) were thoroughly investigated in this study. First, we developed a model for investigating the effective notch stress in rib–deck welds. Then, we performed a parametric analysis to investigate the effects of multiple geometric parameters of a rib–deck weld on the notch stress concentration factors. On this basis, the multiple linear stepwise regression analysis was performed to obtain the optimal regression functions for predicting the notch stress concentration factors. Finally, we employed the proposed formulas in a case study. The notch stress concentration factors estimated from the developed formulas show agree well with the finite element analysis results. The results of the case study demonstrate the feasibility and reliability of the proposed formulas. It also shows that the fatigue design curve of FAT225 seems to be conservative for evaluating the fatigue strength of rib–deck welds.

关键词： notch stress concentration factor rib–deck weld parametric analysis regression analysis parametric equation

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Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea

null

《医学前沿（英文）》 2016年第10卷第3期页码 237-249 doi: 10.1007/s11684-016-0464-9

摘要：

Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways, including Wnt and Notch signaling. The Wnt and Notch pathways are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. Both signaling pathways allow resident supporting cells to regenerate hair cells in the neonatal cochlea. In this regard, Wnt and Notch signaling has gained increased research attention in hair cell regeneration. This review presents the current understanding of the Wnt and Notch signaling pathways in the auditory portion of the inner ear and discusses the possibilities of controlling these pathways with the hair cell fate determiner Atoh1 to regulate hair cell regeneration in the mammalian cochlea.

关键词： inner ear cochlea hair cell regeneration Wnt Notch signaling pathways

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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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Crack propagation with different radius local random damage based on peridynamic theory

《结构与土木工程前沿（英文）》 2021年第15卷第5期页码 1238-1248 doi: 10.1007/s11709-021-0695-y

摘要： Drawing from the advantages of Classical Mechanics, the peridynamic theory can clarify the crack propagation mechanism by an integral solution without initially setting the factitious crack and crack path. This study implements the peridynamic theory by subjecting bilateral notch cracked specimens to the conditions of no local damage, small radius local damage, and large radius local damage. Moreover, to study the effects of local stochastic damage with different radii on the crack propagation path and Y-direction displacement, a comparison and contact methodology was adopted, in which the crack propagation paths under uniaxial tension and displacement in the Y-direction were compared and analyzed. This method can be applied to steel structures under similar local random damage conditions.

关键词： peridynamics stochastic damage bilateral notch crack

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Regeneration of hair cells in the mammalian vestibular system

null

《医学前沿（英文）》 2016年第10卷第2期页码 143-151 doi: 10.1007/s11684-016-0451-1

摘要：

Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicin-induced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.

关键词： utricle hair cell regeneration Atoh1 Notch Wnt

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腐蚀环境下飞机结构疲劳寿命的分析方法

穆志韬

《中国工程科学》 2002年第4卷第3期页码 68-72

摘要：

依据海军现役飞机的腐蚀环境特点及结构件腐蚀损伤深度拟合规律，采用应力场强法和局部应力应变法分别对疲劳缺口系数K_f及疲劳寿命计算模型进行了分析，提出了一种腐蚀环境下飞机结构疲劳寿命的评定方法。该方法以室温大气环境下的寿命评定结论为依据，考虑了结构件腐蚀损伤后潮湿空气、盐雾、盐雾＋SO₂等环境介质对疲劳寿命的影响，并结合国产某型飞机机翼前梁缘条腐蚀损伤部位的疲劳寿命及剩余寿命估算实例进行了分析。

关键词：飞机结构疲劳寿命腐蚀环境疲劳缺口系数

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Structural parameter design method for a fast-steering mirror based on a closed-loop bandwidth

Guozhen CHEN, Pinkuan LIU, Han DING

《机械工程前沿（英文）》 2020年第15卷第1期页码 55-65 doi: 10.1007/s11465-019-0545-y

摘要： When a fast-steering mirror (FSM) system is designed, satisfying the performance requirements before fabrication and assembly is vital. This study proposes a structural parameter design approach for an FSM system based on the quantitative analysis of the required closed-loop bandwidth. First, the open-loop transfer function of the FSM system is derived. In accordance with the transfer function, the notch filter and proportional-integral (PI) feedback controller are designed as a closed-loop controller. The gains of the PI controller are determined by maximizing the closed-loop bandwidth while ensuring the robustness of the system. Then, the two unknown variables of rotational radius and stiffness in the open-loop transfer function are optimized, considering the bandwidth as a constraint condition. Finally, the structural parameters of the stage are determined on the basis of the optimized results of rotational radius and stiffness. Simulations are conducted to verify the theoretical analysis. A prototype of the FSM system is fabricated, and corresponding experimental tests are conducted. Experimental results indicate that the bandwidth of the proposed FSM system is 117.6 Hz, which satisfies the minimum bandwidth requirement of 100 Hz.

关键词： fast-steering mirror structural parameter PI controller bandwidth notch filter

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Mechanical responses of pristine and defective hexagonal boron-nitride nanosheets: A molecular dynamics investigation

Mohammad SALAVATI, Arvin MOJAHEDIN, Ali Hossein Nezhad SHIRAZI

《结构与土木工程前沿（英文）》 2020年第14卷第3期页码 623-631 doi: 10.1007/s11709-020-0616-5

摘要： In this work we conducted classical molecular dynamics (MD) simulation to investigate the mechanical characteristics and failure mechanism of hexagonal boron-nitride (h-BN) nanosheets. Pristine and defective structure of h-BN nanosheets were considered under the uniaxial tensile loadings at various temperatures. The defective structure contains three types of the most common initial defects in engineering materials that are known as cracks, notches (with various length/size), and point vacancy defects (with a wide range of concentration). MD simulation results demonstrate a high load-bearing capacity of extremely defective (amorphized) h-BN nanosheets. Our results also reveal that the tensile strength decline by increasing the defect content and temperature as well. Our MD results provide a comprehensive and useful vision concerning the mechanical properties of h-BN nanosheets with/without defects, which is very critical for the designing of nanodevices exploiting the exceptional physics of h-BN.

关键词： hexagonal boron-nitride mechanical properties crack notch point defects molecular dynamics

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扩容角对圆形巷道岩爆过程的影响

王学滨,潘一山,张智慧

《中国工程科学》 2010年第12卷第2期页码 40-46

摘要：

利用FLAC模拟了不同扩容角时圆形巷道的岩爆过程。为了模拟巷道开挖，利用编写的FISH函数删除巷道内部的单元。岩石服从莫尔库仑剪破坏与拉破坏复合的破坏准则，破坏之后呈现应变软化—理想塑性行为。文章的模拟分为3步：首先，将静水压力施加在模型上，直到达到静力平衡状态；然后，利用编写的FISH函数，开挖巷道；最后，计算重新开始，直到达到静力平衡状态。模拟结果表明，随着扩容角的增加，剪切带变宽，岩爆坑变深，破坏单元数目增多，破坏区变大。当扩容角较低时，高剪切应变集中于“狗耳”形岩爆坑位置，剪切带与巷道周边切线之间的夹角较大；当扩容角较高时，高剪切应变集中于巷道周边的一些位置上，剪切带与巷道周边切线之间的夹角较小。该研究结果与Roscoe，Arthur理论相符。

关键词：扩容角圆形巷道岩爆剪切带 V形坑剪切应变体积应变