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Cellular mechanotransduction in health and diseases:from molecular mechanism to therapeutic targets

Signal Transduction and Targeted Therapy 2023年第8期8卷 3705-3736页

作者： Xingpeng Di Xiaoshuai Gao Liao Peng Jianzhong Ai Xi Jin shiqian qi Hong Li Kunjie Wang Deyi Luo Department of Urology and Institute of Urology National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduP.R.China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengduP.R.China

Cellular mechanotransduction,a critical regulator of numerous biological processes,is the conversion from mechanical signals to biochemical signals regarding cell activities and *** mechanical cues in organisms include hydrostatic pressure,fluid shear stress,tensile force,extracellular matrix stiffness or tissue elasticity,and extracellular fluid *** has been expected to trigger multiple biological processes,such as embryonic development,tissue repair and ***,prolonged excessive mechanical stimulation can result in pathological processes,such as multi-organ fibrosis,tumorigenesis,and cancer immunotherapy *** the associations between mechanical cues and normal tissue homeostasis or diseases have been identified,the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated,and no effective therapies are currently available targeting mechanical cue-related *** review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated *** key effectors responding to mechanical stimulations are listed,such as Piezo channels,integrins,Yes-associated protein(YAP)/transcriptional coactivator with PDZ-binding motif(TAZ),and transient receptor potential vanilloid 4(TRPV4).We also reviewed the key signaling pathways,therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues.

关键词： diseases stimulation therapeutic

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The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response

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Cellular & Molecular Immunology 2021年第8期18卷 1981-1994页

作者： Zhiwen Gu Xueying Chen Wenyong Yang Yu qi Hui Yu Xiaomeng Wang Yanqiu Gong qianqian Chen Bo Zhong Lunzhi Dai shiqian qi Zhiqiang Zhang Huiyuan Zhang Hongbo Hu Department of Rheumatology and Immunology National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China Department of Virology College of Life SciencesDepartment of ImmunologyMedical Research InstituteWuhan UniversityWuhan430072China Department of General Practice and Lab of PTM State Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China Department of Urology State Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China Immunobiology and Transplant Science Center Houston Methodist HospitalHoustonTXUSA77030

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully *** this study,TRIM60 negatively regulated the formation and activation of the TAK1 *** of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not ***-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB *** SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of *** vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and *** *** data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.

关键词： SUMOylation innate immune response TRAM60 TAB2

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DnaQ mediates directional spacer acquisition in the CRISPR-Cas system by a time-dependent mechanism

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The Innovation 2023年第5期4卷 78-86页

作者： Dongmei Tang Tingting Jia Yongbo Luo Biqin Mou Jie Cheng shiqian qi Shaohua Yao Zhaoming Su Yamei Yu qiang Chen Department of Urology.State Key Laboratory of Biotherapy West China HospitalSichuan UniversityChengdu 610041China Department of Biotherapy Cancer Center and State Key Laboratory of BioherapyWest China HospitalSichuan UniversiyChengdu 610041China Precision Medicine Center Precision Medicine Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengdu 610041China

In the spacer acquisition stage of CRISPR-Cas immunity,spacer orientation and protospacer adjacent motif(PAM)removal are two prerequisites for functional spacer ***4 has been implicated in both processing the prespacer and determining the spacer *** Cas4-lacking systems,host 3′–5′DnaQ family exonucleases were recently reported to play a Cas4-like ***,the molecular details of DnaQ functions remain ***,we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system,in which a DnaQ domain naturally fuses with *** presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation *** biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different *** on these results,we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.

关键词： details media directional

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Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4683-4699页

作者： Yanli Chang Jiangli Zhu Xiaopeng Li Yi Deng Birou Lai Yidan Ma Jia Tong Huicong Liu Juanjuan Li Chenyu Yang qiao Chen Chengbiao Lu Yinming Liang shiqian qi Xiaoning Wang Eryan Kong The Third Affiliated Hospital of Xinxiang Medical University XinxiangChina Institute of Psychiatry and Neuroscience Xinxiang Key Laboratory of Protein Palmitoylation and Major Human DiseasesXinxiang Medical UniversityXinxiangChina Department of Urology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and National Collaborative Innovation CenterChengduChina Center of Cryo-Electron Microscopy Zhejiang UniversityHangzhouChina Department of Nutrition Third Medical Center of PLA General HospitalBeijingChina School of Life Sciences Fudan UniversityShanghaiChina

The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

关键词： myelin system Together

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Assessment methods of speech synthesis systems for Chinese

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Chinese Journal of Acoustics 1997年第2期16卷 97-104页

作者： ZHANG Jialu qi shiqian and YU Ge (Institute of Acoustics, Academia Sinica Beijing 100080)Received

A national assessment of the performance of speech synthesis systems for Chinese has been carried out yearly since 1994. The quality of synthetic speech of five different systems were evaluated and diagnosed by using speech intelligibility tests. 16 college students (8 male, 8 female) with no experience with synthetic speech were the listeners, they were asked to do open response task by pencilpaper. In addition, speech naturalness was mea-sured by Mean Opinion

关键词： PSOLA Assessment methods of speech synthesis systems for Chinese

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Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme

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Signal Transduction and Targeted Therapy 2019年第1期4卷 530-537页

作者： qiu Sun Yuehong Hu Yijun Gu Jiangkun Huang Jun He Lan Luo Yi Yang Shuo Yin Chao Dou Tianqi Wang Xianghui Fu Ling He shiqian qi Xiaofeng Zhu Shengyong Yang Xiawei Wei Wei Cheng Division of Respiratory and Critical Care Medicine Center of Infectious DiseasesNational Clinical Research Center for Geriatrics and State Key Laboratory of BiotherapyWest China Hospital of Sichuan University and Collaborative Innovation Center of BiotherapyChengdu 610041China Shanghai Synchrotron Radiation Facility Zhangjiang LabZhangheng Road 239Pudong DistrictShanghai 201203China Department of Medicinal Chemistry Key Laboratory of Drug-Targeting and Drug Delivery System of the Education MinistrySichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China West China School of Public Health Sichuan UniversityChengdu 610041China

S-adenosyl-1-methionine(SAM)-dependent enzymes regulate various disease-related behaviors in all ***,the leporin biosynthesis enzyme LepI,a SAM-dependent enzyme,was reported to catalyze pericyclic reactions in leporin biosynthesis;however,the mechanisms underlying LepI activation and catalysis remain *** study aimed to investigate the molecular mechanisms of ***,we reported crystal structures of LepI bound to SAM/5′-deoxy-5′-(methylthio)adenosine(MTA),S-adenosyl-homocysteine(SAH),and SAM/substrate *** and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities,whereas SAM activated the *** analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133,Arg197,Arg295 around the active site and assisted by SAM with unclear *** present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI,not only strengthening current understanding of the fundamentally biochemical catalysis,but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.

关键词： mechanism. catalysis unusual

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Experimental study on the naturalness of synthetic speech

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Chinese Journal of Acoustics 1993年第3期12卷 258-264页

作者： LU Shinan, ZHANG Jialu and qi shiqian (Institute of Acoustics. Academia Sinica, Beijing 100080)

In the past 10 years a Chinese text-to-speech system including a phonetic library, static tone model and basic synthesis rules had been established in IAAS[1]. The Chinese synthesis of unrestricted vocabulary had been achieved, but further steps must be taken to improve the naturalness of synthesized Chinese. The effect of segmental and suprasegmental features of synthetic speech upon naturalness have been studied by use of subjective assessment method. The results show that the rhythm in time domain and coarticulation occupy a basic position for improving the naturalness of synthetic speech. And the fundamental frequency curve decided by tone model only suit to synthesize short sentence of Chinese. If the synthesis of larger linguistic unit than simple sentence is considered, the fundamental frequency curve should be carefully manipulated. This paper presents the experimental method and results, and discusses the way how to improve the naturalness of synthetic Chinese.

关键词： Chinese synthesis Subjective assessment Naturalness.

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混合线控制动系统制动力精确调节控制策略

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汽车工程 2018年第4期40卷 457-464页

作者：陈志成吴坚赵健何睿齐世迁吉林大学汽车工程学院长春130022

鉴于电子液压制动(electronic hydraulic brake,EHB)系统液压管路复杂且难以集成驻车制动,而电子机械制动(electronic mechanical brake,EMB)很难满足失效备份的需求,本文提出了一种前轴采用EHB,后轴采用EMB的混合线控制动系统(hybrid b... 详细信息

鉴于电子液压制动(electronic hydraulic brake,EHB)系统液压管路复杂且难以集成驻车制动,而电子机械制动(electronic mechanical brake,EMB)很难满足失效备份的需求,本文提出了一种前轴采用EHB,后轴采用EMB的混合线控制动系统(hybrid brake by wire system,HBBW),研究了EHB的双闭环压力跟随PI控制算法和EMB的三闭环制动力跟随PI控制算法,使其制动力能快速准确地跟随目标值。在此基础上,提出了混合制动系统的制动力精确调节PI控制策略,最后基于d SPACE Autobox和Car Sim搭建了HBBW系统的硬件在环(Hi L)试验平台,进行了Hi L测试与算法验证。结果表明,混合线控制动系统可有效地协调工作,实现四轮制动力快速、精确调节,从而提高车辆制动性能。

关键词：混合线控制动系统电子液压制动电子机械制动制动力控制策略硬件在环试验

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ON THE DYNAMIC SPECTRA OF SPEECH

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Chinese Journal of Acoustics 1983年第3期 259-265页

作者：张家騄齐士钤

Using a testing sentence（Ta qu Wuxishi,wo dao Heilongjiang.）well designed for measure-ments of telephone transmission qualality,we studied some dynamic characteristics of *** individually uttered the testing sentence in an anechoic *** conditions included:1. different talker’s efforts（SPL of speech at 1 m from talker’s lips is 55,60,65,70 and 75 dB）,*** utterance rates（normal and speed up）.It is shown that:（1） The long-term averagespectrum of speech is varied with the talker’s effort,and variation especially appeared in low andmid band of speech.（2） The fundamental frequency F0 and formant frequencies F1,F2,F3 areincrased with the increasing of the SPL of speech.（3） If utterance picks up speed,the vowel triangletends to be smaller than normal *** vowels tend to be centralized.（4） As a consequence ofincreasing SPL of speech,vowel-to-consonant ratio is increased,but it is closely related to the mannerof articulation of consonants.

关键词： ON THE DYNAMIC SPECTRA OF SPEECH

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STUDY ON DURATION OF CHINESE CONSONANTS

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Chinese Journal of Acoustics 1982年第1期 88-93页

作者：齐士钤张家騄

The duration of Chinese consonants has been measured by using natural disyllabic *** talkers(5 males and 6 females)and two phonetists,both males,uttered a well designed wordlist in an anechoic chamber at the normal speech sound level of *** results show that:(i)theduration of Chinese consonants is independent of the tone,syllable duration and consonant position inwords;(ii)the consonant duration is closely correlated with the manner of articulation;(iii)the rankorder of the duration of Chinese consonts is 1-unaspiraed voiceless stops,2-unaspirated voicelessaffricates,3-voiced,4-aspirated voiceless stops,5-voiceless fricatives,6-aspirated voicelessaffricates;and(iv)the closure duration of the unaspirated voiceless stops is longer than that of theaspirated voiceless stops.

关键词： STUDY ON DURATION OF CHINESE CONSONANTS

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