Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite ou...Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown.Here,we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination.Cullin3 facilitated spastin degradation and ubiquitination.RING-box protein 1,but not RING-box protein 2,acted synergistically with Cullin3 protein to regulate spastin degradation.Overexpression of Culin3 or BRX1 markedly suppressed spastin expression,and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth.Moreover,USP14 interacted directly with spastin to mediate its deubiquitination.USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation.Although co-expression of spastin and USP14 did not enhance microtubule severing,it did increase neurite length in hippocampal neurons.Taken together,these findings elucidate the intricate regulatory mechanisms of spastin turnover,highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation.The dynamic interplay between these factors governs spastin stability and function,ultimately influencing microtubule dynamics and neuronal morphology.These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.展开更多
本文旨在对3个影响猪达100 kg体重日龄(Age at 100 kg,AGE)和达100 kg体重平均日增重(Average Daily Gain at 100 kg,ADG)的候选基因进行生物信息学分析。运用生物信息学数据库及其软件,分别分析了肉碱O-乙酰转移酶(Carnitine O-acetylt...本文旨在对3个影响猪达100 kg体重日龄(Age at 100 kg,AGE)和达100 kg体重平均日增重(Average Daily Gain at 100 kg,ADG)的候选基因进行生物信息学分析。运用生物信息学数据库及其软件,分别分析了肉碱O-乙酰转移酶(Carnitine O-acetyltransferase,CRAT)、G蛋白偶联受体107(G Protein-Coupled Receptor 107,GPR107)和泛素特异性肽酶20(Ubiquitin Specific Peptidase 20,USP20)3个基因与其编码的产物。结果发现:CRAT基因位于猪的1号染色体,具有15个外显子、14个内含子,共编码626个氨基酸;USP20基因位于猪的1号染色体,具有26个外显子,25个内含子,共编码915个氨基酸;GPR107基因位于猪的1号染色体,具有19个外显子、18个内含子,共编码597个氨基酸;3个蛋白的二级结构主要组成均为无规则卷曲,且均表现出疏水特征,含有磷酸化位点,仅GPR107蛋白检测到信号肽和跨膜结构;猪CRAT、USP20、GPR107在进化过程中与其他哺乳动物之间均具有高度保守性以及序列同源性;CRAT与羟基类固醇17-β脱氢酶4(Hydroxysteroid 17-Beta Dehydrogenase 4,HSD17B4)、囊泡乙酰胆碱转运蛋白(Solute Carrier Family 18 Member A3,SLC18A3)、脂肪酶(Patatin Like Phospholipase Domain Containing 2,PNPLA2)等蛋白互作;USP20与STAM结合蛋白样1(STAM Binding Protein Like 1,STAMBPL1)、β2-肾上腺素能受体(Adrenoceptor Beta 2,ADRB2)、泛素特异性肽酶14(Ubiquitin Specific Peptidase 14,USP14)等蛋白互作;GPR107与LIN52(Lin-52 Homolog,LIN52)、P-选择素(Selectin P,SELP)、G蛋白偶联受体137C(G Protein-Coupled Receptor 137C,GPR137C)等蛋白互作;GO富集分析发现CRAT、USP20、GPR107主要参与脂肪酸的分解代谢、蛋白质稳定性和降解、配子生成过程;CRAT基因在肌肉组织中高表达,USP20基因在下丘脑中高表达,GPR107基因在血管和下丘脑中高表达。本文结果为进一步研究猪生长性状相关的功能基因提供了数据与理论参考。展开更多
Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limite...Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.展开更多
According to surface morphology,microhardness,X-ray diffraction,and static contact angle experiments,the changes in the surface integrity and corrosion resistance of 6061-T6 aluminum alloy after ultrasonic shot peenin...According to surface morphology,microhardness,X-ray diffraction,and static contact angle experiments,the changes in the surface integrity and corrosion resistance of 6061-T6 aluminum alloy after ultrasonic shot peening(USP)were investigated.Results show that the grain size of the material surface is reduced by 43%,the residual compressive stress has an increasing trend,the roughness and hardness are increased by approximately 211.1%and 35%,respectively.And the static contact angle is increased at first,followed by a slight decrease.Weighing,scanning electron microscope,and energy dispersive spectrometer were used to study the samples after a cyclic corrosion test.Results show that USP reduces the corrosion rate by 41.2%.A model of surface corrosion mechanism of USP is developed,and the mechanism of USP to improve the corrosion resistance of materials is discussed.The introduction of compressive residual stresses,grain refinement,increased grain boundaries,increased hardness,and increased static contact angle are the main factors related to the improvement of corrosion resistance in most materials,while increased roughness tends to weaken surface corrosion resistance.展开更多
基金supported by the National Natural Science Foundation of China,No.32071033(to MT)Basic and Applied Basic Research Foundation of Guangdong Province,Nos.2023A1515010140(to MT),2022A1515140169(to MT),2022A1515111096(to ZC)+3 种基金Science and Technology Project of Guangzhou,Nos.202201010015(to YL),2023A03J0790(to TJ)Basic and Applied Basic Research Foundation of Guangzhou,No.2023A04J1285(to ZC)Medical Research Foundation of Guangdong Province,No.A2023147(to ZC)Health Science and Technology Project of Guangzhou,No.20221A011039(to TJ)。
文摘Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown.Here,we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination.Cullin3 facilitated spastin degradation and ubiquitination.RING-box protein 1,but not RING-box protein 2,acted synergistically with Cullin3 protein to regulate spastin degradation.Overexpression of Culin3 or BRX1 markedly suppressed spastin expression,and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth.Moreover,USP14 interacted directly with spastin to mediate its deubiquitination.USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation.Although co-expression of spastin and USP14 did not enhance microtubule severing,it did increase neurite length in hippocampal neurons.Taken together,these findings elucidate the intricate regulatory mechanisms of spastin turnover,highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation.The dynamic interplay between these factors governs spastin stability and function,ultimately influencing microtubule dynamics and neuronal morphology.These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.
文摘本文旨在对3个影响猪达100 kg体重日龄(Age at 100 kg,AGE)和达100 kg体重平均日增重(Average Daily Gain at 100 kg,ADG)的候选基因进行生物信息学分析。运用生物信息学数据库及其软件,分别分析了肉碱O-乙酰转移酶(Carnitine O-acetyltransferase,CRAT)、G蛋白偶联受体107(G Protein-Coupled Receptor 107,GPR107)和泛素特异性肽酶20(Ubiquitin Specific Peptidase 20,USP20)3个基因与其编码的产物。结果发现:CRAT基因位于猪的1号染色体,具有15个外显子、14个内含子,共编码626个氨基酸;USP20基因位于猪的1号染色体,具有26个外显子,25个内含子,共编码915个氨基酸;GPR107基因位于猪的1号染色体,具有19个外显子、18个内含子,共编码597个氨基酸;3个蛋白的二级结构主要组成均为无规则卷曲,且均表现出疏水特征,含有磷酸化位点,仅GPR107蛋白检测到信号肽和跨膜结构;猪CRAT、USP20、GPR107在进化过程中与其他哺乳动物之间均具有高度保守性以及序列同源性;CRAT与羟基类固醇17-β脱氢酶4(Hydroxysteroid 17-Beta Dehydrogenase 4,HSD17B4)、囊泡乙酰胆碱转运蛋白(Solute Carrier Family 18 Member A3,SLC18A3)、脂肪酶(Patatin Like Phospholipase Domain Containing 2,PNPLA2)等蛋白互作;USP20与STAM结合蛋白样1(STAM Binding Protein Like 1,STAMBPL1)、β2-肾上腺素能受体(Adrenoceptor Beta 2,ADRB2)、泛素特异性肽酶14(Ubiquitin Specific Peptidase 14,USP14)等蛋白互作;GPR107与LIN52(Lin-52 Homolog,LIN52)、P-选择素(Selectin P,SELP)、G蛋白偶联受体137C(G Protein-Coupled Receptor 137C,GPR137C)等蛋白互作;GO富集分析发现CRAT、USP20、GPR107主要参与脂肪酸的分解代谢、蛋白质稳定性和降解、配子生成过程;CRAT基因在肌肉组织中高表达,USP20基因在下丘脑中高表达,GPR107基因在血管和下丘脑中高表达。本文结果为进一步研究猪生长性状相关的功能基因提供了数据与理论参考。
基金supported by grants from the Dongguan Science and Technology of Social Development Program(No.20231800940192)the Talent Development Foundation of the First Dongguan Affiliated Hospital of Guangdong Medical University(No.PU2023002).
文摘Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.
基金Introduction of Talent Research Start-up Fund of Anhui University of Science and Technology(2022yjrc35)Colleges and Universities Excellent Young Talents Domestic Visit Research Project of Anhui Province(gxgnfx2022006)。
文摘According to surface morphology,microhardness,X-ray diffraction,and static contact angle experiments,the changes in the surface integrity and corrosion resistance of 6061-T6 aluminum alloy after ultrasonic shot peening(USP)were investigated.Results show that the grain size of the material surface is reduced by 43%,the residual compressive stress has an increasing trend,the roughness and hardness are increased by approximately 211.1%and 35%,respectively.And the static contact angle is increased at first,followed by a slight decrease.Weighing,scanning electron microscope,and energy dispersive spectrometer were used to study the samples after a cyclic corrosion test.Results show that USP reduces the corrosion rate by 41.2%.A model of surface corrosion mechanism of USP is developed,and the mechanism of USP to improve the corrosion resistance of materials is discussed.The introduction of compressive residual stresses,grain refinement,increased grain boundaries,increased hardness,and increased static contact angle are the main factors related to the improvement of corrosion resistance in most materials,while increased roughness tends to weaken surface corrosion resistance.
