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Lama1 upregulation prolongs the lifespan of the dy^(H)/dy^(H) mouse model of LAMA2-related congenital muscular dystrophy

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Journal of Genetics and Genomics 2024年第10期51卷 1066-1078页

作者： Yidan Liu Dandan Tan Kaiyue Ma Huaxia Luo jingping mao Jihang Luo Qiang Shen Luzheng Xu Shiqi Yang Lin Ge Yuxuan Guo Hong Zhang Hui Xiong Department of Pediatrics Peking University First HospitalBeijing 102600China State Key Laboratoyof Vascular Homeostasis and Remodeling The Institute of Cardiovascular SciencesSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Department of Neuroogy The First Affiliated HospitalJiangxi Medical CollegeNanchang UniversityNanchangJiangxi 330006China Bio-X Insttutes Key Laboratoryfor the Genetics of Developmental and Neuropsychiatic DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Department of Genetics Yale School of MedicineNew HavenCT 06510USA Medical and Health Analysis Center Peking UniversityBeijing 100191China Department of Neurology Beijing Children's HospitalCapital Medical UniversityNational Center for Children's HealthBeijing 100045China

LAMA2-related congenital muscular dystrophy(LAMA2-CMD),characterized by laminin-α2 deficiency,is debilitating and ultimately *** date,no effective therapy has been clinically ***-a1,which shares significant similarities with laminin-a2,has been proven as a viable compensatory *** evaluate its clinical applicability,we establish a Lama2 exon-3-deletion mouse model(dy^(H)/dy^(H)).The dy^(H)/dy^(H) mice exhibit early lethality and typical LAMA2-CMD phenotypes,allowing the evaluation of various *** dy^(H)/dy^(H) mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation,a nearly doubled median survival is observed,as well as improvements in weight and *** therapeutical effects are revealed by MRl,serum biochemical indices,and muscle pathology *** LAMA2-CMD with LAMA1 upregulation is feasible,and early intervention can alleviate symptoms and extend ***,we reveal the limitations of LAMA1 upregulation,including high-dose mortality and non-sustained expression,which require further optimization in future studies.

关键词： Disease model Gene therapy CRISPRa Congenital muscular dystrophy LAMA2

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双离合自动变速器电液控制系统油路间的相互影响及液压源参数的选择

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机床与液压 2019年第8期47卷 92-97页

作者：毛晶平孙保群夏光合肥工业大学汽车与交通工程学院安徽合肥230009

为提高双离合自动变速器的工作性能,在分析自主研发的七速对置双离合自动变速器电液控制系统工作原理的基础上,利用AMESim软件,研究换挡过程中同时工作的液压缸间的相互影响及其影响因素,并通过选用合适的液压源参数的方法来降低相互影... 详细信息

为提高双离合自动变速器的工作性能,在分析自主研发的七速对置双离合自动变速器电液控制系统工作原理的基础上,利用AMESim软件,研究换挡过程中同时工作的液压缸间的相互影响及其影响因素,并通过选用合适的液压源参数的方法来降低相互影响程度。仿真结果表明:双离合自动变速器的电液控制系统中,两离合器作动油缸间的相互影响程度最大,并且两作动缸活塞截面积(活塞行程不变)、泵的排量、电机转速、蓄能器容积、油道水力直径等都会影响两缸相互影响的程度。

关键词：电液控制系统相互影响影响因素液压源参数

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DCT液压系统中阀口开度对控制性能的影响

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农业装备与车辆工程 2019年第2期57卷 4-8页

作者：毛晶平孙保群周友合肥工业大学汽车与交通工程学院安徽省合肥市230009

为提高双离合自动变速器(DCT)中的液压控制系统的控制精度,以自主研发的七速对置双离合自动变速器的电液控制系统为研究对象,针对同步器和离合器的不同工作特性,通过对滑阀油口开度的控制来实现对同步器和离合器作动缸的动作控制,从而... 详细信息

为提高双离合自动变速器(DCT)中的液压控制系统的控制精度,以自主研发的七速对置双离合自动变速器的电液控制系统为研究对象,针对同步器和离合器的不同工作特性,通过对滑阀油口开度的控制来实现对同步器和离合器作动缸的动作控制,从而实现动力换挡。仿真结果表明,液压阀油口开度对输出油液的压强和流量有直接影响,通过对油口开度的控制可以使作动缸满足作动要求。

关键词：双离合自动变速器液压控制系统阀口开度动作控制动力换挡

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Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy

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Journal of Genetics and Genomics 2024年第10期 1066-1078页

作者： Yidan Liu Dandan Tan Kaiyue Ma Huaxia Luo jingping mao Jihang Luo Qiang Shen Luzheng Xu Shiqi Yang Lin Ge Yuxuan Guo Hong Zhang Hui Xiong Department of Pediatrics Peking University First Hospital State Key Laboratory of Vascular Homeostasis and Remodeling The Institute of Cardiovascular SciencesSchool of Basic Medical SciencesPeking University Health Science Center Department of Neurology The First Affiliated HospitalJiangxi Medical CollegeNanchang University Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong University Department of Genetics Yale School of Medicine Medical and Health Analysis Center Peking University Department of Neurology Beijing Children's HospitalCapital Medical UniversityNational Center for Children's Health

LAMA2-related congenital muscular dystrophy(LAMA2-CMD), characterized by laminin-a2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-a1,which shares significant similarities with laminin-a2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3-deletion mouse model(dyH/dy H). The dyH/dy H mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dyH/dy H mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1upregulation, a nearly doubled median survival is observed, as well as improvements in weight and *** therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible, and early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal the limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

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Mitophagy in acute central nervous system injuries:regulatory mechanisms and therapeutic potentials

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Neural Regeneration Research 2025年第9期20卷 2437-2453页

作者： Siyi Xu Junqiu Jia Rui mao Xiang Cao Yun Xu Department of Neurology Nanjing Drum Tower HospitalClinical College of Jiangsu UniversityNanjingJiangsu ProvinceChina Department of Neurology Nanjing Drum Tower HospitalChinese Academy of Medical Science&Peking Union Medical CollegeNanjingJiangsu ProvinceChina Department of Neurology Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu ProvinceChina State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing UniversityNanjingJiangsu ProvinceChina Jiangsu Key Laboratory for Molecular Medicine Medical School of Nanjing UniversityNanjingJiangsu ProvinceChina Nanjing Neurology Medical Center NanjingJiangsu ProvinceChina

Acute central nervous system injuries,including ischemic stro ke,intracerebral hemorrhage,subarachnoid hemorrhage,traumatic brain injury,and spinal co rd injury,are a major global health *** optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent *** are susceptible to damage after acute central nervous system injury,and this leads to the release of toxic levels of reactive oxygen species,which induce cell ***,a selective form of autophagy,is crucial in eliminating redundant or damaged mitochondria during these *** evidence has highlighted the significant role of mitophagy in acute central nervous system *** this review,we provide a comprehensive overview of the process,classification,and related mechanisms of *** also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate *** the final section of this review,we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

关键词： autophagy intracerebral hemorrhage ischemic stroke mitochondria mitochondrial biogenesis mitochondrial quality control mitophagy spinal cord injury subarachnoid hemorrhage traumatic brain injury

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Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2025年第1期17卷 176-198页

作者： Zhong-Xia Yang Li-Ting Zhang Xiao-Jun Liu Xue-Bin Peng Xiao-Rong mao The First School of Clinical Medicine Lanzhou UniversityLanzhou 730000Gansu ProvinceChina Department of Infectious Diseases The First Hospital of Lanzhou UniversityLanzhou 730000Gansu ProvinceChina Department of Radiotherapy Gansu Provincial HospitalLanzhou 730000Gansu ProvinceChina

BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal *** has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor *** regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy ***-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different *** hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in *** upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow *** studies were conducted with gene knockout models and pathway *** function of IL-17A in immune evasion was explored through coculture of T cells and HCC *** effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in *** IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by ***-17A enhanced the survival of HCC cells in the coculture ***-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic *** D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression *** combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse *** IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against

关键词： Interleukin-17A Programmed death ligand-1 Interleukin-17A receptor Small mothers against decapentaplegic 2 Hepatocellular carcinoma Immunotherapy

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High Fe‑Loading Single‑Atom Catalyst Boosts ROS Production by Density Effect for Efficient Antibacterial Therapy

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Nano-Micro Letters 2025年第2期17卷 187-203页

作者： Si Chen Fang Huang Lijie mao Zhimin Zhang Han Lin Qixin Yan Xiangyu Lu Jianlin Shi Department of Cardiology Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghai 200092People’s Republic of China Shanghai Institute of Ceramics Chinese Academy of SciencesShanghai 200050People’s Republic of China Shanghai Frontiers Science Center of Nanocatalytic Medicine School of MedicineTongji UniversityShanghai 200092People’s Republic of China

The current single-atom catalysts(SACs)for medicine still suffer from the limited active site ***,we develop a synthetic method capable of increasing both the metal loading and mass-specific activity of SACs by exchanging zinc with *** constructed iron SACs(h^(3)-FNC)with a high metal loading of 6.27 wt%and an optimized adjacent Fe distance of~4 A exhibit excellent oxidase-like catalytic performance without significant activity decay after being stored for six months and promising antibacterial ***,a“density effect”has been found at a high-enough metal doping amount,at which individual active sites become close enough to interact with each other and alter the electronic structure,resulting in significantly boosted intrinsic activity of single-atomic iron sites in h^(3)-FNCs by 2.3 times compared to low-and medium-loading ***,the overall catalytic activity of h^(3)-FNC is highly improved,with mass activity and metal mass-specific activity that are,respectively,66 and 315 times higher than those of commercial Pt/*** addition,h^(3)-FNCs demonstrate efficiently enhanced capability in catalyzing oxygen reduction into superoxide anion(O_(2)·^(−))and glutathione(GSH)*** in vitro and in vivo assays demonstrate the superior antibacterial efficacy of h^(3)-FNCs in promoting wound *** work presents an intriguing activity-enhancement effect in catalysts and exhibits impressive therapeutic efficacy in combating bacterial infections.

关键词： Nanocatalytic medicine Single-atom catalysts Reactive oxygen species(ROS) High metal loading Oxidase catalysis

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Lipid levels and insulin resistance markers in patients with colorectal cancer:Propensity score matching analysis

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World Journal of Gastrointestinal Oncology 2025年第1期17卷 130-142页

作者： Ren-Hao Hu Dong-Yi Yan Ke-Hui Zhang Di Zhang Xi-mao Cui Xiao-Hua Jiang Shun Zhang Department of Gastrointestinal Surgery Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China School of Medicine Tongji UniversityShanghai 200092China Department of Emergency Medicine Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China

BACKGROUND Colorectal cancer(CRC)is a prevalent malignant neoplasm characterized by subtle early *** To investigate the correlation among serum lipid profiles,the triglyceride-glucose(TyG)index,and the atherosclerotic index(AI)in patients with ***,it explored the clinical diagnostic utility of combining serum lipids with cancer antigens in the context of *** A retrospective analysis encompassed 277 patients with CRC and 1034 healthy *** Following propensity score matching,patients with CRC exhibited significantly reduced levels of serum triglyceride(TG),total cholesterol(TC),high-density lipoprotein cholesterol,and low-density lipoprotein cholesterol(LDL-C),as well as a diminished TyG ***,they displayed elevated AI levels compared to their healthy *** in advanced stages exhibited lower serum levels of TG,TC,and LDL-C compared to those in early *** with positive lymph node metastasis demonstrated reduced levels of TG,LDL-C,and the TyG *** operating characteristic analysis revealed that the combination of the TyG index,carcinoembryonic antigen,and carbohydrate antigen 19-9 yielded the highest positive prediction rate for CRC at 75.3%.CONCLUSION Preoperative serum lipid profiles exhibit a robust association with patients with *** concurrent assessment of multiple serum lipids and cancer antigens effectively enhances the diagnostic accuracy for CRC.

关键词： Colorectal cancer Serum lipids Triglyceride-glucose index Atherosclerotic index Diagnostic marker

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AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

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Neural Regeneration Research 2025年第1期20卷 253-264页

作者： Zhengwei Hu Jing Yang Shuo Zhang Mengjie Li Chunyan Zuo Chengyuan mao Zhongxian Zhang Mibo Tang Changhe Shi Yuming Xu Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Academy of Medical Sciences of Zhengzhou University ZhengzhouHenan ProvinceChina NHC Key Laboratory of Prevention and treatment of Cerebrovascular Diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Henan Key Laboratory of Cerebrovascular Diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Institute of Neuroscience Zhengzhou UniversityZhengzhouHenan ProvinceChina Sino-British Research Centre for Molecular Oncology National Centre for International Research in Cell and Gene TherapySchool of Basic Medical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina Department of Gerontology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control *** this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s *** used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse *** overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated *** also alleviated the concentration of microglia and astrocytes around *** APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin *** of HSP70 and HSP40,which have functional relevance to CHIP,were also *** nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of *** research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 ***,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

关键词： adeno-associated virus Alzheimer’s disease APP/PS1 mice carboxyl terminus of Hsp70 interacting protein gene therapy

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BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation

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World Journal of Gastrointestinal Oncology 2025年第1期17卷 214-225页

作者： Qin Wang Qing-Rong Li Lei Xu Zi-Chun Yuan Xiao Liu mao-Ju Tang Man Luo Xiao-Wu Zhong Qiang Ma Xiao-Lan Guo Department of Clinical Laboratory Affiliated Hospital of North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina School of Laboratory Medicine&Translational Medicine Research Center North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic *** are DNA-protein complexes located at the termini of chro-mosomes in eukaryotic cells,which are unreplaceable in maintaining the stability and integrity of ***,an RNA-dependent DNA polymerase,play vital role in telomere length maintain,targeting telomerase is a promising therapeutic strategy for ***150 and KYSE410 cells were cultured and exposed to various concentrations of *** viability was assessed at 48 hours and 72 hours to determine the IC50 *** effects of BIBR1532 on ESCC cell proliferation,migration,and cellular senescence were evaluated using the cell counting kit-8 assay,plate colony formation assay,scratch assay,transwell assay,andβ-galactosidase staining,*** blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,*** values decreased to 37.22μM and 22.71μM,respectively,following a longer exposure of 72 ***1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells,including decreased hTERT expression,inhibition of proliferation and metastasis,and induction of cellular ***,BIBR1532 upregulated the expression of the DDR protein,γ-H2AX,and activated the ataxia telangiectasia and Rad3-related protein(ATR)/check point kinase 1(CHK-1)and ataxia-telangiectasia mutated gene(ATM)/CHK2 ***1532 downregulated the expression of telomere-binding proteins,including telomeric-repeat binding factor 1(TRF1),TRF2,protection of telomeres 1,and TIN2-interacting protein *** a nude mouse xenograft model,BIBR1532 significantly suppressed tumor growth,reduced hTERT expression,and increasedγ-H2AX protein *** and eosin staining of various organs,including the heart,liver,s

关键词： Esophageal squamous cell carcinoma BIBR1532 Human telomerase reverse transcriptase DNA damage response Telomere-binding proteins

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