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Neuroscience Bulletin 2024年第2期40卷 182-200页

作者： Yang Zhu Hao Huang Zhi Chen Yong Tao Ling-Yi Liao Shi-Hao Gao Yan-Jiang Wang Chang-Yue Gao Department of Rehabilitation Medicine Daping HospitalArmy Medical UniversityChongqing 400042China Department of Neurology and center for Clinical Neuroscience Daping HospitalArmy Medical UniversityChongqing 400042China Department of special Medicine Daping HospitalArmy Medical UniversityChongqing 400042China

Intermittent theta burst stimulation(iTBS),a time-saving and cost-effective repetitive transcranial magnetic stimulation regime,has been shown to improve cognition in patients with Alzheimer’s disease(AD).However,the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown.Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation.Here,we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1(ISCA1,an essential regulatory factor for mitochondrial respiration)in the brain of APP/PS1 mice.In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function,which is required for ISCA1.Moreover,iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice.The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD.We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

关键词： Intermittent theta burst stimulation Alzheimer’s disease Iron-sulfur cluster assembly 1 Mitochondrial dysfunction Neurodegeneration

A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang Chunquan Sheng Jiajun Xu Ying Lu Pei Wang The center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China Department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)treatment.However,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback.Ferroptosis,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of NASH.Nitric oxide(NO)is a versatile biological molecule that can degrade extracellular matrix.In this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH model.Compared with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis.ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota dysbiosis.These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： Nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

Casein kinase-2 inhibition promotes retinal ganglion cell survival after acute intraocular pressure elevation

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Neural Regeneration Research 2024年第5期19卷 1112-1118页

作者： Meng Wang Shi-Qi Yao Yao Huang Jia-Jian Liang Yanxuan Xu Shaowan Chen Yuhang Wang Tsz Kin Ng Wai Kit Chu Qi Cui Ling-Ping Cen Joint Shantou International Eye center of Shantou University and The Chinese University of Hong Kong ShantouGuangdong ProvinceChina Shantou University medical College ShantouGuangdong ProvinceChina Beijing Tongren Eye center Beijing Tongren HospitalCapital Medical UniversityBeijingChina Department of Ophthalmology and Visual Sciences The Chinese University of Hong KongHong Kong Special Administrative RegionChina

Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma,the leading cause of irreversible blindness.We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury.To investigate the underlying mechanism,in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor(4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole)by intravitreal injection.We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages.Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors.Furthermore,casein kinase-2 inhibition downregulated the expression of genes(Cck,Htrsa,Nef1,Htrlb,Prph,Chat,Slc18a3,Slc5a7,Scn1b,Crybb2,Tsga10ip,and Vstm21)involved in intraocular pressure elevation.Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation.

关键词： casein kinase-2 glaucoma intraocular pressure elevation macrophages retinal ganglion cells

Cytochrome P45026A1 Contributes to the Maintenance of Neuropathic Pain

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Neuroscience Bulletin 2024年第3期40卷 293-309页

作者： De-Li Cao Ling-Jie Ma Bao-Chun Jiang Qiang Gu Yong-Jing Gao Institute of Pain Medicine and special Environmental Medicine Co-innovation Center of NeuroregenerationNantong UniversityNantong226019China Nantong University medical School Nantong226001China Department of Pain Management The Affiliated Hospital of Nantong UniversityNantong226001China

The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative metabolism of retinoic acid(RA),the active metabolite of vitamin A.Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation(SNL).CYP26A1 was mainly expressed in spinal neurons and astrocytes.HPLC analysis displayed that the content of all-trans-RA(at-RA),the substrate of CYP26A1,was reduced in the spinal cord on day 7 after SNL.Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain.Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine(IL-10)production.The RA receptors RARα,RXRβ,and RXRγwere expressed in spinal neurons and glial cells.The promoter of Il-10 has several binding sites for RA receptors,and at-RA directly increased Il-10 mRNA expression in vitro.Finally,intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia.Collectively,the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation.CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.

关键词： CYP26A1 Microglia Astrocytes ERK P38 IL-10 Neuropathic pain

Advancements in personalized stem cell models for aging-related neurodegenerative disorders

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Neural Regeneration Research 2024年第11期19卷 2333-2334页

作者： Mingxi Weng Ralf Jauch School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina center for Translational Stem Cell Biology Hong Kong Special Administrative RegionChina

Neurodegenerative diseases(NDDs)are a class of disorders characterized by the gradual loss or malfunction of specific cell populations in the nervous system,which can be triggered by genetic or environmental factors.As a result,patients often experience a decline in mobility,sensation,memory,and cognition,which can ultimately lead to a fatal outcome.The global incidence of NDDs,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis(ALS),and multiple sclerosis,is increasing.

关键词： degenerative Huntington sensation

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military medical Research 2024年第1期11卷 34-49页

作者： Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma Department of medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

On the Application of Mixed Models of Probability and Convex Set for Time-Variant Reliability Analysis

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Computer Modeling in Engineering & Sciences 2024年第5期139卷 1981-1999页

作者： Fangyi Li Dachang Zhu Huimin Shi center for Research on Leading Technology of special Equipment School of Mechanical and Electric EngineeringGuangzhou UniversityGuangzhou510006China

In time-variant reliability problems,there are a lot of uncertain variables from different sources.Therefore,it is important to consider these uncertainties in engineering.In addition,time-variant reliability problems typically involve a complexmultilevel nested optimization problem,which can result in an enormous amount of computation.To this end,this paper studies the time-variant reliability evaluation of structures with stochastic and bounded uncertainties using a mixed probability and convex set model.In this method,the stochastic process of a limit-state function with mixed uncertain parameters is first discretized and then converted into a timeindependent reliability problem.Further,to solve the double nested optimization problem in hybrid reliability calculation,an efficient iterative scheme is designed in standard uncertainty space to determine the most probable point(MPP).The limit state function is linearized at these points,and an innovative random variable is defined to solve the equivalent static reliability analysis model.The effectiveness of the proposed method is verified by two benchmark numerical examples and a practical engineering problem.

关键词： Mixed uncertainty probability model convex model time-variant reliability analysis

Adaptive observer-based integral event-triggered antivibration control of a full aircraft active landing gear system with irregular runway excitations

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Science China(Information Sciences) 2024年第6期67卷 248-261页

作者： Wenxiao HU Chenglong DU Fanbiao LI Xinmin CHEN Chunhua YANG Weihua GUI School of Automation Central South University Research center in System Engineering for special Aircrafts Ningbo Institute of Materials Technology and EngineeringChinese Academy of Sciences

This study addresses the antivibration issue of a full aircraft active landing gear system(LGS)under landing impact and runway excitations via a novel adaptive observer-based integral event-triggered control method. First, a full aircraft active LGS comprising a front gear and two synchronized main left and right gears with active suspensions is established, where the information exchange among them is not implemented directly. Second, two adaptive observers are designed separately for the front and main LGSs to identify the varying damping parameters and estimate the system states simultaneously. Third, estimated states are transmitted to a shared network through a novel integral event-triggered mechanism(I-ETM);thus, the front and main LGSs are interconnected, and a networked control scheme for the aircraft LGS is constructed. Additionally, the integrated active control law is designed with the aid of the transmitted states of the front and main LGSs, enhancing the robustness against the pitch vibration of the aircraft.Furthermore, the L2-stability of the hybrid system is guaranteed to depress the vertical vibration effect of the landing impact and irregular runway excitations, thus improving passenger safety and comfort. Moreover,a codesign method is provided to obtain feasible solutions to the gain matrices of the observers and controllers simultaneously. Simulation and comparison results are presented to illustrate the effectiveness and superiority of the proposed control scheme in antivibration and saving communication resources.

关键词： aircraft active landing gear antivibration control integral event-triggered mechanism adaptive observer ${\mathcal{L}}_2$-stability

Cancer statistics for young adults aged 20 to 49 years in China from 2000 to 2017:a population-based registry study

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Science China(Life Sciences) 2024年第4期67卷 711-719页

作者： Yi Teng Changfa Xia He Li Maomao Cao Fan Yang Xinxin Yan Siyi He Mengdi Cao Shaoli Zhang Qianru Li Wanqing Chen Office of Cancer Screening National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

An increasing cancer incidence among adults younger than 50 years has been reported for several types of cancer in multiple countries.We aimed to report cancer profiles and trends among young adults in China.Data from the China Cancer Registry Annual Report were used to estimate incidence and mortality among young adults(ages 20–49 years)in China in 2017,and an age-period-cohort model was employed to estimate the average annual percent change(AAPC)in incidence and mortality from 2000 to 2017.All 25 cancer types were grouped into obesity-or overweight-associated cancers(12 cancer types)and additional cancers(13 cancer types).In 2017,there were 681,178new cases and 214,591 cancer deaths among young adults in China.Among young adults,the most common cancers were thyroid,breast,cervical,liver,lung,and colorectal cancer,and the leading causes of cancer deaths were liver,lung,cervical,stomach,breast,and colorectal cancer.From 2000 to 2017,the cancer incidence increased for all cancers combined among young adults,with the highest AAPC(1.46%)for adults aged 20–24 years,while cancer mortality decreased,with the highest AAPC(-1.63%)for those aged 35–39 years.In conclusion,the cancer incidence in China has increased among young adults,while cancer mortality has decreased for nearly all ages.Cancer control measures,such as obesity control and appropriate screening,may contribute to reducing the increasing cancer burden among young adults.

关键词： young adults incidence mortality trends China

Cancer profiles in China and comparisons with the USA:a comprehensive analysis in the incidence,mortality,survival,staging,and attribution to risk factors

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Science China(Life Sciences) 2024年第1期67卷 122-131页

作者： Siyi He Changfa Xia He Li Maomao Cao Fan Yang Xinxin Yan Shaoli Zhang Yi Teng Qianru Li Wanqing Chen Office of Cancer Screening National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

China faces a disproportionate cancer burden to the population size and is undergoing a transition in the cancer spectrum.We extracted data in five aspects of cancer incidence,mortality,survival,staging distributions,and attribution to risk factors in China,the USA and worldwide from open-source databases.We conducted a comprehensive secondary analysis of cancer profiles in China in the above aspects,and compared cancer statistics between China and the USA.A total of 4,546,400 new cancer cases and 2,992,600 deaths occurred in China in 2020,accounting for 25.1%and 30.2%of global cases,respectively.Lifestyle-related cancers including lung cancer,colorectal cancer,and breast cancer showed an upward trend and have been the leading cancer types in China.41.6%of new cancer cases and 49.3%of cancer deaths occurred in digestive-system cancers in China,and the cancers of esophagus,nasopharynx,liver,and stomach in China accounted for over 40%of global cases.Infection-related cancers showed the highest population-attributable fractions among Chinese adults,and most cancers could be attributed to behavioral and metabolic factors.The proportions of stage I for most cancer types were much higher in the USA than in China,except for esophageal cancer(78.2%vs.41.1%).The 5-year relative survival rates in China have improved substantially during 2000–2014,whereas survival for most cancer types in the USA was significantly higher than in China,except for upper gastrointestinal cancers.Our findings suggest that although substantial progress has been made in cancer control,especially in digestive system cancers in China,there was still a considerable disparity in cancer burden between China and the USA.More robust policies on risk factors and standardized screening practices are urgently warranted to curb the cancer growth and improve the prognosis for cancer patients.

关键词： cancer burden survival rate neoplasm staging risk factors China