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Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

Neural Regeneration Research 2024年第7期19卷 1489-1498页

作者： Jinwang Ye Huali Wan Sihua Chen gong-ping Liu Shenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences and OceanographyShenzhen UniversityShenzhenGuangdong ProvinceChina Department of Laboratory Medicine Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouGuangdong ProvinceChina Co-innovation Center of Neurodegeneration Nantong UniversityNantongJiangsu ProvinceChina Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

关键词： acetylation Alzheimer’s disease cognitive deficits gliosis mitochondria damage neuroinflammation phosphorylation synaptic impairments tau tau immunotherapy

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Glucose metabolic reprogramming-related parameters for the prediction of 28-day neurological prognosis and all-cause mortality in patients after cardiac arrest:a prospective single-center observational study

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World Journal of Emergency Medicine 2024年第3期15卷 197-205页

作者： Subi Abudurexiti Shihai Xu Zhangping Sun Yi Jiang ping gong Department of Emergency Medicine Ruijin Hospital Affi liated to Shanghai Jiaotong University School of MedicineShanghai 200025China Department of Emergency Medicine Shenzhen People's Hospital(the Second Clinical Medical CollegeJinan Universitythe First Affi liated HospitalSouthern University of Science and Technology)Shenzhen 518020China Department of Emergency Medicine the First Affi liated Hospital of Dalian Medical UniversityDalian 116011China Department of Emergency Medicine General Hospital of Tianjin Medical UniversityTianjin 300052China

BACKGROUND:We aimed to observe the dynamic changes in glucose metabolic reprogrammingrelated parameters and their ability to predict neurological prognosis and all-cause mortality in cardiac arrest patients after the restoration of spontaneous circulation(ROSC).METHODS:Adult cardiac arrest patients after ROSC who were admitted to the emergency or cardiac intensive care unit of the First Aflliated Hospital of Dalian Medical University from August 1,2017,to May 30,2021,were enrolled.According to 28-day survival,the patients were divided into a non-survival group(n=82) and a survival group(n=38).Healthy adult volunteers(n=40) of similar ages and sexes were selected as controls.The serum levels of glucose metabolic reprogrammingrelated parameters(lactate dehydrogenase [LDH],lactate and pyruvate),neuron-specific enolase(NSE) and interleukin 6(IL-6) were measured on days 1,3,and 7 after ROSC.The Acute Physiology and Chronic Health Evaluation II(APACHE II) score and Sequential Organ Failure Assessment(SOFA) score were calculated.The Cerebral Performance Category(CPC) score was recorded on day 28 after ROSC.RESULTS:Following ROSC,the serum LDH(607.0 U/L vs.286.5 U/L),lactate(5.0 mmol/L vs.2.0 mmol/L),pyruvate(178.0 μmol/L vs.70.9 μmol/L),and lactate/pyruvate ratio(34.1 vs.22.1) significantly increased and were higher in the non-survivors than in the survivors on admission(all Pdicting 28-day neurological prognosis and an AUC of 0.950(95% CI:0.911–0.989) with 94.7% specificity for predicting 28-day all-cause mortality,which was the highest among the glucose metabolic reprogramming-related parameters tested.CONC

关键词： Glucose metabolic reprogramming Lactate dehydrogenase Cardiac arrest Prognosis

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Hierarchical Control Strategy for Load Regulation Based on Stackelberg Game Theory Considering Randomness

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CSEE Journal of Power and Energy Systems 2024年第3期10卷 929-941页

作者： Tingyu Jiang ping Ju C.Y.Chung Yuzhong gong College of Energy and Electrical Engineering Hohai UniversityNanjing 211100China Department of Electrical Engineering City University of Hong KongHong Kong CF624China Department of Electrical and Computer Engineering University of SaskatchewanSaskatoonSK S7N 5A9Canada CSEE IEEE

Demand response has been recognized as a valuable functionality of power systems for mitigating power imbalances.This paper proposes a hierarchical control strategy among the distribution system operator(DSO),load aggregators(LAs),and thermostatically controlled loads(TCLs);the strategy includes a scheduling layer and an executive layer to provide load regulation.In the scheduling layer,the DSO(leader)offers compensation price(CP)strategies,and the LAs(followers)respond to CP strategies with available regulation power(ARP)strategies.Profits of the DSO and LAs are modeled according to their behaviors during the load regulation process.Stackelberg game is adopted to capture interactions among the players and leader and to obtain the optimal strategy for each participant to achieve utility.Moreover,considering inevitable random factors in practice,e.g.,renewable generation and behavior of users,two different stochastic models based on sample average approximation(SAA)and parameter modification are formulated with improved scheduling accuracy.In the executive layer,distributed TCLs are triggered based on strategies determined in the scheduling layer.A self-triggering method that does not violate user privacy is presented,where TCLs receive external signals from the LA and independently determine whether to alter their operation statuses.Numerical simulations are performed on the modified IEEE-24 bus system to verify effectiveness of the proposed strategy.

关键词： Demand response hierarchical control load regulation self-triggering method Stackelberg game

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Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis

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International Journal of Ophthalmology(English edition) 2024年第6期17卷 1079-1085页

作者： Jin Deng Wen-Tao Sun Ke gong Li-ping Wang Feng-Zhi Li Xi’an People’s Hospital(Xi’an Fourth Hospital) Shaanxi Eye HospitalAffiliated People’s Hospital of Northwest UniversityXi’an 70004Shaanxi ProvinceChina

AIM:To compare the efficacy of pars plana vitrectomy(PPV)combined with internal limiting membrane(ILM)and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis(MF)in highly myopic eyes.METHODS:This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths(ALs)ranging from 26-32 mm treated between January 2020 and January 2022.All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo.Based on the features on spectral-domain optical coherence tomography(SD-OCT),the eyes were divided into the MF-only group(Group A,n=15 eyes),MF with central foveal detachment group(Group B,n=20 eyes),and MF with lamellar macular hole group(Group C,n=13 eyes).According to AL,eyes were further divided into three groups:Group D(26.01-28.00 mm,n=12 eyes),Group E(28.01-30.00 mm,n=26 eyes),and Group F(30.01-32.00 mm,n=10 eyes).The best-corrected visual acuity(BCVA),central foveal thickness(CFT),and complications were recorded.RESULTS:The patients included 16 males and 24 females with the mean age of 56±9.82y.The BCVA and CFT improved in all groups after surgery(Pdifference of the CFT in Group A,B,and C postoperatively(P>0.05).The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D,E,and F.Twenty eyes were injected with sterile air,and 28 eyes were injected with silicone oil for tamponade based on the AL.However,there was no statistically significant difference among Groups D,E,and F in terms of the results of sterile air or silicone oil tamponade.The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade,and the difference was not statistically significant.CONCLUSION:PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.

关键词： axial length myopic foveoschisis highly myopic internal limiting membrane pars plana vitrectomy

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Influence of nonalcoholic fatty liver disease on response to antiviral treatment in patients with chronic hepatitis B:A meta-analysis

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World Journal of Hepatology 2024年第3期16卷 465-476页

作者： Shi-Yi Liu dian Wang Jing Liu Lu-ping Yang gong-Ying Chen Department of Medicine Zhejiang Chinese Medical UniversityHangzhou 310053Zhejiang ProvinceChina Department of Medicine Hangzhou Normal UniversityHangzhou 310011Zhejiang ProvinceChina Department of Infectious and Hepatology diseases Affiliated Hospital of Hangzhou Normal UniversityHangzhou 310015Zhejiang ProvinceChina

BACKGROUND Although hepatitis B virus infection is the leading cause of chronic liver injury globally,nonalcoholic fatty liver disease(NAFLD)is gradually gaining attention as another major chronic liver disease.The number of patients having chronic hepatitis B(CHB)with concomitant hepatic steatosis has increased.AIM To analyze the effect of NAFLD on the response to antiviral treatment in patients with CHB.METHODS Relevant English studies were systematically searched across PubMed,EMBASE,Web of Science,and Cochrane Library until October 2023.Studies in which the treatment outcomes were compared between patients with CHB only and those with CHB and hepatic steatosis were included.RESULTS Of the 2502 retrieved studies,11 articles were finally included.Biochemical response until 48 wk(OR=0.87,95%CI:0.50–1.53,P=0.000)and 96 wk(OR=0.35,95%CI:0.24–0.53,P=0.24)and virological response until 96 wk(OR=0.80,95%CI:0.43–1.49,P=0.097)were lower in patients with hepatic steatosis than in patients with CHB alone.CONCLUSION Hepatic steatosis lowers the biochemical response to antiviral treatment in patients with CHB.

关键词： Nonalcoholic fatty liver disease Hepatitis B virus Antiviral treatment effect Meta-analysis

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Heterostructured Pt-Ni_(3)Mo_(3)N formed via ammonia-containing polyoxometalates for highly efficient electrocatalytic hydrogen evolution in acid medium

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Journal of Energy Chemistry 2024年第5期92卷 698-704页

作者： Bianqing Ren Xue gong Jing Cao Dezheng Zhang Zizhun Wang ping Song Ce Han Weilin Xu State Key Laboratory of Electroanalytical Chemistry Jilin Province Key Laboratory of Low Carbon Chemical PowerChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022JilinChina School of Applied Chemistry and Engineering University of Science and Technology of ChinaHefei 230026AnhuiChina Key Laboratory of Automobile Materials MOE School of Materials Science&EngineeringJilin Provincial International Cooperation Key Laboratory of High-Efficiency Clean Energy MaterialsElectron Microscopy Centerand International Center of Future ScienceJilin UniversityChangchun 130012JilinChina

Constructing heterostructured nanohybrid is considered as a prominent route to fabricate alternative electrocatalysts to commercial Pt/C for hydrogen evolution reaction(HER).In this work,(NH_(4))_(4)[NiH_(6)Mo_(6)O_(4)]·5H_(2)O polyoxometalates(NiMo_(6))are adopted as the cluster precursors for simple fabrication of heterostructured Pt-Ni_(3)Mo_(3)N nanohybrids supported by carbon black(Pt-Ni_(3)Mo_(3)N/C)without using additional N sources.The improved porosity and enhanced electronic interaction of Pt-Ni_(3)Mo_(3)N/C should be attributed to the integration of Pt with NiMo_(6),which favors the mass transport,promotes the formation of exposed catalytic sites,and benefits the regulation of intrinsic activity.Thus,the as-obtained Pt-Ni_(3)Mo_(3)N/C exhibits impressive and durable HER performance as indicated by the low overpotential of 13.7 mV at the current density of 10 mA cm^(-2) and the stable overpotential during continuous working at 100 mA cm^(-2) for 100 h.This work provides significant insights for the synthesis of new highly active heterostructured electrocatalysts for renewable energy devices.

关键词： Polyoxometalates Cluster precursors Heterostructured nanohybrids Hydrogen evolution reaction Electrocatalysis

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Molecule aging induced by electron attacking

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Journal of Energy Chemistry 2024年第6期93卷 519-525,I0013页

作者： ping Song Yining Dong Xue gong Mingbo Ruan Baoxin Ni Xuanhao Mei Kun Jiang Weilin Xu State Key Laboratory of Electroanalytical Chemistry and Jilin Province Key Laboratory of Low Carbon Chemical Power Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022JilinChina School of Applied Chemistry and Engineering University of Science and Technology of Chin1Hefei 230026AnhuiChina Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials Collaborative Innovation Center of Chemistry for Energy MaterialsDepartment of ChemistryFudan UniversityShanghai 200438China

Here we propose a new concept of"molecule aging":with some special treatment,a molecule could be"aged"by losing some unknown tiny particles or pieces from atoms in the molecule,Such"aging"or loss of unknown tiny particles does not change apparently its molecular structure or chemical composition,but some physicochemical properties could be changed irreversibly.We further confirm such"molecule aging"via a long-term electron attacking to age water(H_(2)O)molecules.The IR spectra show no structural difference between the fresh water and the aged one,while the NMR spectra show that the electron attacking can decrease the size of water clusters.Such facts indicate that the electron attacking indeed can"affect"the structure of water molecule slightly but without damaging to its basic molecule frame.Further exploration reveals that the hydrogen evolution reaction(HER)activity of the aged water molecule is lower than the fresh water on the same Pt/C electrocatalyst.The density functional theory calculations indicate that the shortened O-H bond in H_(2)O indeed can present lower HER activity,so the observed size decrease of water clusters from NMR probably could be attributed to the shortening of O-H bond in water molecules.Such results indicate significantly that the molecule aging can produce materials with new functions for new possible applications.

关键词： Aging of molecules Electron attacking Full width at half maxima Hydrogen evolution reaction

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An integrated north–south paleo-Dadu-Anning River: New insights from bulk major and trace element analyses of the Xigeda Formation

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China Geology 2024年第1期7卷 91-103页

作者： Yong Zheng Hai-bing Li Jia-wei Pan ping Wang Ya Lai Zheng gong Key Laboratory of Deep-Earth Dynamics Institute of GeologyChinese Academy of Geological SciencesChina Geological SurveyMinistry of Natural ResourcesBeijing 100037China Jiangsu Donghai Continental Deep Hole Crustal Activity National Observaion and Research Station Lianyungang 222300China Southern Marine Science and Engineering Guangdong Laboratory Guangzhou 511458China Geophysical Exploration Center China Earthquake AdministrationZhengzhou 450002China Institute of Geophysics China Earthquake AdministrationBeijing 100081China

The Xianshuihe-Anninghe fault extends SE–S and constitutes the southeastern margin of the Tibetan Plateau.However,the Dadu River which is associated with the fault does not flow following the path,but makes a 90ºturn within a distance of 1 km at Shimian,heading east,and joins the Yangtze River,finally flowing into the East China Sea.Adjacent to the abrupt turn,a low and wide pass near the Daqiao reservoir at Mianning separates the N–S course of the Dadu River from the headwater of the Anning River which then flows south into the Yunnan Province along the Anninghe fault.Therefore,many previous studies assumed southward flow of the paleo-Dadu River from the Shimian to the Anning River.However,evidences for the capture of the integrated N–S paleo-Dadu-Anning River,its timing,and causes are still insufficient.This study explored the paleo-drainage pattern of the Dadu and Anning Rivers based on bulk mineral and geochemical analyses of the large quantities of fluvial/lacustrine sediments along the trunk of the Dadu and Anning Rivers.Similar with sands in the modern Dadu River,the Xigeda sediments also exhibit a granitoid affinity with the bulk major mineral compositions of quartz(>50%),anorthite(about 10%),orthoclase(about 5%),muscovite(about 5%),and clinochlore(about 4%).Correspondingly,bulk major elements show high SiO_(2),with all samples>60%,and some of them>70%,low TiO_(2)(≤0.75%),P_(2)O_(5)(≤0.55%),FeO*(≤5%),and relatively high CaO(1.02%–8.51%),Na_(2)O(1.60%–2.52%),and K_(2)O(2.17%–2.71%),with a uniform REE patterns.Therefore,synthesizing all these results indicate that these lacustrine sediments have similar material sources,which are mainly derived from its course in the Songpan-Ganzi flysch block,implying that the paleo-Dadu originally flowed southward into the Anning River and provided materials to the Xigeda ancient lake.The rearrangement of the paleo-Dadu River appears to be closely related to the locally focused uplift driven by strong activities of the XianshuiheXiaojiang fault system.

关键词： Dadu River Anninghe fault River diversion Xigeda Formation Tectonic uplift Provenance Songpan-Ganzi flysch Ancient lake Xianshuihe-Xiaojiang fault system Tibetan Plateau

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Predictors of Adverse Pregnancy Outcomes Following Traumatic Injuries

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Current Medical Science 2024年第3期44卷 642-647页

作者： Wan-rong LU ping WU gong SONG Mei-qi GU Zhe XU Li HE National Clinical Research Center for Gynecology and Obstetrics Cancer Biology Research CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Traumatic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective After traumatic injury in pregnant women,providing timely and appropriate management for high-risk patients is crucial for both pregnant women and fetuses.This study aimed to identify risk factors that predict adverse pregnancy outcomes after traumatic injury.Methods A retrospective cohort study including 317 pregnant patients who experienced trauma was conducted.The collected data included general demographics,injury mechanisms and adverse pregnancy outcomes.Patients were divided into two subgroups based on the absence or presence of trauma-related adverse pregnancy outcomes.Univariate and multivariate logistic regressions were conducted to estimate the associations between clinical variables and adverse pregnancy outcomes.Results A total of 41(12.93%)patients experienced adverse pregnancy outcomes within the first 24 h post-trauma.This study revealed that age>35 years(OR=14.995,95%CI:5.024–44.755,Pding(OR=3.226,95%CI:1.093–9.523,P=0.034),positive scan in focused assessment with sonography for trauma(FAST)positive(OR=8.496,95%CI:2.825–25.555,Pding and positive FAST results were risk factors for abnormal delivery.Conclusion Advanced maternal age,third trimester,and positive FAST results should alert multidisciplinary trauma teams to closely monitor patients to prevent adverse pregnancy outcomes.

关键词： adverse pregnancy outcomes predictive factors abnormal delivery trauma

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A fungal CYP from Beauveria bassiana with promiscuous steroid hydroxylation capabilities

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Chinese Chemical Letters 2024年第5期35卷 218-222页

作者： Yu Peng Yue Wang Tian-Jiao Chen Jing-Jing Chen Jin-Ling Yang Ting gong ping Zhu State Key Laboratory of Bioactive Substance and Function of Natural Medicines NHC Key Laboratory of Biosynthesis of Natural ProductsCAMS Key Laboratory of Enzyme and Biocatalysis of Natural DrugsInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Hydroxylation of steroid core is critical to the synthesis of steroid drugs.direct sp^(3) C-H hydroxylation is challenging through chemical catalysis,alternatively,fungal biotransformation offers a possible solution to this problem.However,mining and metabolic engineering of cytochrome P450 monooxygenases(CYPs)is usually regarded as a more eco-friendly and efficient strategy.Herein,we report the mining and identification of a new steroid CYP(CYP68BE1)from Beauveria bassiana by transcriptomics,heterologous expression,in vivo and in vitro functional characterization.The catalytic promiscuity of CYP68BE1 was explored,and CYP68BE1 showed promiscuously and catalytically versatile,which is qualified for monohydroxylation on C11α,C1α,C6βand dihydroxylation on C1β,11αand C6β,11αof six steroids,leading to the production of key steroid intermediates required in the industrial synthesis of some indispensable steroid drugs.Molecular dynamics simulations were performed,revealing the molecular basis of different binding orientations of CYP68BE1 with different substrates.The discovery of CYP68BE1 offers a promising biocatalyst for enriching the steroid structural and functional diversity,which also can be applied to biosynthesize valuable steroid drug intermediates.

关键词： Fungal CYPs Steroid hydroxylase Beauveria bassiana Promiscuous biocatalyst Molecular dynamics

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