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

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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

Encouraging Solution to the Problem of Synthesizing Protein α-Thioester

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Chinese Journal of Chemistry 2024年第10期42卷 1114-1120页

作者： Xinliang Liu Zijun Gao Jie Zhao Farong ye ping Huang ping Wang Center for Chemical Glycobiology Shanghai Key Laboratory for Molecular Engineering of Chiral DrugsFrontiers Science Center for Transformative MoleculesSchool of Chemistry and Chemical EngineeringZhangjiang Institute for Advanced StudyShanghai JiaoTongUniversityShanghai 200240China Shenzhen Research Institute of Shanghai Jiao Tong University ShenzhenGuangdong 518057China

Expressed protein ligation(EPL)provides a powerful tool to access large-size proteins with precise structures.Existing methods for constructing the critical protein thioester for EPL have predominantly relied on the recombinant intein fusion expressed in Escherichia coli(E.coli).Despite its powerful applications,the expression of thioester derived from eukaryotic protein in E.coli inherently suffers from its limited solubility,the inactivity of intein,premature hydrolysis and low yields.To overcome these obstacles,we present herein the facile one-flask synthesis of inaccessible proteinα-thioester via a SUMO-protein-intein(SPI)sandwich model.The utility of SUMO enhances the protein fusion yield and solubility,prevents premature hydrolysis and simplifies the purification process.The inaccessible protein thioester with internal Cys residues can be readily produced and is compatible with the EPL-desulfurization protocol used to prepare complex proteins,which is otherwise difficult to obtain using traditional methods.Its utility has been highlighted through the synthesis of human granulocyte colony-stimulating factor(G-CSF).

关键词： Desulfurization Glycoproteins Glycopeptides Protein expression Peptide thioester

Accurate simulations of pure-viscoacoustic wave propagation in tilted transversely isotropic media

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Petroleum Science 2024年第2期21卷 866-884页

作者： Qiang Mao Jian-ping Huang Xin-Ru mu Ji-Dong Yang Yu-Jian Zhang Geosciences Department China University of Petroleum(East China)Qingdao266580ShandongChina Pilot National Laboratory for Marine Science and Technology(Qingdao) Qingdao266207ShandongChina

Forward modeling of seismic wave propagation is crucial for the realization of reverse time migration(RTM) and full waveform inversion(FWI) in attenuating transversely isotropic media. To describe the attenuation and anisotropy properties of subsurface media, the pure-viscoacoustic anisotropic wave equations are established for wavefield simulations, because they can provide clear and stable wavefields. However, due to the use of several approximations in deriving the wave equation and the introduction of a fractional Laplacian approximation in solving the derived equation, the wavefields simulated by the previous pure-viscoacoustic tilted transversely isotropic(TTI) wave equations has low accuracy. To accurately simulate wavefields in media with velocity anisotropy and attenuation anisotropy, we first derive a new pure-viscoacoustic TTI wave equation from the exact complex-valued dispersion formula in viscoelastic vertical transversely isotropic(VTI) media. Then, we present the hybrid finite-difference and low-rank decomposition(HFDLRD) method to accurately solve our proposed pure-viscoacoustic TTI wave equation. Theoretical analysis and numerical examples suggest that our pure-viscoacoustic TTI wave equation has higher accuracy than previous pure-viscoacoustic TTI wave equations in describing q P-wave kinematic and attenuation characteristics. Additionally, the numerical experiment in a simple two-layer model shows that the HFDLRD technique outperforms the hybrid finite-difference and pseudo-spectral(HFDPS) method in terms of accuracy of wavefield modeling.

关键词： Pure-viscoacoustic TTI wave equation Attenuation anisotropy Seismic modeling Low-rank decomposition method

Clinical study of different prediction models in predicting diabetic nephropathy in patients with type 2 diabetes mellitus

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World Journal of Diabetes 2024年第1期15卷 43-52页

作者： Sha-Sha Cai Teng-ye Zheng Kang-Yao Wang Hui-ping Zhu Department of Nephrology The First People’s Hospital of WenlingWenling 317500Zhejiang ProvinceChina

BACKGROUND Among older adults,type 2 diabetes mellitus(T2DM)is widely recognized as one of the most prevalent diseases.Diabetic nephropathy(DN)is a frequent com-plication of DM,mainly characterized by renal microvascular damage.Early detection,aggressive prevention,and cure of DN are key to improving prognosis.Establishing a diagnostic and predictive model for DN is crucial in auxiliary diagnosis.AIM To investigate the factors that impact T2DM complicated with DN and utilize this information to develop a predictive model.METHODS The clinical data of 210 patients diagnosed with T2DM and admitted to the First People’s Hospital of Wenling between August 2019 and August 2022 were retrospectively analyzed.According to whether the patients had DN,they were divided into the DN group(complicated with DN)and the non-DN group(without DN).multivariate logistic regression analysis was used to explore factors affecting DN in patients with T2DM.The data were randomly split into a training set(n=147)and a test set(n=63)in a 7:3 ratio using a random function.The training set was used to construct the nomogram,decision tree,and random forest models,and the test set was used to evaluate the prediction performance of the model by comparing the sensitivity,specificity,accuracy,recall,precision,and area under the receiver operating characteristic curve.RESULTS Among the 210 patients with T2DM,74(35.34%)had DN.The validation dataset showed that the accuracies of the nomogram,decision tree,and random forest models in predicting DN in patients with T2DM were 0.746,0.714,and 0.730,respectively.The sensitivities were 0.710,0.710,and 0.806,respectively;the specificities were 0.844,0.875,and 0.844,respectively;the area under the receiver operating characteristic curve(AUC)of the patients were 0.811,0.735,and 0.850,respectively.The Delong test results revealed that the AUC values of the decision tree model were lower than those of the random forest and nomogram models(P<0.05),whereas the difference in AUC values of the random forest and colu

关键词： Type 2 diabetes mellitus Diabetic nephropathy Random forest Decision-making tree Nomogram Forecast

Optical Transient Source AT2021lfa:A Possible“Dirty Fireball”

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Research in Astronomy and Astrophysics 2024年第4期24卷 124-133页

作者： Xue-Mei ye Da-Ming Wei Yi-Ming Zhu Zhi-ping Jin Key Laboratory of Dark Matter and Space Astronomy Purple Mountain ObservatoryChinese Academy of SciencesNanjing 210023China School of Astronomy and Space Science University of Science and Technology of ChinaHefei 230026China National Astronomical Observatories/Nanjing Institute of Astronomical Optics&Technology Chinese Academy of SciencesNanjing 210042China CAS Key Laboratory of Astronomical Optics&Technology Nanjing Institute of Astronomical Optics&TechnologyNanjing 210042China

AT2021lfa,also known as ZTF21aayokph,was detected by the Zwicky Transient Facility on 2021 May 4,a 05:34:48 UTC.Follow-up observations were conducted using a range of ground-based optical telescopes,as wel as Swift/XRT and VLA instruments.AT2021lfa is classified as an“orphan afterglow”candidate due to its rapid flux decline and its reddened color(g-r=0.17±0.14 mag).For an optical transient source without promp gamma-ray detection,one key point is to determine its burst time.Here we measure the burst time through fitting the initial bump feature of AT2021lfa and obtain its burst time as 2021 May 3,at 22:09:50 UTC.Using afterglowpy,we model the multi-band afterglow of AT2021lfa and find that the standard model canno reproduce the late radio observations well.Considering that the microphysical parameters ε_(e),ε_(B)(the energy fraction given to electrons and magnetic field),andξN(the fraction of accelerated electrons)may vary with time we then model the afterglow of AT2021lfa taking into account the temporal evolution of the physical parameters ε_(e),ε^(B),and ξ_(N) and find in this case the multi-wavelength observations can be reproduced well.The initial Lorentz factor of AT2021lfa can be estimated from the peak time of the early afterglow,which yields a value of about 18 suggesting that AT2021lfa should be classified as a“dirty fireball.”From the upper limit for the prompt emission energy of AT2021lfa,we obtain that the radiation efficiency is less than 0.02%,which is much smaller than that of ordinary gamma-ray bursts(GRBs).It is also interesting that the fitted values of jet angle and viewing angle are very large,θ_(c)~0.66 rad,θ_(v)~0.53 rad,which may lead to the low Lorentz factor and radiation efficiency.When compared with GRB afterglow samples,it is evident that the onset bump timescale of AT2021lfa satisfies the empirical relationships observed in GRB samples.Additionally,the luminosity of AT2021lfa falls within the range of observations for GRB samples;however,approximately 1 day after the burst,its lumino

关键词： gamma-rays:ISM methods:numerical radiation mechanisms:non-thermal

Miniature tunable Airy beam optical meta-device

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Opto-Electronic Advances 2024年第2期7卷 5-12页

作者： Jing Cheng Zhang mu Ku Chen Yubin Fan Qinmiao Chen Shufan Chen Jin Yao Xiaoyuan Liu Shumin Xiao Din ping Tsai Department of Electrical Engineering City University of Hong KongKowloonHong Kong SAR 999077China State Key Laboratory of Terahertz and Millimeter Waves City University of Hong KongKowloonHong Kong SAR 999077China Centre for Biosystems Neuroscienceand NanotechnologyCity University of Hong KongKowloonHong Kong SAR 999077China Ministry of Industry and Information Technology Key Lab of Micro-Nano Optoelectronic Information System Guangdong Provincial Key Laboratory of Semiconductor Optoelectronic Materials and Intelligent Photonic SystemsHarbin Institute of TechnologyShenzhen 518055China

Tunable Airy beams with controllable propagation trajectories have sparked interest in various fields,such as optical manipulation and laser fabrication.Existing research approaches encounter challenges related to insufficient compactness and integration feasibility,or they require enhanced tunability to enable real-time dynamic manipulation of the propagation trajectory.In this work,we present a novel method that utilizes a dual metasurface system to surpass these limitations,significantly enhancing the practical potential of the Airy beam.Our approach involves encoding a cubic phase profile and two off-axis Fresnel lens phase profiles across the two metasurfaces.The validity of the proposed strategy has been confirmed through simulation and experimental results.The proposed meta-device addresses the existing limitations and lays the foundation for broadening the applicability of Airy beams across diverse domains,encompassing light-sheet microscopy,laser fabrication,optical tweezers,etc.

关键词： metasurface miniature device tunable Airy beam tunable meta-device

Damping capacity of Fe_(83)Ga_(17) magnetostrictive alloy under magnetic field

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Rare Metals 2024年第1期43卷 402-409页

作者： Shao-Wen Yan Xing mu Bing-Jie Liu Li-Hong Xu Shi-Hai Guo Yan Qi Hong-ping Zhang Department of Functional Material Research Central Iron and Steel Research InstituteBeijing 100081China

The damping performance of Fe_(83)Ga_(17) alloys has been investigated in the static magnetic field (H). The results demonstrate that the damping peak value can be adjusted between 0.020 and 0.085 under the magnetic f... 详细信息

关键词： alloy magnetic alloys

Double casing warhead with sandwiched charge:The axial distribution of fragments velocities

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Defence Technology（防务技术） 2024年第4期34卷 201-216页

作者： ping ye Yongxiang Dong Qitian Sun Peizhuo Shi Wang Yao Yongnan Li Yujing Li Mingze Li State Key Laboratory of Explosion Science and Technology Beijing Institute of TechnologyBeijing 100081China

The double casing warhead with sandwiched charge is a novel fragmentation warhead that can produce two groups of fragments with different velocity,and the previous work has presented a calculation formula to determine the maximum fragment velocity.The current work builds on the published formula to further develop a formula for calculating the axial distribution characteristics of the fragment velocity.For this type of warhead,the simulation of the dispersion characteristics of the detonation products at different positions shows that the detonation products at the ends have a much larger axial velocity than those in the middle,and the detonation products have a greater axial dispersion velocity when they are closer to the central axis.The loading process and the fragment velocity vary with the axial position for both casing layers,and the total velocity of the fragments is the vector sum of the radial velocity and the axial velocity.At the same axial position,the acceleration time of the inner casing is greater than that of the outer casing.For the same casing,the fragments generated at the ends have a longer acceleration time than the fragments from the middle.The proposed formula is validated with the X-ray radiography results of the four warheads previously tested experimentally and the 3D smoothedparticle hydrodynamics numerical simulation results of several series of new warheads with different configurations.The formula can accurately and reliably calculate the fragment velocity when the lengthto-diameter ratio of the charge is greater than 1.5 and the thickness of the casing is less than 20%its inner radius.This work thus provides a key reference for the theoretical analysis and the design of warheads with multiple casings.

关键词： Double casing warhead Sandwiched charge Fragment velocity Rarefaction wave Gurney formula Explosive loading

Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function

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National Science Review 2024年第2期11卷 145-154页

作者： Farong ye Cheng Li Feng-Liang Liu Xinliang Liu Peng Xu Rong-Hua Luo Wenping Song Yong-Tang Zheng Tianlei Ying Biao Yu ping Wang Center for Chemical Glycobiology Frontiers Science Center for Transformative Molecules Zhangjiang Institute for Advanced Study School of Chemistry and Chemical Engineering Shanghai Jiao Tong University MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Institute of Infectious Disease and BiosecurityShanghai Engineering Research Center for Synthetic ImmunologySchool of Basic Medical Sciences Shanghai Medical College Fudan University Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Center for Biosafety Mega-Science Kunming Institute of ZoologyChinese Academy of Sciences State Key Laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Shenzhen Research Institute of Shanghai Jiao Tong University

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019（COVID-19）.The receptor-binding domain（RBD） of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure–function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope(Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpepelicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpepconjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

关键词： peptide ligation glycosylation glycoprotein