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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural regeneration research 2025年第1期20卷 174-180页

作者： Yinglong Miao michael s.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-stay-Trim,”“sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

Deep brain stimulation for Tourette’s syndrome

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Translational Neurodegeneration 2020年第1期9卷 20-38页

作者： Wenying Xu Chencheng Zhang Wissam Deeb Bhavana Patel Yiwen Wu Valerie Voon michael s.okun Bomin sun Department of Functional Neurosurgery Ruijin HospitalShanghai Jiao Tong University School of MedicineRuijin Hospital197 Ruijin Er RoadShanghai 200025China Norman Fixel Institute for Neurological Diseases Department of NeurologyCollege of MedicineUniversity of FloridaGainesvilleFL 32608USA Department of Neurology&Institute of Neurology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Psychiatry University of CambridgeCambridgeUK

Tourette syndrome(Ts)is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and vocal *** usually co-occurs with one or multiple psychiatric *** behavioral and pharmacological treatments for Ts are available,some patients do not respond to the available *** these patients,Ts is a severe,chronic,and disabling *** recent years,deep brain stimulation(DBs)of basal ganglia-thalamocortical networks has emerged as a promising intervention for refractory Ts with or without psychiatric *** major challenges need to be addressed to move the field of DBs treatment for Ts forward:(1)patient and DBs target selection,(2)ethical concerns with treating pediatric patients,and(3)DBs treatment optimization and improvement of individual patient outcomes(motor and phonic tics,as well as functioning and quality of life).The Tourette Association of America and the American Academy of Neurology have recently released their recommendations regarding surgical treatment for refractory ***,we describe the challenges,advancements,and promises of the use of DBs in the treatment of *** summarize the results of clinical studies and discuss the ethical issues involved in treating pediatric *** aim is to provide a better understanding of the feasibility,safety,selection process,and clinical effectiveness of DBs treatment for select cases of severe and medically intractable Ts.

关键词： Tourette syndrome Deep brain stimulation Capsulotomy Adaptive close loop Connectivity

Blood biomarkers of Alzheimer’s disease:important considerations for use in clinical practice

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Neural regeneration research 2025年第1期20卷 205-206页

作者： sarah Fullam sean o’Dowd Antoinette o’Connor Department of Neurology Tallaght University HospitalDublinIreland Academic Unit of Neurology Trinity College DublinIreland

Introduction:Fluid and positron emission tomography(PET)biomarkers that enable the detection of the hallmark proteins of Alzheimer’s disease(AD)(amyloid and tau)have revolutionized our approach to the diagnosis of *** evolution of AD diagnostic criteria to include biological characterization(Alzheimer’s Association Working Group,2023)provides an appropriate framework to reduce levels of clinico-pathologic mismatch and improve in-vivo diagnostic *** the therapeutic landscape for neurodegenerative disease evolves,it is increasingly incumbent on clinicians to provide timely,and pathologically precise diagnoses for ***,the expensive and invasive nature of these tests limits their scalability.

关键词： Blood Alzheimer diagnosis

Coarse to Fine: The role of severe Plastic Deformation in Advancing Titanium-Based Medical Implants - A Comprehensive review

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Journal of Wuhan University of Technology(Materials science) 2025年第1期40卷 295-306页

作者： Dragana r Mihajlović Bojan I Međo Ivana Lj Cvijović-Alagić Veljko r Djokić Faculty of Technology and Metallurgy University of BelgradeKarnegijeva 411120 BelgradeSerbia Vinča Institute of Nuclear sci-ences-National Institute of the republic of serbia University of Belgrade11001BeogradSerbia Innovation Centre of the Faculty of Technology and Metallurgy Karnegijeva 411120 BelgradeSerbia

This paper describes severe plastic deformation(sPD)procedures,which are utilized to form an ultrafine-grained structure in metallic *** the sPD process,a solid material sample is subjected to very high loads without a significant change in sample *** the present work,the high-pressure torsion(HPT)process,as one of the sPD techniques,which achieves a high degree of deformation and ensures refinement of the microstructure,will be discussed in more *** that grain size control is accepted as a method to obtain materials with desired characteristics,an overview of the properties of ultrafine-grained titanium-based biomaterials to be used in medicine is ***,particular attention is dedicated to the influences of HPT process parameters,primarily hydrostatic pressure,and number of revolutions during torsion,on the grain size and physical and mechanical characteristics(modulus of elasticity,microhardness,and tensile properties),corrosion resistance,and biocompatibility of the titanium-based biomaterials.A review of the literature indicates that titanium-based materials obtained by the sPD process show improved mechanical and physical properties without losing biocompatibility and corrosion resistance,which suggests that these methods of obtaining implants are something that should be further developed in the future.

关键词： high-pressure torsion process ultrafine-grained titanium-based materials electrochemical anodization physical properties mechanical properties

scalable Ir‑Doped NiFe_(2)o_(4)/Tio_(2)Heterojunction Anode for Decentralized saline Wastewater Treatment and H_(2)Production

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Nano-Micro Letters 2025年第3期17卷 1-18页

作者： sukhwa Hong Jiseon Kim Jaebeom Park sunmi Im michael r.Hoffmann Kangwoo Cho Division of Environmental science and Engineering Pohang University of Science and Technology(POSTECH)Pohang 790−784Korea Linde Laboratory California Institute of TechnologyPasadenaCA 91125USA Institute for Convergence research and Education in Advanced Technology(I‑CrEATE) Yonsei University International CampusIncheon 21983Republic of Korea

Wastewater electrolysis cells(WECs)for decentralized wastewater treatment/reuse coupled with H_(2)production can reduce the carbon footprint associated with transportation of water,waste,and energy *** study reports Ir-doped NiFe_(2)o_(4)(NFI,~5 at%Ir)spinel layer with Tio_(2)overlayer(NFI/Tio_(2)),as a scalable heterojunction anode for direct electrolysis of wastewater with circumneutral pH in a single-compartment *** dilute(0.1 M)NaCl solutions,the NFI/Tio_(2)marks superior activity and selectivity for chlorine evolution reaction,outperforming the benchmark Iro_(2).robust operation in near-neutral pH was *** including operando X-ray absorption spectroscopy unveiled crucial roles of Tio_(2) which serves both as the primary site for Cl−chemisorption and a protective layer for NFI as an ohmic *** electrolysis of NH4+-laden synthetic wastewater demonstrated that NFI/Tio_(2)not only achieves quasi-stoichiometric NH_(4)^(+)-to-N_(2)conversion,but also enhances H_(2)generation efficiency with minimal competing reactions such as reduction of dissolved oxygen and reactive *** scaled-up WEC with NFI/Tio_(2)was demonstrated for electrolysis of toilet wastewater.

关键词： Wastewater electrolysis cell Ir-doped NiFe_(2)o_(4) reactive chlorine species Decentralized H_(2)production on-site wastewater treatment

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

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Neural regeneration research 2025年第7期20卷 1981-1988页

作者： shan Ping Yu Emily Choi michael QJiang Ling Wei Department of Anesthesiology Emory University School of MedicineAtlantaGAUSA Center for Visual and Neurocognitive rehabilitation Atlanta Veterans Affairs Medical CenterDecaturGAUSA

stroke and Alzheimer's disease are common neurological disorders and often occur in the same *** comorbidity of the two neurological disorders represents a grave health threat to older *** review presents a brief background of the development of novel concepts and their clinical *** activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal *** ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic *** Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute ***,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death *** on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic *** N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic *** stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time *** is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related

关键词： Ca^(2+)hypothesis cognitive deficits hyperactivity late-onset Alzheimer's disease neurodegeneration N-methyl-D-aspartate receptors N-methyl-D-aspartate receptor subunits pathogenesis preventive treatment

revisiting cerebral endothelial cells in Alzheimer’s disease

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Neural regeneration research 2025年第10期20卷 2911-2912页

作者： Amira s.Hanafy Department of Neurosurgery University Hospital BonnBonnGermany

Alzheimer’s disease(AD)is the most common neurodegenerative disorder characterized by slow and progressive decline of cognitive and memory *** only approximately 5%of the cases,AD is familial,as often predisposed by genetic mutations(Hoogmartens et al.,2021),while sporadic AD accounts for approximately 95%of the *** amyloid cascade hypothesis is one of the fundamental hypotheses put out to explain AD pathogenesis as dysregulated homeostasis of amyloid-β(Aβ)peptides that leads to the accumulation of Aβplaques in the parenchyma,an anatomical hallmark of AD.

关键词： Alzheimer Aβ cerebral

A comprehensive investigation on nonlinear vibration and bending characteristics of bio-inspired helicoidal laminated composite structures

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Applied Mathematics and Mechanics(English Edition) 2025年第1期46卷 81-100页

作者： s.sAUrABH r.KIrAN D.sINGH r.VAIsH V.s.CHAUHAN school of Mechanical and Materials Engineering Indian Institute of Technology Mandi

Bio-inspired helicoidal composite laminates, inspired by the intricate helical structures found in nature, present a promising frontier for enhancing the mechanical properties of structural designs. Hence, this study provides a comprehensive investigation into the nonlinear free vibration and nonlinear bending behavior of bio-inspired composite plates. The inverse hyperbolic shear deformation theory(IHsDT) of plates is employed to characterize the displacement field, with the incorporation of Green-Lagrange nonlinearity. The problem is modeled using the C0finite element method(FEM), and an in-house code is developed in the MATLAB environment to solve it numerically. Various helicoidal layup configurations including helicoidal recursive(Hr), helicoidal exponential(HE), helicoidal semi-circular(Hs), linear helicoidal(LH), and Fibonacci helicoidal(FH)with different layup sequences and quasi-isotropic configurations are studied. The model is validated, and parametric studies are conducted. These studies investigate the effects of layup configurations, side-to-thickness ratio, modulus ratios, boundary conditions, and loading conditions at different load amplitudes on the nonlinear vibration and nonlinear bending behaviors of bio-inspired composite plates. The results show that the laminate sequence exerts a substantial impact on both nonlinear natural frequencies and nonlinear bending behaviors. Moreover, this influence varies across different side-to-thickness ratios and boundary conditions of the bio-inspired composite plate.

关键词： finite element method (FEM) nonlinear Green-Lagrange inverse hyperbolic shear deformation theory (IHsDT) bio-inspired composite plate helicoidal o322

Complementary roles of glial cells in generating region-specific neuroinflammatory responses and phagocytosis in Parkinson’s disease

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Neural regeneration research 2025年第10期20卷 2917-2918页

作者： Leyre Ayerra Maria s.Aymerich Universidad de Navarra Facultad de CienciasDepartamento de Bioquímica y GenéticaPamplonaSpain CIMA-Universidad de Navarra PamplonaSpain IdisNA Instituto de Investigación Sanitaria de NavarraPamplonaSpain

Neuroinflammation is associated with Parkinson’s disease:reactive gliosis and neuroinflammation are hallmarks of Parkinson’s disease(PD),a multisystem neurodegenerative disorder characterized by a progressive loss of dopaminergic *** has long been considered a mere consequence of neuronal loss,but whether it promotes PD or is a key player in disease progression remains to be *** leukocyte antigen.

关键词： inflammation leukocyte generating