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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

Modeling compositional heterogeneity resolves deep phylogeny of flowering plants

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Plant Diversity 2025年第1期47卷 13-20页

作者： Yongli Wang Yan-Da Li shuo Wang Erik Tihelka michael s.Engel Chenyang Cai Biofuels Institute School of Environmental and Safety EngineeringJiangsu UniversityZhenjiang 212013China Key Laboratory of Palaeobiology and Petroleum stratigraphy Nanjing Institute of Geology and PalaeontologyChinese Academy of SciencesNanjing 210008China school of Earth sciences University of BristolLife Sciences BuildingTyndall AvenueBristol BS81TQUnited Kingdom College of Marine science and Biological Engineering Qingdao University of Science and TechnologyQingdao 266042China Division of Invertebrate Zoology American Museum of Natural HistoryNew YorkNY 10024-5192USA Facultad de Ciencias Biologicas Universidad Nacional Mayor de San MarcosLima 15081Peru Departamento de Entomología Museo de Historia NaturalUniversidad Nacional Mayor de San MarcosLima 15072Peru

Angiosperms experienced one of the most remarkable radiations of land plants and are now the dominant autotrophs in terrestrial *** phylogenomic studies based on large-scale data from plastid,mitochondrial,or nuclear transcriptomes/genomes and increased taxon sampling have provided unprecedent resolution into the phylogeny of flowering ***,owing to ancient rapid radiations,the interrelationships among the five lineages of Mesangiospermae,the vast majority of angiosperms,remain *** we show that,although plastid and mitochondrial genomes lack sufficient phylogenetic signal for resolving deeper phylogeny,the relationships among five mesangiosperm lineages can be confidently resolved under better-fitting models using genome-scale *** to our Bayesian cross-validation and model test in a maximum likelihood framework,siteheterogeneous models(e.g.,CAT-GTR+G4,LG+C20+F+G)outperform site-homogeneous or partition models often used in previous *** site-heterogeneous models,the approximately unbiased test favored our preferred tree recovered from various datasets:Ceratophyllales(coontails)are robustly recovered as sister to monocots,and they together are sister to the clade comprising magnoliids,Chloranthales,and *** phylogenomic analyses resolve the last enigma of the deeper phylogeny of angiosperms and emphasize the efficacy of modeling compositional heterogeneity in resolving rapid radiations of plants.

关键词： Angiosperms Ceratophyllales Phylogenomics Radiation Methodological factors CAT model

The hydrodynamic RAM effect: Review of historic experiments, model developments and simulation

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Defence Technology 2025年第2期44卷 150-178页

作者： Georg A.Heilig michael May Fraunhofer Institute for High-speed Dynamics Ernst-Mach-Institute (EMI)

The Hydrodynamic Ram(HRAM) effect occurs when a high kinetic energy projectile penetrates a fluid filled area, e.g., a liquid filled tank. The projectile transfers its momentum and kinetic energy to the fluid,what causes a sudden, local pressure rise, further expanding as primary shock wave in the fluid and developing a cavity. It is possible that the entire tank ruptures due to the loads transferred through the fluid to its surrounding structure. In the past decades, additionally to experimental investigations, HRAM has been studied using various computational approaches particularly focusing on the description of the Fluid-structure Interaction(FsI). This article reviews the published experimental, analytical and numerical results and delivers a chronological overview since the end of World War II. Furthermore, HRAM mitigation measures are highlighted, which have been developed with the experimental, analytical and numerical toolboxes matured over the past 80 years.

关键词： Fluid-structure-interaction (FsI) Euler-Lagrange-Coupling Hydrodynamic RAM effect HRAM

Like a G6-nal:transcriptional control of G-protein coupled receptors during oligodendroglial development

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Neural Regeneration Research 2025年第7期20卷 2001-2002页

作者： Tim Aberle michael Wegner Institut für Biochemie Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany

Multilayered control of myelination:Quick,saltatory conduction of action potentials along nerve fibers requires the electrical insulation of axons by myelinating *** the central nervous system,this role is taken up by *** are marked by the expression of the lineage determinants sox10 and Olig2 and arise from oligodendrocyte precursor cells(OPCs)during embryonal *** the majority of OPCs differentiate into mature oligodendrocytes when nearby axonal segments require myelination,a small subpopulation of OPCs persist as a progenitor ***,the timing of myelination and maintenance of the OPC pool both need to be precisely *** transcription factors either positively or negatively affect oligodendrocyte differentiation and maintenance of the OPC pool as components of a complex gene regulatory network(reviewed in sock and Wegner,2021).Network activity is additionally influenced by extracellular signaling molecules that bind to receptors on the oligodendroglial cell surface and activate intracellular signaling *** the receptors are linked to the network is poorly understood so far,but pivotal to understanding the overall regulation of central nervous system(CNs)myelination in response to environmental *** insights were recently gained for Gpr37(schmidt et al.,2024),a G-protein coupled receptor(GPCR)with known relevance in differentiating oligodendrocytes(Yang et al,2016).

关键词： gained insulation conduction

NECAB family of neuronal calcium-binding proteins in health and disease

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Neural Regeneration Research 2025年第5期20卷 1236-1243页

作者： Diones Bueno michael K.E.schafer sudena Wang michael J.schmeisser Axel Methner Institute for Molecular Medicine University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Department of Anesthesiology University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Institute of Anatomy University Medical Center of the Johannes Gutenberg-UniversityMainzGermany

The N-terminal EF-hand calcium-binding proteins 1–3(NECAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal G-protein-coupled receptors, while NECAB3 partners with amyloid-β A4 precursor protein-binding family A members 2 and 3, key regulators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NECAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NECAB proteins by controlling the availability of protein–protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interac

关键词： calcium EF hand mitochondria nervous system signal transduction

small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu michael Chopp michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria semaphorin 6A small extracellular vesicles stroke

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

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

Investigation of a NO_(x) emission from coal power plants in Texas, United states and its impact on the environment

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China Geology 2025年第1期8卷 107-116页

作者： Mikalai Filonchyk michael P.Peterson Faculty of Geomatics Lanzhou Jiaotong UniversityLanzhou 730070China Gansu Provincial Engineering Laboratory for National Geographic state Monitoring Lanzhou 730070China Department of Geography and Geology University of Nebraska OmahaOmaha NE 68182USA

Texas is the largest state by area in the Us after Alaska,and one of the top states in the production and consumption of electricity with many coal-fired ***-fired power plants emit greater than 70% of pollutants in the energy *** coal is burned to produce electricity,nitrogen oxides(NO_(x))are released into the air,one of the main pollutants that threaten human health and lead to a large number of premature *** key to effective air quality management is the strict compliance of all plants with emission ***,not all Texas coal plants have the environmental equipment to lower pollutant *** dioxide(NO2)observations from the TROPOspheric Monitoring Instrument(TROPOMI)were used to evaluate the emissions for Texas power *** from both the Emissions and Generation Resource Integrated Database(EGRID)and the Emissions Database for Global Atmospheric Research(EDGAR)were used to examine *** was found that NOx emissions for Texas power plants range from 1.53 kt/year to 10.99 kt/year,with the Martin Lake,Limestone and Fayette Power Project stations being the top *** Parish and Martin Lake stations have the strongest NOx fluxes,with both exhibiting significant seasonal *** of bottom-up inventories for EDGAR and EGRID show a high correlation(r=0.956)and a low root mean square error(0.766).A more reasonable control policy would lead to much reduced NOx emissions.

关键词： NO_(x)emission Enironmental pollution Power plants TROPOMI EDGAR Human health EGRID. Texas