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

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

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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

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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

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starburst amacrine cells,involved in visual motion perception,lose their synaptic input from dopaminergic amacrine cells and degenerate in Parkinson’s disease patients

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Translational Neurodegeneration 2023年第1期12卷 638-653页

作者： Xavier sánchez-sáez Isabel Ortuño-Lizarán Carla sánchez-Castillo Pedro Lax Nicolás Cuenca Department of Physiology Genetics and MicrobiologyUniversity of AlicanteSan Vicente del RaspeigSpain Alicante Institute for Health and Biomedi-cal Research(IsABIAL) AlicanteSpain Ramón Margalef Institute University of AlicanteSan Vicente del RaspeigSpain.

Background The main clinical symptoms characteristic of Parkinson’s disease(PD)are bradykinesia,tremor,and other motor ***,non-motor symptoms,such as visual disturbances,can be identified at early stages of the *** of these symptoms is the impairment of visual motion ***,we sought to determine if the starburst amacrine cells,which are the main cellular type involved in motion direction selectivity,are degenerated in PD and if the dopaminergic system is related to this *** Human eyes from control(n=10)and PD(n=9)donors were available for this *** immunohistochemistry and confocal microscopy,we quantified starburst amacrine cell density(choline acetyltransferase[ChAT]-positive cells)and the relationship between these cells and dopaminergic amacrine cells(tyrosine hydroxylase-positive cells and vesicular monoamine transporter-2-positive presynapses)in cross-sections and wholemount *** First,we found two different ChAT amacrine populations in the human retina that presented different ChAT immunoreactivity intensity and different expression of calcium-binding *** populations are affected in PD and their density is reduced compared to ***,we report,for the first time,synaptic contacts between dopaminergic amacrine cells and ChAT-positive cells in the human *** found that,in PD retinas,there is a reduction of the dopaminergic synaptic contacts into ChAT *** Taken together,this work indicates degeneration of starburst amacrine cells in PD related to dopaminergic degeneration and that dopaminergic amacrine cells could modulate the function of starburst amacrine *** motion perception circuitries are affected in PD,their assessment using visual tests could provide new insights into the diagnosis of PD.

关键词： Parkinson’s disease Retinal neurodegeneration Human retina ChAT amacrine cells Dopaminergic amacrine cells

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sYNTHEsEs anD CHARACTERIZATIONs OF OLIGO(AZOMETHINE ETHER)s DERIVED FROM 2,2'-[1,4-ENYLENEBIs(METHYLENEOXY)]DIBENZALDEHYDE AND 2,2'-[1,2-PHENYLENEBIs(METHYLENEOXY)]DIBENZALDEHYDE

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Chinese Journal of Polymer science 2012年第5期30卷 682-693页

作者： Ismet Kaya süleyman Culhaoglu Canakkale Onsekiz Mart University Faculty of Science and ArtsDepartment of ChemistryCanakkale 17020Turkey

The oligo（azomethine ether）s were synthesized via polycondensation of alkyl diamines with aromatic dialdehydes. Two series of dialdehydes, namely 2,2＇-[1,2-phenylenebis（methyleneoxy）]dibenzaldehyde [2,2＇-1,2-（PBMODB）] and 2,2＇- [1,4-phenylenebis（methyleneoxy）]dibenzaldehyde [2,2＇-I,4-（PBMODB）] were prepared from the condensation reactions of salicylaldehyde with o-xylenedibromide and p-xylenedibromide, respectively. The structures of dialdehydes and oligomers were determined by FT-IR, 1H-NMR and 13C-NMR. The thermal analyses of oligomers were conducted by DsC and TG/DTA techniques, respectively. size exclusion chromatography （sEC） technique was also used to determine molecular weights and molecular weight distributions of oligomers. Electrochemical properties of the synthesized products were investigated.

关键词： Polyazomethine Thermal analysis Dialdehyde Oligoazomethine.

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Fluid dynamics analysis and pyrolysis of brewer’s spent grain in a spouted bed reactor

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Particuology 2019年第1期17卷 199-207页

作者： Marcos A.s. Barrozo Lidja D.M.s. Borel Taísa s. Lira Carlos H. Ataíde school of Chemical Engineering Federal University of UberlandiaBrazil Department of Engineering and Technologies Federal University of Espirito SantoBrazil

Brewer’s spent grain (BsG) is a large-scale agroindustrial waste that could be more efficiently utilized. This waste is composed of lignocellulosic material and so may serve as a good source of biomass for thermochemical conversion. The present study investigated the fluid dynamics behavior of mixtures of sand and BsG in a spouted bed to assess the viability of the thermochemical conversion of this biomass via fast pyrolysis. Fluid dynamics analyses were performed while varying the mass fraction of BsG (6–80%) and the static bed height (6.6–13.4 cm). Empirical equations for predicting the minimum spouting conditions and the mixing index were obtained using a regression technique, and the selected fluid dynamics parameters were employed in the spouted bed pyrolysis. The bio-oil resulting from this process was rich in phenolic compounds, various nitrogenated compounds (representing precursors for pharmaceuticals) and long-chain hydrocarbons. The products obtained from the analytical and spouted bed pyrolysis processes were also compared.

关键词： Brewer’s spent grain Agroindustrial residue spouted bed Fast pyrolysis Particle mixing

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Abscisic acid, a promising therapeutic molecule to prevent Alzheimer’s and neurodegenerative diseases

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Neural Regeneration Research 2020年第6期15卷 1035-1036页

作者： Ana María sánchez-Pérez Department of Medicine Universitat Jaume I

Neuroinflammatory processes induce neuronal damage and underlie the onset of neurodegenerative pathologies,including Alzheimer’s disease(AD)(Calsolaro and Edison,2016).several conditions,ranging from emotional stress to metabolic syndrome,including traumatic brain injury,chronic infections or gut microbiota disruption can cause or aggravate ***,aging is the major factor associated with neurodegenerative diseases.

关键词： degenerative Alzheimer diseases

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Genetic interactions and modifi er genes in Hirschsprung's disease

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World Journal of Gastroenterology 2011年第45期17卷 4937-4944页

作者： Adam s Wallace Richard B Anderson Department of Anatomy and Cell Biology University of Melbourne

Hirschsprung's disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung's disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung's disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung' s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung's disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modif ier genes.

关键词： Neural crest Enteric nervous system Hirschsprung’s disease Aganglionosis Modif ier genes

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Theoretical study of structural and electronic properties of oligo(thiophene-phenylene)s in comparison with oligothiophenes and oligophenylenes

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Chinese Chemical Letters 2008年第1期19卷 123-126页

作者： H.Zgou s.M.Bouzzine s.Bouzakraoui M.Hamidi M.Bouachrine Unité de Recherche sur les Macromolécules et Modélisation Faculté des Sciences et TechniquesB.P.509 Boutalamine5200 ErrachidiaMorocco Unité de Chimie Théorique AppliquéeFaculté des Sciences et TechniquesB.P.509 Boutalamine5200 ErrachidiaMorocco Unité de Chimie Théorique Appliquée Faculté des Sciences et TechniquesB.P.509 Boutalamine5200 ErrachidiaMorocco Unité de Recherche sur les Macromolécules et Modélisation Faculté des Sciences et TechniquesB.P.509 Boutalamine5200 ErrachidiaMorocco

In this work, a quantum-chemical investigation on the structural and opto-electronic properties of oligo（thiophene-phenylene）（4TP） is carried out. The results are discussed in comparison with the properties of corresponding oligothiophene （8T） and oligophenylene （8P）. As the opto-electronic properties of this type of conducting polymers are governed by their electronic band gap, we shall also present a comparison among HOMO, LUMO and band gap energies of these three materials.

关键词： Conjugated polymers Oligothiophene Oligophenylene Oligo(thiophene-phenylene) DFT

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Multiclass recognition of Alzheimer’s and Parkinson’s disease using various machine learning techniques: A study

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International Journal of Modeling, simulation, and scientific Computing 2022年第1期13卷 235-250页

作者： Chetan Balaji D.s.suresh Department of ECE Channabasaveshwara Institute of Technology Tumkur KarnatakaIndia Visvesvaraya Technological University BelagaviKarnatakaIndia

The aging population is primarily affected by Alzheimer’s disease(AD)that is an incur-able neurodegenerative *** is a need for an automated efficient technique to diagnose Alzheimer’s in its early *** techniques are used to diagnose *** and neuroimaging methodologies are widely used to highlight changes in the electrical activity of the brain signals that are helpful for early ***’s disease(PD)is a major neurological disease that results in an average of 50,000 new clinical diagnoses worldwide every *** voice features are majorly used as the main means to diag-nose *** major symptoms of PD are loss of intensity,the monotony of loudness and pitch,reduction in stress,unidentified silences,and *** though various innovative models are proposed by explorers about Alzheimer’s and Parkinson’s classifi-cation diseases,still there is a need for efficient learning methodologies and *** paper provides a review on using machine learning(ML)together with several fea-ture extraction techniques that is helpful in the early detection of AD with Parkinson’*** novelty and objective of this study are that the CAD technique is used to improve the accuracy of early diagnosis of *** proposed technique depends on the nonlinear process for data dimension reduction,feature removal,and classification using kernel-based support vector machine(sVM)*** dimension of the input space is radically diminished with kernel *** the learning set is labeled,it creates sense to utilize this information to make a dependable method of dropping the input space *** different techniques of ML are explained under the major approaches ***,artificial neural network(ANN),deep learning(DL),and ensemble methods.A comprehensive assessment is presented at sVM,ANN,and DL approaches for better detection of Alzheimer’s with PD highlighting future insights.

关键词： Electroencephalograph support vector machine Alzheimer’s disease control normal machine learning

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