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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

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

Flow of micropolar fluid over an off centered rotating disk with modified Darcy's law

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Propulsion and Power Research 2017年第4期6卷 285-295页

作者： N.A.Khan s.Khana A.ara Department of Mathematics University of KarachiKarachiSindh 75270Pakistan Department of Computer science Mohammad Ali Jinnah UniversityKarachiSindh 75400Pakistan

The problem of the steady, incompressible, three dimensional stagnation point flow of a micropolar fluid over an off centered infinite rotating disk in a porous medium is studied in this article. Injection/suction is applied uniformly throughout the surface of porous disk. The Darcy's resistance for the micropolar fluid is also formulated. The partial differential equations are converted into the set of ordinary differential equation by utilizing the suitable transformation. The system of equations is analytically solved by the means of a non-perturbative technique, homotopy analysis method (HAM). The influence of rotational parameter, material parameter, spin gradient viscosity parameter, micro-inertia density parameter, porosity parameter and suction/injection parameter on velocity functions is presented in graphical form and discussed in detail. Verification of the solutions is made by a numerical comparison with the previous study.

关键词： Micropolar fluid stagnation point Modified Darcy'slaw Porous medium

Partition coefficient prediction of Baker's yeast invertase in aqueous two phase systems using hybrid group method data handling neural network

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Chinese Journal of Chemical Engineering 2017年第5期25卷 652-657页

作者： Carlos Eduardo de araújo Padilha sérgio Dantas de Oliveira Júnior Domingos Fabiano de santana souza Jackson araújo de Oliveira Gorete Ribeiro de Macedo Everaldo silvino dos santos Laboratory of Biochemical Engineering Chemical Engineering DepartmentFederal University of Rio Grande do Norte (UFRN)

A hybrid GMDH neural network model has been developed in order to predict the partition coefficients of invertase from Baker's yeast. ATPs experiments were carried out changing the molar average mass of PEG(1500–6000 Da), p H(4.0–7.0), percentage of PEG(10.0–20.0 w/w), percentage of MgsO_4(8.0–16.0 w/w), percentage of the cell homogenate(10.0–20.0 w/w) and the percentage of MnsO_4(0–5.0 w/w) added as cosolute. The network evaluation was carried out comparing the partition coefficients obtained from the hybrid GMDH neural network with the experimental data using different statistical metrics. The hybrid GMDH neural network model showed better fitting(AARD = 32.752%) as well as good generalization capacity of the partition coefficients of the ATPs than the original GMDH network approach and a BPANN model. Therefore hybrid GMDH neural network model appears as a powerful tool for predicting partition coefficients during downstream processing of biomolecules.

关键词： Partitioning Invertase Aqueous Two Phase system GMDH Neural network

small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter

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Neural Regeneration Research 2025年第5期20卷 1411-1413页

作者： Marcos J.arauzo-Bravo Daniela Gerovska Matthias schwab Alexandra Kretz Computational Biology and systems Biomedicine Biodonostia Health Research InstituteSan SebastianSpain Basque Foundation for science IKERBASQUEBilbaoSpainMax Planck Institute for Molecular BiomedicineComputational Biology and Bioinformatics GroupMünsterNorth Rhine-WestphaliaGermany Department of Cell Biology and Histology Faculty of Medicine and NursingUniversity of Basque Country(UPV/EHU)LeioaSpain Department of Neurology Jena University HospitalJenaThuringiaGermany

Comprehensive studies identify motor neuron spectrum disorders including amyotrophic lateral sclerosis(ALs)as globally rising fatal disorders with the highest prevalence in aging populations,influenced by ethnicity and ancestry(GBD 2016 Motor Neuron Disease Colla borators,2018).While~10% of diagnoses involve a family history(fALs),most cases are considered sporadic(sALs).However,population-based studies suggest that even cases without a common index mutation impart heritability(Ryan et al.,2019),indicating a crucial role of rare and as yet unknown genetic denominators.

关键词： amyotrophic sclerosis

Impact of Temporal Population Distribution on Earthquake Loss Estimation:A Case study on sylhet,Bangladesh

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International Journal of Disaster Risk science 2014年第4期5卷 296-312页

作者： sharmin ara Department of Urban and Regional Planning Chittagong University of Engineering and TechnologyChittagong 4349Bangladesh

To estimate human loss in an earthquake-prone area, it is necessary to analyze the role played by the spatiotemporal distribution of the area’s resident population. In order to evaluate earthquake impact, this article focuses on the spatiotemporal distribution of population and five scenario earthquakes that form the basis for loss estimation in the city of sylhet, Bangladesh. Four temporal contexts(weekday, weekly holiday, the 30 days of Ramadan, and strike days) expand the more typical daytime and nighttime settings in which to examine hazard risk. The population distribution for every 2 hour interval in a day is developed for each type of day. A relationship between the occupancy classes and average space(persons per 100 m^2)is used to distribute people in each building regardless of building locations. A total daytime and nighttime population is obtained for each building and the estimated nighttime population is used to model the population for four temporal scenarios in a year based on different factors and weights. The resulting data are employed to estimate population loss for each of the temporal and earthquake scenarios. This study used building-specific human vulnerability curves developed by the Central American Probabilistic Risk Assessment(CAPRA) to obtain possible loss of life estimates. The results reveal that there is a high positive correlation between the spatiotemporal distribution of population and the potential number of casualties.

关键词： Bangladesh CAPRA Distribution modeling Earthquake loss estimation spatiotemporal population distribution Temporal scenarios

A systematic review of progenitor survival and maturation in Parkinsonian models

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Neural Regeneration Research 2025年第11期20卷 3172-3178页

作者： Giulia Comini Eilís Dowd Pharmacology&Therapeutics and Galway Neuroscience Center University of GalwayGalwayIreland

stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell *** current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to *** ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian *** the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March *** screening,76 articles were included in the analysis from which 178 separate transplant studies were *** these,graft survival could be assessed in 52 studies and differentiation in 129 ***,we found that graft survival ranged froms transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.

关键词： cell replacement therapy differentiation embryonic stem cells graft induced pluripotent stem cells Parkinson's disease survival transplant

Anti-angiogenic therapies for metastatic colorectal cancer:Current and future perspectives

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World Journal of Gastroenterology 2013年第44期19卷 7955-7971页

作者： Inês Marques António araújo Ramon Andrade de Mello Faculty of Medicine University of Porto 4200-319 Porto Portugal Molecular Oncology Group Research CenterPortuguese Oncology Institute 4200-072 Porto Portugal Department of Medical Oncology Portuguese Oncology Institute 4200-072 Porto Portugal The Royal Marsden NHs Foundation Trust London SW3 6JJ United Kingdom

Colorectal cancer(CRC)is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the United states,with about 142820 new cases and 50830 deaths expected in *** disease(mCRC)remains a challenge for oncologists worldwide due to its potential ***,chemotherapy regimens containing 5-fluorouracil,leucovorin,oxaliplatin and irinotecan combinations are a standard of care in the metastatic ***,biological therapies involving vascular endothelial growth factor and epidermal growth factor receptor pathways,such as bevacizumab and cetuximab,have emerged as good option for improving mCRC patient ***,aflibercept plus standard chemotherapy has also been approved in second line regimen for mCRC *** review will discuss novel biological drugs and their indications for mCRC patients and will bring future perspectives in this regard.

关键词： Colorectal cancer Bevacizumab Cetuximab Aflibercept FOLFOX FOLFIRI

Deciphering the mechanobiology of microglia in traumatic brain injury with advanced microsystems

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Neural Regeneration Research 2025年第8期20卷 2304-2306页

作者： Anthony Procès sylvain Gabriele Univ.Grenoble Alpes InsermU1216Grenoble Institut des NeurosciencesGrenobleFrance Mechanobiology&Biomaterials Group CIRMAPResearch Institute for BiosciencesUniversity of MonsMonsBelgium

Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary *** minutes ... 详细信息

关键词： traumatic injury damage