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signal integration in the （m）TORC1 growth pathway

Frontiers in Biology 2018年第4期13卷 237-262页

作者： Kailash Ramlaul Christopher H. s. aylett section of structural Biology Department of Medicine Imperial College London SW7 2AZ UK

BACKGROUND： The protein kinase Target Of Rapamycin （TOR） is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 （TORC1） and TORC2 （mTORC1/2 in mammals）, with a set of largely non-overlapping protein partners. （m）TORC 1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell＇s biosynthetic activity, from proteins to lipids, and recycling through autophagy, mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes. METHODOLOGY： Recent years have seen numerous structures determined of （m）TOR, which have provided mechanistic insight into （m）TORC 1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on （m）TORC 1 repression, activation and signal integration. CONCLUsIONs： A molecular understanding of this signal integration pathway is required to understand how （m）TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the （m）TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.

关键词： mTORC 1 nutrient sensing GATOR complex TsC complex Rag GTPases Rheb

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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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儿童持续性部分性癫痫的诊断算法

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癫痫杂志 2021年第3期7卷 265-272页

作者： snehal surana Thomas Rossor Yael Hacohen Hassell J Boyd s D’Arco F aylett s Bhate s Carr L Das K DeVile C Eltze C Hemingway C Kaliakatsos M O’Callaghan F Prabhakar P Robinson R Varadkar s Helen Cross J Hacohen Y 陈晨(译) 慕洁(审) 不详

总结一组持续性部分性癫痫(Epilepsia partialis continua,EPC)患儿的特点,并提出一种整合关键鉴别诊断的诊断算法。对2002年—2019年在三级儿科神经病学中心就诊的EPC患儿进行分析。54例患儿符合EPC诊断标准。中位发病年龄为7岁(0.6~15... 详细信息

总结一组持续性部分性癫痫(Epilepsia partialis continua,EPC)患儿的特点,并提出一种整合关键鉴别诊断的诊断算法。对2002年—2019年在三级儿科神经病学中心就诊的EPC患儿进行分析。54例患儿符合EPC诊断标准。中位发病年龄为7岁(0.6~15岁),中位随访时间为4.3年(0.2~16年)。其中,诊断为Rasmussen脑炎(Rasmussen encephalitis,RE)30例(56%),线粒体疾病12例(22.2%),磁共振成像(MRI)阳性病灶相关局灶性癫痫6例(11.1%),诊断不明5例(9%)。线粒体疾病患儿更早出现EPC,EPC发病年龄每增加一年,诊断线粒体疾病的几率降低26%(P=0.02)。EPC发作前存在发育问题(OR=22,PsF)蛋白水平升高(OR=16)均预示着线粒体疾病。30例RE患儿中有18例(60%)出现EPC发作时,MRI提示明显不对称或一侧半球萎缩,其余患儿出现的中位时间则在EPC发作后6个月(3~15个月)。首选诊断检查为头部MRI。一侧半球萎缩结合临床表现及脑电图改变的偏侧性,提示诊断为RE。对于初次扫描时不能诊断为RE,但临床和影像学表现提示RE的儿童,建议每6个月重复影像学检查以排查进行性一侧半球皮质萎缩,并应考虑脑活检,鞘内炎症的证据(寡克隆带和新蝶呤升高)可为佐证。对于存在双侧半球源性EPC的患儿,建议进行快速DNA聚合酶γ(POLG)基因检测,如为阴性,则应提取外周血DNA进行mtDNA测序及全外显子组测序。线粒体病所致EPC患儿表现出与RE和结构性癫痫不同的临床特征。这一针对EPC患儿的诊断算法有助于进行针对性检查并及时诊断。

关键词：自身免疫性癫痫持续性部分性癫痫线粒体疾病 POLG相关癫痫 Rasmussen脑炎

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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

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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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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

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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

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Understanding activity of butyrate at a cellular level

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Neural Regeneration Research 2025年第8期20卷 2323-2324页

作者： Prapti Chakraborty Angela s.Laird Macquarie University Motor Neuron Disease Research Centre Macquarie Medical SchoolFaculty of MedicineHealth and Human SciencesMacquarie UniversitySydneyAustralia

Butyrate is a short-chain fatty acid of four carbons in length that is a by-product produced by the microbial fermentation of dietary fiber and undigested carbohydrates within the *** the years,butyrate has attracted ... 详细信息

关键词： carbons butyrate fiber

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Microglial dysfunction and genetic risk for neurodegenerative disease

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Neural Regeneration Research 2025年第5期20卷 1401-1402页

作者： Debra s.MacDonald Jay Penney Department of Biomedical sciences AVCUniversity of Prince Edward IslandCharlottetownPECanada

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases a re increasing in prevalence as world populations *** tremendous progress has been made,our understanding of the mechanisms that underlie the development of these diseases remains far from com *** troubling,despite the growing emotional and financial toll being to ken by neurodegenerative disorders,existing treatment options are limited almost exclusively to those that help manage symptoms but that lack the ability to alter the progression of the disease(Liu et al.,2022).

关键词： degenerative diseases

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semantic segmentation of Lumbar Vertebrae Using Meijering U-Net(MU-Net)on spine Magnetic Resonance Images

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Computer Modeling in Engineering & sciences 2025年第1期142卷 733-757页

作者： Lakshmi s V V shiloah Elizabeth Darmanayagam sunil Retmin Raj Cyril Department of Computer science and Engineering College of Engineering GuindyAnna UniversityChennai600025India Department of Information Technology Madras Institute of TechnologyAnna UniversityChrompetChennai600044India

Lower back pain is one of the most common medical problems in the world and it is experienced by a huge percentage of people *** to its ability to produce a detailed view of the soft tissues,including the spinal cord,nerves,intervertebral discs,and vertebrae,Magnetic Resonance Imaging is thought to be the most effective method for imaging the *** semantic segmentation of vertebrae plays a major role in the diagnostic process of lumbar *** is difficult to semantically partition the vertebrae in Magnetic Resonance Images from the surrounding variety of tissues,including muscles,ligaments,and intervertebral discs.U-Net is a powerful deep-learning architecture to handle the challenges of medical image analysis tasks and achieves high segmentation *** work proposes a modified U-Net architecture namely MU-Net,consisting of the Meijering convolutional layer that incorporates the Meijering filter to perform the semantic segmentation of lumbar vertebrae L1 to L5 and sacral vertebra ***-colour mask images were generated and used as ground truth for training the *** work has been carried out on 1312 images expanded from T1-weighted mid-sagittal MRI images of 515 patients in the Lumbar spine MRI Dataset publicly available from Mendeley *** proposed MU-Net model for the semantic segmentation of the lumbar vertebrae gives better performance with 98.79%of pixel accuracy(PA),98.66%of dice similarity coefficient(DsC),97.36%of Jaccard coefficient,and 92.55%mean Intersection over Union(mean IoU)metrics using the mentioned dataset.

关键词： Computer aided diagnosis(CAD) magnetic resonance imaging(MRI) semantic segmentation lumbar vertebrae deep learning U-Net model

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