Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders:progress of experimental models based on disease pathogenesis

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.

Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

A promising approach for quantifying focal stroke modeling and assessing stroke progression:optical resolution photoacoustic microscopy photothrombosis

To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

基于PCA-TOPSIS的重庆市县域经济密度综合测度及时空演变

经济密度是衡量区域经济发展水平和聚集程度的重要指标之一。以重庆市38个县(区)所辖范围为研究区,建立了人均和地均相结合的综合测度指标体系,采用主成分分析确定指标权重,将PCA-TOPSIS评价法运用到经济密度综合测度中,依据测度对象与最优值的相对接近程度,综合测度1997年、2001年、2006年和2013年重庆市县域经济密度,获得各个时间断面经济密度综合指数及其排名。通过利用ArcGIS制图功能绘制重庆市经济密度等级分布图,揭示其空间分异演变规律,利用Moran’s I,LISA和热点分析分别探索了县域经济密度的全局和局部空间自相关及其时空演变规律,并讨论影响经济密度高低的主要因素。通过对县域经济密度的综合测度及时空演变的探究,为实现城市科学定位和制定中长期发展战略提供科学依据。

基于PCA-TOPSIS法的电子商务环境下冷链物流综合绩效评价

基于电子商务发展的网络化、信息化、柔性化、智能化、创新化等特点,在平衡计分卡供应链绩效评价思想的基础上,构建了一套全面的冷链物流综合绩效评价指标体系,并采用PCA-TOPSIS法作为衡量方法,保证了整个指标体系衡量过程的实用性、可靠性和有效性,从而更好地为企业进行冷链物流综合绩效评价提供借鉴和帮助。

基于威胁分级和PCA-TOPSIS的导弹目标威胁度综合评估方法

针对在弹道导弹威胁度评估中定量与定性指标的选取和两类指标难以统一合理分析的问题,提出一种将威胁分级和PCA-TOPSIS综合运用的方法。对于定性指标,通过威胁分级可以保留语义特征,而定量指标利用PCATOPSIS分析,可以客观而准确的表现各方案间的差异,这样综合利用定性描述和定量分析的特点,实现从主、客观两方面对弹道导弹目标威胁度的综合评价。通过仿真示例的设计和分析可知,该算法在弹道导弹目标的威胁度评估方面得到了较好的结果,将不同导弹目标的威胁度进行了合理的排序。

采用STAMP-24Model的多组织事故分析

安全生产事故往往由多组织交互、多因素耦合造成,事故原因涉及多个组织。为预防和遏制多组织生产安全事故的发生,基于系统理论事故建模与过程模型(Systems-Theory Accident Modeling and Process,STAMP)、24Model,构建一种用于多组织事故分析的方法,并以青岛石油爆炸事故为例进行事故原因分析。结果显示:STAMP-24Model可以分组织,分层次且有效、全面、详细地分析涉及多个组织的事故原因,探究多组织之间的交互关系;对事故进行动态演化分析,可得到各组织不安全动作耦合关系与形成的事故失效链及管控失效路径,进而为预防多组织事故提供思路和参考。

基于改进24Model-ISM-SNA建筑工人不安全行为关联路径研究

建筑施工现场环境复杂,为有效控制不安全行为发生,基于行为安全“2-4”模型对360份具有代表性的建筑安全事故调查报告进行分析,提取出22个不安全行为的主要影响因素。利用灰色关联分析方法(GRA)改进的集成ISM-SNA模型,将不安全行为风险因素划分为表层、过渡层与深层,然后对风险因素进行可视化分析、中心度分析及凝聚子群分析,揭示了各致因因素间的关联关系和传导路径。结果表明,建筑工人不安全行为影响因素可划分成7级3阶的多级递阶结构,安全意识、现场监管、外部环境是建筑工人不安全行为的关键影响因素,同时现场监管和隐患排查到位能有效降低不安全行为的发生。

基于24Model的地铁内涝事故原因分析与评估

为降低地铁内涝事故灾害风险,基于事故致因“2-4”模型,分析了地铁内涝事故致灾因子,采用层次分析法构建了地铁内涝事故原因分析指标体系,确定了各风险因子的权重,并利用模糊综合评价法对地铁内涝事故进行了定量评估,识别出关键的影响因素。结果表明:地铁内涝事故一级指标中不安全动作与物态因素最重要,其中影响最大的指标包括擅自更改建筑设计、未按照要求检查水位情况、未及时排水、出入口不符合防汛标准等因素;习惯性不安全行为的权重位居第二,表明该指标因素较为重要,同时安全管理体系得分位居第二,表明该指标因素较易发生。对关键指标采取防范措施,可有效降低风险,从而减少地铁内涝事故的发生。

基于24Model-D-ISM的地铁站火灾疏散影响因素研究

为预防地铁站火灾事故,深入了解地铁站火灾人员疏散影响因素间的内在联系与层次结构,基于第6版“2-4”模型(24Model)分析63起地铁站火灾疏散事故,充分考虑各个因素之间的交互作用,提取19个影响地铁站人员疏散的关键因素,建立地铁站火灾人员疏散影响因素指标体系;采用算子客观赋权法(C-OWA)改进决策试验与评价实验法(DEMATEL),确定地铁站火灾人员疏散的重要影响因素;在此基础上,采用解释结构模型(ISM)分析各个因素间的层次结构及相互作用路径,构建地铁站火灾人员疏散影响因素的多级递阶结构模型。研究结果表明:疏散引导、恐慌从众行为、人员拥挤为地铁站火灾人员疏散的关键影响因素;地铁站火灾人员疏散受表层因素、中间层因素、深层因素共同作用的影响,其中,疏散教育与培训、设施维护与检查、疏散预案等因素是根源影响因素,重视根源影响因素的改善有利于从本质上预防和控制事故的发生。

中国创业绩效的时空演变——基于PCA-TOPSIS模型和区域的视角

基于创业数量和创业质量视角,本文构建包含成业绩效、增长绩效和就业绩效3个维度的评价指标体系,同时使用PCA-TOPSIS模型对2008—2016年省域创业绩效进行测度,并重点从创业绩效的时序变化和区域差异视角展开分析。研究表明:考察期内大多数省(市、区)创业绩效呈波动上升趋势,东部地区省份排名比较稳定;四大经济区域的区际创业绩效差距明显,并且呈现“东中西依次递减,东北地区穿插其中”这一典型的经济地理特征。这一结果为地区创业政策措施的制定和区域创业的协调发展提供了客观依据。

PCA-TOPSIS模型在EPC铁路工程项目风险评估中的应用

以铁路工程项目为对象,进行铁路施工风险的识别、分析、评估与预测。首先,通过文献以及德尔菲法识别出海外EPC总承包项目风险因素,构建EPC铁路工程项目的风险评价指标体系;其次,建立基于熵权法的PCA-TOPSIS风险评估预测模型,通过熵权法判别各个风险因素的重要性,采用风险评估模型评价各项风险发生的可能性,开展项目风险判断和评价;最后,以某海外铁路路段为案例,评估该工程风险等级,验证PCA-TOPSIS风险评估预测方法的有效性。

基于PCA-TOPSIS耦合模型的煤矿安全生产管理评价

为了量化评价煤矿的安全生产管理水平,本文提出了一种基于PCA-TOPSIS耦合模型的煤矿安全生产管理评价方法。基于事故致因“4M”要素理论,本文从人员要素、设备要素、环境要素、管理要素四方面总结了影响煤矿安全生产的17个评价指标,并构建了PCA-TOPSIS耦合评价模型。首先采用PCA模型计算了各评价因素的权重,然后将权重代入TOPSIS模型,最终得到了各评价煤矿的安全管理指数(SMI)。利用此评价模型对陕北榆神府矿区的六个典型煤矿的安全生产管理水平进行了评价,研究结果表明,该矿区的SMI分布在0.473~0.584之间,四个煤矿的安全管理水平为良,两个煤矿的安全管理水平为中。该评价模型可以使煤矿清晰地掌握其安全生产管理现状,可以为煤矿针对性地提高安全管理水平提供参考。

PCA-TOPSIS法在激光熔覆工艺参数优化中的应用

为了改善H13钢抗疲劳磨损性能,利用4kW光纤激光器在H13钢表面激光熔覆Ni60A合金涂层。利用正交试验分析各工艺参数对熔池尺寸的影响。运用光学显微镜和扫描电镜分析涂层的显微组织形貌,通过显微硬度计测试涂层截面的显微硬度分布。依据单道熔覆层的熔池尺寸,采用PCA-TOPSIS法作为评价方法。以熔宽最大、熔深和熔高最小为优化目标,得出最佳工艺参数为激光功率(P)2.2kW,扫描速度(V)20mm/s,送粉率(F)26.42g/min。该工艺参数下的熔覆层与基体呈现良好的冶金结合、无气孔裂纹等缺陷,熔覆层截面显微硬度平均高达800HV,是基体的(3~4)倍。

24Model与LCM原因因素定义对比研究

为探究损失致因模型(LCM)原因因素定义与事故致因“2-4”模型(24Model)存在的异同和优缺点,梳理2个模型各层面原因和结果的定义,对比定义内容及其对事故原因分析等安全实务的指导作用,并以一起瓦斯爆炸事故为例加以实证分析,获得二者分析结果之间的差异。研究结果表明:LCM是首个将管理因素纳入事故致因分析的一维事件序列模型,可明确各层面原因因素的定义和因素间的逻辑关系,但部分定义存在交叉重复的问题,并没有揭示安全工作指导思想等深层次事故致因因素;24Model作为系统性事故致因模型,对各类因素的定义均以组织为主体,描述事件、事故、安全的概念内涵,划分个体安全动作、安全能力和组织安全管理体系的类别并给出含义解析,探究组织安全文化层面的问题并以32个元素体现;2个模型的事故原因分析方法均建立在对各层级原因因素定义的基础上,并适用于模型理论体系本身。

内江自贡地区旅游竞争力评价--基于FA-PCA-TOPSIS模型

在内江自贡同城化背景下,对内江自贡地区旅游竞争力进行评价并对相关影响因素进行分析,对于两市未来旅游产业的融合发展具有一定的指导意义。以内江自贡地区为研究对象,构建了旅游竞争力的评价指标体系,综合利用因子分析(FA)、主成分分析(PCA)和TOPSIS三种方法的优势,构建了FA-PCA-TOPSIS模型,以2018年的截面数据为基础,定量评价内江自贡地区在四川省内的旅游竞争力。评价结果表明:自贡市的旅游竞争力处于四川省中等水平,仍有进一步提升的空间;内江市的旅游竞争力在省内排名靠后,亟待进一步加强;内江市在旅游核心竞争力、经济支撑竞争力和环境支撑竞争力三个方面的省内排名均低于自贡市5〜6位;内江市在入境旅游、优质旅游资源和环境支撑等指标上的表现较差,是制约其旅游竞争力的关键因素。最后,提出在同城化的背景下提升内江自贡地区旅游竞争力的建议。

Anisotropic time-dependent behaviors of shale under direct shearing and associated empirical creep models

Understanding the anisotropic creep behaviors of shale under direct shearing is a challenging issue.In this context,we conducted shear-creep and steady-creep tests on shale with five bedding orientations (i.e.0°,30°,45°,60°,and 90°),under multiple levels of direct shearing for the first time.The results show that the anisotropic creep of shale exhibits a significant stress-dependent behavior.Under a low shear stress,the creep compliance of shale increases linearly with the logarithm of time at all bedding orientations,and the increase depends on the bedding orientation and creep time.Under high shear stress conditions,the creep compliance of shale is minimal when the bedding orientation is 0°,and the steady-creep rate of shale increases significantly with increasing bedding orientations of 30°,45°,60°,and 90°.The stress-strain values corresponding to the inception of the accelerated creep stage show an increasing and then decreasing trend with the bedding orientation.A semilogarithmic model that could reflect the stress dependence of the steady-creep rate while considering the hardening and damage process is proposed.The model minimizes the deviation of the calculated steady-state creep rate from the observed value and reveals the behavior of the bedding orientation's influence on the steady-creep rate.The applicability of the five classical empirical creep models is quantitatively evaluated.It shows that the logarithmic model can well explain the experimental creep strain and creep rate,and it can accurately predict long-term shear creep deformation.Based on an improved logarithmic model,the variations in creep parameters with shear stress and bedding orientations are discussed.With abovementioned findings,a mathematical method for constructing an anisotropic shear creep model of shale is proposed,which can characterize the nonlinear dependence of the anisotropic shear creep behavior of shale on the bedding orientation.

PCA-TOPSIS法在不锈钢电弧增材工艺参数优化中的应用

为了提高不锈钢电弧增材工艺的增材效率,利用308不锈钢丝材在304不锈钢基体上进行电弧增材。利用正交试验法设计工艺参数,运用光学显微镜分析增材组织的形貌,通过显微硬度计测试增材组织的显微硬度分布。依据熔覆层的熔池尺寸,采用PCA-TOPSIS法作为评价方法。以熔宽、余高最大,熔深最小为优化目标,通过MATLAB计算得出最佳工艺参数为电弧电流I=200 A,焊接速度V_(s)=42 cm/min,送丝速度V_(f)=180 cm/min。结果表明,该工艺参数下的熔覆层与基体呈现良好的冶金结合,无气孔和裂纹等缺陷。

Projecting Wintertime Newly Formed Arctic Sea Ice through Weighting CMIP6 Model Performance and Independence

Precipitous Arctic sea-ice decline and the corresponding increase in Arctic open-water areas in summer months give more space for sea-ice growth in the subsequent cold seasons. Compared to the decline of the entire Arctic multiyear sea ice,changes in newly formed sea ice indicate more thermodynamic and dynamic information on Arctic atmosphere–ocean–ice interaction and northern mid–high latitude atmospheric teleconnections. Here, we use a large multimodel ensemble from phase 6 of the Coupled Model Intercomparison Project(CMIP6) to investigate future changes in wintertime newly formed Arctic sea ice. The commonly used model-democracy approach that gives equal weight to each model essentially assumes that all models are independent and equally plausible, which contradicts with the fact that there are large interdependencies in the ensemble and discrepancies in models' performances in reproducing observations. Therefore, instead of using the arithmetic mean of well-performing models or all available models for projections like in previous studies, we employ a newly developed model weighting scheme that weights all models in the ensemble with consideration of their performance and independence to provide more reliable projections. Model democracy leads to evident bias and large intermodel spread in CMIP6 projections of newly formed Arctic sea ice. However, we show that both the bias and the intermodel spread can be effectively reduced by the weighting scheme. Projections from the weighted models indicate that wintertime newly formed Arctic sea ice is likely to increase dramatically until the middle of this century regardless of the emissions scenario.Thereafter, it may decrease(or remain stable) if the Arctic warming crosses a threshold(or is extensively constrained).