Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

Microglia lactylation in relation to central nervous system diseases

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Lipid droplets in the nervous system:involvement in cell metabolic homeostasis

Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Heterogeneity of mature oligodendrocytes in the central nervous system

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

High mobility group box 1 in the central nervous system:regeneration hidden beneath inflammation

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.

不同预时效挤压态Mg−Gd−Y−Zn−Zr合金的再结晶行为和强化机制

通过控制预时效时间制备3种不同状态的试样,研究不同预时效状态对挤压态Mg−9.5Gd−4Y−2.2Zn−0.5Zr(质量分数,%)合金的动态再结晶行为(DRX)和性能的影响。结果表明,欠时效挤压(UAE)样品的细晶体积分数为17.4%,而峰时效挤压(PAE)和过时效挤压(OAE)样品的细晶体积分数分别达到89.7%和50.4%。在晶粒内部和晶界处分布的致密、细小的β颗粒相通过粒子激发形核机制显著提高了形核位点和位错密度。然而,致密针状γ'相抑制位错滑移,延迟DRX形核。PEA和OAE样品中细小晶粒的差异归因于原始颗粒相的数量和尺寸的不同,而其拉伸性能的差异归因于不同的显微组织。由于晶界强化和析出强化机制的贡献更大,PAE样品具有更优异的拉伸性能。

Gd对Fe_(66)Cr_(2)Nb_(4)Y_(6)B_(22)合金的非晶形成能力和力学性能的影响

Gd作为优异的中子吸收剂,在中子吸收元素中具有最大的热中子俘获截面。采用铜金属型铸造法研究了Fe_(66)Cr_(2)Nb_(4)Y_(6-x)Gd_(x)B_(22)(x=2,4,5,6 at.%)合金的非晶形成能力及力学性能。结果表明:当Gd含量为2 at.%和4 at.%时,两种合金的非晶形成能力分别为3 mm和4 mm。进一步提高Gd含量,合金的非晶形成能力低于3 mm。Fe_(66)Cr_(2)Nb_(4)Y_(2)Gd_(4)B_(22)合金具有最大的非晶形成能力,其过冷液相区ΔT_(x)、约化玻璃转变温度T_(rg)和非晶形成能力判定参数γ均达到最大值,分别为56 K,0.6673和0.4241。但是Fe_(66)Cr_(2)Nb_(4)Y_(6-x)Gd_(x)B_(22)(x=2 at.%,4 at.%,5 at.%)非晶合金的抗压强度和显微硬度随Gd含量的增加而降低。

GD2抗体达妥昔单抗β治疗神经母细胞瘤护理专家共识

基于国内外临床研究报告以及本研究参与人员临床实践经验,通过文献分析、专家函询及专家研讨对神经节苷脂-2(GD2)抗体达妥昔单抗β治疗神经母细胞瘤的相关内容进行深入研究,最终形成包括准备以及要求、药品配制、药品输注、输注期间护理以及不良反应观察与护理等内容的GD2抗体达妥昔单抗β治疗神经母细胞瘤护理专家共识。

2型糖尿病Gd-EOB-DTPA增强MRI肝肾影像改变

目的:探讨2型糖尿病(T2D)患者钆塞酸二钠(Gd-EOB-DTPA)增强MRI肝胆期的肝肾影像改变。方法:搜集82例接受Gd-EOB-DTPA增强MRI腹部检查的患者(肝肾功能正常),其中T2D患者34例(观察组),非T2D患者48例(对照组)。两位医师分别计算肝胆期肝脏相对信号强度(RL)、肾皮质和髓质相对信号强度(Rrc、Rrm)、肾皮髓质信号强度的相对差异(Rc-m)。采用独立样本t检验或Mann-Whitney U检验比较观察组与对照组的相关参数差异。选择组间差异有统计学意义的变量,使用受试者工作特征(ROC)曲线分析其鉴别T2D的效能;采用组内相关系数(ICC)评估其可重复性。结果:观察组的RL、Rc-m均较对照组降低,差异有统计学意义(P<0.05),两组的Rrc、Rrm差异均无统计学意义(P>0.05)。RL和Rc-m鉴别T2D的ROC曲线下面积分别为0.78和0.72,诊断敏感度分别为77.10%和64.60%,特异度分别为70.60%和79.40%。RL和Rc-m的观察者间一致性均较好,RL和Rc-m的ICC分别为0.91和0.89。结论:T2D患者Gd-EOB-DTPA增强MRI肝胆期肝肾RL和Rc-m降低。RL和Rc-m在一定条件下可能有助于鉴别T2D,其测量可重复性较好。

基于CMA-GD模式的江西蜜柚冻害精细化预警技术开发

通过将蜜柚受冻温度指标与冻害防御措施气象指标相结合的策略,构建了蜜柚冻害预警气象等级指标,进而应用CMA-GD模式(华南区域中尺度数值模式)的江西省智能网格预报区域2 m气温逐小时预报产品,对2020/2021年度越冬期江西蜜柚冻害进行预警试验,分析基于CMA-GD模式开展逐小时蜜柚冻害预警的可行性。结果表明,构建的蜜柚越冬期冻害气象等级指标能反映蜜柚实际受冻症状和冻害程度;基于CMA-GD模式的蜜柚冻害等级预警产品,能提前3 d比较准确地捕捉到冻害发生发展的变化过程,可为启动蜜柚冻害预警、提前掌握蜜柚冻害程度较重时间节点和蜜柚冻害发生发展阶段提供科技支撑。

含不同初始织构的Mg−Gd−Y−Zn−Zr合金热轧板材的显微组织和力学性能

通过光学显微镜、扫描电子显微镜、电子背散射衍射、透射电子显微镜和拉伸试验研究含不同初始织构的Mg−4.7Gd−3.4Y−1.2Zn−0.5Zr(质量分数,%)合金热轧板材的显微组织和力学性能。结果表明,初始织构为0001//RD(板材轧向)的板材获得相对较粗的晶粒和双峰基面织构;而初始织构为0001//TD(板材横向)的板材动态再结晶程度更高,因此,获得更细的晶粒尺寸和较强的0001//ND基面织构。此外,在两种板材中均发现沿RD拉长的不规则形状LPSO相,这种LPSO相导致各向异性的承载强化行为,并进一步引起板材的屈服各向异性。对强化机理的分析表明,晶界强化对轧制板材的强化效果最好。由于具有较小的晶粒尺寸和LPSO相带来的承载强化效果,初始织构为0001//TD的板材在RD方向上获得最高的屈服强度。

Mg-Gd-Y-Zn-Zr合金碎屑固相再生工艺研究

通过热压烧结以及挤剪复合成形工艺对Mg-7Gd-4Y-2Zn-0.4Zr合金碎屑进行固相再生。在碎屑中添加体积分数5%、7%和9%的SiC颗粒,研究了SiC颗粒含量对固相再生坯料微观组织和力学性能的影响。结果表明,热压烧结后坯料中的界面明显,O元素在烧结界面富集。此外,微观组织中存在大块SiC颗粒,不同试样的塑性均较差。相比于其它试样,SiC体积分数7%的热烧结试样的综合性能最优,其抗拉强度为232 MPa,伸长率为1.76%。挤剪复合成形后,微观组织中的烧结界面消失,平均晶粒尺寸细化至10μm。此外,原本团聚分布的SiC颗粒均匀、弥散地分布在合金内部。SiC体积分数5%的固相再生坯料具有较优的综合力学性能,其抗拉强度为269 MPa,伸长率为12.2%,相比于固溶态合金分别提升了24.5%和62.7%。

针刺背腧穴治疗老年期抑郁症患者对GDS及TESS评分的影响

探讨针刺背腧穴疗法对老年期抑郁症患者抑郁程度、药物不良反应、认知功能、生活能力、生活质量的影响。方法 在2019年1月至2021年12月内选取本院收治的70例抑郁症患者(均为老年患者),通过随机数字表法分组,对照组(34例,常规西药疗法),试验组(36例,针刺背腧穴疗法)。对比两组的抑郁程度(GDS)、药物不良反应(TESS)、认知功能(MoCA)、日常生活能力(ADL)和生活质量(SF-36)评分。结果 经过治疗后两组的GDS和TESS评分均出现了降低趋势,且试验组评分更低,而两组的MoCA、ADL和SF-36评分均出现了增强趋势,且试验组评分更高(P<0.05)。结论 在老年抑郁症患者的常规西医治疗方案上加用针刺背腧穴疗法能够更好地改善患者抑郁症状,消减其药物不良反应影响程度,并改善患者的神经认知功能,从而提高患者整体生活质量水平。

表达鸡传染性喉气管炎病毒gD蛋白的重组嵌合型新城疫病毒La Sota株的构建

为构建表达鸡传染性喉气管炎病毒(ILTV)糖蛋白D(gD)的重组新城疫病毒(NDV)La Sota株,本研究将ILTV强毒株gD基因胞外域与NDV F基因信号肽、跨膜域和胞质尾区融合,并插入到含有NDV基因VII型F和HN基因的嵌合型La Sota株感染性cDNA克隆pLa Sota-VIIF/HN的P和M基因之间,将获得的重组感染性克隆pLa Sota-VIIF/HN-gD与辅助质粒pCIneo-NP-P-L共转染BHK-21细胞,拯救出表达gD蛋白的重组嵌合型NDV La Sota株rLaSota-VIIF/HN-gD,并采用血凝试验鉴定正确后,将重组病毒在9日龄SPF鸡胚中连续传至10代,提取10代重组病毒基因组RNA,反转录成c DNA作为模板,以ILTV gD基因插入位点两侧的鉴定引物进行PCR鉴定;采用第10代重组病毒感染BHK-21细胞,以ILTV gD蛋白多克隆抗体作为一抗进行间接免疫荧光试验(IFA);分别对鸡红细胞吸附的重组病毒感染的鸡胚尿囊液上清和从红细胞上解离下来的纯化的重组NDV病毒粒子经western blot鉴定,并对重组病毒对鸡胚的致病性和在鸡胚中的复制动态进行初步研究。PCR结果显示ILTV gD基因能够在重组病毒中稳定存在;IFA和western blot鉴定结果显示,重组病毒能够正确表达ILTV的gD蛋白,而且gD蛋白嵌合表达在重组病毒颗粒上。鸡胚致病性试验和鸡胚中的复制动态试验结果显示,重组病毒保持了La Sota疫苗株的低致病性和良好的复制特性,rLaSota-VIIF/HN-gD的鸡胚平均死亡时间(MDT)为168 h,1日龄雏鸡脑内接种该重组病毒的致病指数(ICPI)为0.20,鸡胚半数感染量(EID_(50))峰值可达10^(-8.66)/100μL。本研究所制备的重组病毒r LaSota-VIIF/HN-gD为研制基因VII型NDV和ILTV的二联活疫苗奠定了基础。

浅析化工生产中GDS系统的故障与维修

本文简述了GDS系统在化工生产中的重要作用,阐述了GDS系统的功能、特征、组成、要求和注意的问题,总结归纳了实际生产中的使用情况和故障案例,论述了GDS系统产生故障的原因及日常维护措施。

促伪狂犬病毒gD蛋白可溶性表达标签的筛选及融合蛋白生物学活性的检测

为筛选有助于伪狂犬病病毒(PRV)gD蛋白可溶性表达的标签,并检测其融合蛋白的生物学活性,本研究通过PCR扩增PRV gD基因后,分别连接携带MBP、SUMO、NusA和GST 4个不同促溶标签的原核表达载体,构建重组质粒pET21b-MBP-gD、pET21b-SUMO-gD、pET21b-NusA-gD和pET21b-GST-gD。经双酶切和基因测序鉴定正确后分别转化大肠杆菌BL21(DE3),采用IPTG诱导后经SDS-PAGE检测各重组蛋白的表达,筛选可溶性表达效果最好的标签。结果显示,各重组质粒经酶切鉴定均获得852 bp的目的条带与各自的载体条带,均与预期相符,进一步测序结果显示插入基因序列与密码子优化后的PRV gD基因序列一致。SDS-PAGE检测结果显示,MBP标签融合gD蛋白的可溶性表达量最大,GST标签次之,SUMO标签和NusA标签融合的gD蛋白则均以包涵体形式表达。因此,选用重组MBP-gD蛋白(rMBP-gD)做后续鉴定。将rMBP-gD经Ni-NTA柱纯化后采用western blot和间接ELISA检测其反应原性;采用间接免疫荧光试验(IFA)检测该重组蛋白与PK15细胞的结合;将该重组蛋白与PRV-GFP共孵育PK15细胞后,经流式细胞术检测其竞争结合PK15细胞,从而抑制PRV的感染情况。结果显示,rMBP-gD具有反应原性,且可以结合PK15细胞,rMBP-gD蛋白可竞争结合PK15细胞抑制PRV的感染。上述结果首次证实,可溶性原核表达的rMBP-gD表达效果好,且具有生物学活性,本研究为PRV基因工程亚单位疫苗的后续研究奠定了基础。

Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.