血管性痴呆的发病与突触可塑性

目的：血管性痴呆是主要由脑血管疾病引起的获得性、慢性、进行性认知障碍，是老年期痴呆的主要类型。其发病机制尚不明确。突触损伤可能是其早期的病理改变，与其认知功能障碍关系密切。 资料来源：应用计算机检索Medline1990—01／2004—12关于血管性痴呆、脑缺血及认知障碍与突触改变的文章，检索词包括“cerebral is-chemia and synapse；cognitive impairment and synapse；vascular demen-tia and synapse；demetian and synapse，long-termp rotection”等，并限定文章语言种类为English。应用计算机检索维普全文数据库1990—01／2004-12关于血管性痴呆、脑缺血及认知障碍与突触改变的文章，检索词为“突触结构，可塑性，血管性痴呆、突触功能，突触蛋白”。并限定语言种类为中文。 资料选择：对资料进行初审，选择脑缺血时突触改变、认知障碍时突触改变、血管性痴呆时突触改变的文章，然后筛除与以上要求无明显联系的文章。排除重复性研究。 资料提炼：共收集到78篇相关的中英文文献，排除43篇，纳入35篇，其中涉及血管性痴呆与突触13篇，脑缺血与突触17篇，认知障碍与突触22篇。资料综合：突触是神经元之间的结构和功能的接触点，突触的可塑性是学习记忆的神经生物学基础，血管性痴呆的发病过程中突触改变可能是其重要机制。突触形态结构的可塑性和传递效能的可塑性的物质基础都涉及神经元和突触部位的某些蛋白质、受体、神经递质、离子及信使分子的物理化学变化。目前研究较多的突触蛋白是突触膨体素、突触素、突触后致密结构-95等。 结论：突触损伤在血管性痴呆发病的早期即存在，且与其认知功能障碍密切相关。对血管性痴呆发病中突触可塑性的研究有利于进一步阐明其发病机制，从而更有效地对其进行防治。     

突触形成调控蛋白的研究与进展：

背景：干细胞在体外也被证实可以分化为神经元细胞,然而干细胞分化成神经细胞后如何形成突触连接而实现信息传递功能,以及突触形成的调控机制是什么,这些尚未可知。目的：通过对2000年以来影响突触形成调控蛋白的实验研究检索,总结这些蛋白在突触研究中的作用。方法：以“synapse、synaptogenesis”为检索词,应用计算机检索中国知网和pubmed数据库相关文章,排除蘑复性研究,保留39篇文章做进‘步分析。结果与结论：突触形成的过程主要包括3个方面的相关内容：①突触结构的形成。②些突触由无活性剑有活性的转换。③非必要突触的消除。而与之相关的蛋白及其功能得以肯定并得到初步研究的主要育血小板反应蛋白、突触分化诱导基凶产物、突触细胞黏附分子、主要组织相容性复合物I型、肌细胞增强因子2、脆性X智力低下蛋白等。这些蛋白在突触的形成,发育和成熟过程中发挥着重要作用。     

MLC1在调节星形胶质细胞-突触相互作用中的新角色

星形胶质细胞膜蛋白MLC1的功能丧失是伴皮质下囊肿的巨脑性白质脑病(MLC)的主要遗传原因,这一罕见病的特征是脑内离子和水稳态失衡。MLC1蛋白主要分布于大脑中的液体屏障周围,例如在星形胶质细胞接触血管的终足和接触脑膜的突起中。该蛋白是否在其他星形胶质细胞结构域中发挥作用尚不清楚。本研究表明MLC1存在于星形胶质细胞远端突起中,也称为突触周围星形胶质细胞突起(PAP)或星形胶质细胞小叶;在海马CA1区域它们与兴奋性突触密切相互作用。我们发现在Mlc1缺失小鼠中,向兴奋性突触延伸的PAP末端缩短。这一改变会影响谷氨酸能突触传递,导致自发释放事件的速率降低,并在具有挑战性的条件下减慢谷氨酸的再摄取。此外,虽然野生型小鼠中的PAP在恐惧调节过程从突触回缩,但我们发现在Mlc1缺失小鼠中,这种结构可塑性在本已更短的PAP出现障碍。最后,Mlc1缺失小鼠显示情境恐惧记忆减少。总之,本研究揭示了星形胶质细胞蛋白MLC1在调节PAP结构方面的意想不到的作用。MLC1的缺失会改变兴奋性突触传递,阻止恐惧调节诱导的正常PAP重塑,并破坏情境恐惧记忆表达。因此,MLC1是调节星形胶质细胞-突触相互作用的新参与者。     

牙买加人中与人T-细胞白血病/淋巴瘤病毒有关的淋巴网肿瘤

自从Gallo等发现人T-细胞白血病/淋巴瘤病毒(HTLV)以来,若干流行病学的研究已经证实了一种特殊形式的T-细胞恶性疾病,它与HTLV感染密切有关。血清流行病学的工作显示出HTLV与日本的成人T细胞白血病(ATL)有关。现已从淋巴样恶性肿瘤患者血清中检测出抗HTLV抗体。本文报道牙买加人中ATL发病率。作者共调查了89例牙买加患者(56例淋巴增殖疾病、33例非淋巴系统疾病),用两种血清学方法检测HTLV全病毒抗原的抗体,64份标本采用固相放射免疫测定(RIA),87份采用新建立的间接酶联免疫吸附试验法(ELISA)。其结果:     

沉默突触及其在神经系统疾病中的研究进展

突触可塑性是大脑可塑性的重要组成,也是脑卒中后功能恢复机制研究的重要方向,而沉默突触作为没有传递功能的突触,存在于大脑的各个时期和各个部位,其与功能性突触的转化是突触可塑性的重要表现,对进一步研究脑卒中后功能恢复的机制以及其他各种神经系统疾病的发生、发展机制具有重要意义。本文献综述表明,沉默突触存在于大脑的任何阶段（发育期、成年期或老年期）,且发挥着不同的作用,而沉默突触的形成、激活和消除机制对于研究和干预神经系统疾病具有重要意义。     

星形胶质细胞在突触可塑性中的研究进展

星形胶质细胞是脑内数量占比最高的细胞,其可通过终足包绕神经元的胞体、轴突和树突形成三突触结构。在生理和病理情况下,星形胶质细胞对突触的形成、成熟、维持以及突触可塑性的调节有重要作用。突触可塑性是认知和学习记忆的基础。阐明星形胶质细胞对突触可塑性的调节机制,可为我们进一步认识大脑功能以及中枢神经系统疾病的治疗提供新的思路。因此,本文将对星形胶质细胞在生理和病理情况下对突触可塑性的研究进展进行综述。     

川芎嗪联合运动训练对急性脑梗死模型大鼠星形胶质细胞与突触和运动功能影响的实验研究

目的研究川芎嗪联合运动训练对急性脑梗死模型大鼠星形胶质细胞、突触和运动功能的影响及相关性。方法将96只大脑中动脉闭塞脑梗死模型大鼠随机分为模型对照组(A组)、运动训练组(B组)、川芎嗪组(C组)和川芎嗪联合运动训练组(D组),每组24只。C组和D组大鼠在手术后24 h开始给予川芎嗪治疗,A、B两组大鼠在相同时间给予剂量相当的生理盐水,B组和D组大鼠术后24 h开始进行康复训练。分别在7 d、14 d、21 d、42 d对各组大鼠的星形胶质细胞、突触、突触素等指标和大鼠的运动功能进行评价。结果 D组大鼠21 d、42 d的运动功能评分为比A和B组高(P0.01)。术后第42 d时,A、B、C、D组在8 000倍视野下的星形胶质细胞个数组间t检验表明A、B组间差异显著(P0.05),A、C差异有显著性(P0.05),A、D两组间差异极显著(P0.01),B、C组间差异无统计学意义(P0.05)。星形胶质细胞和突触数目呈同步增多。免疫组化染色观察显示,D组脑梗死周边区GFAP和突触素阳性信号密度值也在21 d,42 d高于A、B和C组(P0.01)。结论川芎嗪联合运动训练可促进急性脑梗死大鼠星形胶质细胞的增殖,有利于突触重建及其功能修复,促进运动功能恢复。     

灵长类C型逆转病毒(长臂猿白血病病毒和猿猴肉瘤病毒)提高新鲜人血B-淋巴母细胞生长的诱发率

将21例EB病毒血清阳性的正常人血白细胞与感染长臂猿白血病病毒(GALy)“-”猿猴肉瘤病毒/猿猴肉瘤相关病毒(SiSV/SiSAV)的蝙蝠肺纤维母细胞系(CCL88)混合培养,5天后将白细胞分出单独悬浮培养,结果获得11株淋巴母细胞系。对照与未感染病毒的CCL88细胞混合培养,仅得1株细胞。用8例EB病毒血清阴性的正常人血白细胞作同样试验则无1例成系。用不致癌的缗钱内源性病毒(BaEV)及猫白血病病毒(FeLV)作试验亦无上述效应。所得的细胞系经形态学、细胞化学、免疫学和功能检查可确定为多克隆的B-淋巴母细胞系。这些细胞有EB病毒核抗原(EBNA)。经标准染色体检查和G带分析它们的核型正常,但接种1至3周后约80%无胸腺裸鼠局部出现有瘤外,并能在软琼脂上形成集落。这些研究指出:在一定条件下GALV-SiSN/SiSAVC型逆转病毒直接或间接地增加人类B淋巴细胞的转化率。作者对C型病毒此作用的可能机制进行了讨     

Gephyrin：抑制性突触后蛋白网络的核心骨架蛋白

Gephyrin是中枢神经系统(CNS)抑制性突触后蛋白网络的核心骨架蛋白,具有参与抑制性突触形成、稳定抑制性突触受体、调节突触可塑性等作用。Gephyrin翻译后修饰对Gephyrin功能的正常发挥具有重要调节作用。Gephyrin结构和功能异常与癫痫、精神分裂症等多种神经精神疾病的发生有关。     

成人T细胞白血病/淋巴瘤

成人 T细胞白血病 (adult T cell leukemia,ATL)是周围性T细胞淋巴瘤的一种特殊类型 ,早在 1976年 ,由日本高月清教授首先提出 ,它是由人 T细胞白血病毒 (human T cell leukemialymphoma virus- 1,HTL V- 1)感染引起的一种高度白血病样的疾病。各个脏器可有明显浸润 ,并多有皮肤浸润 ,治疗不利 ,预后凶险。以白血病病态占优势者 ,称为 ATL,以淋巴结肿大占优势者 ,称成人 T细胞淋巴瘤。由于 HTL V- 1型病毒与一部分 T细胞非霍奇金淋巴瘤 (NHL)的发病确有关联 ,故又称为成人 T细胞白血病 /淋巴瘤 (adult T cell leukemia/ lymphoma…     

DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC-T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient.Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA-expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN- DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC-T cells conjugates.Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.     

In vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain

The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell–antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer–target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor–rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in vivo has cast doubts on its functional relevance. Herein, we demonstrate that the in vivo formation of SMAC at immunological synapses between effector CD8⁺ T cells and target cells precedes and mediates clearance of virally infected brain astrocytes.     

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

Viruses that infect T cells, including those of the lentivirus genus, such as HIV-1, modulate the responsiveness of infected T cells to stimulation by interacting APCs in a manner that renders the T cells more permissive for viral replication. HIV-1 and other primate lentiviruses use their Nef proteins to manipulate the T cell/APC contact zone, the immunological synapse (IS). It is known that primate lentiviral Nef proteins differ substantially in their ability to modulate cell surface expression of the TCR-CD3 and CD28 receptors critical for the formation and function of the IS. However, the impact of these differences in Nef function on the interaction and communication between virally infected T cells and primary APCs has not been investigated. Here we have used primary human cells to show that Nef proteins encoded by HIV-2 and most SIVs, which downmodulate cell surface expression of TCR-CD3, disrupt formation of the IS between infected T cells and Ag-presenting macrophages or DCs. In contrast, nef alleles from HIV-1 and its simian precursor SIVcpz failed to suppress synapse formation and events downstream of TCR signaling. Our data suggest that most primate lentiviruses disrupt communication between virally infected CD4⁺ Th cells and APCs, whereas HIV-1 and its SIV precursor have largely lost this capability. The resulting differences in the levels of T cell activation and apoptosis may play a role in the pathogenesis of AIDS.     

骨髓胚胎样干细胞的形态结构特征观察

目的观察胚胎样干细胞(ELSCs)的形态结构特征。方法分别采用无血清培养基在明胶包被过的培养瓶和传统方法在未包被的培养瓶中分离骨髓胚胎样干细胞和间充质干细胞(MSCs),以MSCs为对照,在光学显微镜下观察ELSCs的细胞形态,在透射电镜下观察ELSCs的超微结构,并采用染色体技术分析传代细胞的核型。结果与MSCs相比,ELSCs体积更小、形态纤细均一,传代后细胞贴壁快,在细胞培养瓶中均匀分布生长,不易老化。第四代ELSCs的绝大多数细胞膜显示显著的花多样伪足,细胞浆中有丰富的粗面内质网。而部分MSCs的细胞膜光滑,部分MSCs膜表面有微绒毛,多数细胞胞浆内有空泡和丰富的粗面内质网而且明显扩张形成内质网池,内含中等电子密度的分泌物。第十代ELSCs和MSCs都有正常的核型。结论 ELSCs具有比MSCs更不成熟的细胞形态结构特征,传代10代后细胞仍然是安全的。     

Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses.

After accumulation of target cell human leukocyte antigen (HLA)-C at inhibitory natural killer (NK) cell immune synapses, some HLA-C transfers from target cells to NK cell plasma membranes and cytoplasm. This unexpected intercellular transfer of HLA-C is dependent on NK receptor recognition, since HLA-Cw6 or -Cw4 but not -Cw3 transfer to an NK transfectant expressing killer Ig-like receptor (KIR)2DL1. Strikingly, live-cell time-lapse laser scanning confocal microscopy shows vesicles containing target cell green fluorescent protein-tagged HLA-C migrating away from immune synapses into NK cells. Unlike clustering of HLA-C at the immune synapse, intercellular transfer of HLA-C is dependent on NK cell ATP, but not target cell ATP. However, the intercellular transfer of HLA-C is not dependent on active polymerization of the actin cytoskeleton. In addition, different arrangements of HLA-C are seen at inhibitory NK immune synapses, and these alter as NK synapses mature, but in a fashion distinct from that seen upon T cell activation.     

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8⁺ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells.     

Cdc42-mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the immune synapse

The immune synapse (IS) forms as dendritic cells (DCs) and T cells interact in lymph nodes during initiation of adaptive immunity. Factors that contribute to the formation and maintenance of IS stability and function have been mostly studied in T cells, whereas little is known about events occurring during synapse formation in DCs. Here, we show that DCs activated by Toll-like receptor (TLR) agonists reorient the microtubule-organizing center (MTOC) toward the interacting T cell during antigen-specific synapse formation through a mechanism that depends on the Rho GTPase Cdc42. IL-12, a pivotal cytokine produced by DCs, is found enriched around the MTOC at early time points after TLR ligation and is dragged to the DC-T cell interface in antigen-specific synapses. Synaptic delivery of IL-12 induces activation of pSTAT4 and IFN-γ neosynthesis in CD8(+) naive T cells engaged in antigen-specific conjugates and promotes the survival of antigen-primed T cells. We propose that DC polarization increases the local concentration of proinflammatory mediators at the IS and that this represents a new mechanism by which T cell priming is controlled.     

沉默MEF2C基因对髓母细胞瘤Daoy细胞形态结构的影响

目的 探讨抑制人MEF2C基因后对髓母细胞瘤Daoy细胞形态结构的影响作用.方法 实验分为两组：对照组和干扰组.对照组Daoy细胞培养感染阴性慢病毒液,干扰组Daoy细胞培养感染MEF2C-RNAi慢病毒液.光镜下观察培养细胞的大体形态,然后利用透射电镜观察细胞的超微结构变化情况.同时将两组细胞分别接种至裸鼠背部皮下,观察裸鼠成瘤情况以及肿瘤组织的光镜下结构和电镜下超微结构变化情况.结果 干扰组Daoy细胞生长较对照组细胞生长缓慢,种植裸鼠后成瘤重量较对照组轻;光镜下显示对照组瘤组织细胞较干扰组瘤组织细胞排列密集;电镜下显示干扰组瘤组织细胞排列疏松,核固缩,凋亡小体形成.结论 沉默MEF2C基因可以引起异染色质减少、凋亡小体形成,影响细胞的形态结构,抑制肿瘤细胞生长,为其肿瘤生物治疗提供了实验依据.     

人类免疫缺陷病毒感染儿童抗病毒治疗后外周血单个核细胞线粒体DNA含量检测

目的 研究我国人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染儿童抗逆转录病毒治疗(active anti-retrovirus therapy,ART)后外周血单个核细胞(peripheral blood mononuclear cells,PBMC)线粒体DNA含量及其相关影响因素.方法 选择96例ART的HIV感染患儿、30例未治疗的HIV感染患儿及55例正常对照儿童,检测PBMC线粒体DNA含量,结合儿童的临床信息及实验室检测结果进行综合分析.结果 ART组患儿PBMC内线粒体DNA含量为(17.39±9.31),明显低于未治疗组患儿(26.35±11.74)及对照组儿童(28.37±12.14)PBMC内线粒体DNA含量,差异有统计学意义(P＜0.01);患儿ART后PBMC内线粒体DNA含量与基线CD4+T淋巴细胞计数、基线病毒载量、性别、年龄及HIV感染途径均无相关性.结论 PBMC线粒体DNA含量可反映儿童抗病毒治疗后的线粒体损伤毒性,可能成为线粒体毒性检测指标.