Immunotherapeutic approaches to Alzheimer's disease

Although neurodegenerative diseases such as Alzheimer's disease are not classically considered mediated by inflammation or the immune system, in some instances the immune system may play an important role in the degenerative process. Furthermore, it has become clear that the immune system itself may have beneficial effects in nervous system diseases considered neurodegenerative. Immunotherapeutic approaches designed to induce a humoral immune response have recently been developed for the treatment of Alzheimer's disease. These studies have led to human trials that resulted in both beneficial and adverse effects. In animal models, it has also been shown that immunotherapy designed to induce a cellular immune response may be of benefit in central nervous system injury, although T cells may have either a beneficial or detrimental effect depending on the type of T cell response induced. These areas provide a new avenue for exploring immune system-based therapy of neurodegenerative diseases and will be discussed here with a primary focus on Alzheimer's disease. We will also discuss how these approaches affect microglia activation, which plays a key role in therapy of such diseases.     

Identification of Bphs,an autoimmune disease locus,as histamine receptor H1

Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. We report that congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cell and vascular responses regulated by histamine after PTX sensitization.     

Ontogeny of gastric acid secretion in the rat: evidence for multiple response systems

Gastric acid secretion has been thought to depend on histamine stimulation of the parietal cell. However, in the 2-week-old rat neither exogenous histamine nor the H-2 receptor agonist impromidine stimulates acid secretion, whereas pentagastrin and the cholinergic agent bethanechol are potent stimuli. At this age, the effect of pentagastrin in acid secretion is not blocked by the H-2 receptor antagonist cimetidine, nor is it potentiated by impromidine. These data suggest that, in the rat pup, the acid secretory response to pentagastrin and cholinergic agents occurs before the histamine-mediated system is functional and operates independently of the actions of histamine.     

Odor cues during slow-wave sleep prompt declarative memory consolidation

Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed causes memory consolidation during sleep. Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.     

RNA silencing: the genome's immune system

Genomes are databases sensitive to invasion by viruses. In recent years, a defense mechanism has been discovered, which turns out to be conserved among eukaryotes. The system can be compared to the immune system in several ways: It has specificity against foreign elements and the ability to amplify and raise a massive response against an invading nucleic acid. The latter property is beginning to be understood at the molecular level.     

The role of somatic hypermutation in the generation of antibody diversity

The immune system is capable of establishing an enormous repertoire of antibodies before its first contact with antigen. Most antibodies that express germ-line sequences are of relatively low affinity. Once antigen enters the system, it stimulates a somatic mutational mechanism that generates antibodies of higher affinity and selects for the expression of those antibodies to produce a more effective immune response. The details of the mechanism and regulation of somatic hypermutation remain to be elucidated.     

Private lives: reflections and challenges in understanding the cell biology of the immune system

The immune system comprises a variety of cell types whose activities must be carefully regulated to act as a coherent unit for the purpose of host defense. To perform their autonomous functions, immune cells must rely on the same basic organizational features that apply to all cells, although immune cells often exhibit remarkable degrees of specialization and adaptation. The study of these specializations has lagged behind advances in understanding the immune response and cell biology individually. As a result, there are great opportunities, but also great challenges, for new conceptual discoveries by taking a more cell-biological approach to probing the function of the immune system.     

Influence of clonal selection on the expression of immunoglobulin variable region genes

The humoral immune response of the mouse to certain antigens is characterized by the dominant expression of a single or limited number of related, immunoglobulin variable region (V) structures by antibody-secreting lymphocytes. Such dominance could be due to preferred expression of these V regions in the B cell population prior to the immune response or could result from the action of selective or regulatory mechanisms during the immune response. Expression of a heavy chain variable region (VH) gene segment that partially encodes a V region structure that dominates the immune response to para-azophenylarsonate (Ars) in strain A mice was examined in the B cell population of Ars nonimmune mice. This VH gene segment participates in encoding several hundred thousand different V region structures expressed in this B cell population. The immune system is therefore capable of recurrently selecting a single V region structure from such a repertoire for dominant expression by antibody-secreting lymphocytes during an immune response.     

Evidence for an antiaphrodisiac in the sweat bee Lasioglossum (Dialictus) zephyrum

Male Lasioglossum (Dialictus) zephyrum in the field are attracted to models impregnated with the odor of virgin females. The number of males responding increases with increasing odor concentration. Once a male has contacted a model, its attractiveness to other males is reduced, suggesting that the male may contribute an antiaphrodisiac cue so that other males avoid mated females.     

Interleukin-2: inception, impact, and implications

Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.     

拖拉机线控液压转向系统的联合仿真

随着农业机械的智能化、自动化程度不断提高,线控转向技术在拖拉机等农用车辆上的应用得到了重视和研究,为了指导拖拉机线控液压转向的研究,缩短开发周期。本文在分析线控液压转向系统的控制算法与结构的基础上,建立其联合仿真模型。基于AMESim软件平台建立液压系统模型,以及整车模型;利用Simulink分别建立模糊免疫PID、模糊PID、常规PID的控制器模型,通过Visual C++6.0实现接口通讯,完成了传动比为1时的转角响应、转角跟随的联合仿真,以及在拖拉机车速15 km/h,方向盘转角180°,传动比为9时的横摆角速度响应、质心侧偏角响应等联合仿真。模糊免疫PID控制可以获得0.272 s的阶跃响应时间、1.182°的跟随误差、3%的横摆角速度响应超调量、0.85°/s的质心侧偏角响应稳态值,均优于常规PID与模糊PID。联合仿真具有较强的参考价值,模糊免疫PID控制应用于线控液压转向系统可以获得理想的控制效果。     

节流式高效异味处理及热能回收系统研究

对节流式高效异味处理及热能回收系统的结构设计、技术原理进行总结,对该系统处理烟厂高温高湿尾气效果进行阐述。实践证明:烟厂生产过程中产生的高温高湿的尾气经该系统处理后,尾气低温排放,尾气中的异味成分去除率80.0%,颗粒物排放浓度2.00 mg/m~3,符合国家相关法规,系统的换热效率高,换热效率平均值为63.66%;该系统运行稳定、可靠,运行过程中耗水量100 kg/h,二次污染小,节能减排效果明显。     

生殖后期甘肃鼢鼠性识别与尿液气味关系研究

[目的]寻找甘肃鼢鼠繁殖率偏低的原因。[方法]通过生殖后期甘肃鼢鼠对尿液气味的选择,探求雄性甘肃鼢鼠繁殖规律。[结果]繁殖后期甘肃鼢鼠对陌生同性和异性个体尿液气味的行为反应试验表明,雄性对其他同性和异性尿液气味反应明显,其他个体尿液气味对雄性甘肃鼢鼠有抑制效果;而雌性甘肃鼢鼠对其他个体尿液气味无明显反应。在繁殖期包括繁殖后期雌性甘肃鼢鼠对同性和异性气味忌避作用下降,攻击性减弱;而雄性仍对其他气味有敏锐反应。这可能与雄性是繁殖期社会关系的主要维持者和繁殖后期的主要扩散者有关。[结论]该研究为阐明甘肃鼢鼠繁殖率偏低的原因和社会行为适应策略奠定基础。     

Histamine-mediated delayed permeability response after scald burn inhibited by cimetidine or cold-water treatment

Scald injury to one ear of the hairless mouse induced significant (P < .05) delayed edema formation in remote, uninjured skin. This remote edema formation was completely inhibited by immediate cold-water treatment of the scalded ear. Cold-water treatment significantly reduced histamine loss from the scalded ear, and the edema-inhibiting effect of the treatment could be mimicked by treating the animal prior to injury with the H2-histamine receptor antagonist cimetidine or a drug that causes histamine depletion. These observations suggest (i) that a histamine-mediated, delayed permeability response occurs after thermal injury that causes remote edema formation and (ii) that one mechanism of remote edema inhibition by cold-water treatment is the prevention of histamine release from thermally injured tissues.     

昆虫感受气味物质的分子机制

在昆虫触角中,位于嗅觉感器神经树突膜上的气味受体蛋白与同源配位体相互作用将化学信号转换为神经活动.在与气味受体相互作用前,这些疏水性的配位体必须进入和穿过含有高度聚集气味降解酶的水环境,气味分子和气味结合蛋白OBP相互作用,在水腔和感器的表皮毛壁的交界面上与气味分子结合,通过扩散穿过水腔,将气味运送到神经细胞膜受体.接收后传入中枢神经系统.中枢神经系统对所有感官器官接收信号进行整合,最后使效应器官产生行为反应.对昆虫感受气味物质的分子机制进行了探讨.     

3类除臭剂的除臭效果与VOCs消减分析

[目的]对市场上化学型、植物型与生物型3种类型除臭剂的使用效果进行比较,分析去除的VOCs物质。[方法]在等体积密闭空间内预置相同臭源,定量喷洒除臭剂,人工嗅辩评价除臭效果。以全二维气相色谱法分析消减的VOCs物质。[结果]植物型除臭剂使用效果最好,在用量为100ml的试验初始阶段大部分样品可使臭源的恶臭强度降到3以下;加入200ml后,所有样品的恶臭强度均降到2以下。生物型除臭剂表现次之,当喷洒200ml除臭剂时,使臭源的恶臭强度降到3以下。化学型除臭剂效果稍差,用量为100ml时的除臭效果不明显,加大使用量后逐渐产生效果。其中H-3在加入200ml后,随着添加量的增加除臭效果变弱。利用全二维气相色谱定量分析了除臭前后VOCs物质,发现2种标志性恶臭物质戊醛与邻二甲苯减少量较大,同时对1,4-二恶烷、乙苯、1,2-二氯丙烷、四氯乙烯、三氯乙烯、甲醇（这6种有毒有害污染物属于美国国家环保署规定的重点控制有害污染物）具有明显的消减作用。[结论]除臭剂效能从高到低排序为植物型、生物型、化学型,药剂量与除臭效果并非正比关系,除臭剂的使用对臭源中标志性恶臭物质有明显的消减作用。     

New paradigms in type 2 immunity

Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called "type 2 immune response," which confers protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli.     

浙江白术挥发油化学成分研究

目的：以药材气味为指标,准确区分不同产地、不同炮制品种白术样品;研究浙江白术挥发油的化学成分。方法：采用电子感官Alpha M．O．S传感器矩阵系统,对不同产地及不同炮制品种白术样品的复杂气味基质进行定性;常规硅胶柱层析分离纯化白术挥发油的化学成分,用核磁共振和X-射线衍射法鉴定其结构。结果：不同产地及不同炮制品种的白术样品其气味间存在显著差异,相对比而言,炮制工艺对样品气味特征的影响远比产地差异的作用大。白术内酯I的晶体属正交晶系,空间群为P212121。晶胞参数：a=8．756（1）,b=12．012（2）,C=12．555（1）h,V=1320．5（2）A^3,Z=4。Dx=1．169g／cm^3。最终可靠因子R1=0、041,wR2=0．1219。独立衍射点为1391个,可观察点（IFl^2≥2σlFl^2）为1328个。结果表明白术内酯I由2个反式联接的椅式六元环和1个五元内酯环组成。晶态下不存在分子内和分子间氢键联系,分子间以范德华力维系其在空间的稳定排列。结论：气味指纹分析技术对不同白术样品具有很高的灵敏度,能够有效的区分具有细小差异的样品;白术内酯I首次从浙江白术中分离得到,白术内酯I单晶首次从白术中制备得到。     

拟南芥免疫相关基因启动子对免疫信号分子的响应强度分析

为对比不同的植物抗病相关基因对植物免疫激发子的响应强度,筛选出响应强度较高的报告基因,从拟南芥中克隆5个植物免疫相关基因(WRKY33、FRK1、WRKY29、PR2和PDF1.2)的启动子序列,构建目的基因启动子驱动的萤光素酶(Luciferase,LUC)表达载体,并将其转化到拟南芥原生质体中瞬时表达;经植物免疫激发子(FLG22与PEP1)处理后,进行LUC活性检测,判断目的基因启动子的激活情况,分析上述目的基因启动子对免疫信号分子的响应强度。结果显示:经FLG22与PEP1处理后,拟南芥原生质体细胞中WRKY33响应强度为最高,与对照相比分别上调11.2与4.5倍,WRKY29响应强度次之,分别为对照的10.0与3.1倍;与WRKY相比,FRK1响应强度明显降低,而PR2与PDF1.2均无明显响应。上述结果表明在拟南芥原生质体瞬时表达体系中WRKY33可高效响应植物免疫激发子,pWRKY33::LUC原生质体表达体系可作为一种高效的PTI反应报告系统,用于新型植物免疫激发子的筛选鉴定。