Programming the magnitude and persistence of antibody responses with innate immunity

Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.     

智能涡流转速计的设计

目前广泛使用的不含微型机的数字式转速计,其电路比较复杂,测量范围与精度不能兼顾,而且采样时间长,难以测得瞬时转速,文章介绍一种智能涡流转速计的硬件设计。在单片机的控制下,将传感器输出的信号转换成瞬时转速并显示,具有体积小,集成度高,功能强等优点,可在转速测量方面得到广泛的应用。     

基于不同归一化参数的单自由度体系 残余位移比离散性研究

结构弹塑性特征的差异会引起残余位移较大的离散性,使得强震下结构残余位移难以准确预测.为准确评估和预测震后结构残余位移,实现精细化的抗震设计和评估,有必要研究结构残余位移的离散性.鉴于此,基于大量分类地震动记录,选用不同的归一化参数分别定义残余位移比,通过非线性时程分析建立单自由度体系残余位移比谱,研究弹塑性特征参数(延性系数和强度折减系数)以及场地条件对残余位移比离散性的影响,建立了残余位移比变异系数谱的拟合公式.结果表明:残余位移与弹塑性谱位移的相关性比与弹性谱位移更好;结构残余位移比离散性受场地类别的影响较小;残余位移比变异系数谱分别随延性系数和强度折减系数的增大而增大;选择弹塑性谱位移作为归一化参数可以减小结构残余位移比离散性.     

Presence of the H blood group antigen on a carcinoembryonic antigen (CEA). Enzymatic transformation of H to A and B specificities]

The carcinoembryonic antigen (CEA-M) was purified from a hepatic metastasis obtained from a blood group O patient with a cancer of the rectum. Using 125I-labelled-CEA and blood group antisera, H specificity was found on the CEA-M; the addition of anti-H to anti-CEA does not modify the binding of labelled-CEA-M to its antibodies (86%), this result leads us to conclude that H and CEA determinants are carried by the same molecule. However the low percentage of binding (30% with 1/10 anti-H) suggests that only a few CEA-M molecules do carry the H antigenic determinant. Finally, glycosyltransferases were used to modify the H specificity into blood group A and B specificities.     

氰酸钠合成工艺的优化

考察氰酸钠合成工艺中溶剂种类、溶剂用量、原料物质的量之比、反应温度及反应时间对产品纯度和收率的影响,采用红外光谱确证产物的结构。在N,N-二基甲酰胺(DMF)和甲苯作溶剂下,n(碳酸钠)∶n(尿素)=1∶2.6,m(原料)∶m(DMF)∶m(甲苯)=1∶5∶1,反应温度140℃,反应时间13 h条件下,产品纯度可达98.7%,收率可达99.2%。     

Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin

Anthrax poses a clear and present danger as an agent of biological terrorism. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells--which are pivotal to the establishment of immunity against pathogens--and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response.     

Recent advances in the biosynthesis of modified tetrapyrroles: the discovery of an alternative pathway for the formation of heme and heme d 1

Hemes (a, b, c, and o) and heme d ₁ belong to the group of modified tetrapyrroles, which also includes chlorophylls, cobalamins, coenzyme F₄₃₀, and siroheme. These compounds are found throughout all domains of life and are involved in a variety of essential biological processes ranging from photosynthesis to methanogenesis. The biosynthesis of heme b has been well studied in many organisms, but in sulfate-reducing bacteria and archaea, the pathway has remained a mystery, as many of the enzymes involved in these characterized steps are absent. The heme pathway in most organisms proceeds from the cyclic precursor of all modified tetrapyrroles uroporphyrinogen III, to coproporphyrinogen III, which is followed by oxidation of the ring and finally iron insertion. Sulfate-reducing bacteria and some archaea lack the genetic information necessary to convert uroporphyrinogen III to heme along the “classical” route and instead use an “alternative” pathway. Biosynthesis of the isobacteriochlorin heme d ₁, a cofactor of the dissimilatory nitrite reductase cytochrome cd ₁, has also been a subject of much research, although the biosynthetic pathway and its intermediates have evaded discovery for quite some time. This review focuses on the recent advances in the understanding of these two pathways and their surprisingly close relationship via the unlikely intermediate siroheme, which is also a cofactor of sulfite and nitrite reductases in many organisms. The evolutionary questions raised by this discovery will also be discussed along with the potential regulation required by organisms with overlapping tetrapyrrole biosynthesis pathways.