Natural products and the search for novel vaccine adjuvants

Vaccines that protect against intracellular infections such as malaria, Leishmania and Chlamydia require strong cellular responses based on CD4⁺ T cells and CD8⁺ T cells in addition to antibodies. Such cell-mediated responses can be potentiated with adjuvants. However, very few adjuvants have been licensed for use in humans; thus there is an urgent need for the discovery of new non-toxic adjuvants in order to produce more efficacious vaccines. Until recently, the mechanisms of how adjuvants worked remained largely unknown, but, it is becoming clearer that many function via host germline-encoded pattern recognition receptors (PRRs) expressed by most immune and non-immune cells. Most PRRs sense infection and transmit a series of signals that ultimately lead to the development of immunity. PRR mediated signalling can be harnessed to search for new vaccine adjuvants. Dendritic cells (DCs) express many PRRs and are remarkably effective at directing T cell immunity. Natural products (NPs) have been the basis of many drugs and are a rich source of immune activators and/or regulators of the immune response. Here we review PRRs in the context of NPs and propose the use of DCs as biological probes to help identify novel immune type molecules and adjuvants within collections of NPs.     

Variable epitope libraries: new vaccine immunogens capable of inducing broad human immunodeficiency virus type 1-neutralizing antibody response

The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response. Moreover, we demonstrated that these T cells recognize more than 50% of heavily mutated variants (5 out of 10 amino acid positions were mutated in each epitope variant) of HIV-1 gp120 V3 loop-derived cytotoxic T lymphocyte epitope (RGPGRAFVTI) in mice. The constructed VELs had complexities of 10 000 and 12 500 individual members, generated as plasmid DNA or as M13 phage display combinatorial libraries, respectively, and with structural composition RGPGXAXXXX or XGXGXAXVXI, where X is any of 20 natural amino acids. Here, we demonstrated that sera from mice immunized with these VELs are capable of neutralizing 5 out of 10 viral isolates from Tier 2 reference panel of subtype B envelope clones, including HIV-1 isolates which are known to be resistant to neutralization by several potent monoclonal antibodies, described previously. These data indicate the feasibility of the application of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against antigenically variable pathogens.     

从大容量噬菌体抗体库中筛选人源性抗角蛋白scFv

目的从大容量噬菌体抗体库中筛选人源性抗角蛋白单链抗体(scFv),测定其特异性结合活性并进行基因序列分析。方法以混合分子量人表皮角蛋白包被固相,对构建的大容量噬菌体抗体库进行筛选,经4轮“吸附洗脱扩增”后,挑取单克隆,用ELISA法测定特异性结合活性,并对阳性克隆抗体基因进行DNA指纹分析及序列同源性分析。结果经4轮筛选,获得9株可表达抗人角蛋白单链抗体的克隆,酶切鉴定正确后,经DNA指纹分析及序列同源性分析证明为不同的抗体基因。结论利用噬菌体抗体库技术获得了人源性抗角蛋白单链抗体,为临床应用研究提供了具有更广阔应用前景的人源小分子抗体。     

Biomarker discovery and compound evaluation using two-hybrid proteomic systems

Many proteomic technologies require a heavy investment in expertise and technology, which place these approaches beyond many labs and small companies. However, proteomic approaches are ideal for pilot experiments, identifying relevant biomarkers and protein pathways for development or analysis of therapeutic compounds. The two-hybrid proteomic systems are available and affordable to most researchers, requiring little more than standard microbiological equipment. The screens rapidly generate data, identifying protein interactions that can be used to construct small local protein networks. Using data from large-scale projects, these small local protein networks can be used to identify the larger cellular pathways that are being affected by therapeutic compounds in the screen. The foundation for the two-hybrid proteomic systems are commercially available, as are high quality cDNA libraries. The straightforwardness of the two-hybrid proteomic system allows smaller groups to focus their resources on critical cellular pathways and molecular targets by taking advantage of a trusted molecular assay and an ever growing set of postgenomic era databases.     

Novel strategies for solid-phase construction of small-molecule combinatorial libraries

During the past decade we witnessed a rapid advance in the new field of chemical science, combinatorial chemistry. The pharmaceutical industries invested heavily in accelerating the development of this new technology. As a result, it has become an extremely important tool in lead identification and optimization in current pharmaceutical research. It also quickly crossed the boundaries of the original chemical discipline and demonstrated great potential in many other important areas, such as searching for novel and highly efficient catalysts and superconductive material. Researchers from both academic and industrial laboratories have directed great effort towards the development of novel strategies for combinatorial synthesis.     

高校图书馆文献信息资源建设绩效审计实施路径

分析了高校图书馆文献信息资源建设和绩效评价的研究现状,结合绩效审计的流程,总结了适合高校图书馆文献信息资源建设绩效审计的具体步骤,并详细阐述了步骤中绩效审计证据采集、评价和绩效审计评价标准的确定等关键环节,以期为当前高校图书馆文献信息资源建设提供参考。     

Soil DNA libraries for anticancer drug discovery

Soil has the largest population of microbes of any habitat, but only about 0.3% of soil microbes are cultivable with current techniques. Cultured soil microbes have been an incredibly productive source of drugs, for example the cancer chemotherapeutics doxorubicin hydrochloride, bleomycin, daunorubicin and mitomycin. Unfortunately, the current yield of new drugs from soil microbes is low due to repeated cultivation of the same small fraction of cultivable microbes. Uncultured soil species represent a tremendous untapped resource of new antineoplastic agents. Methods have recently been developed to access the diversity of secondary metabolites from uncultured soil microbes. Briefly, total DNA is extracted from soil samples, purified, partially digested, and fragments inserted into vectors for expression in readily fermented microbes such as Escherichia coli. Clones expressing enzymatic and antibiotic activities that are encoded by novel sequences have been reported.     

现代医院图书馆与人文关怀

通过人文布局、人文员工、人文服务、人文制度、人文网络、人文安全等方面阐述医院图书馆人文关怀的具体表现和实践。     

试论医院图书馆的知识管理

为了深化图书馆的管理，适应知识经济时代读者的需求，综合国内各专家对知识管理的论述，结合医院图书馆的现状。指出了医院图书馆医院图书馆实施知识管理的重要性，并提出了实现知识管理的途径。     

基层医院图书馆网络信息安全问题及对策

描述了基层医院图书馆目前存在的网络信息安全问题及其严重性，介绍了基层医院图书馆网络安全问题的主要表现，同时建议采用几种网络安全技术和产品，并从整体上提出一套基层医院图书馆网络解决方案，强调基层医院图书馆网络信息安全重在管理。