罗非昔布对胃癌细胞上清液中培养的树突状细胞分化成熟和功能的影响

目的：从免疫学角度分析罗非昔布（Rofecoxib）抗癌作用的机制。方法：将人外周血分离的单核细胞加入含重组人粒细胞巨噬细胞集落刺激因子和重组人白细胞介素的培养液中,随机分为空白组（PBS培养液）,干预组（胃癌细胞上清液＋罗非昔布,150mg/L）,对照组（胃癌细胞上清液）使其分化为树突状细胞（denstritic cell,DC）。混合培养48h后,动态观察DC成熟过程中的形态学变化,流式细胞术检测DC成熟表型（CD40、CD80）,混合T淋巴细胞增殖反应检测DC功能。结果：与对照组比较,空白组、干预组DC的CD40、CD80表达明显在增加（P〈0.05）,T细胞增殖作用明显增强（P〈0.05）。结论：罗非昔布可通过促进DC成熟,并增加DC的免疫活性而发挥抗癌作用。     

移动Agent技术的研究与应用

随着Internet平台和开放应用的快速发展，如何在面向对象技术的基础上发展新型的软件方法学成为软件新技术面临的重要挑战之一．本文以移动Agent技术、系统和应用为切入点，在对移动Agent关键技术，如移动机制、通信机制和安全机制等进行研究的基础上，提出了我们自行设计与实现的移动Agent系统Mogent，并探讨其在软件主流技术等方面的应用．     

一种改进的移动Agent主动通信算法

通信机制是Agent技术研究的重要课题，该文在移动Agent主动通信算法的基础上，提出了一种改进的移动Agent主动通信算法，解决了可靠通信问题，通过设置时间变量和超速等待，在Agent高速移动的情况下，强迫Agent停止移动，避免消息长时间不能传递的问题，完成可靠的消息传递。     

基于多Agent技术的产品包装设计

提出了基于多Agent技术的产品包装设计方法，并给出了相应的产品包装设计系统模型．研究了设计过程中各Agent功能的划分。分析了在功能驱动下的典型产品包装设计过程．将包装功能实现过程中Agent间的协作机制归纳为形式选择Agent首发机制、Agent工作顺序机制、结构Agent优先机制和包装功能实现程度记分机制。最后，给出了一个产品包装设计实例。     

移动Agent安全方案的分析与研究

针对移动Agent在其生命周期内的安全威胁,提出了一个完整、健壮的移动Agent安全方案.首先以层次授权建立了Agent社会的结构方案,这种由上自下的安全授权机制解决了整个Agent社会对Agent和Agent平台用户身份的鉴别;其次为了保护通讯的安全性,将Agent平台架构在SSL协议之上;最后利用模糊技术确保了移动Agent在迁移过程中的代码安全.     

基于多智能体的分布式智能诊断方法研究

在传统智能诊断基础上，将多Agent技术应用于动态、分布、实时和不确定的复杂系统故障诊断领域，以求解复杂过程诊断问题．提出了基于MAS的分布式智能故障诊断方法和过程；讨论了基于模式聚类的故障求解机制及对诊断问题任务的辨识、分解；研究了多Agent的约束和关联；设计了应用Agent工作状态的表达机制；确定了应用Agent间的工作状态影响关系及多Agent间的交互、协作和通讯；构建了多Agent模糊关联模型；给出了多Agent诊断系统局部诊断决策与全局诊断决策的集成描述结构：实现了一种分布式Agent诊断系统结构及其原型系统．工程应用表明，该系统能快速、准确地进行故障成因分析，并给出有效的决策意见，取得了与专家相似的诊断结果．     

一种结构化的多Agent任务分配机制

对多Agent协作环境下的任务机制进行了讨论,在结合集中式和分布式分配机制的基础上,提出了一种基于熟人联盟的结构化多Agent的任务分配机制,该机制将任务分配分为投标层、指示层、任务分配层三步进行,有效地降低了通信的代价,提高了协调的效率.     

Agent平台信任机制研究

随着网络和计算机技术的迅猛发展,信任管理技术已经成为支撑基于Internet的电子商务、分布式应用、系统安全的关键性技术之一,尤其是在移动Agent的平台保护中的应用.文中将对Agent实体的信任机制从定义、关系、性质等方面进行研究,提出了保护Agent实体的两个模型,即:Agent平台与Agent之间的和Agent平台保护模型和Agent平台之间的Agent平台保护模型.     

复合电源双向DC/DC变换器R-S-T控制策略

为了提高复合电源双向DC/DC变换器工作过程中的动态特性,提出一种用于三通道交错并联双向Buck/Boost变换器的R-S-T控制策略.分析该变换器在Buck模态下工作过程,建立了交流小信号模型,得出控制变量到状态变量的传递函数,在此基础上设计了R-S-T控制器并对其进行参数整定.相较于传统的PI控制,R-S-T控制策略具有更好的动态和稳态响应特性,最后通过仿真和实验验证了此方案的正确性和可行性.     

一种Internet环境下移动Agent通信机制

移动Agent间的通信机制是开发移动Agent系统的基础,但以前的通信机制均无法适用于目前规模庞大的Internet环境,本文提出了一种新颖的Internet环境下的移动Agent的通信机制ASRP.该机制包括移动Agent的创建、寻址、通信模型以及对通信失效问题的解决等,具有简单,高效,可靠等优点.     

Reduction‐Sensitive Dextran Nanogels Aimed for Intracellular Delivery of Antigens

Targeting of antigens to dendritic cells (DCs) to induce strong cellular immune response can be established by loading in a nano‐sized carrier and keeping the antigen associated with the particles until they are internalized by DCs. In the present study, a model antigen (ovalbumin, OVA) is immobilized in cationic dextran nanogels via disulfide bonds. These bonds are stable in the extracellular environment but are reduced in the cytosol of DCs due to the presence of glutathione. Reversible immobilization of OVA in the nanogels is demonstrated by the fact that hardly any release of the protein occurred at pH 7 in the absence of glutathione, whereas rapid release of OVA occurs once the nanogels are incubated in buffer with glutathione. Furthermore, these OVA conjugated nanogels show intracellular release of the antigen in DCs and boost the MHC class I antigen presentation, demonstrating the feasibility of this concept for the aimed intracellular antigen delivery.     

Modulation of Dendritic Cells by Lipid Grafted Polyelectrolyte Microcapsules

Polyelectrolyte microcapsules are fabricated by layer‐by‐layer deposition of dextran sulfate and poly‐L ‐arginine layers at the surface of calcium carbonate template microparticles followed by core removal to produce hollow microcapsules. In the context of vaccination, these biodegradable LbL capsules emerge as promising antigen carriers and are believed to have potential for the co‐delivery of antigens and immunomodulators associated within the same particle to enhance and steer the type of immune response. To this end, it is shown that LbL microcapsules can be functionalized at their surface with lipid layers containing immunopotentiators of lipid nature. The potency of the different lipid modified microcapsules to activate dendritic cells (DCs) is demonstrated by increased expression levels of the migration marker CCR7 and the maturation markers CD40 and CD86. Additionally, the DCs cytokine secretion profile is evaluated. The findings reveal that the lipid grafted microcapsules are superior to non‐modified microcapsules in DC activation and suggest their potential as immune modulating antigen delivery systems.     

Immune Complexes Mimicking Synthetic Vaccine Nanoparticles for Enhanced Migration and Cross‐Presentation of Dendritic Cells

The well‐designed activation of dendritic cells (DCs) by enhancing the delivery of antigens and immunostimulatory adjuvants into DCs is a key strategy for efficient cancer immunotherapy. Antigen‐antibody immune complexes (ICs) are known to directly bind to and cross‐link Fc‐gamma receptors (FcγRs) on DCs, which induce enhanced migration of DCs to draining lymph nodes through the up‐regulation of the chemokine receptor CCR7 and cross‐presentation inducing cytotoxic T lymphocyte (CTL) response against tumor antigen. In this study, ICs mimicking synthetic vaccine nanoparticles (NPs) are designed and synthesized by the coating of poly (lactic‐co‐glycolic acid) (PLGA) NPs containing adjuvant (CpG oligodeoxynuleotides (ODNs) as toll‐like receptor 9 ligands) with ovalbumin (OVA) proteins (as model antigens) and by the formation of OVA–OVA antibody ICs. Through the combination of FcγRs‐mediated efficient antigen uptake and CpG ODNs‐based immunostimulation, the secretion of TNF‐α (12.3‐fold), IL‐6 (7.29‐fold), and IL‐12 (11‐fold), homing ability to lymph nodes (7.5‐fold), and cross‐presentation (83.8‐fold IL‐2 secretion) are dramatically increased in DCs treated with PLGA(IC/CpG) NPs. Furthermore, mice vaccinated with DCs treated with PLGA(IC/CpG) NPs induced significant tumor (EG7‐OVA) growth inhibition as well as prolonged survival through CTL‐mediated enhanced cytotoxicity, antigen‐specific responses, and IFN‐γ secretion.     

Ferroptosis and Pyroptosis Co-Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.     

Negatively Charged Magnetite Nanoparticle Clusters as Efficient MRI Probes for Dendritic Cell Labeling and In Vivo Tracking

Cell labeling and tracking via magnetic resonance imaging (MRI) has drawn much attention for its noninvasive property and longitudinal monitoring functionality. Employing of imaging probes with high labeling efficiency and good biocompatibility is one of the essential factors that determine the outcome of tracking. In this study, negatively charged superparamagnetic iron oxide (PAsp‐PCL/SPIO) nanoclusters are developed for dendritic cell (DC) labeling and tracking in vivo. PAsp‐PCL/SPIO has a diameter of 124 ± 41 nm in DLS, negatively charged surface (zeta potential = ?27 mV), and presents high T ₂ relaxivity (335.6 Fe mm ^?1 s^?1) and good DC labeling efficiency. Labeled DCs are unaffected in their viability, proliferation, and differentiation capacity, and have an excellent MR imaging sensitivity in vitro. To monitor the migration of DCs into lymphoid tissues in vivo, which will be related to the final immunotherapy results, T ₂‐wighted and T ₂‐map imaging of popliteal nodes at different points in time are acquired under a clinical 3 T scanner after subcutaneous injection of a certain number of labeled DCs at hindleg footpads of mice. The signal intensities decreasing and T ₂ values shortening of ipsilateral popliteal nodes are significant and display a time‐ and dose‐dependence, showing DCs' migration to the draining lymph nodes.     

Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

Cationic Lipids-Mediated Dual-Targeting of Both Dendritic Cells and Tumor Cells for Potent Cancer Immunotherapy

Impaired antigen presentation either in dendritic cells (DCs) or tumor cells impedes the triggering of antitumor immunity or tumor cell killing, resulting in failures of multiple types of cancer immunotherapy. Herein, the strategy of using dual-targeting nanomedicines to simultaneously improve the presentation of tumor antigens by both DCs and tumor cells is proposed. It is shown that tuning of surface charge of nanoparticles (NPs) by incorporating different amounts of cationic lipids alters the in vivo NP tissue accumulation and cellular targeting profiles. NPs with moderately positive surface charge (≈20 mV) achieve efficient accumulation in tumors and lymph nodes and dual-targeting to both DCs and tumor cells. As a proof-of-concept demonstration, siRNA against YTH N6−methyladenosine RNA binding protein 1 (YTHDF1) is delivered by the dual-targeting NPs to inhibit excessive antigen degradation in both DCs and tumor cells. For DCs, YTHDF1 downregulation promotes tumor antigen cross-presentation and cross-priming of antigen-specific T cells. For tumor cells, it enhances the presentation of endogenous tumor antigens and hence improves both the recognition and killing of tumor cells by primed antigen-specific T cells. The dual-targeting nanomedicines generate efficient antitumor immunity.     

Utility-based scheduling disciplines for adaptive applications overthe Internet

This letter presents packet scheduling disciplines based on application utility functions and network traffic measurements. The disciplines support different classes of adaptive applications over the Internet, providing differentiation, fairness, and dynamic allocation of network resources. They are composed of a decision procedure, where a fairness criterion based on utility functions is used; and a measurement procedure, which considers the statistics involving packet arrivals and departures. The underlying algorithm is then applied to emulate the proportional differentiation services, and is shown-via simulation-that its results outperform the best alternative algorithms published in the literature     

A new notion for functional flexibility: a summary

When we design a combinatorial logic circuit, Don't Cares (DCs) play an important role in many aspects. DCs are traditionally expressed by using incompletely specified functions. We explain how to express DCs by using Compatible Sets of Permissible Functions (CSPFs) as an example.