A novel laser vaccine adjuvant increases the motility of antigen presenting cells

Background

Development of a potent vaccine adjuvant without introduction of any side effects remains an unmet challenge in the field of the vaccine research.

Methodology/Principal Findings

We found that laser at a specific setting increased the motility of antigen presenting cells (APCs) and immune responses, with few local or systemic side effects. This laser vaccine adjuvant (LVA) effect was induced by brief illumination of a small area of the skin or muscle with a nondestructive, 532 nm green laser prior to intradermal (i.d.) or intramuscular (i.m.) administration of vaccines at the site of laser illumination. The pre-illumination accelerated the motility of APCs as shown by intravital confocal microscopy, leading to sufficient antigen (Ag)-uptake at the site of vaccine injection and transportation of the Ag-captured APCs to the draining lymph nodes. As a result, the number of Ag⁺ dendritic cells (DCs) in draining lymph nodes was significantly higher in both the 1° and 2° draining lymph nodes in the presence than in the absence of LVA. Laser-mediated increases in the motility and lymphatic transportation of APCs augmented significantly humoral immune responses directed against a model vaccine ovalbumin (OVA) or influenza vaccine i.d. injected in both primary and booster vaccinations as compared to the vaccine itself. Strikingly, when the laser was delivered by a hair-like diffusing optical fiber into muscle, laser illumination greatly boosted not only humoral but also cell-mediated immune responses provoked by i.m. immunization with OVA relative to OVA alone.

Conclusion/Significance

The results demonstrate the ability of this safe LVA to augment both humoral and cell-mediated immune responses. In comparison with all current vaccine adjuvants that are either chemical compounds or biological agents, LVA is novel in both its form and mechanism; it is risk-free and has distinct advantages over traditional vaccine adjuvants.     

RNA干扰在疾病治疗方面的应用研究

RNA干扰是由双链RNA引起的序列特异的基因沉默现象。由于RNA干扰能在细胞组织及动物模型中沉默疾病相关基因,因此,RNA干扰也是各种疾病治疗的有效手段。在哺乳动物细胞内诱导RNA干扰可以通过导入小干扰RNA（siRNA）,或是以质粒、病毒为载体表达短的发夹RNA（shRNA）而实现。本文介绍了RNA干扰在疾病治疗方面的应用,并就其面临的挑战进行讨论。     

Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents

Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), linolenic acid, and linoleic acid were linked to the C-2' position of the second-generation taxoids that could overcome MDR caused by overexpressed ABC transporters. The new conjugates, tested in vivo, exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian cancer xenografts in mice. Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity.     

二甲双胍对斑马鱼骨骼发育及损伤修复的机制研究

二甲双胍(metformin,MET)是治疗糖尿病的一线药物,对骨骼疾病也有一定的治疗效果,但具体作用机制尚不明确.本研究利用斑马鱼(Danio rerio)构建骨质疏松模型,通过荧光观察、骨骼染色、半定量PCR、原位杂交及ELISA等技术方法,探究MET对斑马鱼骨骼发育及损伤修复的作用机制.首先通过胚胎致死率、骨骼矿...     

A joint modeling approach for analyzing marker data in the presence of a terminal event

In many medical studies, markers are contingent on recurrent events and the cumulative markers are usually of interest. However, the recurrent event process is often interrupted by a dependent terminal event, such as death. In this article, we propose a joint modeling approach for analyzing marker data with informative recurrent and terminal events. This approach introduces a shared frailty to specify the explicit dependence structure among the markers, the recurrent, and terminal events. Estimation procedures are developed for the model parameters and the degree of dependence, and a prediction of the covariate‐specific cumulative markers is provided. The finite sample performance of the proposed estimators is examined through simulation studies. An application to a medical cost study of chronic heart failure patients from the University of Virginia Health System is illustrated.     

诱导多潜能干细胞(iPSCs)的研究与应用进展

诱导多潜能干细胞(induced pluripotent stem cells,iPSCs)是体细胞在外源因子作用下,经直接细胞核程序重整而重新获得多潜能的干细胞.iPSCs在疾病的模型建立与机理研究、细胞治疗、药物的发现与评价等方面有着巨大的潜在应用价值.在过去几年中,科学家们致力于改进体细胞重编程技术并取得许多突破.然而,为实现其在临床上的应用,必须克服体细胞重编程效率低和iPSCs成瘤风险两大挑战,而且重编程机制有待进一步阐明.结合iPSCs最新研究成果,评述了有关领域国内外研究进展,重点讨论当前存在问题,并展望未来研究方向.     

Up-regulation of MDP and tuftsin gene expression in Th1 and Th17 cells as an adjuvant for an oral Lactobacillus casei vaccine against anti-transmissible gastroenteritis virus

The role of muramyl dipeptide (MDP) and tuftsin in oral immune adjustment remains unclear, particularly in a Lactobacillus casei (L. casei) vaccine. To address this, we investigated the effects of different repetitive peptides expressed by L. casei, specifically the MDP and tuftsin fusion protein (MT) repeated 20 and 40 times (20MT and 40MT), in mice also expressing the D antigenic site of the spike (S) protein of transmissible gastroenteritis virus (TGEV) on intestinal and systemic immune responses and confirmed the immunoregulation of these peptides. Treatment of mice with a different vaccine consisting of L. casei expressing MDP and tuftsin stimulated humoral and cellular immune responses. Both 20MT and 40MT induced an increase in IgG and IgA levels against TGEV, as determined using enzyme-linked immunosorbent assay. Increased IgG and IgA resulted in the activation of TGEV-neutralising antibody activity in vitro. In addition, 20MT and 40MT stimulated the differentiation of innate immune cells, including T helper cell subclasses and regulatory T (Treg) cells, which induced robust T helper type 1 and T helper type 17 (Th17) responses and reduced Treg T cell immune responses in the 20MT and 40MT groups, respectively. Notably, treatment of mice with L. casei expressing 20MT and 40MT enhanced the anti-TGEV antibody immune responses of both the humoral and mucosal immune systems. These findings suggest that L. casei expressing MDP and tuftsin possesses substantial immunopotentiating properties, as it can induce humoral and T cell-mediated immune responses upon oral administration, and it may be useful in oral vaccines against TGEV challenge.     

The impact of urbanization on body size of Barn Swallows Hirundo rustica gutturalis

Urbanization implies a dramatic impact on ecosystems, which may lead to drastic phenotypic differences between urban and nonurban individuals. For instance, urbanization is associated with increased metabolic costs, which may constrain body size, but urbanization also leads to habitat fragmentation, which may favor increases in body mass when for instance it correlates with dispersal capacity. However, this apparent contradiction has rarely been studied. This is particularly evident in China where the urbanization process is currently occurring at an unprecedented scale. Moreover, no study has addressed this issue across large geographical areas encompassing locations in different climates. In this regard, Barn Swallows (Hirundo rustica) are a suitable model to study the impact of urbanization on wild animals because they are a widely distributed species tightly associated with humans. Here, we collected body mass and wing length data for 359 breeding individuals of Barn Swallow (H. r. gutturalis) from 128 sites showing different levels of urbanization around the whole China. Using a set of linear mixed‐effects models, we assessed how urbanization and geography influenced body size measured using body mass, wing length, and their regression residuals. Interestingly, we found that the impact of urbanization was sex‐dependent, negatively affecting males’ body mass, its regression residuals, and females’ wing length. We also found that northern and western individuals were larger, regarding both body mass and wing length, than southern and eastern individuals. Females were heavier than males, yet males had slightly longer wings than females. Overall, our results showed that body mass of males was particularly sensitive trait to urbanization, latitude, and longitude, while it only showed a weak response to latitude in females. Conversely, while wing length showed a similar geographical pattern, it was only affected by urbanization in the case of females. Further research is needed to determine whether these phenotypic differences are associated with negative effects of urbanization or potential selective advantages.     

KIF2C:a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide.HCC is refractory to many standard cancer treatments and the prognosis is often poor,highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments.Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors.Nevertheless,the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated.In this study,we found that KIF2C expression was significantly upregulated in HCC,and that KIF2C up-regulation was associated with a poor prognosis.Utilizing both gain and loss of function assays,we showed that KIF2C promoted HCC cell proliferation,migration,invasion,and metastasis both in vitro and in vivo.Mechanistically,we identified TBC1D7 as a binding partner of KIF2C,and this interaction disrupts the formation of the TSC com-plex,resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction.Additionally,we found that KIF2C is a direct target of the Wnt/β-catenin pathway,and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling.Thus,the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling,which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.     

长江下游平原区生态网络识别与优化——以常州市金坛区为例

生态网络识别与优化是保障区域生态安全格局,开展国土空间生态保护修复的重要研究手段。立足图论和景观生态学理论方法,以长江下游平原区的金坛区为例,利用遥感影像、土地利用数据、POI数据等,通过最小面积阈值、最佳距离阈值分析,识别了区域现状生态网络,开展了生态盲区指导下的生态网络优化,并对优化前后的生态网络性能、区域生境斑块重要性进行评价,取得以下研究结果：①开展生态盲区指导下生态网络优化,可显著提升区域景观连接度,且在生态水网区域具有较强适用性;②研究区存在生态景观断裂,生态网络布局亟待优化,经优化Harary指数增加了10.92倍,整体连接度指数提升了43.45%,可能性连接度指数提升了99.58%;③国土空间生态保护修复应重点关注关键区域整治,可采取重点斑块生态保护、关键节点生态修复、特殊区域生态建设等差异化生态网络修复策略。