TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are bone marrow stromal cells that can differentiate into multiple lineages. We previously demonstrated that BMP9 is one of the most potent BMPs to induce osteogenic differentiation of MSCs. BMP9 is one of the least studied BMPs. Whereas ALK1, ALK5, and/or endoglin have recently been reported as potential BMP9 type I receptors in endothelial cells, little is known about type I receptor involvement in BMP9-induced osteogenic differentiation in MSCs. Here, we conduct a comprehensive analysis of the functional role of seven type I receptors in BMP9-induced osteogenic signaling in MSCs. We have found that most of the seven type I receptors are expressed in MSCs. However, using dominant-negative mutants for the seven type I receptors, we demonstrate that only ALK1 and ALK2 mutants effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic ossification in MSC implantation assays. Protein fragment complementation assays demonstrate that ALK1 and ALK2 directly interact with BMP9. Likewise, RNAi silencing of ALK1 and ALK2 expression inhibits BMP9-induced BMPR-Smad activity and osteogenic differentiation in MSCs both in vitro and in vivo. Therefore, our results strongly suggest that ALK1 and ALK2 may play an important role in mediating BMP9-induced osteogenic differentiation. These findings should further aid us in understanding the molecular mechanism through which BMP9 regulates osteogenic differentiation of MSCs.     

Lysophosphatidic acid acyltransferase β (LPAATβ) promotes the tumor growth of human osteosarcoma

Background

Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.

Methodology/Principal Findings

Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.

Conclusions/Significance

Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors.     

The Economic Burden of Malaria on Households and the Health System in Enugu State Southeast Nigeria

Background

Malaria is the number one public health problem in Nigeria, responsible for about 30% of deaths in under-fives and 25% of deaths in infants and 11% maternal mortality. This study estimated the economic burden of malaria in Nigeria using the cost of illness approach.

Methods

A cross-sectional study was undertaken in two malaria holo-endemic communities in Nigeria, involving both community and hospital based surveys. A random sample of 500 households was interviewed using interviewer administered questionnaire. In addition, 125 exit interviews for inpatient department stays (IPD) and outpatient department visits (OPD) were conducted and these were complemented with data abstraction from 125 patient records.

Results

From the household survey, over half of the households (57.6%) had an episode of malaria within one month to the date of the interview. The average household expenditure per case was 12.57US$ and 23.20US$ for OPD and IPD respectively. Indirect consumer costs of treatment were higher than direct consumer medical costs. From a health system perspective, the recurrent provider costs per case was 30.42 US$ and 48.02 US$ for OPD and IPD while non recurrent provider costs were 133.07US$ and 1857.15US$ for OPD and IPD. The mode of payment was mainly through out-of-pocket spending (OOPS).

Conclusion

Private expenditure on treatment of malaria constitutes a high economic burden to households and to the health system. Removal of user fees and interventions that will decrease the use of OOPS for treatment of malaria will significantly decrease the economic burden of malaria to both households and the health system.     

山水林田湖草生态保护修复试点工程布局及技术策略

习近平总书记提出的山水林田湖草生命共同体理念对我国新时代生态保护修复工作具有重要的指导意义,开展山水林田湖草整体保护、系统修复、综合治理是解决我国生态环境问题的重要途径,也是推进生态文明建设的必然要求。2016以来,财政部、原国土资源部、原环境保护部在全国24个省（自治区、直辖市）共安排25个山水林田湖草生态保护修复工程试点,对现有试点工程布局和技术策略进行全面剖析,能够为全面推进生态保护修复工作提供依据。在介绍山水林田湖草生态保护修复工程概念和主要任务的基础上,揭示试点工程布局特征,总结生态保护修复技术策略,同时探讨试点目前已经取得的效益、工程实施所存在的问题,并提出相关的建议。研究表明,25个试点大多分布于我国生态安全战略格局骨架区域,并且基本都属于国家重点生态功能区,对维护国家生态安全、提升区域生态功能具有重要意义;总结25个试点实施措施可以发现,工程技术策略主要包含了重要生态系统保护修复、生物多样性保护、流域水环境保护治理、污染与退化土地修复治理、矿山生态修复、土地综合整治等内容。试点工程的实施,开始取得生态、社会和经济等多重效益,但也存在工程宏观布局不尽完善、生态系统理念没能贯彻、自然恢复策略有待实施、监测评价管理缺乏科学、区域全面发展尚需提升等问题。未来应从完善国家宏观生态战略格局保障体系、加强区域生态系统状况和恢复力调查评价、优化工程项目实施规模和时序、研究和实践自然恢复标准与技术、开展长期跟踪监测与进行适应性管理等方面构建山水林田湖草生态保护修复工程技术和制度体系。     

草原生态环境损害因果关系判定路径

近年来,随着生态环境损害鉴定评估技术指南等相关文件的陆续出台,我国的生态环境损害鉴定评估工作已逐渐向专业化、程序化、标准化的方向发展,相关作用机理、技术方法方面的研究也逐渐深入。草原是我国占地面积最大的生态系统,是生态文明建设的核心区域。然而近些年来,草原生态环境损害事件屡有发生,迫切需要依据草原生态环境损害机制与特点制定具有针对性的鉴定评估技术与方法,保障草原生态环境损害鉴定评估工作的顺利开展。以草原生态环境损害为研究对象,对其鉴定评估的重要环节——因果关系的判定进行了探讨,提出了判定的一般过程与基本思路,即损害发生的可能性分析、损害行为识别、损害路径推演、其他损害行为存在的可能性分析与不确定性阐述五个过程,同时提出了因果关系判定准则与理论依据,以期为草原生态环境损害鉴定评估工作及相关政策的制定者提供科学依据。     

景感营造在自然保护区生态系统服务提升中的应用研究

自然保护区是生态建设的核心载体之一,是保护自然生态系统、历史遗迹、自然景观和生物多样性的主要方式,为维护国家生态安全,实现可持续发展提供重要的生态支撑。如何更好的保护自然生态系统、提升生态系统服务、促进区域的和谐发展,实现自然保护区及周边区域的景感营造已成为自然保护区研究的重要内容之一。运用景感生态学的理论和景感营造的理念,规范自然保护区管理范畴,以更好的提升自然生态系统的完整性、系统性和可持续性为目标,从更加满足人们的愿景和社会的需求角度出发,以我国北部典型草原区达里诺尔国家级自然保护区为研究对象,通过景感营造的方法,对其景感生态管理模式进行分析。文章明确了自然保护区景感营造原则,探索其景感营造的实践过程,并借助管理这一载体,把人的愿景和社会的需求与自然保护区的最终发展目标融入管理理念中。通过景感营造这一过程来改善、提升和维持自然保护区所能提供的各项生态系统服务,确保自然保护区在满足人类需求的同时,能够最大限度的、可持续的发挥其功效。     

8-OHdG在医学领域的应用与研究进展

氧化应激带来的氧化损伤是造成人体多种损伤和病变的重要因素。8-羟基脱氧鸟苷(8-hydroxy-2’-deoxyguanosine,8-OHdG)作为DNA氧化损伤产物是广泛用于研究疾病中氧化损伤机制的关键标志物。国内外大量研究已普遍应用8-OHdG作为分析指标,该文着眼于近年来研究动向,就8-OHdG的作用机理与检测方法,以及职业与环境暴露的危害评价、辅助疾病早期诊断、治疗和新药研发等方面的应用作一综述。     

Conditionally immortalized mouse embryonic fibroblasts retain proliferative activity without compromising multipotent differentiation potential

Mesenchymal stem cells (MSCs) are multipotent cells which reside in many tissues and can give rise to multiple lineages including bone, cartilage and adipose. Although MSCs have attracted significant attention for basic and translational research, primary MSCs have limited life span in culture which hampers MSCs' broader applications. Here, we investigate if mouse mesenchymal progenitors can be conditionally immortalized with SV40 large T antigen and maintain long-term cell proliferation without compromising their multipotency. Using the system which expresses SV40 large T antigen flanked with Cre/loxP sites, we demonstrate that mouse embryonic fibroblasts (MEFs) can be efficiently immortalized by SV40 large T antigen. The conditionally immortalized MEFs (iMEFs) exhibit an enhanced proliferative activity and maintain long-term cell proliferation, which can be reversed by Cre recombinase. The iMEFs express most MSC markers and retain multipotency as they can differentiate into osteogenic, chondrogenic and adipogenic lineages under appropriate differentiation conditions in vitro and in vivo. The removal of SV40 large T reduces the differentiation potential of iMEFs possibly due to the decreased progenitor expansion. Furthermore, the iMEFs are apparently not tumorigenic when they are subcutaneously injected into athymic nude mice. Thus, the conditionally immortalized iMEFs not only maintain long-term cell proliferation but also retain the ability to differentiate into multiple lineages. Our results suggest that the reversible immortalization strategy using SV40 large T antigen may be an efficient and safe approach to establishing long-term cell culture of primary mesenchymal progenitors for basic and translational research, as well as for potential clinical applications.