A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells,and modulated the expression of the human equilibrative transporter-1

ABSTRACT

Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O₂ tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC₅₀s. However, the simultaneous addition of NHI-1 was synergistic (combination index < 1). Flow cytometry demonstrated that hypoxia caused a G1 arrest, whereas the combination of NHI-1 significantly increased gemcitabine-induced cell death. Finally, the mRNA expression levels of the human equilibrative transporter-1 (hENT1) were significantly down-regulated under hypoxia, but treatment with NHI-1 was associated with a recovery of hENT1 expression. In conclusion, our data show that hypoxia increased MPM resistance to gemcitabine. However, cell death induction and modulation of the key transporter in gemcitabine uptake may contribute to the synergistic interaction of gemcitabine with the LDH-A inhibitor NHI-1 and support further studies for the rational development of this combination.     

Pou4f2‐GFP knock‐in mouse line: A model for studying retinal ganglion cell development

Pou4f2 acts as a key node in the comprehensive and step‐wise gene regulatory network (GRN) and regulates the development of retinal ganglion cells (RGCs). Accordingly, deletion of Pou4f2 results in RGC axon defects and apoptosis. To investigate the GRN involved in RGC regeneration, we generated a mouse line with a POU4F2‐green fluorescent protein (GFP) fusion protein expressed in RGCs. Co‐localization of POU4F2 and GFP in the retina and brain of Pou4f2‐GFP/+ heterozygote mice was confirmed using immunofluorescence analysis. Compared with those in wild‐type mice, the expression patterns of POU4F2 and POU4F1 and the co‐expression patterns of ISL1 and POU4F2 were unaffected in Pou4f2‐GFP/GFP homozygote mice. Moreover, the quantification of RGCs showed no significant difference between Pou4f2‐GFP/GFP homozygote and wild‐type mice. These results demonstrated that the development of RGCs in Pou4f2‐GFP/GFP homozygote mice was the same as in wild‐type mice. Thus, the present Pou4f2‐GFP knock‐in mouse line is a useful tool for further studies on the differentiation and regeneration of RGCs.     

调节性T 细胞在发热结缔组织病患者外周血中的表达及临床意义

目的:研究Treg细胞在发热CTD患者外周血表达对结核感染的诊断价值。方法:对103例发热CTD患者进行T-SPOT.TB试验,将39例阳性者设为实验组-1,进行抗结核治疗,将64例阳性者设为实验组-2,另选取40例健康者作为对照组,检测三组外周血CD4+CD25+Treg细胞、Foxp3基因、IL-10、TGF-β的表达。结果:实验组CD4+CD25+Foxp3 Treg细胞占CD4+T比例高于对照组(P0.05),实验组-1治疗前外周血CD4+CD25+Foxp3 Treg细胞占CD4+T比例高于实验组-1治疗后、实验组-2(P0.05);实验组TGF-β表达量低于对照组(P0.05),实验组-1治疗前低于实验组-1治疗后及实验组-2(P0.05);实验组-1治疗前IL-10表达量低于实验组-1治疗后、实验组-2及对照组(P0.05)。结论:CD4+CD25+Foxp3 Treg细胞在发热CTD伴有结核感染患者外周血中的表达升高,其变化可作为结核感染诊断的辅助性指标。     

The insights of Let‐7 miRNAs in oncogenesis and stem cell potency

The ability of the classic tumour‐suppressive let‐7 family to inhibit carcinogenesis, tumour progression, recurrence and pluripotency of cancer stem cells has generated significant interest in the field of cancer research. Through suppressing and degrading downstream‐targeted mRNAs, let‐7 affected most aspects of cell biology. It is perplexing how let‐7 affects oncogenesis, as the large influx of new miRNAs and other kinds of non‐coding RNAs are continuously defined. In this review, we delineate the complex functions of let‐7 and discuss the future direction of let‐7 research.     

生物多样性与稳定性机制研究进展

随着全球生物多样性的迅速丧失,生物多样性与生态系统稳定性的关系已成为人类面临的重要科学问题。许多研究表明生物多样性与稳定性存在正相互关系,但其内在机制尚不能被很好地理解并且存在争议。对生物多样性与稳定性的研究历史做简短的回顾,然后根据时间稳定性的计算方法将时间稳定性分为平均值、方差之和以及协方差之和3个统计组成部分,在此基础上对现在常见的生物多样性-稳定性机制进行分类和详细介绍。并对现在生物多样性和稳定研究的争论进行总结。建议未来生物多样性稳定性关系的研究应该建立更加综合的理论,增加实验时间,应用整合分析(meta-analysis)对已发表实验结果进行综合分析,此外,应多关注非生物量/多度的属性,控制物种属性而不是仅仅控制物种的数量。     

生境异质性对鼎湖山常绿阔叶林群落功能多样性的影响

物种共存机制一直以来是群落生态学的研究热点。为了探讨异质生境条件下鼎湖山常绿阔叶林群落功能多样性变化,找到其变化的主要环境驱动因子,该研究利用位于鼎湖山20 hm~2监测样地第2次群落调查数据并选择代表不同生境(海拔和地形)的27个样方(20 m×20 m),于2013年夏季在样地内所选样方中测定所有胸径≥1 cm树种的叶片功能性状。所测性状包括形态学性状(比叶面积、叶片干物质含量、叶面积以及叶片长宽比)和化学计量学性状(叶片碳、氮、磷的含量),结合地形和土壤数据并通过分析功能多样性随环境梯度的变化,探讨了环境过滤和竞争在鼎湖山群落物种共存中的相对重要性。结果表明:功能分歧度和群落权重平均值与环境因素关系密切,尤其是海拔、凹凸度和土壤养分。环境条件较好区域(微尺度高海拔、高凹凸度和土壤养分含量)的植物采取统一的养分有效保存(低SLA,高LDMC)的适应策略(功能分歧度低),环境过滤所起作用更强;植物在相反的环境条件下,采取快速生长策略(高SLA,低LDMC),能够更好地适应环境的变化,且性状变化是多样的(功能分歧度高),在该条件下竞争作用更为显著。叶面积和叶片氮含量的分歧度在环境条件较好的区域增大,这与其他功能性状不一致,说明不同生态位轴(环境因素)影响不同性状的分歧度变化,并且在局域尺度上植物为了更好地适应环境变化采取了多样的适应策略。     

Differential Expression of microRNAs and their Regulatory Networks in Skin Tissue of Liaoning Cashmere Goat during Hair Follicle Cycles

MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that negatively regulate gene expression. Herein, we investigated a selective number of miRNAs for their expression in skin tissue of Liaoning Cashmere goat during hair follicle cycles, and their intracellular regulatory networks were constructed based on bioinformatics analysis. The relative expression of six miRNAs (mir-103-3p, -15b-5p, 17-5p, -200b, -25-3p, and -30c-5p) at anagen phase is significantly higher than that at catagen and/or telogen phases. In comparison to anagen, the relative expression of seven miRNAs (mir-148a-3p, -199a-3p, -199a-5p, -24-3p, -30a-5p, -30e-5p, and -29a-3p) was revealed to be significantly up-regulated at catagen and/or telogen stages. The network analyses of miRNAs indicated those miRNAs investigated might be directly or indirectly involved in several signaling pathways through their target genes. These results provided a foundation for further insight into the roles of these miRNAs in skin tissue of Liaoning Cashmere goat during hair follicle cycles.     

外源H2O2对盐碱混合胁迫下裸燕麦幼苗生长和抗性生理的影响

为探讨信号分子过氧化氢（H₂O₂）增强裸燕麦盐碱耐性的作用及其生理机制,以裸燕麦品种‘定莜6号’为材料,在日光温室内用珍珠岩培养幼苗至三叶一心期时叶面喷施0.01 mmol·L^-1 H₂O₂的同时根部浇灌75 mmol·L^-1盐碱混合溶液（NaCl：Na₂SO₄：NaHCO₃：Na₂CO₃=12：8：9：1）或添加H₂O₂淬灭剂二甲基硫脲（DMTU）,研究对幼苗生长及叶片光合色素含量、活性氧代谢和渗透调节物质积累的影响。结果表明：喷施H₂O₂能够缓解盐碱混合胁迫对裸燕麦幼苗生长的抑制,提高幼苗根长、株高和植株干重及叶片叶绿素a、叶绿素b、总叶绿素、类胡萝卜素含量和超氧化物歧化酶、过氧化物酶、过氧化氢酶、抗坏血酸过氧化物酶活性,降低超氧阴离子、H₂O₂、丙二醛、抗坏血酸、谷胱甘肽和游离氨基酸含量,促进抗氧化物质类黄酮、总酚和原花青素及渗透调节物质可溶性蛋白质、可溶性糖和脯氨酸积累。添加DMTU部分或完全逆转了H₂O₂的上述作用。采用隶属函数综合评价显示,喷施H₂O₂提高了盐碱混合胁迫下裸燕麦幼苗的综合评价值D,添加DMTU完全逆转了H₂O₂对D值的提升作用。表明外源H₂O₂通过参与活性氧代谢和渗透调节物质积累等生理代谢调控缓解盐碱混合胁迫诱导的氧化伤害和生长抑制,从而提高裸燕麦对盐碱胁迫的适应能力。     

Mental illness and well‐being: an affect regulation perspective

Mental health crucially depends upon affective states such as emotions, stress responses, impulses and moods. These states shape how we think, feel and behave. Often, they support adaptive functioning. At other times, however, they can become detrimental to mental health via maladaptive affect generation processes and/or maladaptive affect regulation processes. Here, we present an integrative framework for considering the role of affect generation and regulation in mental illness and well‐being. Our model views affect generation as an iterative cycle of attending to, appraising and responding to situations. It views affect regulation as an iterative series of decisions aimed at altering affect generation. Affect regulation decisions include identifying what, if anything, should be changed about affect, selecting where to intervene in the affect generation cycle, choosing how to implement this intervention, and monitoring the regulation attempt to decide whether to maintain, switch or stop it. Difficulties with these decisions, often arising from biased inputs to them, can contribute to manifestations of mental illness such as clinical symptoms, syndromes and disorders. The model has a number of implications for clinical assessment and treatment. Specifically, it offers a common set of concepts for characterizing different affective states; it highlights interactions between affect generation and affect regulation; it identifies assessment and treatment targets among the component processes of affect regulation; and it is applicable to prevention and treatment of mental illness as well as to promotion and restoration of psychological well‐being.     

NF‐κB/NKILA signaling modulates the anti‐cancerous effects of EZH2 inhibition

A wealth of evidence supports the broad therapeutic potential of NF‐κB and EZH2 inhibitors as adjuvants for breast cancer treatment. We contribute to this knowledge by elucidating, for the first time, unique regulatory crosstalk between EZH2, NF‐κB and the NF‐κB interacting long non‐coding RNA (NKILA). We define a novel signaling loop encompassing canonical and non‐canonical actions of EZH2 on the regulation of NF‐κB/NKILA homeostasis, with relevance to breast cancer treatment. We applied a respective silencing approach in non‐transformed breast epithelial cells, triple negative MDA‐MB‐231 cells and hormone responsive MCF‐7 cells, and measured changes in EZH2/NF‐κB/NKILA levels to confirm their interdependence. We demonstrate cell line‐specific fluctuations in these factors that functionally contribute to epithelial‐to‐mesenchymal transition (EMT) remodelling and cell fate response. EZH2 inhibition attenuates MDA‐MB‐231 cell motility and CDK4‐mediated MCF‐7 cell cycle regulation, while inducing global H3K27 methylation and an EMT phenotype in non‐transformed cells. Notably, these events are mediated by a cell‐context dependent gain or loss of NKILA and NF‐κB. Depletion of NF‐κB in non‐transformed cells enhances their sensitivity to growth factor signaling and suggests a role for the host microenvironment milieu in regulating EZH2/NF‐κB/NKILA homeostasis. Taken together, this knowledge critically informs the delivery and assessment of EZH2 inhibitors in breast cancer.