RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

基于NB-IoT技术的智能LED灯杆监控系统的研制

针对传统LED灯杆在远程监控、自动巡检、实时单灯调控、故障定位处理等方面存在的问题,本文提出基于窄带物联网(narrow band internet of things,NB-IoT)技术的智能LED灯杆监控系统的研制方案,采用STM32L151单片机作为主控芯片,控制多种传感器采集路灯信息,通过NB-IoT模块与核心...     

Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.     

Telomeres and meiosis in health and disease

Beyond their role in replication and chromosome end capping, telomeres are also thought to function in meiotic chromosome pairing, meiotic and mitotic chromosome segregation as well as in nuclear organization. Observations in both somatic and meiotic cells suggest that the positioning of telomeres within the nucleus is highly specific and believed to be dependent mainly on telomere interactions with the nuclear envelope either directly or through chromatin interacting proteins. Although little is known about the mechanism of telomere clustering, some studies show that it is an active process. Recent data have suggested a regulatory role for telomere chromatin structure in telomere movement. This review will summarize recent studies on telomere interactions with the nuclear matrix, telomere chromatin structure and factors that modify telomere chromatin structure as related to regulation of telomere movement.     

基于仿真驱动的高速公路主动限速效用评价与推荐

传统的路侧被动限速方式对于特定的惩处区域以外缺少管控,间接导致车辆行为在时空上的不一致性甚至突变,影响了交通的通行效率与安全性。从车侧主动限速方式入手,提出主动限速效用评价与推荐方法,结合道路线形、交通流量、车型比例,开展多情景主动、被动限速交通仿真,利用安全间接分析模型及交通流运行状态,从安全与效率2个层面提取效用评价指标及其权重,采用集成学习方法进行预测分析。结果显示：主动限速方式相较于被动限速方式更有利于提高安全性和调节效率,而在主动限速方面,GBDT(gradient boosting decision tree)回归模型的预测稳定性和准确率更高(R²=0.984)。     

建筑小区地下空间对海绵城市建设目标可达性的影响

为探究城市地下空间对海绵城市建设目标可达性的影响,以苏州市某建筑小区为研究对象,解析研究区内绿地有效性,并逐步构建低影响开发(low impact development,LID)措施布设方案,采用SWMM(storm water management model)模型模拟不同LID布置方案的径流削减效果.结果表明,地...     

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.     

青藏高原土地利用与覆被变化的时空特征

青藏高原土地利用与土地覆被变化(LUCC)研究是区域土地科学与全球变化科学研究的重要内容,也是保障高原生态安全屏障功能稳定与提升的科学基础.本文通过对已有LUCC数据与成果的再分析,研究了高原整体LUCC时空特征、典型区LUCC的时空过程及典型类型的变化过程与机制.结果表明:青藏高原土地利用与土地覆被结构稳定,一级地类变化面积比例低于7%,并以单次变化为主,土地覆被状况总体改善.近年来高寒草地覆被状况整体好转、局部退化,林地恢复良好,耕地基本稳定,建设用地显著扩张,裸地轻微减少.人口较为密集的河湟谷地与"一江两河"地区,建设用地、耕地、人工林地等增加明显;藏北高原和三江源等牧区,超载过牧和生态建设的作用均有体现;珠穆朗玛峰国家级自然保护地区土地覆被类型多样、变化复杂,并表现出对气候变化和人类活动有较强的敏感性.高原土地变化研究中还存在现有数据产品数量不足、精度不高,土地利用变化过程及其环境效应认识不够深入等问题,需要加强野外监测和遥感技术的结合,关注LULC在不同时空尺度下的变化特征,同时注重土地利用与土地覆被类型转化和类内渐变,使高原LUCC研究更好地服务于高原生态安全屏障建设和区域可持续发展.     

面向跟踪任务需求的主动传感器调度方法

以多传感器多目标跟踪为背景,针对跟踪任务需求中辐射风险控制问题,提出一种面向跟踪任务需求的主动传感器调度方法。该方法首先结合不敏卡尔曼滤波,给出了仅考虑跟踪任务需求的传感器调度策略;然后建立基于部分可观马尔可夫决策过程的辐射模型,并采用隐马尔可夫模型滤波器动态更新传感器辐射;最后考虑跟踪任务需求和传感器约束,将辐射风险控制下传感器调度问题转化为非线性约束下寻优问题。仿真实验结果验证了所提方法有效性。