（11.7-11.13/2011）
恒峰g22国际集团:陶国新 

　　重要内容：过表白dPGC-1耽搁果蝇寿命；分歧微环境中的肠干细胞之间的相互转换；脂肪细胞去除NCoR降低了PPARγ磷酸化加强了 PPARγ 的作用和胰岛素敏感性；生物钟造成表皮干细胞的异质性；磷酸酰甘油抑造感冒病毒A的习染；用尝试鼠的胚胎干细胞造就出脑垂体。

　　焦点动态：过表白dPGC-1耽搁果蝇寿命。

1.过表白dPGC-1耽搁果蝇寿命
【动态】
　　哺乳动物的PGC-1转录共激活物是其能量代谢，蕴含线粒体生物合成和呼吸作用的关键调节因子，这已体此刻在蕴含神经退行性病变和心肌病变等很多病变中。而美国科学家最新的钻研批注果蝇PGC-1同系物（dPGC-1）过表白足以增长线粒体活性。并且，在消化路的干细胞和祖细胞中组织特异性的过表白dPGC-1耽搁了果蝇寿命。过表白dPGC-1的长命的果蝇肠路春秋有关的变动推迟了，因而推进了老龄果蝇组织的不变性。总而言之，这些了局批注dPGC-1可能在个别组织的细胞变动和整个有机体双重水平上延缓衰老。这些发现指出一种可能性，即在像肠这样的更新很快的组织中PGC-1活性的变动可能是哺乳动物长命的重要决定成分。

【点评】
　　这一钻研了局批注PGC-1作用加强提高了果蝇线粒体的活性和作用，耽搁了果蝇的寿命。对于钻研哺乳动物尤其是人类的衰老和抗衰总是重要的借鉴。

【参考论文】
Cell Metabolism, 2011; 14 (5): 623 DOI:10.1016/j.cmet.2011.09.013
Modulation of Longevity and Tissue Homeostasis by the Drosophila PGC-1 Homolog
Michael Rera, Sepehr Bahadorani, Jaehyoung Cho, et al. 

In mammals, the PGC-1 transcriptional coactivators are key regulators of energy metabolism, including mitochondrial biogenesis and respiration, which have been implicated in numerous pathogenic conditions, including neurodegeneration and cardiomyopathy. Here, we show that overexpression of the Drosophila PGC-1 homolog (dPGC-1/spargel) is sufficient to increase mitochondrial activity. Moreover, tissue-specific overexpression of dPGC-1 in stem and progenitor cells within the digestive tract extends life span. Long-lived flies overexpressing dPGC-1 display a delay in the onset of aging-related changes in the intestine, leading to improved tissue homeostasis in old flies. Together, these results demonstrate that dPGC-1 can slow aging both at the level of cellular changes in an individual tissue and also at the organismal level by extending life span. Our findings point to the possibility that alterations in PGC-1 activity in high-turnover tissues, such as the intestine, may be an important determinant of longevity in mammals.

2.分歧微环境中的肠干细胞之间的相互转换
【动态】
　　肠上皮干细胞的鉴别和定位一向是个必要内容钻研的事件。+4微环境中的细胞循环很慢，保留象征，而另一种干细胞微环境位于腺窝底部，内住窝底柱状细胞（CBC）。CBC分歧于+4细胞，二者之间的关系尚不明显，但二者都能产生所有肠上皮细胞系。美国科学家最近发现Hopx，一种非典型同源盒蛋白，是+4细胞的新的特异性象征。表白Hopx的细胞可能产生CBC以及所有成熟的肠上皮细胞系。反之，CBC也可能产生Hopx阳性的+4细胞。这些发现批注在他们的微环境中活跃的和静止的干细胞之间存在一种双向的谱系关系。

【点评】
　　该钻研意表发现割裂速度分歧的两种肠干细胞可能相互产生对方，实现了谁是真正的肠干细胞的争论。

【参考论文】
Science, 2011; DOI: 10.1126/science.1213214
Interconversion Between Intestinal Stem Cell Populations in Distinct Niches
N. Takeda, R. Jain, M. R. LeBoeuf, et al.
Intestinal epithelial stem cell identity and location has been the matter of substantial research. Cells in the +4 niche are slow-cycling and label retaining, while a distinct stem cell niche located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a novel and specific marker of +4 cells. Hopx-expressing cells give rise to CBCs and all mature intestinal epithelial lineages. Conversely, CBCs can give rise to +4 Hopx positive cells. These findings demonstrate a bidirectional lineage relationship between active and quiescent stem cells in their niches.

3.脂肪细胞去除NCoR降低了 PPARγ 磷酸化加强了 PPARγ 的作用和胰岛素敏感性
【动态】
　　胰岛素抗性、组织发炎和脂肪组织职能阻碍是肥胖和2型糖尿病的特点。美国和瑞典的科学家成立了敲除脂肪细胞特异性核受体辅抑造物（NCoR）的老鼠模型（AKO）来钻研脂肪细胞生物学、葡萄糖和胰岛素体内平衡中NCoR的职能。除了肥胖增多，AKO老鼠的葡萄糖耐受性提高了，肝脏、肌肉和脂肪中胰岛素敏感性加强了。脂肪组织巨噬细胞浸润和炎症削减了。AKO老鼠脂肪组织中PPAR响应基因上调，CDK5 介导的 PPAR 273号丝氨酸磷酸化削减，产生了结构上处于活化状态的PPAR。由此判断NCoR是一种适配蛋白，作用是加强CDK5联系和磷酸化PPAR的能力。脂肪细胞NCoR
的主导作用是反抑造PPAR 和推进PPAR 273号丝氨酸磷酸化, 因而 去除NCoR导致 脂肪天生、炎症削减和全身胰岛素敏感性加强，仿照了TZD药物医治的状态。

【点评】
　　NCoR职能的说明，有助于进一步相识肥胖和2型糖尿病的病理。对于研发通过加强胰岛素敏感性伎俩的医治2型糖尿病提供了新的思路。

【参考论文】
Cell, Volume 147, Issue 4, 815-826, 11 November 2011
Adipocyte NCoR Knockout Decreases PPARγ Phosphorylation and Enhances PPARγ Activity and Insulin Sensitivity

Pingping Li, WuQiang Fan, Jianfeng Xu, et al.
Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPAR response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPAR ser-273 phosphorylation was reduced, creating a constitutively active PPAR state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPAR. The dominant function of adipocyte NCoR is to transrepress PPAR and promote PPAR ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

4.生物钟造成表皮干细胞的异质性
【动态】
　　鼠类表皮干细胞交替进行休眠和活跃周期，保障组织更新。然而，在每轮状态发生中只有一种干细胞亚群处于活跃期，意味着所有干细胞以分歧反映状态共存。西班牙瑞典和美国科学家用生物钟汇报器老鼠模型证明摆布职位的毛囊干细胞微环境蕴含处于生物钟相反相但共存的细胞群，他们在分化时期已形成响应内稳态线索的偏差。主题的生物钟蛋白Bmal1以振荡方式调节干细胞调控基因的表白，以产生先天活化偏差大幼分歧的细胞群。通从前除Bmal或Per1/2粉碎该蛋白的平衡，别离导致休眠干细胞的持续堆集或解除。干细胞节律失调也会导致表皮提前衰老和鳞状癌的削减。他门的了局批注生物钟微调表皮干细胞的一时行为，该扰动影响内平衡和肿瘤发生的诱因。

【点评】
　　该钻研了局意味着表皮干细胞的活化受到生物钟的节造，生物节律的粉碎导致表皮干细胞再生能力受影响，组织提前衰老，更易诱发皮肤癌。

【参考论文】
Nature, 2011; DOI: 10.1038/nature10649
The circadian molecular clock creates epidermal stem cell heterogeneity
Peggy Janich, Gloria Pascual, Anna Merlos-Suárez, et al.
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.

5. 磷酸酰甘油抑造感冒病毒A的习染
【动态】
　　A型感冒病毒（IAV）是世界性的公共卫生问题，每年导致500,000人殒命。棕榈；王；姿狨；视停≒OPG）是肺部表表活性剂的次要成分，最近发显熹有潜在的调节先天免疫的作用。美国科学家的最新钻研证明POPG是很强的IAV抗病毒剂。在人体支气管上皮细胞造就中，POPG显著地调节IL-8的出产和IAV引起的细胞殒命。这种脂类还抑造病毒对细胞膜的粘附及随后在MDCK细胞中的复造。H1N1-PR8-IAV和H3N2-IAV两种病毒株与POPG有很高的亲和力但对结构类似的脂类   磷脂酰胆碱亲和力却很低。在有POPG的情况下在老鼠鼻内接种H1N1-PR8-IAV显著抑造 了炎症细胞的浸润和支气管肺泡灌洗诱导的IFN-，以及习染5天后肺部的病毒数量。这些发现确认补充POPG 是一种潜在的医治IAV习染的重要的新步骤。

【点评】
　　该钻研发此刻肺部天然存在的一种脂类可能在细胞造就和动物模型中抑造感冒病毒习染、炎症反映、病毒传布和习染引起的细胞殒命。补充此类脂类有助于加强机体对感冒病毒的抵抗力。

【参考论文】
American Journal of Respiratory Cell and Molecular Biology, 2011; DOI: 10.1165/rcmb.2011-0194OC
Phosphatidylglycerol Suppresses Influenza A Virus Infection
M. Numata, P. Kandasamy, Y. Nagashima, et al.
Influenza A virus (IAV) is a worldwide public health problem causing 500,000 deaths each year. Palmitoyl-oleoyl-phosphatidylglycerol (POPG) is a minor component of pulmonary surfactant, which has recently been reported to exert potent regulatory functions upon the innate immune system. In this report we demonstrate that POPG acts as a strong anti-viral agent against IAV. POPG markedly attenuated IL-8 production and cell death induced by IAV in cultured human bronchial epithelial cells. The lipid also suppressed viral attachment to the plasma membrane and subsequent replication in MDCK cells. Two virus strains, H1N1-PR8-IAV and H3N2-IAV bind to POPG with high affinity but exhibit only low affinity interactions with the structurally related lipid palmitoyl-oleoyl-phosphatidylcholine. Intranasal inoculation of H1N1-PR8-IAV in mice, in the presence of POPG, markedly suppressed the development of inflammatory cell infiltrates and the induction of IFN- recovered in bronchoalveolar lavage, and viral titers recovered from the lungs after 5 days of infection. These findings identify supplementary POPG as a potentially important new approach for treatment of IAV infections.
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6.用尝试鼠的胚胎干细胞造就出脑垂体
【动态】
　　脑垂体是位于大脑下部的一个内排泄器官，它排泄多种激素，在身段成长发育、调节血压、女性乳汁排泄等多方面都阐扬着重要作用。这是一个极度复杂的器官，若是职能受损也不易医治。日本科学家最近在特殊的三维造就环境中用尝试鼠的胚胎干细胞造就出脑垂体，并且造就出的脑垂体在移植给正本脑垂体出缺点的尝试鼠后，可能正常排泄激素。这批注医生也许能够用这种步骤来医治人类的有关疾病。本次钻研显示，对于那些脑垂体出缺点而有关激素水平降落的尝试鼠，若是植入人为造就的脑垂体，有关激素水平会出现回升。这显示了人为造就的脑垂体拥有排泄激素的正常职能。

【点评】
　　该钻研利用特殊的三维造就环境将尝试鼠的胚胎干细胞造就成可能正常排泄激素的脑垂体，对于有关疾病的病理学钻研有所援手，但是由于对人类移植脑垂体必要思考的问题更多，要真正通过移植人为造就的脑垂体来医治疾病，即便有此可能，也还必要很长的功夫。

【参考论文】
Nature (2011)  doi:10.1038/nature10637 Published online 09 November 2011
Self-formation of functional adenohypophysis in three-dimensional culture
Hidetaka Suga, Taisuke Kadoshima, Maki Minaguchi, et al.
The adenohypophysis (anterior pituitary) is a major centre for systemic hormones. At present, no efficient stem-cell culture for its generation is available, partly because of insufficient knowledge about how the pituitary primordium (Rathke’s pouch) is induced in the embryonic head ectoderm. Here we report efficient self-formation of three-dimensional adenohypophysis tissues in an aggregate culture of mouse embryonic stem (ES) cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with hedgehog signalling. Self-organization of Rathke’s-pouch-like three-dimensional structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotrophin releasing hormone and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Thus, functional anterior pituitary tissue self-forms in ES cell culture, recapitulating local tissue interactions.