（10.3-10.9/2011）
恒峰g22国际集团:陶国新 

重要内容：在多种成体干细胞和祖细胞中发现Sox2转录因子
；内源性化合物援手老鼠逆转糖尿
；鼓和脂肪酸与不鼓和脂肪酸对肥胖和糖尿病的分歧影响
；抗习染的新机造
；抗癌药物可能用于医治血吸虫
；不经过干细胞和祖细胞的细胞类型直接转变。

焦点动态：在多种成体干细胞和祖细胞中发现Sox2转录因子。

1. 在多种成体干细胞和祖细胞中发现Sox2转录因子
【动态】
转录因子Sox2维持早期胚胎细胞的多能性并调节胚胎发育期数种上皮的形成。在成体组织中Sox2是否持续起作用还不太明显。美国科学家的最新钻研批注在以前未知其表白的几种成体的上皮组织细胞中发现Sox2的表白，蕴含胃、子宫颈、肛门、睾丸和多种腺体。遗传谱系追踪和移植尝试证明表白Sox2的细胞在其组织中不休的滋天生熟细胞，纪录了其自我更新和分化的潜能。与这些发现一致，在老鼠中去除Sox2的细胞导致上皮组织体内平衡的粉碎和细胞殒命。发育命运图显示Sox2阳性的成体细胞起源于胚胎Sox2阳性的组织前体。因而，该钻研了局在多种成体内胚层和表胚层干细胞驻地发现Sox2的表白，而这对于正常的组织再生和存活极度关键。

【点评】
该钻研在成体干细胞中发现了在胚胎时期起重要作用的转录因子，批注人体再生的潜能一向伴随人的成长。

【参考论文】
Cell Stem Cell, October, 2011 DOI: 10.1016/j.stem.2011.09.001 
Sox2 Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice
Katrin Arnold, Abby Sarkar, Mary Anna Yram, et al.
The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We show here that Sox2 marks adult cells in several epithelial tissues where its expression has not previously been characterized, including the stomach, cervix, anus, testes, lens, and multiple glands. Genetic lineage tracing and transplantation experiments demonstrate that Sox2-expressing cells continuously give rise to mature cell types within these tissues, documenting their self-renewal and differentiation potentials. Consistent with these findings, ablation of Sox2(+) cells in mice results in a disruption of epithelial tissue homeostasis and lethality. Developmental fate mapping reveals that Sox2(+) adult stem cells originate from fetal Sox2(+) tissue progenitors. Thus, our results identify Sox2 expression in numerous adult endodermal and ectodermal stem cell compartments, which are critical for normal tissue regeneration and survival.

2. 内源性化合物援手老鼠逆转糖尿病
【动态】
可能是由于高卡路里的饮食压倒了我们自适应的代谢蹊径，现代生涯方式下II 型糖尿病盛行开来。其中一种代谢蹊径是受哺乳动物NAD+生物合成限速酶烟酰胺磷酸核糖基转移酶（NAMPT）以及NAD+依赖的蛋白脱乙
；窼IRT1调控。美国科学家最近钻研显示在代谢器官中NAMPT调控的NAD+生物合成被高脂饮食严重侵害。出乎意料的是，烟酰胺单核苷酸（NMN），一种NAMPT的反映产品和NAD+的关键中央体，通过复原高脂饮食诱导的II型糖尿病老鼠的NAD+水平减轻了葡萄糖耐受不良。NMN也提高了肝对胰岛素的敏感性并复原了与氧化压力、炎症反映以及生物钟有关的基因表白，部门原因是激活SIRT1。并且，在衰老时，多个器官都发生显著的NAD+ 和 NAMPT水平降落，在衰老引起的II型糖尿病老鼠中NMN可能改善葡萄糖耐受不良和脂类组成。这些发现使得有可能对饮食和衰老导致的II型糖尿病进行营养药过问医治。

【点评】
这些了局批注营养过问对于代谢疾病是可能起作用的。

【参考论文】
Cell Metabolism, 5 October 2011; 14(4) pp. 528 - 536 DOI:10.1016/j.cmet.2011.08.014
Nicotinamide mononucleotide, a key NAD intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice
Jun Yoshino, Kathryn F. Mills, Myeong Jin Yoon, Shin-ichiro Imai.
Highlights
NAMPT-mediated NAD+ biosynthesis is compromised in metabolic organs by HFD
NMN ameliorates defects in NAD+ biosynthesis and glucose metabolism in T2D mice
NMN enhances hepatic insulin sensitivity by reversing gene expression caused by HFD
NMN also ameliorates defects in glucose and lipid metabolism in age-induced T2D mice
Summary
Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.

3. 鼓和脂肪酸与不鼓和脂肪酸对肥胖和糖尿病的分歧影响
【动态】  
鼓和脂肪酸对健全有不良作用，比不鼓和脂肪酸更可能引起胰岛素抗性，某些不鼓和脂肪酸阐扬
；ば缘挠幸孀饔。鼓和脂肪酸，而非不鼓和脂肪酸，激活已知在人和老鼠与肥胖和胰岛素抗性有关的JNK激酶。但是若何分辨鼓和脂肪酸和不鼓和脂肪酸还不明显。瑞士和美国的科学家最近证明鼓和脂肪酸通过激活c-Src来激活JNK激酶和抑造胰岛素信号。鼓和脂肪酸扭转了c-Src的膜散布，使其打入细胞内膜，在那里被激活。相反的，已知对葡萄糖代谢有有益作用的不鼓和脂肪酸依附自身豆蔻
；し纁-Src的膜分配和激活，阻止JNK激活。消费致糖尿病的高脂饮食引起c-Src 在鼠科脂肪细胞不溶于洗涤剂的膜区域分配和激活。

【点评】
该钻研揭示了鼓和脂肪酸和不鼓和脂肪酸对肥胖和糖尿病的分歧影响的机理，为改善饮食结构提供了科学凭据。

【参考论文】
Cell, 2011; 147 (1): 173-184 DOI: 10.1016/j.cell.2011.08.034  
Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
Ryan G. Holzer, Eek-Joong Park, Ning Li, Helen Tran, et al.
Highlights
c-Src is necessary for JNK activation by saturated free fatty acids
Saturated fatty acids activate c-Src and alter its membrane distribution
Adipocytes of obese mice exhibit altered c-Src distribution and activation
Unsaturated fatty acids prevent altered c-Src distribution and JNK activation
Summary
Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.

4. 抗习染的新机造
【动态】
在病原体侵入地位存在免疫影象是免疫
；さ那疤。然而，保障在表围界面有免疫力的机造还不明显。一个国际合作钻研最近证明，在与活化的CD8αβ+ T细胞上CD8αα相互作用的树突细胞上诱导的非传统的重要组织相容性复合物MHC I 族分子胸腺白血病抗原（TL），调节依赖亲和力的影象前体细胞的选择。并且，上皮细胞上TL的组成性表白导致陆续选择成熟的CD8αβ+ 影象T细胞。对于在肠粘膜产生CD8αβ+ 影象T细胞和堆集抗原高度敏感的CD8αβ+ 影象T细胞形成在病原体最大的入口的第一路防线，TL和CD8αα驱动的影象过程是必须的。

【点评】
该机理的说明为开发新的疫苗提供了方向。

【参考论文】
Nature Immunology, 2011; DOI: 10.1038/ni.2106
Mucosal memory CD8 T cells are selected in the periphery by an MHC class I molecule
Yujun Huang, Yunji Park, Yiran Wang-Zhu, et al. 
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ+ T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ+ memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ+ memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ+ memory T cells that form the first line of defense at the largest entry port for pathogens.

5. 抗癌药物可能用于医治血吸虫病
【动态】
血吸虫病是寄生虫引起的传染病。澳大利亚的科学家报路了在日本血吸虫中鉴别和鉴定Bcl-2调节的凋亡蹊径
；蜃檠А⑸锘Ш突谙赴幕碜暄形仵杈独砺厶峁┝酥ぞ，类似于人体中受促存活的Bcl-2样分子抑造的只蕴含BH3的蛋白，以及推进线粒体表膜穿透的Bax-Bak样蛋白。Bcl-2蛋白已被成功能于开发BH3仿照物药物出格是癌症医治药，而该钻研发现一种血吸虫促存活蛋白sjA与已知的BH3仿照物ABT-737结合，为BH3仿照物类抗癌药物用于医治血吸虫病提供了理论基础。

【点评】
血吸虫细胞凋亡蹊径的钻研发现了能与已知BH3仿照物类抗癌药相结合的促存活蛋白，为开发此类血吸虫病医治药物提供了理论凭据。

【参考论文】
PNAS, 2011; 108 (17): 6999 DOI: 10.1073/pnas.1100652108
From the Cover: Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes
E. F. Lee, O. B. Clarke, M. Evangelista, et al.
Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

6. 不经过干细胞和祖细胞的细胞类型直接转变
【动态】
早前的工作批注未成熟的B细胞经
；岜蛔家蜃覥CAAT/加强子结合蛋白α转变为巨噬细胞。西班牙和瑞典的科学家利用这一系统系统分析了在转分化细胞中是否临时性的重新激活了在祖细胞中被限度的基因甚至逆分化。转分化细胞的转录谱分析批注大部门基因陆续上调或下调，在5天内阐发出巨噬细胞的表型。另表，尝试还观察到一幼组未成熟骨髓标志物的短暂重新激活，以及低水平的祖细胞象征Kit和FMS样的酪氨酸激酶3和少量非本细胞系的基因。而重要的是，没有观察到甄别造血干细胞和祖细胞的蕴含c-Kit和FMS样的酪氨酸激酶3的膜标志物的重新表白，即便CCAAT/加强子结合蛋白α是在合适造血干细胞和祖细胞成长的前提下造就的未成熟B细胞中被激活的或该转录因子是以功夫限度性的方式激活的。总体看来，该钻研的发现切合以下观点：从未成熟B细胞到巨噬细胞的转变根基是直接的，不涉及显著的逆分化。

【点评】
该钻研批注存在以下可能：从一种体细胞不经过所谓逆分化为干细胞和祖细胞就可能直接转变为另一种体细胞。

【参考论文】
Proc Natl Acad Sci, 108: 17016- 17021 DOI: 10.1073/pnas.1112169108
CCAAT/enhancer binding protein α (C/EBP α)-induced transdifferentiation of pre-B cells into macrophages involves no overt retrodifferentiation
Di Tullio, A. et al.
Earlier work has shown that pre-B cells can be converted into macrophages by the transcription factor CCAAT/enhancer binding protein α at very high frequencies. Using this system, we performed a systematic analysis of whether during transdifferentiation the cells transiently reactivate progenitor-restricted genes or even retrodifferentiate. A transcriptome analysis of transdifferentiating cells showed that most genes are up- or down-regulated continuously, acquiring a macrophage phenotype within 5 d. In addition, we observed the transient reactivation of a subset of immature myeloid markers, as well as low levels of the progenitor markers Kit and FMS-like tyrosine kinase 3 and a few lineage-inappropriate genes. Importantly, however, we were unable to observe the reexpression of cell-surface marker combinations that characterize hematopoietic stem and progenitor cells, including c-Kit and FMS-like tyrosine kinase 3, even when CAAT/enhancer binding protein α was activated in pre-B cells under culture conditions that favor growth of hematopoietic stem and progenitor cells or when the transcription factor was activated in a time-limited fashion. Together, our findings are consistent with the notion that the conversion from pre-B cells to macrophages is mostly direct and does not involve overt retrodifferentiation.