导读一
干细胞尤其是ES细胞的多能分化性已经毋庸置疑了，但是已经分化的细胞的复制也在器官组织的更新维护中起到重要的作用。
Adult pancreatic betta-cells are formed by self-duplication rather than stem-cell differentiation
**胰腺betta细胞是自身复制形成而非来自干细胞的分化
How tissues generate and maintain the correct number of cells is a fundamental problem in biology. In principle, tissue turnover can occur by the differentiation of stem cells, as is well documented for blood, skin and intestine, or by the duplication of existing differentiated cells. Recent work on adult stem cells has highlighted their potential contribution to organ maintenance and repair. However, the extent to which stem cells actually participate in these processes in vivo is not clear. Here we introduce a method for genetic lineage tracing to determine the contribution of stem cells to a tissue of interest. We focus on pancreatic betta-cells, whose postnatal origins remain controversial. Our analysis shows that pre-existing betta-cells, rather than pluripotent stem cells, are the major source of new betta-cells during adult life and after pancreatectomy in mice. These results suggest that terminally differentiated -cells retain a significant proliferative capacity in vivo and cast doubt on the idea that adult stem cells have a significant role in betta-cell replenishment.
生物学基础问题之一就是组织如何产生并维持正常的细胞数目。总的来说，组织更新可以通过干细胞分化完成，这在血液、皮肤和肠道中已经报道很多了，或者更新还可以通过已存分化细胞的复制来完成。最近对**干细胞的研究明确了它们对器官维持和修复的潜在作用。但是，体内干细胞参与这些过程的真正程度还不清楚。这里作者介绍了一种遗传连锁追踪的方法（追踪分化细胞种系来源的方法，可以利用到其他器官的细胞来源分析以及肿瘤细胞的来源等）来明确干细胞对感兴趣的器官的贡献。作者研究了胰腺betta细胞，目前对其出生后来源还有争议。作者分析表明预先存在的betta细胞而不是多能干细胞是成年和小鼠胰切除术后主要的新betta细胞的来源。这些结果提示终末分化的细胞在体内仍保留了明显的增殖能力并对**干细胞对betta细胞补充的重要作用观点提出疑问。（生物谷报道）
导读二
p53调节网络中又添新成员，这次是一个负调节因子。
The ubiquitin ligase COP1 is a critical negative regulator of p53
泛素连接酶COP1是p53关键的负调节物质
COP1 (constitutively photomorphogenic 1) is a RING-finger-containing protein that functions to repress plant photomorphogenesis, the light-mediated programme of plant development. Mutants of COP1 are constitutively photomorphogenic, and this has been attributed to their inability to negatively regulate the proteins LAF1 and HY5. The role of COP1 in mammalian cells is less well characterized. Here we identify the tumour-suppressor protein p53 as a COP1-interacting protein. COP1 increases p53 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent fashion, independently of MDM2 or Pirh2, which are known to interact with and negatively regulate p53. Moreover, COP1 serves as an E3 ubiquitin ligase for p53 in vitro and in vivo, and inhibits p53-dependent transcription and apoptosis. Depletion of COP1 by short interfering RNA (siRNA) stabilizes p53 and arrests cells in the G1 phase of the cell cycle. Furthermore, we identify COP1 as a p53-inducible gene, and show that the depletion of COP1 and MDM2 by siRNA cooperatively sensitizes U2-OS cells to ionizing-radiation-induced cell death. Overall, these results indicate that COP1 is a critical negative regulator of p53 and represents a new pathway for maintaining p53 at low levels in unstressed cells.
COP1（组成性光形态发生1）是一个作用为抑制植物（研究模型是拟南芥）光形态发生（光介导的植物发育程序）的环指包含蛋白，这种抑制归功于它们不能负调节蛋白LAF1和HY5（光介导发育的正调节物质）。哺乳动物细胞COP1的作用还不是很清楚。作者确认肿瘤抑制蛋白p53可以与COP1相互作用。COP1通过将p53靶向至蛋白酶以泛素依赖模式降解以增加其更新，这个过程独立于已知的和p53相互作用并负调节p53的MDM2或者Pirh2（RING-finger-containing proteins）。此外，在体外和体内COP1对于p53作为一种E3泛素连接酶并且抑制p53依赖的转录和凋亡。使用短RNA干扰(siRNA)耗竭COP1可以稳定p53并将细胞阻止于细胞周期G1期。此外，作者发现COP1是p53可诱导的基因并证实通过siRNA耗竭COP1和MDM2协作使得U2-OS对于电离辐射诱导的细胞死亡敏感。总之，这些结果表明COP1是p53关键的负调节物质并提出了一个在未应激细胞中维持p53于较低水平的途径。（生物谷报道）
导读三
将细胞的自分泌因子在受力后的浓度变化与外界受力后的机械转导相联系起来。
Mechanotransduction through growth-factor shedding into the extracellular space
通过生长因子脱落入细胞外区域进行机械转导
Physical forces elicit biochemical signalling in a diverse array of cells, tissues and organisms, helping to govern fundamental biological processes. Several hypotheses have been advanced that link physical forces to intracellular signalling pathways, but in many cases the molecular mechanisms of mechanotransduction remain elusive. Here we find that compressive stress shrinks the lateral intercellular space surrounding epithelial cells, and triggers cellular signalling via autocrine binding of epidermal growth factor family ligands to the epidermal growth factor receptor. Mathematical analysis predicts that constant rate shedding of autocrine ligands into a collapsing lateral intercellular space leads to increased local ligand concentrations that are sufficient to account for the observed receptor signalling; direct experimental comparison of signalling stimulated by compressive stress versus exogenous soluble ligand supports this prediction. These findings establish a mechanism by which mechanotransduction arises from an autocrine ligand–receptor circuit operating in a dynamically regulated extracellular volume, not requiring induction of force-dependent biochemical processes within the cell or cell membrane.
物理力诱发各种细胞、组织和生物的生化信号转导以协助管理基础生物反应。已经提出了几个假说来连接物理力和细胞内信号转导通路但是许多情况中机械转导的机制还不清楚。作者发现压力可以收缩上皮细胞周围的侧面胞间隙并通过自分泌上皮生长因子配体结合至上皮生长因子受体触发细胞信号转导。数学分析预测自分泌配体以常数频率脱落入萎陷的侧面胞间隙可以引起足以解释观察到的信号转导的局部配体浓度增加；直接实验比较由压力和外源可溶性配体刺激产生的信号转导也支持这个预测。这些发现建立了机械转导产生于在动态调节的细胞外容量中的自分泌配体－受体回路，这不需要细胞或者细胞膜内的力依赖的生化反应诱导。（生物谷报道）
| 导读四 氧化氮合酶在哺乳动物中研究已经很清楚了，但是在植物中发现的同源物所起的作用完全不相同。 Nitration of a peptide phytotoxin by bacterial nitric oxide synthase Nitric oxide (NO) is a potent intercellular signal in mammals that mediates key aspects of blood pressure, hormone release, nerve transmission and the immune response of higher organisms. Proteins homologous to full-length mammalian nitric oxide synthases (NOSs) are found in lower multicellular organisms. Recently, genome sequencing has shown that some bacteria contain genes coding for truncated NOS proteins; this is consistent with reports of NOS-like activities in bacterial extracts. Biological functions for bacterial NOSs are unknown, but have been presumed to be analogous to their role in mammals. Here we describe a gene in the plant pathogen Streptomyces turgidiscabies that encodes a NOS homologue, and we reveal its role in nitrating a dipeptide phytotoxin required for plant pathogenicity. High similarity between bacterial NOSs indicates a general function in biosynthetic nitration; thus, bacterial NOSs constitute a new class of enzymes. Here we show that the primary function of Streptomyces NOS is radically different from that of mammalian NOS. Surprisingly, mammalian NO signalling and bacterial biosynthetic nitration share an evolutionary origin. 氧化氮（NO）是一种哺乳动物中介导如血压，激素释放，神经传导和高等生物免疫反应的有力的细胞间信号。与全长哺乳动物氧化氮合酶（NOSs）同源的蛋白在低等多细胞生物中也有发现。最近，基因组测序发现一些细菌含有编码缩短NOS蛋白的基因；这与细菌提取物具有NOS样活性的报道一致。细菌NOSs的生物功能还是未知的，但是推测与其在哺乳动物中的同源物类似。作者描述了植物致病菌Streptomyces turgidiscabies中一种编码NOS同源物的基因并揭示了其在植物致病性中所需的对植物毒素二肽的硝化作用。细菌NOSs之间高度的相似性表明其生物合成硝化这个普遍功能；因此细菌NOSs形成了一类新的酶。作者说明链霉菌NOS的初步功能与哺乳动物NOS的完全不同。令人惊奇的是，哺乳动物NO信号转导和细菌生物合成硝化两种功能共享一个进化起源。（生物谷报道） |
导读五：
冠心病与炎症反应之间的关系研究由来已久，目前新发现一个炎症因子基因多态性位点与心肌梗死的发病相关联。
Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro
LGALS2的功能变异导致心肌梗死危险率升高并调节体外alpha淋巴毒素分泌
Myocardial infarction (MI) has become one of the leading causes of death in the world. Its pathogenesis includes chronic formation of plaque inside the vessel wall of the coronary artery and acute rupture of the artery, implicating a number of inflammation-mediating molecules, such as the cytokine lymphotoxin-alpha (LTA). Functional variations in LTA are associated with susceptibility to MI. Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family. Our case–control association study in a Japanese population showed that a single nucleotide polymorphism in LGALS2 encoding galectin-2 is significantly associated with susceptibility to MI. This genetic substitution affects the transcriptional level of galectin-2 in vitro, potentially leading to altered secretion of LTA, which would then affect the degree of inflammation; however, its relevance to other populations remains to be clarified. Smooth muscle cells and macrophages in the human atherosclerotic lesions expressed both galectin-2 and LTA. Our findings thus suggest a link between the LTA cascade and the pathogenesis of MI.
心肌梗死（MI）已经成为全球首要导致死亡的原因之一。其发病机制包括冠状动脉血管壁那慢性斑块形成和动脉的急性破裂，这其中包含了几种炎症－介导分子的参与如细胞因子淋巴毒素alpha（LTA）。LTA的功能变异与MI的易感性相关联。作者发现LTA蛋白结合galectin-2，后者是半乳糖结合凝集素家族成员。作者在日本人群中进行的病例对照关联研究显示编码galectin-2的LGALS2中的一个单核苷酸多态性与MI的易感性明显相关。该遗传替换在体外影响galectin-2的转录水平，潜在引起LTA的表达水平改变而导致炎症程度变化；但是其对于其他人群的相关性还需要进一步明确。人类动脉粥样硬化病变中的平滑肌细胞和巨噬细胞表达galectin-2和LTA。作者的发现提示LTA级联反应和MI的发病机制之间的关系。
