（12.12-12.18/2011）
恒峰g22国际集团:陶国新 

重要内容：出格的GATA因子是内胚层上皮-间质转化的守旧诱导物
；影响疤痕形成的物理成分
；蛋白亚磺
；谙赴藕磐分械闹匾鹘谧饔
；HIV病毒进入细胞核的“钥匙”
；确定造血干细胞的发源
；葡聚糖水凝胶对三度烧伤的医治成效。

焦点动态：影响疤痕形成的物理成分。

1. 出格的GATA因子是内胚层上皮-间质转化的守旧诱导物
【动态】
上皮-间质转化（EMT）使静止的上皮细胞转变为有移动能力的间充质细胞状态，西班牙科学家最近证明果蝇内胚层的EMT依赖GATA因子Srp。当Srp异位激活后作用类似于高效的EMT触发剂。Srp通过下调但不阻断联接蛋白dE钙粘素（dE-Cad）而影响内胚层的EMT。并且，Srp通过直接抑造crumbs(crb)基因重定位dE-Cad。他们的钻研还显示Srp的直接同源物人GATA-6在哺乳动物细胞中诱导类似的转变。类似于Srp，人GATA-6通过下调但不阻断E-Cad起作用，并诱导抑造Crumbs 的直接同源物crb2。总的看来，他们的钻研发现一套在发育学和病理学中GATA因子是选择性的守旧的触发物抑造上皮细胞的上皮个性而赋予其迁徙能力。

【点评】
该钻研发现上皮-间质转化依赖GATA因子，对于深刻相识生物发育以及肿瘤发展有推作为用。

【参考论文】
Developmental Cell, 2011; 21 (6): 1051 DOI: 10.1016/j.devcel.2011.10.005
Specific GATA Factors Act as Conserved Inducers of an Endodermal-EMT
The epithelial-to-mesenchymal transition (EMT) converts cells from static epithelial to migratory mesenchymal states (Hay, 1995 ). Here, we demonstrate that EMT in the Drosophila endoderm is dependent on the GATA-factor Serpent (Srp), and that Srp acts as a potent trigger for this transition when activated ectopically. We show that Srp affects endodermal-EMT through a downregulation of junctional dE-Cadherin (dE-Cad) protein, without a block in its transcription. Moreover, the relocalization of dE-Cad is achieved through the direct repression of crumbs (crb) by Srp. Finally, we show that hGATA-6, an ortholog of Srp, induces a similar transition in mammalian cells. Similar to Srp, hGATA-6 acts through the downregulation of junctional E-Cad, without blocking its transcription, and induces the repression of a Crumbs ortholog, crb2. Together, these results identify a set of GATA factors as a conserved alternative trigger to repress epithelial characteristics and confer migratory capabilities on epithelial cells in development and pathogenesis.

2. 影响疤痕形成的物理成分
【动态】
纤维增生旺盛是受伤后常见的并发症，原因尚不了然。一个常被忽视的创伤建复的关键成分是机械力，机械力通过细胞内蕴含焦点粘连激酶（FAK）在内的焦点粘连成分调节细胞-基质相互作用。美国斯坦福大学的科学家最近报路了皮肤危险后FAK被激活，这一过程被机械力负载所加强。在疤痕增活泼物模型中，敲除成纤维细胞特异性的FAK的老鼠显著比对照老鼠炎症和纤维化都少。他们发现FAK通过细胞表有关激酶（ERK）物理性的触发单核细胞化学引诱物-1（MCP-1，也叫CCL2）的排泄，这是一种与人体纤维病变有关的高效趋化因子。类似地，敲除MCP-1的老鼠形成的疤痕最幼，意味着炎症趋化因子蹊径是FAK通过力传导诱导纤维化的重要机理。用幼分子抑造FAK可能在人体细胞中阻断这些作用，并且通过调节MCP-1信号和炎症细胞的招募而削减尝试动物的疤痕形成。这些发现合在一路批注机械力通过炎症FAK–ERK–MCP-1蹊径调节纤维化以及针对FAK的分子战术可能有效的解除机械力与病理疤痕形成的关联。

【点评】
该钻研阐了然机械力能够通过加强炎症反映诱导组织纤维化增生。解除机械力的影响可能改善纤维化情况。

【参考论文】
Nature Medicine, 2011; DOI: 10.1038/nm.2574
Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling
Victor W Wong, Kristine C Rustad, Satoshi Akaishi, et al.
Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK–ERK–MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.

3. 蛋白亚磺
；谙赴藕磐分械闹匾鹘谧饔
【动态】
蛋白亚磺
；且恢址牒蠼ㄊ，在高档真核生物中逐步显示出其重要性。但是，钻研其多样性的作用还是很有挑战性的，尤其是在天然的细胞环境内。美国科学家最近开发利用DYn-2，一种新的化学选择性探针检测人体细胞内的亚磺
；牡鞍。他们的钻研批注表皮成长因子受体介导的信号导致过氧化氢的产生和下游蛋白的氧化。另表，他们还证明DYn-2可能细胞内亚磺
；实牟罹，这种差距与靶蛋白的定位差距有关。他们还发现过氧化氢在表皮成长因子受体的关键活性位点半胱氨酸（Cys797）进行直接建饰可能加强其酪氨酸激酶活性。总起来看，他们的发现显示亚磺
；抢嗨朴诹姿峄娜中孕藕呕，牵扯到其他受体酪氨酸激酶和针对蛋白中氧化敏感的半胱氨酸的不成逆抑造剂。
【点评】
蛋白亚磺
；谙赴藕诺鹘谥凶饔玫奶岣，会推进以调节蛋白亚磺
；副甑囊┪镒暄泻涂。但是更重要的意思在于，这批注蛋白翻译后建饰有多种方式都很重要，性命自身的调节远比我们已知的更为复杂奇妙。

【参考论文】
Nature Chemical Biology, 11 December 2011 DOI: 10.1038/nchembio.736
Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity
Candice E Paulsen, Thu H Truong, Francisco J Garcia, et al.
Protein sulfenylation is a post-translational modification of emerging importance in higher eukaryotes. However, investigation of its diverse roles remains challenging, particularly within a native cellular environment. Herein we report the development and application of DYn-2, a new chemoselective probe for detecting sulfenylated proteins in human cells. These studies show that epidermal growth factor receptor–mediated signaling results in H2O2 production and oxidation of downstream proteins. In addition, we demonstrate that DYn-2 has the ability to detect differences in sulfenylation rates within the cell, which are associated with differences in target protein localization. We also show that the direct modification of epidermal growth factor receptor by H2O2 at a critical active site cysteine (Cys797) enhances its tyrosine kinase activity. Collectively, our findings reveal sulfenylation as a global signaling mechanism that is akin to phosphorylation and has regulatory implications for other receptor tyrosine kinases and irreversible inhibitors that target oxidant-sensitive cysteines in proteins.

4. HIV病毒进入细胞核的“钥匙”
【动态】
慢病毒像HIV-1横穿核膜孔复合物（NPC）并习染终末分化的不割裂细胞，它们若何做到的还不明显。以前的钻研已发现胞浆NPC蛋白Nup358/RaBP2是HIV-1辅因子。最近英国和美国的科学家报路HIV-1病毒壳（CA）直接结合到Nup358/RaBP2的亲环素（cyclophilin, Cyp）结构域。该Cyp与三重TRIM5的融合产生了一种新的HIV-1复造抑造剂，与体内的一种相互作用一致。与CypA结合到HIV-1 CA相反，Nup358的结合对环孢霉素的抑造不敏感，借此能够分辨CypA和Nup358的影响。抑造CypA削减了对Nup358和核篮蛋白Nup153的依赖，批注CypA调节病毒参加的核内转运机造的选择。相比野生型病毒，HIV-1 病毒壳的Cyp结合突变G89V和P90A在高密度转录单元的基因区域有更多整合和有关特点。野生型病毒在环孢霉素存在时的整合偏差性与高密度转录区域有类似的扭转。相反，HIV-1 CA在使抱病毒对Nup358 或 TRN-SR2 删除（CA N74D, N57A）更不敏感的壳表表另一区域的扭转导致整合到少有转录单元的基因区域。两组CA突变在HeLa细胞和人单核细胞源巨噬细胞的复造中受到侵害。他们的发现将HIV-1衔接亲环素与整合指标和复造效能联系起来，并对病毒亲环素招募的守旧性提供了新见解。

【点评】
该钻研阐了然艾滋病毒HIV-1与亲环素的相互作用决定了往核内转运的蹊径、整合的指标以及复造的效能。对于开发新的抗艾滋病药物会有推作为用。

【参考论文】
PLoS Pathogens, 2011; 7 (12): e1002439 DOI: 10.1371/journal.ppat.1002439 
HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency
Torsten Schaller, Karen E. Ocwieja, Jane Rasaiyaah, et al.
Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment.

5. 确定造血干细胞的发源
【动态】
造血干细胞（HSCs）和更早一波的限造性的网织红细胞/骨髓祖细胞（EMPs）在孕体生血内皮细胞时分辨隔来。从胚胎干细胞或诱导多能干细胞可能体表出产EMPs，但出产HSCs的致力大多失败了。EMPS和HSCs的形成都必要转录因子Runx1及其非DNA-结合伴侣核结合因子β (CBFβ)。美国科学家最近的钻研显示孕体中EMP和HSC形成中对CBFβ的必要在功夫和空间上是分歧的。在表白Tek的细胞中CBFβ的泛内皮表白对形成EMP已经足够，但对HSC形成却还不够。另一方面，在表白Ly6a的细胞中，CBFβ的表白对形成HSC足够但对形成EMP还不够。其数据批注EMPs和HSCs是从生血内皮细胞的分歧群分化来的，而Ly6a特异性的象征产生HSC的生血内皮。
【点评】
该钻研比力精确地确定了造血干细胞的前体细胞并发现了其特异性标志Ly6a。

【参考论文】
Cell Stem Cell, 2011; 9 (6): 541 DOI: 10.1016/j.stem.2011.10.003 
Erythroid/Myeloid Progenitors and Hematopoietic Stem Cells Originate from Distinct Populations of Endothelial Cells
Michael J. Chen, Yan Li, Maria Elena De Obaldia, et al.
Hematopoietic stem cells (HSCs) and an earlier wave of definitive erythroid/myeloid progenitors (EMPs) differentiate from hemogenic endothelial cells in the conceptus. EMPs can be generated in vitro from embryonic or induced pluripotent stem cells, but efforts to produce HSCs have largely failed. The formation of both EMPs and HSCs requires the transcription factor Runx1 and its non-DNA binding partner core binding factor β (CBFβ). Here we show that the requirements for CBFβ in EMP and HSC formation in the conceptus are temporally and spatially distinct. Panendothelial expression of CBFβ in Tek-expressing cells was sufficient for EMP formation, but was not adequate for HSC formation. Expression of CBFβ in Ly6a-expressing cells, on the other hand, was sufficient for HSC, but not EMP, formation. The data indicate that EMPs and HSCs differentiate from distinct populations of hemogenic endothelial cells, with Ly6a expression specifically marking the HSC-generating hemogenic endothelium.

6. 葡聚糖水凝胶对三度烧伤的医治成效
【动态】
对深度烧伤的创伤愈合成效而言血管新生是个关键的决定成分。美国约翰霍普金斯医学院的科学家以为基于葡聚糖的水凝胶可能作为疏导性平台推进3度烧伤的血管新生和皮肤再生。葡聚糖水凝胶软而韧，有机遇提高烧伤医治成效。他们首先造订了一套用葡聚糖水凝胶医治老鼠烧伤的法式，其中遵循临床规范削除全厚层烧伤皮肤，而后用葡聚糖水凝胶和敷料层覆盖伤处。该法式能保障整个愈合期间水凝胶可能无缺无损固定在伤处以简化烧伤医治的处置。一项3周的对照钻研批注葡聚糖水凝胶推进了带有齐全附件的真皮再生。水凝胶平台推进了早期炎症细胞浸润导致其急剧降解，推进了生血管细胞向愈合中伤处的浸润。内皮细胞进入水凝胶平台在第7日起头可能新生血管，使得血流比医治和不医治的对照组显著增长。到第21天，用水凝胶医治的烧伤处产天生熟的上皮结构有毛囊和皮脂腺。医治5周后，水凝胶推进了头发的新生，并且表皮状态和厚杜纂正常老鼠皮肤类似。总的看来，他们的证据显示定造的单独使用葡聚糖水凝胶，不加任何成长因子、细胞因子或细胞，可能推进显著的血管新生和皮肤再生，并可能引出新的皮肤创伤医治步骤。

【点评】
该钻研发此刻烧伤老鼠削痂后单独使用葡聚糖水凝胶可能推进血管新生和正常皮肤的再生。

【参考论文】
PNAS December 27, 2011 vol. 108 no. 52 20976-20981
Dextran hydrogel scaffolds enhance angiogenic responses and promote complete skin regeneration during burn wound healing
Guoming Suna, Xianjie Zhangb, Yu-I Shena, et al.

Neovascularization is a critical determinant of wound-healing outcomes for deep burn injuries. We hypothesize that dextran-based hydrogels can serve as instructive scaffolds to promote neovascularization and skin regeneration in third-degree burn wounds. Dextran hydrogels are soft and pliable, offering opportunities to improve the management of burn wound treatment. We first developed a procedure to treat burn wounds on mice with dextran hydrogels. In this procedure, we followed clinical practice of wound excision to remove full-thickness burned skin, and then covered the wound with the dextran hydrogel and a dressing layer. Our procedure allows the hydrogel to remain intact and securely in place during the entire healing period, thus offering opportunities to simplify the management of burn wound treatment. A 3-week comparative study indicated that dextran hydrogel promoted dermal regeneration with complete skin appendages. The hydrogel scaffold facilitated early inflammatory cell infiltration that led to its rapid degradation, promoting the infiltration of angiogenic cells into the healing wounds. Endothelial cells homed into the hydrogel scaffolds to enable neovascularization by day 7, resulting in an increased blood flow significantly greater than treated and untreated controls. By day 21, burn wounds treated with hydrogel developed a mature epithelial structure with hair follicles and sebaceous glands. After 5 weeks of treatment, the hydrogel scaffolds promoted new hair growth and epidermal morphology and thickness similar to normal mouse skin. Collectively, our evidence shows that customized dextran-based hydrogel alone, with no additional growth factors, cytokines, or cells, promoted remarkable neovascularization and skin regeneration and may lead to novel treatments for dermal wounds.