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天下生命科学前沿动态周报（十二）
（06.07--06.13 / 2010）
一竞技国际集团:陶国新
本周动态包括以下内容：新型人体多功效干细胞 ；控制流感病毒复制的“开关” ；T细胞基因刷新制造癌细胞杀手 ；红酒和绿茶中多酚类化合物抗癌的机理 ；慢性熏染使γ滋扰素激活休眠的造血干细胞 ；肿瘤抑制因子ｐ５３在生殖细胞减数破碎中也有心理作用。
1. 新型人体多功效干细胞
【摘要】科技日报 宣布时间：2010-6-10 11:05:53
据物理学家组织网6月9日(北京时间)报道，美国研究职员使用成人细胞和生长因子LIF，研发出了一种新的人体多功效干细胞，其与现在使用的干细胞相比，不再那么难以操控。举行该研究的美国马萨诸塞州总医院再生医学研究中心(MGH-CRM)和哈佛干细胞研究所的研究职员体现，新细胞能够被用来制造更好的细胞模子以用于疾病研究，或许也可用来矫正引发疾病的基因变异。该研究的向导者、MGH-CRM的尼尔斯·盖吉森体现，此前科学家已能够很熟练地操控老鼠干细胞，但操控人体干细胞却并非易事。研究小组发明，制造老鼠干细胞的生长因子决议了干细胞的功效，因此，使用该发明就可制造出新型人体干细胞。
第一个哺乳动物胚胎干细胞泉源于老鼠。可是首先，该研究中所用到的一些手艺，包括引入统一基因的差别版本或让某特定的基因变得不活跃等手段，似乎对人体干细胞不起作用 ；其次，滋生速率差别，人体胚胎干细胞滋生速率要更慢 ；再次，长成状态差别，人体胚胎干细胞会长成平滑的二维群落，而老鼠胚胎干细胞则会形成细密的三维群落 ；最后，使用单个的细胞来滋生胚胎干细胞很是难题。因而试图通过基因操控来制造人体胚胎干细胞颇为难题。研究职员已能证实，生长因子才是区分差别的胚胎干细胞的要害，在制造老鼠胚胎干细胞时用的是生长因子LIF ；而在对成人的细胞举行了重新编程后，获得的人体诱导多功效干细胞(iPSC)，其拥有人类胚胎干细胞的许多特征，将它也放在包括了生长因子LIF的作育皿中举行作育，就获得了新型人体干细胞。
这种人体干细胞与老鼠的胚胎干细胞很是相像，研究职员也证实，它能够经得住一个标准的基因使用手艺的磨练：会交流匹配的DNA序列，并且可以有针对性地钝化或者矫正某个特定的基因。如想操控该新细胞，需一直增添LIF，同时让其变为iPSC细胞时所使用的5个基因也要一连表达。若是这两个条件欠缺其一，这种添加了人体LIF生长因子和5个重新编程因子的人体诱导多功效干细胞(hLR5-iPSC)会变回为标准的iPSC。 盖吉森体现，在hLR5-iPSC干细胞变回到iPSC之前，引入hLR5-iPSC干细胞的基因转变会一直保存，研究职员可以使用其来爆发细胞系，用于新药研发，甚至实现基于干细胞的基因矫正治疗。
【点评】
点评：通过一直提供LIF生长因子和一连表达5个重新编程因子，可以控制人体诱导多醒目细（iPSC）坚持在更原始的多醒目细胞状态，该手艺最大的用处就是便于建设iPSC细胞系，可是还不可改变基因重新编程的iPSC没有临床应用价值的情形。
【原文摘录】Cell Stem Cell, Volume 6, Issue 6, 535-546, 4 June 2010
A Murine ESC-like State Facilitates Transgenesis and Homologous Recombination in Human Pluripotent Stem Cells
Christa Buecker, Hsu-Hsin Chen, Jose Maria Polo, Laurence Daheron, Lei Bu, Tahsin Stefan Barakat, Patricia Okwieka, Andrew Porter, Joost Gribnau, Konrad Hochedlinger and Niels Geijsen
Murine pluripotent stem cells can exist in two functionally distinct states, LIF-dependent embryonic stem cells (ESCs) and bFGF-dependent epiblast stem cells (EpiSCs). However, human pluripotent cells so far seemed to assume only an epiblast-like state. Here we demonstrate that human iPSC reprogramming in the presence of LIF yields human stem cells that display morphological, molecular, and functional properties of murine ESCs. We termed these hLR5 iPSCs because they require the expression of five ectopic reprogramming factors, Oct4, Sox2, Klf4, cMyc, and Nanog, to maintain this more naive state. The cells are metastable and upon ectopic factor withdrawal they revert to standard human iPSCs. Finally, we demonstrate that the hLR5 state facilitates gene targeting, and as such provides a powerful tool for the generation of recombinant human pluripotent stem cell lines.
2. 控制流感病毒复制的“开关”
【摘要】科技日报 2010-6-7 10:31:18
据报道，美国科学家首次发明流感病毒的复制保存一个控制“开关”——小病毒核糖核酸（svRNA），并有望据此研发出能够治疗所有类型流感的药物。甲型流感病毒包括8个单体RNA片断，每个片断都有两个使命：通过转录历程制造卵白 ；通过复制历程制造出新的病毒片断。由于每个单体必需执行两个功效，病毒必需让某一个历程优先完成，先转录然后再最先复制。通过使用超高通量测序手艺，纽约西奈山医学院的研究职员首次找到了甲型流感病毒中的一个svRNA，并确定它就是控制病毒从转录过渡到复制的“开关”。超高通量测序手艺是对古板测序手段的一次革命性改变，它一次就可对几十万到几百万条DNA分子举行序列测定，使得对一个物种的转录组和基因组举行详尽全貌的剖析成为可能，以是又被称为深度测序。该研究的向导者之一、西奈山医学院微生物学家本杰明·腾奥弗体现，这项研究的意义十分重大。在流感病毒中，svRNA始终如一职位于病毒RNA片断之间，并且在每种流感病毒中都泛起。若是我们能够阻止svRNA的活性，就能控制病毒不要转向复制历程，从而阻止其扩散。另外的一个利益是，若是病毒只能转录，那它就只能一直爆发卵白，反而最终会强化抗体的反应能力。
腾奥弗指出，理论上讲，通过抑制svRNA就可以阻止病毒片断的复制，但现在的问题是，我们还不相识svRNA的“事情细节”，我们也希望能够找到一种要领，让基于RNA的对抗剂进入人体中，用来抑制svRNA的功效，让病毒不转向复制历程。不过，这个问题可能还需要几年才华解决。由于乙型流感和丙型流感病毒的复制战略和甲型流感病毒的一样，这个发明也就意味着我们将最终能够研制出一种能够治疗所有流感病毒的药物。虽然甲型H1N1流感的阴影正在消逝，但我们历来没有遗忘，仅季节性流感每年就要夺去全天下25万人的生命。一说到流感，你可能马上想起疫苗。然而，流感病毒的进化和变异非�？�，疫苗也必需随之一直更新，并且还不见得有用。以是，科学家们一方面试图培育出万能流感疫苗，另一方面也从治疗的角度起劲开发通用抗流感药物，从而对流感病毒形成前后夹击之势。腾奥弗和他的团队今天带给我们的正是后者的希望。
【点评】
点评：从理论上发明了可以研制出对抗所有流感病毒熏染的药物的战略。
【原文摘录】Published online before print June 1, 2010, doi: 10.1073/pnas.1001984107
Influenza A virus-generated small RNAs regulate the switch from transcription to replication
Jasmine T. Perez, Andrew Varble, Ravi Sachidanandam, Ivan Zlatev, Muthiah Manoharan,
Adolfo García-Sastre, and Benjamin R. tenOever
The discovery of regulatory small RNAs continues to reshape paradigms in both molecular biology and virology. Here we describe examples of influenza A virus-derived small viral RNAs (svRNAs). svRNAs are 22–27 nt in length and correspond to the 5′ end of each of the viral genomic RNA (vRNA) segments. Expression of svRNA correlates with the accumulation of vRNA and a bias in RNA-dependent RNA polymerase (RdRp) activity from transcription toward genome replication. Synthesis of svRNA requires the RdRp, nucleoprotein and the nuclear export protein NS2. In addition, svRNA is detectable during replication of various influenza A virus subtypes across multiple host species and associates physically with the RdRp. We demonstrate that depletion of svRNA has a minimal impact on mRNA and complementary vRNA (cRNA) but results in a dramatic loss of vRNA in a segment-specific manner. We propose that svRNA triggers the viral switch from transcription to replication through interactions with the viral polymerase machinery. Taken together, the discovery of svRNA redefines the mechanistic switch of influenza virus transcription/replication and provides a potential target for broad-range, anti-influenza virus-based therapeutics.
3. T细胞基因刷新制造癌细胞杀手
【摘要】 《科学》期刊新揭晓的一项研究发明通过敲除T细胞必需基因Bcl11b能够获得类似NK细胞的ITNK细胞，在体外实验和老鼠动物模子上这种细胞能够祛除癌细胞和预防肿瘤的形成和转移。并且可以维持存活至少3个月，没有发明携带该细胞的老鼠泛起异常。【点评】
点评：该发明为癌症的免疫疗法提供了新的线索。
【原文摘录】Published Online June 10, 2010 Science DOI: 10.1126/science.1188063
Reprogramming of T cells to Natural Killer-like cells upon Bcl11b deletion.
Peng Li, Shannon Burke, Juexuan Wang, Xiongfeng Chen, Mariaestela Ortiz, Song-Choon Lee, Dong Lu, Lia Campos, David Goulding, Bee Ling Ng, Gordon Dougan, Brian Huntly, Bertie Gottgens, Nancy A. Jenkins, Neal G. Copeland, Francesco Colucci, and Pentao Liu.
T cells develop in the thymus and are critical for adaptive immunity. Natural killer (NK) lymphocytes constitute an essential component of the innate immune system in tumor surveillance and defense against microbes and viruses. Here, we show that the transcription factor Bcl11b was expressed in all T cell compartments and was indispensable for T-lineage development. When Bcl11b was deleted, T cells from all developmental stages acquired NK cell properties and concomitantly lost or decreased T cell–associated gene expression. These induced T-to-natural-killer (ITNK) cells, which were morphologically and genetically similar to conventional NK cells, killed tumor cells in vitro and effectively prevented tumor metastasis in vivo. Therefore, ITNKs may represent a new cell source for cell-based therapies.
4. 红酒和绿茶中多酚类化合物抗癌的机理
【摘要】SphK1/S1P信号通路是与许多癌症的希望及治疗对抗相关的，最新的研究证实绿茶里的儿茶素（ＥＧＣＧ），红酒中的白藜芦醇（Ｒｅｓｖｅｒａｔｒｏｌ），或者各自提取的混淆多酚类都能在体内外实验中抑制前线腺癌细胞的生长，是通过抑制SphK1/S1P信号通路实现的，第一次从分子生物学解读诠释了此类食物中多酚化合物在癌症预防和治疗中的分子靶标。
【点评】
点评：该研究提供了确定的证据，有助于明确绿茶和红酒的抗癌保健功效，也为抗癌药物的研究提供了新靶点。
【原文摘录】The FASEB Journal, 2010; DOI: 10.1096/fj.10-160838
The sphingosine kinase-1 survival pathway is a molecular target for the tumor-suppressive tea and wine polyphenols in prostate cancer
Leyre Brizuela, Audrey Dayon, Nicolas Doumerc, Isabelle Ader, Muriel Golzio, Jean-Claude Izard, Yukihiko Hara, Bernard Malavaud, and Olivier Cuvillier
The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway has been associated with cancer promotion and progression and resistance to treatments in a number of cancers, including prostate adenocarcinoma. Here we provide the first evidence that dietary agents, namely, epigallocatechin gallate (EGCg, IC5075 μM), resveratrol (IC5040 μM), or a mixture of polyphenols from green tea [polyphenon E (PPE), IC5070 μM] or grapevine extract (vineatrol, IC5030 μM), impede prostate cancer cell growth in vitro and in vivo by inhibiting the SphK1/S1P pathway. We establish that SphK1 is a downstream effector of the ERK/phospholipase D (PLD) pathway, which is inhibited by green tea and wine polyphenols. Enforced expression of SphK1 impaired the ability of green tea and wine polyphenols, as well as pharmacological inhibitors of PLD and ERK activities, to induce apoptosis in PC-3 and C4-2B cells. The therapeutic efficacy of these polyphenols on tumor growth and the SphK1/S1P pathway were confirmed in animals using a heterotopic PC-3 tumor in place model. PC-3/SphK1 cells implanted in animals developed larger tumors and resistance to treatment with polyphenols. Furthermore, using an orthotopic PC-3/GFP model, the chemopreventive effect of an EGCg or PPE diet was associated with SphK1 inhibition, a decrease in primary tumor volume, and occurrence and number of metastases. These results provide the first demonstration that the prosurvival, antiapoptotic SphK1/S1P pathway represents a target of dietary green tea and wine polyphenols in cancer.
5. 慢性熏染使γ滋扰素激活休眠的造血干细胞
【摘要】 全身熏染会迅速消耗体内的淋巴细胞和中性粒细胞，造血系统的祖细胞会增产免疫细胞来恢复体内平衡。最新的动物实验研究了造血干细胞在这一历程中的行为，发明在鸡结核杆菌慢性熏染大的老鼠中造血干细胞恒久的增多的增殖反应必需有γ滋扰素的加入，这一结论也在γ滋扰素缺失的老鼠身上获得验证。
【点评】
点评：该研究有助于更好的明确一些慢性熏染病患的免疫系统重修要素，更深入明确造血系统怎样恢复免疫细胞的数目。
【原文摘录】Nature, 2010; 465 (7299): 793 DOI: 10.1038/nature09135
Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection
Megan T. Baldridge, Katherine Y. King, Nathan C. Boles, David C. Weksberg, Margaret A. Goodell
Lymphocytes and neutrophils are rapidly depleted by systemic infection. Progenitor cells of the haematopoietic system, such as common myeloid progenitors and common lymphoid progenitors, increase the production of immune cells to restore and maintain homeostasis during chronic infection, but the contribution of haematopoietic stem cells (HSCs) to this process is largely unknown. Here we show, using an in vivo mouse model of Mycobacterium avium infection, that an increased proportion of long-term repopulating HSCs proliferate during M. avium infection, and that this response requires interferon-γ (IFN-γ) but not interferon-α (IFN-α) signalling. Thus, the haematopoietic response to chronic bacterial infection involves the activation not only of intermediate blood progenitors but of long-term repopulating HSCs as well. IFN-γ is sufficient to promote long-term repopulating HSC proliferation in vivo; furthermore, HSCs from IFN-γ-deficient mice have a lower proliferative rate, indicating that baseline IFN-γ tone regulates HSC activity. These findings implicate IFN-γ both as a regulator of HSCs during homeostasis and under conditions of infectious stress. Our studies contribute to a deeper understanding of haematological responses in patients with chronic infections such as HIV/AIDS or tuberculosis.
6. 肿瘤抑制因子ｐ５３在生殖细胞减数破碎中也有心理作用
【摘要】 肿瘤抑制因子ｐ５３生物学作用不但体现在抑制肿瘤爆发，最近的动物实验批注生殖细胞的减数破碎历程，特殊是拓扑异构酶Ｓｐｏ１１催化的ＤＮＡ双链解开激活了ｐ５３的功效，并一直保存于无法举行减数破碎ＤＮＡ修复的细胞中。这一发明确证了ｐ５３在减数破碎中有心理作用，也提醒了ｐ５３的抑制肿瘤爆发的作用可能是在执行更原始的与基因重组相关的功效时分派的。
【点评】
点评：ｐ５３抑制肿瘤天生的作用看来有可能是其最本源的功效的附带功效。
【原文摘录】Science, 2010; 328 (5983): 1278 DOI: 10.1126/science.1185640
Meiotic Recombination Provokes Functional Activation of the p53 Regulatory Network
Wan-Jin Lu, Joseph Chapo, Ignasi Roig, John M. Abrams
The evolutionary appearance of p53 protein probably preceded its role in tumor suppression, suggesting that there may be unappreciated functions for this protein. Using genetic reporters as proxies to follow in vivo activation of the p53 network in Drosophila, we discovered that the process of meiotic recombination instigates programmed activation of p53 in the germ line. Specifically, double-stranded breaks in DNA generated by the topoisomerase Spo11 provoked functional p53 activity, which was prolonged in cells defective for meiotic DNA repair. This intrinsic stimulus for the p53 regulatory network is highly conserved because Spo11-dependent activation of p53 also occurs in mice. Our findings establish a physiological role for p53 in meiosis and suggest that tumor-suppressive functions may have been co-opted from primordial activities linked to recombination.