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pathway requires the HAT activity of pCAF.188It is thus plausible that activation of different signaling pathways could in?uence the group of coactivators that are required for NR mediated transactivation.

PGC Family of Co-Integrator Proteins

There are three members of the PPARγcoactivator(PGC) family,PGC-1R,PGC-1 ,and the PGC-1-related coactivator PRC.However,PGC-1R is the most extensively character-ized member of the family.Like many protein cofactors, PGC1R coactivates multiple NRs.PGC-1R is selectively expressed mainly in skeletal muscle,cardiac muscle,white fat,and liver.189PGC-1R binds to NR-LBDs with high af?nity and,similar to SRCs,contains a triplet-LXXLL-motif for binding to NRs through their AF-2domains.PGC-1R does not have intrinsic HAT activity and serves as a molecular scaffold that recruits additional factors such as CBP or p300.190The physiological role of PGC-1R has been well characterized as a master regulator of energy homeo-stasis in fat,liver and muscle.191Speci?cally in liver, PGC1-R plays a prominent role in the regulation of genes involved in energy metabolism and glucose homeostasis. PGC-1R is induced in liver by fasting and up-regulates the expression of key genes that participate in gluconeogen-esis,192fatty acid oxidation,193and bile acid synthesis.194 PGC-1R interacts with a multitude of signaling pathways that affect both its expression and/or phosphorylation status. Agents that increase cyclic AMP signaling such glucagon, catecholamines,and glucocorticoids induce PGC-1R expres-sion in liver.192This cyclic AMP/PKA-dependent induction of PGC-1R is mediated by phosphorylation and activation of the transcription factor CREB which directly regulates the PGC-1R promoter.195On the other hand,LKB1/AMPK signaling appears to regulate the repression PGC-1R gene expression.In LKB1de?cient liver,transducer of regulated CREB activity2(TORC2),a transcriptional coactivator of CREB,was dephosphorylated and entered the nucleus, driving expression of PGC-1R.196

In insulin-stimulated skeletal muscle,PGC-1R gene expres-sion is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FOXO1.197In addition to insulin,obesity and saturated fatty acids decrease PGC-1R gene expression and function via p38MAPK-dependent transcriptional pathways.198 Moreover,palmitate,a common saturated fatty acid,reduces PGC-1R expression in skeletal muscle through a mechanism involving MAPK-ERK and NF-κB activation.199

It is worth noting that the most prominent PGC-1R post-translational modi?cation in terms of control of its activity and physiological output is acetylation.200,201Methylation can also enhance PGC-1R activity.202However,this review will focus on the effect of phosphorylation of PGC-1R.Cytokines such as IL-1R,IL-1 ,and TNF R have been shown to activate the transcriptional activity of PGC-1R in muscle through direct phosphorylation by p38MAPK resulting in increased stability

(189)Larrouy,D.;Vidal,H.;Andreelli,F.;Laville,M.;Langin,D.

Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.Int.J.Obes.Relat.Metab.Disord.1999,23(12), 1327–32.

(190)Puigserver,P.;Spiegelman, B.M.Peroxisome proliferator-activated receptor-gamma coactivator1alpha(PGC-1alpha): transcriptional coactivator and metabolic regulator.Endocr.Re V.

2003,24(1),78–90.

(191)Spiegelman,B.M.;Heinrich,R.Biological control through regulated transcriptional coactivators.Cell2004,119(2),157–

67.

(192)Yoon,J.C.;Puigserver,P.;Chen,G.;Donovan,J.;Wu,Z.;Rhee, J.;Adelmant,G.;Stafford,J.;Kahn,C.R.;Granner,D.K.;

Newgard,C.B.;Spiegelman,B.M.Control of hepatic gluco-neogenesis through the transcriptional coactivator PGC-1.Nature 2001,413(6852),131–8.

(193)Vega,R.B.;Huss,J.M.;Kelly,D.P.The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.Mol.Cell.Biol.2000,20(5),1868–

76.

(194)Shin,D.J.;Campos,J.A.;Gil,G.;Osborne,T.F.PGC-1alpha activates CYP7A1and bile acid biosynthesis.J.Biol.Chem.

2003,278(50),50047–52.(195)Herzig,S.;Long,F.;Jhala,U.S.;Hedrick,S.;Quinn,R.;Bauer,

A.;Rudolph,D.;Schutz,G.;Yoon,C.;Puigserver,P.;Spiegel-

man,B.;Montminy,M.CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.Nature2001,413(6852),179–

83.

(196)Shaw,R.J.;Lamia,K.A.;Vasquez,D.;Koo,S.H.;Bardeesy, N.;Depinho,R.A.;Montminy,M.;Cantley,L.C.The kinase LKB1mediates glucose homeostasis in liver and therapeutic effects of metformin.Science2005,310(5754),1642–6. (197)Southgate,R.J.;Bruce,C.R.;Carey,A.L.;Steinberg,G.R.;

Walder,K.;Monks,R.;Watt,M.J.;Hawley,J.A.;Birnbaum, M.J.;Febbraio,M.A.PGC-1alpha gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclu-sion of FoxO1in insulin-stimulated skeletal muscle.FASEB J.

2005,19(14),2072–4.

(198)Crunkhorn,S.;Dearie,F.;Mantzoros,C.;Gami,H.;da Silva, W.S.;Espinoza,D.;Faucette,R.;Barry,K.;Bianco,A.C.;Patti, M.E.Peroxisome proliferator activator receptor gamma coac-tivator-1expression is reduced in obesity:potential pathogenic role of saturated fatty acids and p38mitogen-activated protein kinase activation.J.Biol.Chem.2007,282(21),15439–50. (199)Coll,T.;Jove,M.;Rodriguez-Calvo,R.;Eyre,E.;Palomer,X.;

Sanchez,R.M.;Merlos,M.;Laguna,J.C.;Vazquez-Carrera, M.Palmitate-mediated downregulation of peroxisome prolifera-tor-activated receptor-gamma coactivator1alpha in skeletal muscle cells involves MEK1/2and nuclear factor-kappaB activation.Diabetes2006,55(10),2779–87.

(200)Lerin,C.;Rodgers,J.T.;Kalume,D.E.;Kim,S.H.;Pandey,

A.;Puigserver,P.GCN5acetyltransferase complex controls

glucose metabolism through transcriptional repression of PGC-1alpha.Cell Metab.2006,3(6),429–38.

(201)Rodgers,J.T.;Lerin,C.;Haas,W.;Gygi,S.P.;Spiegelman,

B.M.;Puigserver,P.Nutrient control of glucose homeostasis

through a complex of PGC-1alpha and SIRT1.Nature2005,434 (7029),113–8.

(202)Teyssier,C.;Ma,H.;Emter,R.;Kralli,A.;Stallcup,M.R.

Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation.Genes De V.2005,19(12),1466–73.

reviews Staudinger and Lichti 32MOLECULAR PHARMACEUTICS VOL.5,NO.1

and half-life and activation of PGC-1R protein.203p38MAPK phosphorylates PGC-1R at three residues(T262,S265,and T298)that occur in a region previously shown to interact with NRs;however,it remains to be seen whether phosphorylation of PGC-1R affects NR docking.Further studies performed in primary hepatocytes con?rm that PGC-1R phosphorylation by p38MAPK is necessary for free fatty acid induced activation of PEPCK,a PGC-1R-target gene involved in gluconeogen-esis.204The precise mechanism by which p38MAPK-mediated phosphorylation of PGC-1R alters the amount and activity of PGC-1R will likely provide important physiological,and perhaps therapeutic,insight.Kralli’s group has also shown that activation of p38MAPK leads to an increase in PGC-1R activity.They propose that a repressor binds to the PGC-1R -LXXLL-motif and that the interaction is terminated upon activation of p38MAPK.205This suggests a model where the repressor and NRs compete to recruit PGC-1R to an inactive or active state and that cellular signaling such as ligand or kinase signaling can shift the equilibrium between the two states.

In addition to p38MAPK,two recent reports show that PGC-1R is phosphorylated by AMPK and Akt/PKB.AMPK activation in muscle increases the expression of genes required for glucose uptake,fatty acid oxidation,and mitochondrial https://www.doczj.com/doc/5d8714747.html,ing primary muscle cells and PGC-1R knockout mice,Jager et al.demonstrated that the effect of AMPK mediated gene expression is dependent on PGC-1R function.Furthermore,AMPK phosphorylates PGC-1R at T177and S583,which is required for PGC-1R dependent induction of the PGC-1a promoter.206In liver, the mechanism by which insulin regulates lipid synthesis and degradation are largely unknown.Insulin treatment,through protein kinase Akt2/protein kinase B(PKB)resulted in the phosphorylation and inhibition of PGC-1R.207Akt phosphor-ylates PGC-1R at S570which prevents the recruitment of PGC-1R to its target promoters.207Repression of PGC-1R activity by phosphorylation impairs its ability to promote gluconeogenesis and fatty acid oxidation in liver.PGC-1R has an additional role in the regulation of this pathway.PGC-1R coactivates PPAR R in the expression of tribbles homo-logue TRB-3,a fasting inducible inhibitor of Akt/PKB.208 This mechanism by which insulin signaling regulates PGC-1R activity could provide insight into alternative drug targets for the treatment of type-2-diabetes.

Therapeutic Obstacles and Opportunities NRs control many aspects of biology including develop-ment,reproduction,and homeostasis through target gene activation.The ability to modulate by their activity using fat-soluble molecules makes them extremely attractive drug targets.As our understanding of NR signaling increases,so does our appreciation of the complexity of their regulation. It is possible that management of diseases in the future will include therapies that not only target NRs but also coregulator proteins and signaling pathways that are critical in the modulation of their function.

PPARs are the targets of some commonly used drugs in the treatment of hyperlipidemia and type-2-diabetes.Activa-tion of PPAR R by?brates causes the up-regulation of genes involved in the -oxidation of fatty acids.This results in the decreased synthesis of triglycerides and decreased LDL secreation by the liver.67Glitazones such as rosiglitazone and pioglitazone are PPARγagonists.PPARγis known to regulate glucose homeostasis and adipogenesis,making it an attractive target for the treatment of type-2-diabetes. However,recent evidence has indicated an increased risk of heart attacks with rosiglitazone(marketed as Avandia)and the FDA released a safety alert on the drug in May2007.209 Further research surrounding the signaling events and co-regulator proteins that affect PPARγactivity in multiple tissues may be useful in separating the therapeutic effects from the toxic effects of drugs like rosiglitazone.

One therapeutic challenge and opportunity in development of drugs that target NRs are selective therapeutic modulators (SRMs).SRMs are NR ligands that exhibit agonistic or antagonistic activity in a cell-or tissue-dependent manner.The classic SRM is tamoxifen,which can selectively activate or inhibit ERs and is commonly used in the treatment of breast cancer.Tamoxifen exhibits agonist(estrogen-like)activity in uterus and antagonist(antiestrogen-like)activity in breast.210 SRM-induced alterations in the conformation of NRs may affect the ability of the receptor to bind to coregulators or to be phosphorylated.The expression pro?le of speci?c coactivator proteins and corepressor proteins in a given cell type may affect the relative agonist vs antagonist activity of SRMs.However, as evidenced in this review,it is likely that cellular signaling events contribute to SRM activity due to altered activation,

(203)Puigserver,P.;Rhee,J.;Lin,J.;Wu,Z.;Yoon,J.C.;Zhang,

C.Y.;Krauss,S.;Mootha,V.K.;Lowell,B.B.;Spiegelman,

B.M.Cytokine stimulation of energy expenditure through p38

MAP kinase activation of PPARgamma coactivator-1.Mol.Cell 2001,8(5),971–82.

(204)Collins,Q.F.;Xiong,Y.;Lupo,E.G.,Jr.;Liu,H.Y.;Cao,W.

p38Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes.J.Biol.Chem.2006, 281(34),24336–44.

(205)Knutti,D.;Kressler,D.;Kralli,A.Regulation of the transcrip-

tional coactivator PGC-1via MAPK-sensitive interaction with

a repressor.Proc.Natl.Acad.Sci.U.S.A.2001,98(17),9713–

8.

(206)Jager,S.;Handschin,C.;St-Pierre,J.;Spiegelman,B.M.AMP-activated protein kinase(AMPK)action in skeletal muscle via direct phosphorylation of PGC-1{alpha}.Proc.Natl.Acad.Sci.

U.S.A.2007.

(207)Li,X.;Monks,B.;Ge,Q.;Birnbaum,M.J.Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcrip-tion coactivator.Nature2007,447(7147),1012–6.(208)Koo,S.H.;Satoh,H.;Herzig,S.;Lee,C.H.;Hedrick,S.;

Kulkarni,R.;Evans,R.M.;Olefsky,J.;Montminy,M.PGC-1

promotes insulin resistance in liver through PPAR-alpha-

dependent induction of TRB-3.Nat.Med.2004,10(5),530–4. (209)Nissen,S.E.;Wolski,K.Effect of rosiglitazone on the risk of

myocardial infarction and death from cardiovascular causes.

N.Engl.J.Med.2007,356(24),2457–71.

(210)Smith,C.L.;O’Malley,B.W.Coregulator function:a key to

understanding tissue speci?city of selective receptor modulators.

Endocr.Re V.2004,25(1),45–71.

Signal Transduction and Nuclear Receptors reviews

VOL.5,NO.1MOLECULAR PHARMACEUTICS33

文献阅读与翻译(精华版)

Unit 1 general description of literature reading and translation 1.Definition of Literature Literature is a general term for professional writings in the form of books, papers, and other documentations. As an important means for preserving knowledge, literatures have become precious resources or treasures for the mankind, which have greatly contributed to the social progress of the human race. 2.Classification of Literature 1) Textbooks(课本) a kind of professional writing(一种专业的写作) 2) Monographs(专著) various viewpoints and discussions 3) Papers(论文) the theoretical analysis and experimental description title, author, affiliation, abstract, keywords, introduction, theoretical analysis and/or experimental description, results and discussion or conclusion, acknowledgments, references 4) Encyclopedias(百科全书) every branch of knowledge 5) Periodicals (期刊) a series of publications 6)Special Documentation(特殊文档) all the printed materials 3.Linguistic Features of Scientific Literature stylistically (文体上) scientific literature is a kind of form writing; syntactically(结构上)scientific literature has rigorous grammatical structures and in most cases is rather unitary; Morphologically(语法上)scientific literaure is featured by high specialization,the use of technical terms and jargons ,unambiguous implication and the fixed sense of the word Principles or Criteria of Translation Whenever principles or criteria of translation are under discussion in China, Yan Fu’s three- character guide”-----xin, da, ya, namely, faithfulness (信), expressiveness (达), and elegance (雅). These three principle has always been regarded as a plumb-line for measuring the professional level of translation and a goal for translators to strive after. However, in the application of this principle, people come to find some unsatisfactory aspects of the three-character guide and have put foreword a variety of new standards or criteria of translation. Despite a variety of opinions, two criteria are almost unanimously accepted by all, namely, the criterion of faithfulness/accuracy (忠实/准确) and that of smoothness (流畅). We may also take these two criteria as the principle scientific literature translation. By faithful/accuracy, we mean to be faithful not only to the original contents, to the original meaning and views, but also to the original form and style. By smoothness, we mean not only easy and readable rendering, but also idiomatic expression in the target language, free form stiff formula and mechanical copying form dictionaries. Unit 2 professional papers 2.1.Definition of professional papers A professional paper is a typewritten paper in which professionals present their views and research findings on a chosen topic. It is variously known as the “research paper”, “course paper”, “thesis paper” or “library paper”. The task of the author of a paper is essentially the same: to read on a particular topic, gather information about it, and report the findings in it. 2.2.Classification of professional papers

把下面的短文加上标点并翻译成现代汉语(精)

P384答案 把下面的短文加上标点并翻译成现代汉语: 标点: 陈康肃公尧咨善射,当世无双,公亦以此自矜。尝射于家圃,有卖油翁释担而立,睨之,久而不去。见其发矢十中八九,但微颔之。康肃问曰:“汝亦知射乎?吾射不亦精乎?”翁曰:“无他,但手熟尔。”康肃忿然曰:“尔安敢轻吾射!”翁曰:“以我酌油知之。”乃取一葫芦置于地,以钱覆其口,徐以勺酌油沥之,自钱孔入而钱不湿。因曰:“我亦无他,惟手熟尔。”康肃笑而遣之。(欧阳修《卖油翁》) 译文: 陈康肃公尧咨善于射箭,当世没有人能跟他相比。康肃公也以此自负。他曾经在家中菜园里射箭,有一个卖油的老人放下担子站在那里,用眼睛斜视很久没有离去。看见康肃公射箭十中八九,只是微微点头。康肃公问他说:“你也懂得射箭吗?我射箭技术不是很精湛吗?”老人说:“没什么,只是手熟罢了。”康肃公很生气地说:“你怎么敢轻视我的射箭技术!”老人说:“根据我的舀油就知道。”于是就拿了一个葫芦放在地上,用一枚铜钱盖在葫芦口上,慢慢地用勺子舀了油滴进葫芦里,油从钱孔滴入而钱却没有湿。老人于是说道:“我也没什么,只是手熟罢了。”康肃公笑着打发他走了。 标点: 平公射鴳不死,使竖襄搏之,失。公怒,拘将杀之。叔向闻之,夕,君告之。叔向曰:“君必杀之。昔吾先君唐叔射兕于徒林,殪,以为大甲,以封于晋。今君嗣吾先君唐叔,射鴳不死,搏之不得,是扬吾君之耻者也。君其必速杀之,勿令远闻。”君忸怩,乃趣赦之。(《国语·晋语八》) 译文: 晋平公射鴳没有射死,命令仆人襄去抓它,没有抓到。平公很生气,把襄抓起来要杀了他。叔向听说了,晚上赶去拜见晋平公,晋平公告诉了他这件事。叔向说:“您一定要杀了他。从前我们的先君唐叔在徒林射犀牛,射死了以后,用犀牛皮做了一副铠甲,因此被封在晋。如今您继承我们的先君唐叔,可是射鴳射不死,抓又抓不到,这件事是宣扬我君的耻辱啊。您一定要赶快杀了他,不要让这事传扬出去。”晋平公很不自在,就赶快放了竖襄。 标点: 后特征为洛阳令。时湖阳公主苍头白日杀人,因匿主家,吏不能得。及主出行,而以奴骖乘,宣于夏门亭候之。乃驻车叩马,以刀画地,大言数主之失,叱奴下车,因格杀之。主即还宫诉帝。帝大怒,召宣,欲箠杀之。宣叩头曰:“愿乞一言而死。”帝曰:“欲何言?”宣曰:“陛下圣德中兴,而纵奴杀良人,将何以理天下乎?臣不须箠,请得自杀。”即以头击楹,流血被面。帝令小黄门持之,使宣叩头谢主,宣不从。强使顿之,宣两手据地,终不肯俯。主曰:“文叔为白衣时,藏亡匿死,吏不敢至门。今为天子,威不能行一令乎?”帝笑曰:“天子不与白衣同。”因敕“强项令”。出,赐钱三十万。宣悉以班诸吏。由是搏击豪强,莫不震慄。京师号为“卧虎”。歌之曰:“枹鼓不鸣董少平。”(《后汉书·酷吏列传》) 译文: 后来特地征召董宣为洛阳令。当时湖阳公主家的奴仆白天杀人,因藏匿在公主家里,官吏不能抓捕到。等到公主出行,用这个家奴当随从,董宣就在夏门亭等候他们。于是就拦住车马,用刀在地上画着,大声数落公主的过失,呵斥那个家奴下车,就杀了那个家奴。公主立即回宫向皇帝告状。皇帝很生气,召来董宣,要用鞭子打死他。董宣磕头说:“请让我说

外文翻译初稿

外文翻译: 发现者,管理者?吸引,激励和留住知识型员工 吸引,激励和保留知识型员工已成为一个以知识为基础和劳动力市场紧张,在不断变化的知识管理实践和技术的全球趋同已重新界定工作性质的重要。虽然就业的做法和团队为基础的工作的个性化可能提供的个人和组织的灵活性,使人力资源的竞争优势和组织战略变得更加这一探索性研究确定的最和最有效的的人力资源战略,知识密集型企业在新加坡(KIFs)用于吸引,激励和留住这些工人。最流行的策略并不总是最有效的,似乎有独特的“捆绑”人力资源管理知识工作者的做法。这些措施有所不同,根据是否是外国或本地的所有权。统计学意义的结果为基础的架构,改善管理知识工作者的这些做法的有效性、建议。跨文化研究是有必要建立这些做法的扩散程度。 德鲁克在1989年创造“知识工人”一词,它是描述谁携带它们的个人,,而不是作为一个强大的资源知识组织,自己的。知识工作,可以说是一个知识分子的性质和以及合格员工形糊不清知识工作者和知识密集的企业(KIFs)的概念(Alvesson1993年)。乌尔里希(1998)断言说,随着知识工作的增加,智力资本是一家公司的只有可观的资产。福格特(1995)定义为一个人与知识工作者动机和能力,共同创造新的见解和能力,沟通,教练和便于实施的新思路。这项工作是不可重复性和结果为导向,用两个“传统”的科学方法和需要连续学习,直觉,新的思维和想象力。但其中一些概念可能矛盾,有些理想化,根据Alvesson(1993年:1000年至1004年)。他指出知识工作者的工作是更恰当地定性为“含糊不清密集的”比“知识密集”。这些工人可能同时拥有传统知识的类型连接科学和理性的分析问题的解决和必要的知识,以及作为一个特定的主体,需要处理的复杂性和不确定性的能力。后者需要直觉,创造性,灵活性和社交技巧。 一个新兴的文学和具体的人力资源战略研究证据,为吸引,激励和保留这些做法和组织蓝图工人(男爵和汉南,2002年,休伊特&Associates公司,2001年)。 Alvesson和Karreman 2001年),从文献和案例研究的审查,认为“知识管理的可能性,或更多的,作为一个管理人员或实践操作比对促进知识的创造“(2001年:1)切合做法的信息。知识工作者个人与个人的知识,并组织越来越多地寻求如何转化为社会共享的部署知识组织的目标。 我们的研究探讨有效的人力资源战略和措施,吸引、激励和留住知识型工人。我们的工作,认为跨国公司和当地知识密集的企业(KIFs)在六个部门,有两个主要目的: 1、确定最佳或最有效的人力资源管理知识的做法和工人,吸引提出了一个模式,激励和保 留这些工人; 探索的概念,负责管理人力资源的做法是否有一组特殊的一般的知识型工人和其他工人。 2、第二个目的是: ●提供一个以知识为基础的企业大多数受访者接受的通用定义;比较有关的知识型员工的可接受的和不可接受的营业额 ●其他员工和人力资源的做法套件; ●查明原因和采取的措施,以解决高层次知识 流动率; ●识别知识工作者从事的就业形式。这些包括为核心的全职员工,并作为非核心员工与就业分包,转包,咨询,兼职,定期,临时,休闲或家庭雇佣条款。 我们的结论认为超越东亚范围内的调查结果的相关性,跨文化比较研究的进一步指示。鉴于探索上述目标的性质,实证的方法是调查而不是假设检验。 文献回顾

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