2012-03MerrillLynchAgConference
物理学家李政道-文档资料
家世
李政道的曾祖父李子义是江苏东吴大学（即现
在的苏州大学）的前身苏州博习书院创建人之 一。李政道的伯祖父曾任东吴大学教务长达数 十年，伯父也在博习医院和东吴大学任职数十 年。 1950年代，台湾时期，李政道在台湾的母亲张 明璋女士和二哥李崇道(李崇道毕业于广西大 学农学院，曾任中兴大学校长、农委会主委)、 二嫂许淑英，因在家里留宿一位旧时广西大学 同学，以“掩护匪谍”罪名入狱。张明璋女士 去世后，李政道将母亲核物理、统计力学、流体 力学、天体物理方面的工作也颇有建树。 1949年与罗森布拉斯和杨振宁合作提出普适费米弱 作用和中间玻色子的存在。 1951年提出水力学中二维空间没有湍流。 1952年与派尼斯合作研究固体物理中极化子的构造。 1954年发表了量子场论中的著名的“李模型”理论。 1957年与奥赫梅和杨振宁合作提出电荷共轭不守恒 和时间不反演的可能性。1959年与杨振宁合作，研 究了硬球玻色气体的分子动理论，对研究氦Ⅱ的超流 动性作出了贡献。
1964-84 哥伦比亚大学费米物理讲座教授 1984- 哥伦比亚大学全级教授 1986- 中国高等科学技术中心（CCAST, WL）主任 1986- 北京现代物理中心主任（北京大学） 1988- 浙江现代物理中心主任（浙江大学） 1997-2003 RIKEN-BNL研究中心主任 2004- RIKEN-BNL研究中心名誉主任 2006至今 北京大学高能物理研究中心主任 1985-93 普林斯顿高等研究院理事会成员 1990－ 以色列特拉维夫大学董事会成员
1946年，20岁的李政道到美国留学，被芝加哥大学 研究生院录取。3年后便以“有特殊见解和成就” 通过了博士论文答辨，被誉为“神童博士”，其时 年仅23岁。 1956年，李政道与杨振宁一起发表了一篇文章，推 翻了物理学中心信息之—宇称守恒，解决了当时的 θ－τ之谜─就是后来称为的K介子有两种不同的衰变 方式：一种衰变成偶宇称态，一种衰变成奇宇称态。 如果弱衰变过程中宇称守恒，那么它们必定是两种 宇称状态不同的K介子。但是从质量和寿命来看， 它们又应该是同一种介子。他们通过分析，认识到 很可能在弱相互作用中宇称不守恒，并提出了几种 检验弱相互作用中宇称是不是守恒的实验途径。次 年，这一理论预见得到吴健雄小组的实验证实。因 此，李政道和杨振宁的工作迅速得到了学术界的公 认，并共同获得了1957年诺贝尔物理学奖。
2012年度国际国内有关学术会议汇总
2012年度国际国内学术会议清单
为了便于我所科研人员提前了解有关学术会议信息，科技处对2012年国际国内相关学术会议进行了汇总，希望感兴趣的人员能积极参加有关会议，多与同行进行学术交流，以提高自身学术水平与交流能力，促进我所学科发展。
（注：2012年国际会议需按照本年度外事批复计划执行，未列入外事计划者，本年度将无法执行。
有意向参加有关国际会议者，请提前准备，本年底将通知大家统一上报明年参会计划。
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科学技术处
2012年2月23日
2012国际相关学术会议清单
2012国内相关学术会议清单。
聚赖氨酸 应用
Biochemical Engineering Journal 65 (2012) 70–81Contents lists available at SciVerse ScienceDirectBiochemical EngineeringJournalj o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /b ejReviewReview on production and medical applications of -polylysineSwet Chand Shukla a ,Amit Singh b ,Anand Kumar Pandey c ,Abha Mishra a ,∗aSchool of Biochemical Engineering,Institute of Technology,Banaras Hindu University,Varanasi 221005,India bDepartment of Pharmacology,Institute of Medical Sciences,Banaras Hindu University,Varanasi 221005,India cSchool of Biomedical Engineering,Institute of Technology,Banaras Hindu University,Varanasi 221005,Indiaa r t i c l ei n f oArticle history:Received 3May 2011Received in revised form 28March 2012Accepted 2April 2012Available online 11 April 2012Keywords:-PolylysineHomopolyamideS.albulus Lysinopolymerus Conjugate Drug carrier Targetinga b s t r a c t-Polylysine (-PL)is a homopolyamide linked by the peptide bond between the carboxylic and epsilon amino group of adjacent lysine molecules.It is naturally occurring biodegradable and nontoxic towards human.This review article gives an insight about the various -PL producing strains,their screening procedures,mechanism of synthesis,characterization,and its application in the medical field.The poly cationic nature of -PL at physiological pH makes it as one of the potential candidates in the field of drug delivery.Most of the biomedical applications till date use synthetic ␣-PLL as a raw material.However,it is believed that naturally occurring -PL would be an ideal substitute.© 2012 Elsevier B.V. All rights reserved.Contents 1.Introduction ..........................................................................................................................................712.Origin and distribution of -PL ......................................................................................................................713.Mechanism of synthesis .............................................................................................................................714.Biosynthesis and molecular genetics ................................................................................................................715.Microbial production of -polylysine ................................................................................................................726.Screening and detection of -PL production in microbial system...................................................................................737.Purification and characterization of -PL ............................................................................................................738.Conformation of -PL ................................................................................................................................749.Application of polylysine in medicine ...............................................................................................................749.1.Polylysine as a drug carrier ...................................................................................................................749.2.Polylysine as nanoparticles...................................................................................................................759.3.Polylysine as a gene carrier...................................................................................................................759.4.Polylysine as liposomes ......................................................................................................................769.5.Polylysine as interferon inducer .............................................................................................................769.6.Polylysine as lipase inhibitor .................................................................................................................779.7.Polylysine as hydrogel ........................................................................................................................779.8.Polylysine as coating material................................................................................................................779.9.Other applications ............................................................................................................................7810.Conclusion ..........................................................................................................................................78References ...........................................................................................................................................78Abbreviations:Pls,polylysine synthetase;NaSCN,sodium thiocynate;FTIR,Fourier transform infrared spectroscopy;NMR,nuclear magnetic resonance spectroscopy;MION,monocrystalline iron oxide nanoparticle;NPs,nanoparticles;IgM,immunoglobulin M.∗Corresponding author.Tel.:+919451887940.E-mail address:abham.bce@itbhu.ac.in (A.Mishra).1369-703X/$–see front matter © 2012 Elsevier B.V. All rights reserved./10.1016/j.bej.2012.04.001S.C.Shukla et al./Biochemical Engineering Journal 65 (2012) 70–81711.Introduction-Polylysine (-PL)is a basic polyamide that consists of 25–30residues of l -lysine with an -amino group-␣-carboxyl group link-age (Fig.1).Polyamide can be grouped into two categories,one in which the polyamide consists of only one type of amino acid linked by amide bonds called homopolyamide and the other which consists of different amino acids in their chain called proteins [1].Furthermore,proteins are biosynthesized under the direction of DNA,while the biosynthesis of homopolyamides is catalyzed by peptide synthetases.Therefore,the antibiotics that are inhibitors of translation such as chloramphenicol,do not affect the biosyn-thesis of polyamides.Proteins in general exhibit exact length,whereas homopolyamides show a remarkable variation in molec-ular weight.Amide linkages in proteins are only formed between ␣-amino and ␣-carboxylic groups (␣-amide linkages),whereas amide bonds in homopolyamide involve other side chain functions such as -and ␥-carboxylic with -amino groups [1].Particularly,chemically synthesized polylysine were found to have linkages between ␣-carboxyl and ␣-amino group.Many workers investi-gated various applications of ␣-PL in the drug delivery system.However,␣-PL was reported to be toxic to human beings,and there-fore,research has now been diverted towards finding naturally occurring polymers [2,3].-PL is an unusual naturally occurring homopolyamide having linkages between the -amino group and ␣-carboxylic group,and it shows high water solubility and sta-bility.No degradation is observed even when the -PL solution is boiled at 100◦C for 30min or autoclaved at 120◦C for 20min [4].-PL was discovered as an extracellular material of Streptomyces albulus ssp.Lysinopolymerus strain 346during screening for Dra-gendorff’s positive substances [5–7].Mutation studies were made by nitrosoguanidine treatment on wild type Lysinopolymerus strain 346to enhance the -PL production.As a result of mutation,S-(2-aminoethyl)-l -cysteine and glycine resistant mutant were isolated,with four times higher amounts of -PL than the wild type [8].-PL is a cationic surface active agent due to its positively charged amino group in water,and hence they were shown to have a wide antimi-crobial activity against yeast,fungi,Gram positive,Gram negative bacterial species [4,9].The excreted polymer is absorbed to the cell surfaces by its cationic property,leading to the striping of outer membrane and by this mechanism the growth of microbes sensi-tive to -PL is inhibited.-PL degrading enzyme plays an important role in self-protection of -PL producing microbes [9].Due to its excellent antimicrobial activity,heat stability and lack of toxicity,it is being used as a food preservative [10,11].Naturally occurring -PL is water soluble,biodegradable,edible and nontoxic toward humans and the environment.Therefore,-PL and its derivatives have been of interest in the recent few years in food,medicine and electronics industries.Derivatives of -PL are also available which offers a wide range of unique applications such as emul-sifying agent,dietary agent,biodegradable fibers,highly water absorbable hydrogels,drug carriers,anticancer agent enhancer,biochip coatings,etc.Polylysine exhibits variety of secondary struc-tures such as random coil,␣-helix,or -sheet conformations in aqueous solution.Moreover,transitions between conformations can be easily achieved using,salt concentration,alcohol con-tent,pH or temperature as an environmental stimulus.There is aH NH*CH 2CH 2CH 2CH 2CH NH 2CO*OHnFig.1.Chemical structure of epsilon polylysine.growing interest in using -PL and its derivatives as biomaterials and extensive research has been done leading to a large number of publications [4,12–15].The present review focuses on various pro-cess parameters for maximal yield of polymer by microbial system more specifically by actinomycetes,probable biosynthetic route and its application,especially in pharmaceutical industries.2.Origin and distribution of -PLNot much is known about the -PL producing microbial species existing in the environment.It is observed that -PL producers mainly belong to two groups of bacteria’s:Streptomycetaceae and Ergot fungi .Besides Streptomyces albulus ,a number of other -PL producing species belonging to Streptomyces,Kitasatospora and an Ergot fungi,Epichole species have been isolated [16].Recently,two Streptomyces species (USE-11and USE-51)have been isolated using two stage culture method [17].3.Mechanism of synthesis-Polylysine (-PL)is a homopolymer characterized by a pep-tide bond between ␣-carboxyl and -amino groups of l -lysine molecules.Biosynthetic study of -PL was carried out in a cell-free system by using a sensitive radioisotopic -PL assay method,suggested that the biosynthesis of -PL is a non ribosomal peptide synthesis and is catalyzed by membrane bound enzymes.In vitro ,-PL synthesis was found to be dependent on ATP and was not affected by ribonuclease,kanamycin or chloramphenicol [18].In a peptide biosynthesis,amino acids are activated either by adeny-lation or phosphorylation of carboxyl group.Adenylation occurs in translation and in the nonribosomal synthesis of a variety of unusual peptides [19,20];Phosphorylation has been suggested for the biosynthesis of glutathione [21].In the former,ATP is con-verted to AMP and pyrophosphate by adenylation,and in the latter,phosphorylation leads to ADP and phosphate as the final prod-ucts.The synthesis of -PL,a homopolypeptide of the basic amino acid l -lysine,is similar to that of poly-(␥-d -glutamate)in terms of adenylation of the substrate amino acid [18].Through the exper-imental observations,the probable mechanism of synthesis was suggested by Kawai et al.showed that in the first step of -PL biosynthesis l -lysine is adenylated at its own carboxyl groups with an ATP-PPi exchange reaction.The active site of a sulfhydryl group of an enzyme forms active aminoacyl thioester intermediates,lead-ing to condensation of activated l -lysine monomer.This is the characteristic feature of nonribosomal peptide synthetase enzyme [22–24].-PL producing strain of Streptomyces albulus was found to pro-duce -PL synthetase (Pls).A gene isolated from the strain was identified as a membrane protein with adenylation and thiolation domains which are characteristic features of the nonribosomal pep-tide synthetases (NRPSs).-PL synthetase has six transmembrane domains surrounding three tandem soluble domains without any thioesterase and condensation domain.This tandem domain itera-tively catalyzes l -lysine polymerization using free l -lysine polymer as an acceptor and Pls-bound l -lysine as a donor,thereby yielding chains of diverse length (Fig.2).Thus,-PL synthetase acts as a ligase for peptide bond formation [25].Yamanaka et al.suggested that -PL synthetase function is regulated by intracellular ATP and found that acidic pH conditions are necessary for the accumulation of intracellular ATP,rather than the inhibition of the -PL degrading enzyme [26].4.Biosynthesis and molecular geneticsThe precursor of -PL biosynthesis was identified to be l -lysine by radiolabeling studies using [14C]-l -lysine in Streptomyces72S.C.Shukla et al./Biochemical Engineering Journal 65 (2012) 70–81Fig.2.Mechanism for synthesis of -polylysine.albulus 346[18].However,a high-molecular-weight plasmid (pNO33;37kbp)was detected in -PL-producing S.albulus ,and the replicon of pNO33was used to construct a cloning vector for S.albu-lus strain [27].The order and number of NRPSs modules determine the chain length of the -PL [24,28].However,the chain length of -PL was shortened by the use of aliphatic hydroxy-compound and -cyclodextrin derivative [29,30].-PL with more than nine l -lysine residues severely inhib-ited the microbial growth while the -PL with less than nine l -lysine residues showed negligible antimicrobial activity.All the strains producing -PL from glycerol showed lower number aver-age molecular weight (M n )than those obtained from glucose [31].The -PL-degrading activity was detected in both -PL tolerant and -PL producing bacteria.The presence of -PL-degrading activity in Streptomyces strains is closely related with -PL-producing activ-ity,which indicates that tolerance against -PL is probably required for -PL producers.The presence of -PL degrading enzyme is detri-mental to industrial production of -PL.Therefore,-PL degrading enzyme of S.albulus was purified,characterized and the gene encoding an -PL degrading enzyme of S.albulus was cloned,and analyzed [32].The -PL-degrading enzyme of S.albulus is tightly bound to the cell membrane.The enzyme was solubilized by NaSCN in the presence of Zn 2+and was purified to homogeneity by phenyl-Sepharose CL-4B column chromatography,with a molecular mass of 54kDa.The enzymatic mode of degradation was exotype mode and released N-terminal l -lysine’s one by one.Streptomyces vir-giniae NBRC 12827and Streptomyces noursei NBRC 15452showed high -PL-degrading aminopeptidase activity and both strains have the ability to produce -PL,indicating a strong correlation between the existence of -PL degrading enzyme and -PL produc-ing activity [33].-PL degrading enzymes were also found in -PL tolerant microorganisms,Sphingobacterium multivorum OJ10and Chryseobacterium sp.OJ7,which were isolated through enrichmentof the culture media with various concentrations of -PL.S.mul-tivorum OJ10could grow well,even in the presence of 10mg/ml -PL,without a prolonged lag phase.The -PL-degrading enzyme activity was also detected in the cell-free extract of -PL tolerant S.multivorum OJ10.The enzyme catalyzed an exotype degradation of -PL and was Co 2+or Ca 2+ion activated aminopeptidase.This indicates the contribution of -PL-degrading enzymes to the toler-ance against -PL [34].An -PL degrading enzyme of -PL tolerant Chryseobacterium sp.OJ7,was also characterized and the purified enzyme catalyzed the endotype degradation of -PL,in contrast to those of Streptomyces albulus and Sphingobacterium multivorum OJ10.Probably,their possession of proteases enables their growth in the presence of a high -PL concentration.-PL degradation was also observed by commercially available proteases,such as Pro-tease A,Protease P and Peptidase R [34,35].5.Microbial production of -polylysinePolylysine can be synthesized by chemical polymerization start-ing from l -lysine or its derivatives.Researchers described two different routes to polymerize lysine residues without the use of protection groups.However,linear -PLL can be obtained by applying 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as an activating agent for the polycondensation of l -lysine in an aqueous medium.In contrast to this,␣-poly(l -lysine)can be obtained by using dicyclohexyl carbodiimide and 18-crown-6ether in chloro-form [36].Dendrimeric ␣,-polylysine were synthesized by using solid phase peptide synthesis method and used dendritic ␣,-polylysine as a delivery agent for oligonucleotides [37,38].Moccia et al.for the first time reported ␣,-polylysine by assembling Fmoc and Boc protected l -lysine monomers by solid phase synthesis [39].Guo et al.synthesized -PL-analogous polypeptides with not only similar ␣-amino side groups but also similar main chain throughS.C.Shukla et al./Biochemical Engineering Journal65 (2012) 70–8173microwave assisted click polymerization technique[40].Recently, Roviello et al.synthesized a cationic peptide based on l-lysine and l-diaminobutyric acid for thefirst time by solid phase synthesis [41].-PL was discovered as an extracellular material produced by filamentous actinomycetes group of micro-organism Streptomyces albulus ssp.Lysinopolymerus strain346more than35years ago [5].It is synthesized by a nonribosomal peptide synthetase and released extracellularly.In actinomycetes group of organisms l-lysine is synthesized through the diaminopimelic acid pathway. Diaminopimelate is formed via l-aspartate(Asp)produced by com-bining oxaloacetate in the tricarboxylic acid cycle with ammonium as a nitrogen source.Citrate was found to be facilitator for the production much more than other organic acids of TCA cycle[24].Studies revealed that decline in pH during the fermentation pro-cess is an essential condition for the accumulation of-PL.Shima et al.carried out two-step cultivation method for S.albulus.Strain wasfirst grown for24h in a culture medium containing glycerol as carbon source with yeast extract,then in second step medium was replaced by glucose,citric acid with(NH4)2SO4[42].It was found that the mutant of strain346decreases the culture pH from its initial value of6.8–4.2by36h,and slowly decreased thereafter to 3.2at96h.The accumulation of-PL in the broth increased signifi-cantly when the culture pH was about4.0.The fed batch cultivation was adopted to enhance the-PL production with two distinct phases.In phase I,cell was grown at pH(6.8)optimum for cul-ture growth then in phase II,the pH was kept around4.0by the addition of glucose.Depletion of glucose causes an increase in pH of the culture broth leading to the degradation of the produced -PL.Thus the pH control strategy in fed batch culture success-fully enhanced the yield of-PL to almost9fold[43].The airlift bioreactor(ABR)was also evaluated and compared with jar fer-mentor for-PL production.The results showed that the production level of-PL in a ABR with a power consumption of0.3kW/m3was similar to that in a5-l jar fermentor with power consumption of 8.0kW/m3.The leakage of intracellular nucleic acid(INA)-related substance into the culture broth in the ABR was70%less than that in the jar fermentor.Thus,ABR system with low intracel-lular nucleic acid-related substances minimize the difficulties of downstream processing for recovery and purification of the poly-mer products.Furthermore,the use of ABR is promising tool for the low-cost production of-PL of high purity[44].In some-PL producing strains,the production of-PL is unstable and depen-dent on cell density which can cause problem such as high viscosity and low oxygen transfer efficiency.Furthermore,increase of agita-tion speeds leads to the rise of shear stresses which might cause undesired effects on mycelial morphology,product formation,and product yields.Bioprocesses using immobilized cells on various inert supports can increase overall productivity and minimize pro-duction costs[45].Bankar et al.reported that aeration and agitation of the fermentation broth markedly affect-PL production,cell mass formation,and glycerol utilization.Fermentation kinetics per-formed revealed that-PL production is growth-associated,and agitation speed of300rpm and aeration rate at2.0vvm supports higher yields of-PL[46].Many efforts have been made to opti-mize the media in order to enhance the productivity of-PL.Shih and Shen applied response surface methodology for optimization of-PL production by Streptomyces albulus IFO14147[47].It was found that-PL production started on agar plated with iron two or three days earlier than that on plates without iron.Manganese and cobalt were also found to have stimulating effect on-PL produc-tion.Kitasatospora kifunense strain produces-PL of shorter chain length about8–17lysine residues[48].Metabolic precursors such as amino acids,tricarboxylic acid cycle intermediates and cofactors have been investigated for improved production of-PL.Addition of citric acid after24h and l-aspartate after36h of fermentation medium had a significant effect on-PL production[49].Zhang et al.investigated the production of-PL on immobilized cells of Kitasatospora sp.MY5-36on bagasse,macroporous silica gel,syn-thetic sponge,loofah sponge and found that loofah sponge gave highest production of-PL in shakeflask culture[50].6.Screening and detection of-PL production in microbial systemNishikawa and Ogawa developed a simple screening method to detect-PL producing microbes.Screenings were carried out on agar plates containing either basic or acidic dyes.The dyes used were,Poly R-478,Remazol Brilliant Blue-R(RBBR)and Methylene blue.The screening method was based on the rationale interac-tion that occurs between charged groups of the secreted-PL and charged group of the basic or acidic dyes.A synthetic glycerol(SG) medium containing either0.02%of acidic dye Poly R-478/RBBR or0.002%of Methylene blue was used for the primary screen-ing.The SG medium was composed of glycerol10g,ammonium sulfate0.66g,sodium dihydrogen phosphate0.68g,magnesium phosphate heptahydrate0.25g,yeast extract0.1g,and1.0ml of Kirk’s mineral solution in1l of distilled water.The pH was adjusted to7.0with1M NaOH solution,and the medium was solidified by adding1.5%agar.The plates were incubated at28◦C for about one week;microbes forming specific colonies interacting with dyes were picked up and purified after several culture transfers.The acidic dye condensed around the organism’s colonies while basic dye was excluded from the surrounding zone.A zone of at least five mm in diameter for each colony was needed to visualize the interaction between secreted substances and dyes[16].The concentrations of-PL in the culture broth can be deter-mined by using either the spectrophotometric method or HPLC method.The colorimetric method is based on the interaction between-PL and methyl orange,which is an anionic dye,and thus the interaction of cationic-PL with anionic methyl orange in the reaction mixture led to form a water insoluble complex[51].The HPLC method for-PL detection was reported by Kahar et al.in which HPLC column(Tsk gel ODS-120T,4.6mm×250mm)with a mobile phase comprising of0.1%H3PO4was used[43].7.Purification and characterization of-PL-PL a cationic polymer,can be isolated at neutral pH,and puri-fied from the culture broth by ion exchange chromatography using an Amberlite IRC-50(H+form)column[5,52].The culture super-natant can be passed through an Amberlite IRC-50column at pH 8.5with successive washing by0.2N acetic acid and water.The elution can be made with0.1N hydrochloric acid,and the eluate can be neutralized with0.1N sodium hydroxide to pH6.5.Sub-sequent purification can be done by using CM-cellulose column chromatography to get-PL in homogeneity.The purification of the product can be monitored by UV absorption at220nm and fur-ther characterized by amino acid analysis.The molecular weight of-PL can be estimated by gelfiltration on a Sephadex column [16,53].Kobayashi et al.extracted the-PL from Kitasatospora kifu-nense.The pH of the culturefiltrate wasfirst adjusted to7.0,and the aliquot was mixed with Gly-His-Lys acetate salt as an inter-nal peptide standard.The resulting mixture was then applied to Sep-Pak Light CM cartridge.The cartridge was washed with water and-PL was eluted with0.1M HCl.The eluate was lyophilized and the residue was dissolved in0.1%pentafluoropropionic acid [46].Recently,ultra-filtration technique for fractionation of-PL of different molecular weight has been applied.The-PL with molec-ular weight higher than2kDa form a-turn conformation whereas molecular weight smaller than2kDa possesses a random coil74S.C.Shukla et al./Biochemical Engineering Journal65 (2012) 70–81conformation.The fraction of-PL with molecular weight higher than2kDa was found to have significant antibacterial activity, while the fraction with molecular weight smaller than2kDa shows nominal antibacterial activity[54].8.Conformation of-PLStructure and conformation studies are prerequisite to under-stand the functional behavior of-PL.Numerous workers have investigated the conformation and the molecular structure of microbially produced-PL by NMR,IR and CD spectroscopy[55,56]. The thermal property of crystalline-PL was determined by Lee et al.[52].The glass transition temperature(T g)and the melting point(T m)was observed to be88◦C and172.8◦C respectively.The results from pH dependent IR and CD spectra,1H and13C NMR chemical shifts together with that of13C spin-lattice relaxation times T1indicated that-PL assumes a-sheet conformation in aqueous alkaline solution.-PL at acidic pH might be in an electro-statically expanded conformation due to repulsion of protonated ␣-amino group,whereas at elevated pH(above p K a of the␣-amino group)the conformation was found to be similar to the antiparallel -sheet.The molecular structure and conformation of microbial-PL was studied by FT-IR and Raman spectroscopy.-PL was found to assumed a-sheet conformation in the solid state and solid state 13C NMR also revealed that-PL existed as a mixture of two crys-talline forms.Spin-lattice relaxation times yield two kinds of T1s corresponding to the crystalline and amorphous components,with the degree of crystallinity as63%[57].Solid-state high-resolution13C and15N NMR spectra of micro-bial-PL derivatives with azo dyes have been measured.These chemically modified-PL’s Exhibit15N NMR signals characteristic of the binding mode at the␣-amino groups.The spectral analy-sis reveals that the-PL/DC sample contains a small amount of ion complexes with methyl orange(MO).It has been shown that side chain␣-amino group of-PL does not make a covalent bond with methyl orange(MO)but forms a poly-ion complex,(-PL)-NH3+SO3−-(MO).On the other hand,dabsyl chloride(DC)makes covalent bond with-PL to form sulfonamide,(-PL)-NH-SO2-(DC). However,a few tens percent of DC change to MO by hydrolysis to form a poly-ion complex,(-PL)-NH3+SO3−-(MO)[58].Rosenberg and Shoham characterized the secondary structure of polylysine with a new parameter namely,the intensity ratio of the bands of charged side chain amine NH3+and amide NH bands.The enthalpy of the secondary structure transition,which is observed in PLL at the change of pH from11to1amounts to4.7kJ mol−1[59].9.Application of polylysine in medicinePolylysine is available in a large variety of molecular weights. As a polypeptide,polylysine can be degraded by cells effortlessly. Therefore,it has been used as a delivery vehicle for small drugs[60]. The epsilon amino group of lysine is positively charged at phys-iological pH.Thus,the polycationic polylysine ionically interacts with polyanion,such as DNA.This interaction of polylysine with DNA has been compacted it in a different structure that has been characterized in detail by several workers[61–66].In addition,the epsilon amino group is a good nucleophile above pH8.0and there-fore,easily reacts with a variety of reagents to form a stable bond and covalently attached ligands to the molecule.Several coupling methods have been reported for preparation of conjugated of-PL [67–70].(a)Modification of epsilon amino groups of polylysine with bifunctional linkers containing a reactive esters,usually add a reac-tive thiol group to the polylysine molecule and consequent reaction with a thiol leads to a disulfide or thioether bond,respectively.This has been used to couple large molecules,such as proteins to polylysine.(b)Compounds containing a carboxyl group can be acti-vated by carbodiimide,leading to the formation of an amide bond with an epsilon amino group of polylysine.(c)Aldehydes,such as reducing sugars or oxidized glycoprotein,form hydrolysable schiff bases with amino groups of-PL,which can be selectively reduced with sodium cyanoborohydride to form a stable secondary amine.(d)Isothiocyanate reacts with epsilon amino groups by forming a thiourea derivative.(e)Antibody coupling can also be done specif-ically to the N-terminal amino group of polylysine[71,72].A variety of molecules such as proteins,sugar molecules and other small molecules have been coupled to polylysine by using these methods.Purification of the conjugates are usually being achieved by dialysis or gelfiltration in conjunction with ion-exchange chromatography or preparative gel electrophoresis. Fractionation of the ligand–polylysine ratio and conjugate size can be done by using acid urea gel electrophoresis in combination with cation-exchange HPLC,ninhydrin assay and ligand analysis (sugar,transferrin,etc.)[73].Galactose terminated saccharides such as galactose,lactose and N-acetylgalactosamine were found to be accumulated exclusively in the liver,probably by their hepatic receptor.These conjugates could therefore be excellent carriers for a drug delivery system to the liver.The other saccharides such as the mannosyl and fucosyl conjugates are preferentially delivered to the reticuloendothelial systems such as those in the liver,spleen and bone marrow.In particular,fucosyl conjugates accumulated more in the bone marrow than in the spleen whereas xylosyl con-jugates accumulated mostly in the liver and lung.Generally,the accumulated amount in the target tissue increased with increasing molecular weight and an increased number of saccharide units on each monomer residues of polymer[74].One of the disadvantages of polylysine from the pharmaceu-tical point of view is its heterogeneity with respect to molecular size.The size distribution of polylysine with degrees of polymer-ization(dp)can be reduced by gel permeation chromatography. Al-Jamal et al.studied sixth generation(G6)dendrimer molecules of␣-poly-l-lysine(␣-PLL)to exhibit systemic antiangiogenic activ-ity that could lead to solid tumor growth arrest.Their work showed that G6PLL dendrimer have an ability to accumulate and persist in solid tumor sites after systemic administration and exhibit antian-giogenic activity[75].Sugao et al.reported6th generation dendritic ␣-PLL as a carrier for NFB decoy oligonucleotide to treat hepatitis [76].Han et al.synthesized a new anti-HIV dendrimer which con-sisted of sulfated oligosaccharide cluster consisting with polylysine core scaffold.The anti-HIV activity of polylysine-dendritic sulfated cellobiose was found to have EC50-3.2g/ml for viral replication which is as high as that of the currently clinically used AIDs drugs. The results also indicated that biological activities were improved because of dendritic structure in comparison to oligosaccharide cluster which were reported to have low anti-HIV activity[77].9.1.Polylysine as a drug carrierPolylysine can be used as a carrier in the membrane transport of proteins and drugs.Shen and Ryser reported that␣-PLL was found to be easily taken up by cultured cells.In fact,the conju-gation of drug to polylysine markedly increased its cellular uptake and offers a new way to overcome drug resistance related to defi-cient transport[60,78,79].Resistance toward methotrexate has been encountered in the treatment of cancer patients.The poly lysine conjugates of methotrexate(MTX)were taken up by cells at a higher rate than free drugs form.This increased uptake can overcome drug resistance due to deficient MTX transport.Addi-tion of heparin at a high concentration restores growth inhibitory effect of MTX-poly lysine[11,60].Shen and Ryser worked conjuga-tion of␣-PLL to human serum albumin and horseradish-peroxidase。
2012年奥巴马胜选演讲全文(中英文对照版)
2012 年奥巴马胜选演讲全文Thank you so much.非常感谢你们。
Tonight, more than 200 years after a former colony won the right to determine its own destiny, the task of perfecting our union moves forward.今夜，的任务又向前推进了一步。
It moves forward because of you. It moves forward because you reaffirmed the spirit that has triumphed over war and depression, the spirit that has lifted this country from the depths of despair to the great heights of hope, the belief that while each of us will pursue our own individual dreams, we are an American family and we rise or fall together as one nation and as one people.这一进程是因为你们而向前推进的，的精神，都在追求自己的个人梦想、信仰。
Tonight, in this election, you, the American people, reminded us that while our road has been hard, while our journey has been long, we have picked ourselves up, we have fought our way back, and we know in our hearts that for the United States of America the best is yet to come.今夜，在此次选举中，你们这些美国人民提醒我们，虽然我们的道路一直艰难，虽然我们的旅程一直漫长，对美利坚合众国来说，最美好一切属于未来。
2012美国总统大选辩论第三场-中文
2012美国大选第三场辩论国总统大选第三场、也是最后一场辩论22日在美国佛罗里达州博卡拉顿的林恩大学举行。
本场辩论以美国外交政策为主题。
由于总统奥巴马与共和党总统候选人罗姆尼在前两场辩论中战成平手，且目前选情胶着，第三场辩论的重要性大增，受关注程度更高。
现场，两人可谓开足火力，激烈碰撞。
主持人：大家晚上好，我们在佛罗里达州博卡拉顿的林恩大学，这次问题并没有和我们总统的候选人进行沟通，所以我们现在这次辩论当中观众不要喝彩或者是喝倒彩，欢迎奥巴马总统和罗姆尼州长。
罗姆尼：我们必须要确保我们能够把这些恐怖分子都绳之以法，这是最重要的，更重要的是我们必须要找到方法，让穆斯林国家能够反对激进主义，我们正确做法是让反美的，比如穆斯林的激进分子集团，让他们改变他们的做法，我们怎么样能够帮助世界来反对恐怖主义，我们现在应该让我们的外资援助，用这些方法能够来应对这些问题。
第二点就是教育。
第三点就是我们必须要有平等。
第四点就是法制。
我们必须要有一个法制的社会，那么在过去的几年当中，我们看到的是中东地区的动乱，我们看到了中东地区非常严重的动乱，还有基地组织，都扰乱了中东地区的和平，我们在这里看到中东地区是有一些进展，但是还是有很多的悲剧发生，我们看到埃及有8000万人口，我们希望能够确保在埃及还有中东地区能够有一些进展。
叙利亚问题，我们现在叙利亚总统阿萨德仍然在台上镇压民众，伊朗也是很重要的问题。
他也影响到了地区的安全和和平。
奥巴马：罗姆尼州长我非常高兴，你认为基地组织是一个威胁，你回答这个问题的时候是俄国并不是基地组织。
当我们说到外交政策的时候，你其实用的是90年代的外交政策，你当时说的是，你并不是很在乎在伊拉克发生的事情，但是在几个星期之前，你说我们应该现在在伊拉克增兵，现在我们所面临的一个挑战，当然我知道你现在也没有这个条件来实施外交政策，但是我想说的是你的外交政策上的观点是错误的。
比如说我们在大规模杀伤性武器问题上，你说我们现在应该在伊拉克增兵，你说我们应该通过和俄国的条约，你的答案并不是肯定的，你说可能要从阿富汗撤兵，这个要看清楚。
内部参考资料.doc
内部参考资料外事与港澳台工作通讯2003年12月同济大学外事办公室与港澳台事务办公室主编本期导读校际交往 (2)万钢副校长会见英国女王大学副校长一行王伯伟校长助理会见日本九州大学访问团一行周祖翼副书记会见美国丹佛大学工程与计算机学院院长国际会议 (2)木结构技术研讨会在我校举行第二届二氧化氯(C102)与水处理技术国际研讨会在我校举行2000年汉诺威世博会学术交流与合作会在锦江小礼堂举行智能结构及结构诊断与控制交流会在我校举行授予荣誉称号 (3)授予张伟韬博士我校兼职教授称号授予Wagner先生我校顾问教授称号新签协议 (4)与爱尔兰三一大学签署谅解备忘录与美国加州大学伯克莱分校高科技管理项目（MOT）签订联合授课合作协议校领导出访 (4)虞丽娟副书记访问美国周家伦书记访问爱尔兰、英国和德国陈成澍副校长访问日本综合信息 (5)德国Carl Hanser出版社代表团来访万钢副校长参加德国博世股份公司副总裁Bohr博士举办的晚宴黄自萍校长助理会见法国阿尔卑斯大区伊泽省政府主席代表团一行王伯伟校长助理会见日本水道技术中心理事长滕原正弘一行外办举行圣诞·新年招待会港澳台动态 (7)万钢副校长出席“光华奖学金”颁奖典礼香港理工大学“就业探索考察交流团”来我校访问交流校际交往法国Valenciennes大学国际交流部负责人来访12月1日，法国Valenciennes大学国际交流部负责人Ingrid女士来访我校，外办副主任李梅博士接待了来宾。
法国Valenciennes大学是法国北部的新兴大学，是法国尝试学制改革的四所试点学校之一。
该校此次来访旨在我校机械、机电等与汽车相关领域招收一批学生赴法攻读硕士学位。
之后，来访者还访问了我校汽车学院，商谈合作。
万钢副校长会见英国女王大学副校长一行12月2日上午，女王大学Kennith Bell副校长、外办Robin Harley主任和中国事务负责人王黎明博士一行就两校合作事宜拜访我校。
CGCLSTCS发布的国际顶级学术会议一览表 (2012年度版)
CGCL/STCS发布的国际顶级学术会议一览表 (2012年度版) Rank A-11.National Conference on Artificial Intelligence (AAAI)2.International Conference on Architectural Support for Programming Languages and Operating Systems (ASPLOS)3.ACM Conference on Computer and Communication Security (CCS)4.ACM Conference on Human Factors in Computing Systems (CHI)5.Annual International Cryptology Conference (CRYPTO)6.IEEE Conference on Computer Vision and Pattern Recognition (CVPR)ENIX Conference on File and Storage Techniques (FAST)8.IEEE Symposium on Foundations of Computer Science (FOCS)9.ACM Symposium on the Foundations of Software Engineering (FSE)10.International Symposium on High Performance Computer Architecture (HPCA)11.International Conference on Data Engineering (ICDE)12.IEEE International Conference on Computer Vision (ICCV)13.International Conference on Machine Learning (ICML)14.IEEE International Conference on Network Protocols (ICNP)15.International Conference on Software Engineering (ICSE)16.International Joint Conference on Artificial Intelligence (IJCAI)17.IEEE Conference on Computer Communications (INFOCOM)18.International Symposium on Computer Architecture (ISCA)19.ACM SIGKDD International Conference on Knowledge Discovery and Data Mining (KDD)20.Annual IEEE/ACM International Symposium on Microarchitecture (MICRO)21.ACM International Conference on Multimedia (MM)22.International Conference on Mobile Computing and Networking (MobiCom)ENIX Symposium on Networked Systems Design and Implementation (NSDI)24.International Conference on Object Oriented Programming, Systems, Languages and Applications (OOPSLA)ENIX Conference on Operating System and Design (OSDI)26.ACM Conference on Programming Language Design and Implementation (PLDI)27.Annual ACM Symposium on Principles of Distributed Computing (PODC)28.ACM Symposium on Principles of Programming Languages (POPL)29.IEEE Real-Time Systems Symposium (RTSS)30.ACM SIGCOMM Conference (SIGCOMM)31.ACM Conference on Computer Graphics and Interactive Techniques (SIGGRAPH)32.ACM Annual International ACM SIGIR Conference on Research and Development in Information Retrieval_r(SIGIR)33.International Conference on Management of Data and Symposium on Principles of Database Systems (SIGMOD/PODS)34.ACM Symposium on Operating Systems Principles (SOSP)35.IEEE Symposium on Security and Privacy (SP)36.Annual ACM Symposium on Theory of Computing (STOC)ENIX Annual Technical Conference (USENIX)38.International Conference on Very Large Data Bases (VLDB)39.IEEE Visualization Conference (Vis)40.International World Wide Web Conference (WWW)Rank A-21. International Conference on Dependable Systems and Networks (DSN)2. International Symposium on High Performance Distributed Computing (HPDC)3. International Conference on Distributed Computing Systems (ICDCS)4. ACM International Conference on Supercomputing (ICS)5. ACM/IFIP/USENIX International Middleware Conference (Middleware)6. ACM SIGPLAN Symposium on Principles and Practice of Parallel Programming (PPoPP)7. Supercomputing (SC’XY) Conference8. ACM Conference on Measurement and Modeling of Computer Systems (SIGMETRICS)9. Annual ACM Symposium on Parallel Algorithms and Architectures (SPAA)10. ACM International Conference on Virtual Execution Environments (VEE)Rank B1. Annual Computer Security Applications Conference (ACSAC)2. International Symposium on Code Generation and Optimization (CGO)3. ACM International Conference on emerging Networking EXperiments and Technologies (CoNEXT)4. ACM Conference on Computer Supported Cooperative Work (CSCW)5. Annual Eurocrypt Conference (Eurocrypt)6. European Conference on Computer Systems (EuroSys)7. Workshop on Hot Topics in Networking (HotNets)8. Workshop on Hot Topics in Operating Systems (HotOS)9. IEEE International Conference on Data Mining (ICDM)10. USENIX Internet Measurement Conference (IMC)11. IEEE International Parallel and Distributed Processing Symposium (IPDPS)12. International Semantic Web Conference (ISWC)13. IEEE/ACM International Workshop on Quality of Service（****IWQoS*****）14. USENIX Large Installation System Administration Conference (LISA)15. International Symposium on Modeling, Analysis, and Simulation of Computer & Telecommunication Systems (MASCOTS)16. ACM Multimedia Systems Conference (MMSys)17. ACM International Symposium on Mobile Ad Hoc Networking and Computing (MobiHoc)18. ACM International Conference on Mobile Systems, Applications, and Services (MobiSys)19. IEEE Symposium on Mass Storage Systems/NASA Goddard Conference on Mass Storage Systems and Technologies (MSS/MSST)20. Annual Network & Distributed System Security Symposium (NDSS)21. International Conference on Parallel Architectures and Compilation Techniques (PACT)22. IEEE International Conference on Pervasive Computing and Communications (PerCom)23. IFIP International Symposium on Computer Performance Modeling, Measurement and Evaluation (Performance)24. SIAM Conference on Parallel Processing for Scientific Computing (PP)25. IEEE Real-Time and Embedded Technology and Applications Symposium (RTAS)26. USENIX Security Symposium (Security)27. ACM Conference on Embedded Networked Sensor Systems (SenSys)28. ACM Symposium on Cloud Computing (SOCC)29. ACM-SIAM Symposium on Discrete Algorithms (SODA)30. International Symposium on Reliable Distributed Systems (SRDS)。
四色定理及其计算机证明
四⾊定理及其计算机证明为了⿊这个：“OpenAI发⽂表⽰，他们已经为Lean创建了⼀个神经定理证明器，⽤于解决各种具有挑战性的⾼中奥林匹克问题，包括两个改编⾃IMO的问题和来⾃AMC12、AIME竞赛的若⼲问题。
该证明器使⽤⼀个语⾔模型来寻找形式化命题(formal statement)的证明。
”The four color theorem was proved in 1976 by Kenneth Appel and Wolfgang Haken after many false proofs and counterexamples (unlike the five color theorem, proved in the 1800s, which states that five colors are enough to color a map)...The Appel and Haken proof attracted a fair amount of criticism. Part of it concerned the proof style: the statement of the Four Colour Theorem is simple and elegant so many mathematicians expected a simple and elegant proof that would explain, at least informally, why the theorem was true - not opaque IBM 370 assembly language programs.System/370 Model 148The new model also offers increased system throughput -- the amount of time it takes to perform a given amount of work -- compared to the Models 135 and 145. The Model 148 is available with 1,048,576 or 2,097,152 characters of memory. ⾼达1MB或2MB内存。
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North America 22%
Australia 31%
Off-Patent South 76.4%America
16% Europe 21% Asia 8% NZ 3%
Other herbicides Insecticides 22% 10% Phenoxies 23% Fungicides 12% Glyphosate Other 20% 9%
Broad distribution base and market access
A4 Paper Guide L
Regional Regional HQ HQ
Crop protection
Crop protection production(1) production
Seeds
Seeds production production
2007
2008
2009
Total $44.2b
Source: Phillips McDougall
2010
3
2012 Global Agriculture Conference
Active ingredients representing a significant value will lose patent protection over coming years….
2011 revenues by product segment
Seed 2%
2011 revenues by geography
….and selling into a number of market and crop segments
7
2012 Global Agriculture Conference
…. and provide an important potential source of growth for Nufarm
4
2012 Global Agriculture Conference
Nufarm has developed core capabilities and positions to address the opportunities that accompany a changing industry landscape….
Bank of America Merrill Lynch
2012 Global Agriculture Conference
Doug Rathbone
Chief Executive
March, 2012
2012 Global Agriculture Conference
Nufarm is the leading listed off-patent focused crop protection company
Registrations 2002 Off-Patent 76.4%
Registrations 2011
AUD (mm)
Projected revenues via new product introductions
600
And a pipeline of new product introductions which will fuel future growth
The off-patent segment is the largest segment in the industry, and is growing….
2010 total industry sales
50 45 40 25 20
2000-2010 CAGR 4.1%
Industry revenue growth patent v off-patent
Sumitomo
Nufarm products being distributed by Sumitomo • Over 20 products across Mexico, Italy, Spain, South Africa and Australia • 15 herbicides • 3 fungicides • 2 insecticides Development projects • 2 evaluation agreements • 10 development agreements • Brazil, Argentina, USA, S.E. Asia, Australia, Europe
Improved efficacy
Greater tank mix compatibility
9
2012 Global Agriculture Conference
A balanced manufacturing base and global sourcing capability
Fully integrated global scale manufacturing assets to support core chemistry positions
Broad distribution base and market access Diversification across geographies, products and market segments
Strong product development and regulatory skills
Proven product development and regulatory skills
1600 1400 1200 1000 800 600 400 200 0 NAFTA Europe Asia Latin America Medaf ANZ
Development laboratories in Australia, USA, France & UK Extensive global regulatory affairs team
New formulations
Mixtures
Packaging
Off-Patent 76.4% Proprietary formulation Reduced volatility Combines three A.I.'s Seed treatment application Broad insect/fungus protection in wheat, barley and oats Patented QuikPour system Fully recyclable Winner of Australian packaging design award
Annual revenues: $2 billion Broad product portfolio Sales in approximately 100 countries
Growing seeds platform
2
2012 Global Agriculture Conference
Products coming off-patent 2011-2016
Product Category Herbicides Insecticides Off-Patent Fungicides 76.4% Other TOTAL
Source: Phillips McDougall
2010 sales value (US$m) 2,237 1,858 1,151 10 5,256
Ability to innovate and differentiate Balance between integrated manufacturing and flexible sourcing Proven ability to 'partner' and collaborate
5
2012 Global Agriculture Conference
Nufarm distribution of Sumitomo chemistry
Austria, Belgium, Brazil, Canada, Germany, Hungary, Indonesia, Netherlands, New Zealand, Romania, Spain, UK
Development projects • 3 evaluation agreements • 14 development agreements • Australia, Argentina, Brazil, Europe Manufacturing and logistics • Toll manufacturing for Sumitomo Australia • 4 insecticides, 1 fungicide, 1 herbicide
2012 Global Agriculture Conference
Strong partnering capabilities
Commercial relationships with leading crop protection companies Range of activities including: Licensed products / brands Product development Toll manufacturing Distribution
11
2012 Go relationship
The Sumitomo relationship is realising significant synergies for Nufarm. Nufarm’s alliance with Sumitomo spans distribution, manufacturing and R&D