effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors
组蛋白脱乙酰酶抑制剂使癌细胞对表皮生长因子抑制剂敏感[发明专利]
![组蛋白脱乙酰酶抑制剂使癌细胞对表皮生长因子抑制剂敏感[发明专利]](https://img.taocdn.com/s3/m/2d263cc9af45b307e9719733.png)
专利名称：组蛋白脱乙酰酶抑制剂使癌细胞对表皮生长因子抑制剂敏感
专利类型：发明专利
发明人：萨米尔·E·威塔,小保罗·A·邦恩,哈里·A·德拉布金,罗伯特·M·格米尔,丹尼尔·钱
申请号：CN200680016308.9
申请日：20060313
公开号：CN101175492A
公开日：
20080507
专利内容由知识产权出版社提供
摘要：本发明公开了组蛋白脱乙酰酶抑制剂和表皮生长因子受体(EGFR)抑制剂的组合用于治疗癌症的用途。
申请人：科罗拉多大学董事会
地址：美国科罗拉多州
国籍：US
代理机构：北京市柳沈律师事务所
更多信息请下载全文后查看。
T.S.Eliot艾略特英文介绍
• After a year in Paris, he returned to Harvard to pursue a doctorate in philosophy, but returned to Europe and settled in England in 1914. • The following year, he married Vivienne HaighWood and began working in London, first as a teacher, and later for Lloyd's Bank.
tripleidentitiesotherobservations1917年荒原thewasteland1922年诗集19091925poems190919251925年圣灰星期三ashwednesday1930年老负鼠的猫经oldpossum?sbookpracticalcats1939年焦灼的诺顿burntnorton1941年四个四重奏fourquartets1943年诗集collectedpoems1962年lovesongalfredprufrockmodernistmovement岩石therock1934年cathedral1935年家庭聚会thefamilyreunion1939年鸡尾酒会thecocktailparty1950年老政治家theelderstatesman1958年tripleidentitiessacredwood神木essaysorder风格及秩序论文集elizabethanessays伊丽莎白论文集afterstrangegods拜异教之神influenced1theimagistmovement2thesymbolistmovementarthursymonsenglishcriticmatthewarnoldinfluencemostsuccessfulliterarydictatoramericanliteraryhistorywhowieldedmostdecisiveinfluenceoverliterarydevelopmentlongtime
DIDS_阴离子运输抑制剂_67483-13-0_Apexbio
Limited solubility
Store at +4°C
For obtaining a higher solubility , please warm the tube at 37°C and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
实验操作
细胞实验: 细胞系 溶解方法
反应时间 应用
来源于 6-8 周龄 Sprague-Dawley 大鼠的 DRG（背根神经节）神经 元细胞
在 DMSO 中的溶解度>10mM。为了获得更高的浓度，可以将离心 管在 37℃加热 10 分钟和/或在超声波浴中震荡一段时间。原液可 以在-20℃以下储存几个月
0.1, 1, 3, 10, 100μm 作用 2min，加入第一滴药物开始同时观察
在 DGR 神经元中，尽管 DIDS 并没有诱导 TRPV1（瞬时受体电位 香草酸亚型 1 型）自身的活化，但是显著提高了辣椒素或低 pH 诱导的 TRPV1 电流。DIDS 可以以激动剂依赖的方式改变 TRPV1 通道功能。
请测试所有化合物在室内的溶解度，实际溶解度和理论值可能略 有不同。这是由实验系统的误差引起的，属于正常现象。
参考文献: [1] Wulff, Heike. "New light on the “Old” chloride channel blocker DIDS." ACS chemical biology 3.7 (2008): 399-401. [2] Hogg, R. C., Q. Wang, and W. A. Large. "Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein." British journal of pharmacology 111.4 (1994): 1333-1341. [3] Nelson, Mark T., et al. "Chloride channel blockers inhibit myogenic tone in rat cerebral arteries." The Journal of Physiology 502.2 (1997): 259-264. [4] Lyons, John C., Brian D. Ross, and Chang W. Song. "Enhancement of hyperthermia effect in vivo by amiloride and DIDS." International Journal of Radiation Oncology* Biology* Physics 25.1 (1993): 95-103
【精品】翻译综合
一个抑制肿瘤的连续模型-------艾丽斯H伯杰，阿尔弗雷德G. Knudson 与皮埃尔保罗潘多尔菲今年，也就是2011 年，标志着视网膜母细胞瘤的统计分析的第四十周年，首次提供了证据表明，肿瘤的发生，可以由两个突变发起。
这项工作提供了“二次打击”的假说，为解释隐性抑癌基因（TSGs）在显性遗传的癌症易感性综合征中的作用奠定了基础。
然而，四十年后，我们已经知道，即使是部分失活的肿瘤抑制基因也可以致使肿瘤的发生。
在这里，我们分析这方面的证据，并提出了一个关于肿瘤抑制基因功能的连续模型来全方位的解释肿瘤抑制基因在癌症过程中的突变。
虽然在1900 年之前癌症的遗传倾向已经被人认知，但是，是在19 世纪曾一度被忽视的孟德尔的遗传规律被重新发现之后，癌症的遗传倾向才更趋于合理化。
到那时，人们也知道，肿瘤细胞中的染色体模式是不正常的。
接下来对癌症遗传学的理解做出贡献的人是波威利，他提出，一些染色体可能刺激细胞分裂，其他的一些染色体 a 可能会抑制细胞分裂，但他的想法长期被忽视。
现在我们知道，这两种类型的基因，都是存在的。
在这次研究中，我们总结了后一种类型基因的研究历史，抑癌基因（TSGs），以及能够支持完全和部分失活的肿瘤抑制基因在癌症的发病中的作用的证据。
我们将抑制肿瘤的连续模型与经典的“二次打击”假说相结合，用来说明肿瘤抑制基因微妙的剂量效应，同时我们也讨论的“二次打击”假说的例外，如“专性的单倍剂量不足”，指出部分损失的抑癌基因比完全损失的更具致癌性。
这个连续模型突出了微妙的调控肿瘤抑制基因表达或活动的重要性，如微RNA（miRNA）的监管和调控。
最后，我们讨论了这种模式在┲⒌恼锒虾椭瘟乒 讨械挠跋臁！岸 未蚧鳌奔偎?第一个能够表明基因的异常可以导致癌症的发生的证据源自1960 年费城慢性粒细胞白血病细胞的染色体的发现。
后来，在1973 年，人们发现这个染色体是是第9 号和第22 号染色体异位的结果，并在1977 年，在急性早幼粒细胞白血病患者中第15 号和第17 号染色体易位被识别出来。
身体意象量表评分标准 情感 认知 行为
身体意象量表评分标准情感认知行为《身体意象量表评分标准与情感、认知、行为关系探析》一、引言随着社会的发展和人们对身心健康的重视，身体意象量表评分标准在心理学领域逐渐受到关注。
身体意象是个体对自身外貌、身体功能和运动能力的主观认知和评价。
情感、认知和行为在个体的身体意象中起着重要作用，对身体意象的评分标准有着深远影响。
本文将从深度和广度两个维度出发，对身体意象量表评分标准与情感、认知、行为的关系进行全面探讨，以期为读者提供有价值的信息和观点。
二、身体意象量表评分标准的概念和内容身体意象量表评分标准是评价个体身体意象的一种客观标准。
它通过对个体对自身身体的认知，情感体验和行为表现进行量化评分，以反映个体对自身身体的满意度和接受程度。
在身体意象量表评分标准中，通常包括对个体体型满意度、身体功能评价和运动能力评价等内容。
在身体意象量表评分标准中，情感、认知和行为在个体的身体意象评价中起着重要作用。
接下来，我们将分别探讨这三个方面与身体意象量表评分标准的关系。
三、情感对身体意象量表评分标准的影响情感是个体对自身身体的主观体验和情绪反应，对身体意象的评价起着重要作用。
研究表明，消极情感如焦虑、抑郁会导致个体对身体的评价偏差，出现身体不满意的情况，从而影响身体意象量表的评分结果。
而积极的情感体验则会使个体更加接纳自己的身体，对身体意象的评价更加客观和积极。
在实际的身体意象量表评分中，我们需要考虑个体的情感体验对身体意象的影响，为个体提供情感支持和帮助，使其更客观地对自身身体进行评价。
四、认知对身体意象量表评分标准的影响认知是个体对自身身体的认知过程，在身体意象量表评分中起着决定性作用。
个体对自身身体的认知偏差会影响身体意象量表的评分结果，从而影响个体的心理健康和身体满意度。
在评定身体意象量表的评分标准时，需要考虑个体的认知特点，并进行合理的认知干预，帮助个体更加客观地认知自己的身体。
五、行为对身体意象量表评分标准的影响个体的行为方式对身体意象的评价也有着重要影响。
弗里德里希·哈伯兰德教授——欧洲大豆业的先驱
■No.5.2018人物One can hardly overestimate the impact of FriedrichHaberlandt on the introduction of soybeans in Europe.His life is an archetype of an influential multinational academic in the Austrian-Hungarian Empire of the 19th century.After first finding out about the soybean in 1873,he was the first to conduct systematic trials with soybeans in Europe.He distributed his knowledgeto experts and users in many countries.In his vision of the potential of soybeans for European farmers and for feeding the growing population,he predicted develop⁃ments,which took place many generations after his early death.Although seemingly unsuccessful at first sight,his efforts formed a crucial starting point for the effective integration of soybeans in the Western Hemisphere.Friedrich Haberlandt was born on February 21stin 1826in Preßburg,now known as Bratislava,the capital of modern Slovakia (Shurtleff/Aoyagi 2008).Because his father,Gottlieb Haberlandt,was a craftsman in a German speaking community,he grew up in a tri-lingual environment learning Hungarian and Slovak languagesin his youth alongside German.He finished high school in his hometown where he also studied law for one year.He was a liberal and even volunteered in therevolution of 1848.He completed his studies in natural sciences at the establishment of higher education in Ungarisch-Altenburg (Mosonmagyaróvár in modernHungary)where he also started his academic career as an assistant professor.His thinking was highly influenced by the revolutionary works of scientists such as Justus von Liebig at that time.He lived in a time of fundamental technological and economic change.Rationalization processes and scientific knowledge were applied to many areas of society such as agriculture and diet (Kingsbury,中图分类号：S565.1文献标志码：E文章编号：1674-3547(2018)05-0001-02Friedrich Haberlandt-thePioneer of Soybean in EuropeGeorg Weissenböck 1,Dennis Böhmer 2,Leopold Rittler 3（1.Institute of Rural History,3109St.Pölten,Austria;2.University of Natural Resources and Life Sciences,Vienna.Institute for Plant Breeding,3430Tulln an der Donau,Austria;3.Donau Soja Organisation,1010Vienna,Austria）■No.5.2018人物2009).In 1853,Friedrich Haberlandt married Katharina Köhler.They had three daughters and three sons.His oldest son,Gottlieb Haberlandt (1854)became a famous botanist.Another son,Michael Haberlandt (1860)became an outstanding ethnologist and founded the museum for ethnology in Vienna in 1895.Friedrich Haberlandt was appointed professor for mathematics,zoology,botany and agricultural production in 1854.During the following period,he developed his distinct interest and sensitive talent for observation and an extensive activity in scientific networks (Haberlandt 1933).He left the college in 1869after the Austro-Hungarian Compromise.In Görz (Gorizia/Gorica inmodern Italy and Slovenia),he founded and led a research centre for silkworm breeding.When the first agricultural college in Austria,the Hochschule für Bodenkultur (the current University of Natural Resources and Life Sciences,Vienna)was founded 1872,Haberlandt was appointed outright professor,and later became rector of the university.He kept this position until his death in 1878.In the course of his research,he worked extensively on the soybeanas a protein supplier.【参考译文】弗里德里希·哈伯兰德教授——欧洲大豆业的先驱对于弗里德里希·哈伯兰德（Friedrich Haber⁃landt ）教授将大豆引进到欧洲所带来的巨大影响，无论给予多高的评价都不过分。
Fan is to monoid as scheme is to ring a generalization of the notion of a fan
a rX iv:mat h /36221v2[mat h.AG ]8J ul24F AN IS TO MONOID AS SCHEME IS TO RING HOW ARD M THOMPSON Abstract.This paper generalizes the notion of a toric variety.In particular,these generalized toric varieties include examples of non-normal non-quasi-projective toric varieties.Such an example seems not to have been noted before in the literature.This generalization is achieved by replacing a fan of strictly rational poly-hedral cones in a lattice with a monoided space,that is a topological space equipped with a distinguished sheaf of monoids.For a classic toric variety,the underlying topological space of this monoided space is its orbit space under the action of the torus.And,if σis a cone,then the stalk of the structure sheaf of the monoided space at the point corresponding to σis the monoid S σ=σ∨∩M that is usually associated to σ.When applied to the affine toric variety associated to some cone σ,the monoided space so obtained is isomor-phic to the spectrum of the monoid S σ,where the spectrum of a monoid is defined in analogy with the definition of the spectrum of a ring.More gener-ally,we will call a monoided space that is locally isomorphic to the spectrum of a monoid a fan and we form schemes from these fans by taking monoid algebras and glueing.Introduction In recent years,various mathematicians have studied non-separated toric vari-eties or not necessarily normal toric varieties or combinatorial gadgets for describ-ing toric varieties other than a fan of strictly rational polyhedral cones in a lattice.For examples,see A’Campo-Neuen &Hausen [1],Sturmfels [7]and Berchtold &Hausen [2]respectively.Following DeMeyer,Ford &Miranda [3],we define a topology on a fan ∆in R d by declaring the open sets to be its subfans.Then,like Kato [6],we make such fans into monoided spaces by associating a sheaf of monoids to each ∆.Our sheaf of monoids is similar to but differs from Kato’s.Observing that this new monoided space is locally isomorphic to the spectrum of some monoid in the same sort ofway a scheme is locally isomorphic to the spectrum of some ring,we define any monoided space that is locally isomorphic to the spectra of monoids to be a fan.The monoid algebra functor can then be used to associate a scheme to such a fan.The advantages of the approach presented here are:1)some of the intuition built up from studying schemes can be carried over to this new gadget;2)for any toric variety,not just the projective ones,the gadget presented here comes equipped with an abstract analog of the moment map and often torus invariant objects on the toric variety descend to this gadget via this map;3)when the toric variety is projective this new gadget is the corresponding polytope equipped with some extra structure and the associated abstract moment map is,essentially,the moment map;4)this gadget permits the consideration of non-normal toric varieties2HOWARD M THOMPSONthat are neither affine nor projective,in fact the scheme under consideration need not be a variety;5)at the same time,the collection of schemes built using thesegadgets is small enough that all the normal varieties in it are classic toric varieties.1.Basic NotionsDefinition1.1.Let S be a commutative monoid.We say a subset a⊆S is an ideal if a+S⊆a.We say an ideal p⊂S is prime if its complement is a submonoid of S.The spectrum of S is a pair(Spec S,M)consisting of a topological space Spec S and a sheaf of monoids M on Spec S defined as follows:The underlying set of Spec S is the collection of prime ideals of S,the open sets of the form D(f)={p∈Spec S|f∈S\p}form a base for the topology of Spec S,andΓ(D(f),M)=S+N(−f).I should warn you that I will use the same notion for both rings and monoids.In this paper,if A is a ring,then Spec A is the set of prime ideals of A as a ring withits standard topology,etc.A monoided space is a pair(∆,M)consisting of a topological space∆and a sheafof monoids M on∆.A morphism of monoided spaces consists of a continuous map ϕ:∆→∆′and local homomorphism of sheaves of monoidsϕ#:M∆′→ϕ∗M∆. That is,for every pointσ∈∆,the homomorphism of monoidsϕ#σ:M∆′,ϕ(σ)→ϕ∗M∆,σmaps non-units to non-units.We say a monoided space(∆,M)is a fan if every point of∆has an open neigh-borhood U such that there exists a monoid S with(U,M|U)∼=(Spec S,M Spec S).Every monoid S has a unique maximal ideal S+=S\S∗so there is no distinct notion of a locally monoided space.Furthermore,every pointσon a fan(∆,M) has a unique smallest open neighborhood and this neighborhood is isomorphic to Spec Mσ.If∆is a fan and A is a ring,we associate a scheme to this pair using the monoid algebra functor A→A[∆]:That is,if Spec S and Spec S′are open subsets of the fan∆,and f∈S is such that D(f)⊆Spec S′,we glue the affine schemes Spec A[S]and Spec A[S′]along Spec S f.Here the map A[S f]→A[S′]is the one induced by the restriction map S f→S′from∆.This makes sense because the canonical inclusions of the form S֒→A[S];s→t s(We write elements of A[S]or more expansively,A[t;S],as polynomials in t with coefficients in A and exponents in S.)induce a continuous map A[∆]→∆.The pullback of D(s)⊆Spec S is D(t s)⊆Spec A[S].More generally,if∆is a fan and X is a scheme,we may−−→X to this pair.associate the X-scheme X[∆]=X×Spec Z Z[∆]pr12.The fan of a classic toric varietyDefinition2.1.Let∆be a fan in a lattice N∼=Z d,that is,let∆be a collectionof strongly convex rational polyhedral cones in the R-vector space N R=N⊗Z R. We associate to∆a monoided space as follows.The underlying topological space,∆top,is the collection{σ∈∆}equipped with the topology whose open sets are the subfans of∆.That is,the open sets are subsets of∆that are also fans in N. And,the sheaf of monoids on∆top is the sheaf M such thatΓ(σtop,M|σ)=Sσ(=σ∨∩M).Here we have identified the coneσwith the fan in N consisting ofσand its faces and M=Hom Z(N,Z).Theorem2.2.If∆is a fan in N,then(∆top,M)is a fan.FAN IS TO MONOID AS SCHEME IS TO RING3 Proof.It suffices to prove(σtop,M|σ)∼=Spec Sσfor allσ∈∆.This is straightfor-ward.Notice that,if one starts with the normal fan of a polytope,then topological space we obtain is isomorphic to the set of faces of the polytope equipped with the topology such the the star of a face is the smallest open subset containing that face. More generally,it is worth noting that∆top is homeomorphic to the orbit space of the classic toric variety associated to∆.3.When is k[∆]a normal k-variety?This section is devoted to proving:If∆is a fan and k is afield,then k[∆]is a normal k-variety if and only if it is a classic toric variety.Here by k-variety we mean an integral,separated scheme offinite type over k.Theorem3.1.[5,Exercise II.3.5]If f:X→Y is a morphism of schemes offinite type,then for every open affine subset V=Spec B⊆Y,and for every open affine subset U=Spec A⊆f−1(V),A is afinitely generated B-algebra.In particular,if k[∆]is a k-scheme offinite type,then the stalks of M are all finitely generated monoids.Recall that a monoid S is said to be torsion-free if ns=ns′for some positive integer n implies s=s′in S.Theorem3.2.[4,Theorem8.1]Let A be a nonzero ring.The monoid algebra A[S] is an integral domain if and only if A is an integral domain and S is torsion-free and cancellative.As a consequence of this proposition,if k[∆]is integral,then the stalks of M are all cancellative,torsion-free monoids.In particular,if k[S]is a domain,the S embeds in a group it e Z S to denote this group and identify S with its image in Z S.If S is afinitely generated,cancellative torsion-free monoid Z S is afinitely gen-erated,torsion-free Abelian group.That is,Z S∼=Z n for some non-negative integer n.Consider the rational polyhedral cone R≥0S= l i=1r i⊗s i|r i≥0,s i∈S in thefinitely generated R-vector space,R S=R⊗Z Z S,generated by S.Identify S and Z S with their images in R S.If s∈Z S∩R≥0S,then ns=s′∈S for some positive integer n and some s′∈S.So,the image of s in k[Z S∩R≥0S],t s,satisfies the monic polynomial x n−t s′with coefficients in k[S].Therefore,if s∈Z S∩R≥0S and k[S]is integrally closed,then s∈S.In other words,if Spec k[S]is a normal k-variety,then S is a rational polyhedral cone in somefinite dimensional vector space intersected with a sublattice generated by a basis of the vector space.More briefly,if X=Spec k[S]is a normal k-variety,then X is an affine toric variety.So far,we know that if X=k[∆]is a normal integral scheme offinite type over k,then X can be glued together from affine toric varieties along open torus invariant subvarieties.We now wish to show that if in addition X is separated, then X is a classic toric variety.Theorem3.3.Suppose X=k[∆]is a normal integral scheme offinite type over k.If X is separated,then X is a classic toric variety.Proof.We have already established that X is glued together from a collection of affine toric varieties.We need to show that the cones corresponding to these toric varietiesfit together to form a fan of strictly rational polyhedral cones in a lattice.4HOWARD M THOMPSONSince on each of the fans of these affine toric varieties the generic point is the unique smallest open set,all these generic points are identified by the gluing.So, there is afixed lattice M,the stalk of M at the generic point,containing every monoid S that occurs.Furthermore,M=Z S for every monoid S and R≥0S is dual to a strictly convex rational polyhedral cone in N,where N=Hom Z(M,Z). So,it makes sense to ask whether X comes from a fan.All we have to prove is:The intersection of any two cones in this collection is a face of each.We know the intersection U=Spec k[S1]∩Spec k[S2]⊆X is affine since X is separated.Furthermore,U is torus invariant.So,U comes from a subfan of the cone,σ,in N corresponding to Spec k[S1].Since U is also affine,U corresponds to a face ofσ.References1.A.A’Campo-Neuen and J.Hausen,Toric prevarieties and subtorus actions,Geom.Dedicata87(2001),no.1-3,35–64.MR2002h:140852.F.Berchtold and J.Hausen,Bunches of cones in the divisor class group—a new combinatoriallanguage for toric varieties,Int.Math.Res.Not.(2004),no.6,261–302.MR20410653.F.R.DeMeyer,T.J.Ford,and R.Miranda,The cohomological Brauer group of a toric variety,J.Algebraic Geom.2(1993),no.1,137–154.MR93i:140514.R.Gilmer,Commutative semigroup rings,Chicago Lectures in Mathematics,University ofChicago Press,Chicago,Ill.,1984.MR85e:200585.R.Hartshorne,Algebraic geometry,Springer-Verlag,New York,1977,Graduate Texts in Math-ematics,No.52.MR57#31166.K.Kato,Toric singularities,Amer.J.Math.116(1994),no.5,1073–1099.MR95g:140567.B.Sturmfels,Gr¨o bner bases and convex polytopes,University Lecture Series,vol.8,AmericanMathematical Society,Providence,RI,1996.MR97b:13034Department of Mathematics,University of Michigan,Ann Arbor,Michigan48109 E-mail address:hmthomps@。
学习outcome英文翻译
SummaryIn this study, the main objectives for constructing logisticand Cox regression models were accomplished. For logisticregression analysis, the explanatory variables contributingto the probability of a student passing the USMLE Step 1were identified. It was evident that the MCA T (physicaland biological sciences) scores, number of sophomorecourses failed, and medical school freshman GPAs weresignificantly associated with the USMLE Step 1performances. The study results confirmed that MCATscores and medical school course performances weresignificant predictors of the USMLE Step 1 (Chen et al.,2001; and Haught and Walls, 2002). The implication of thestudy results was that the medical school should continueits effort to recruit and admit qualifying students with highMCA T scores, and to strengthen teaching and learning toensure student success on the licensure examination.With regard to Cox regression analysis, the methodindicated that academic difficulty was significantlyaccounted for by risk factors such as MCA T verbalreasoning score, gender, and number of sophomore coursesfailed. Moreover, students in the five-year curriculum trackexperienced academic difficulty during the first semesterof their sophomore year, peaked at the second semesterof the sophomore year and maintained the same level ofrisk through the rest of the study period. The researchresults were consistent with the literature stating that anincrease in the relative risk for a student experiencingacademic difficulty was significantly associated with a lowMCA T score (Huff and Fang, 1999), and students at riskfor academic difficulty remained at risk throughout the firstthree years of medical school (Fang, 2000). The implicationof this study was that the medical school addressedacademic difficulty issues through academic developmentand support services.在这项研究中，完成了构建Logistic和Cox回归模型的主要目标。
浅析玄学派诗人约翰丶邓恩诗歌的意象特征
浅析玄学派诗人约翰丶邓恩诗歌的意象特征一诗歌中的“跳蚤”意象在我们中国人的审美观念里,用来赞颂美好事物的东西本身应该是完美的。
相形之下,邓恩对于爱情与婚姻的另一妙喻“跳蚤”则显得那么另类,让人难以接受。
任谁也无法将让人见之即厌的“跳蚤”与人类视之神圣的爱情与婚姻联系起来,这恐怕是邓恩另一次大胆的尝试。
《跳蚤》一诗这样写道:看这个小跳蚤你就明白你对我的否定是多么渺小它先吮吸我的血液,然后是你我们的血液在它体内融合在一起你知道这不能向人提及这种罪恶和耻辱足以令少女失掉首级然后它在求爱前尽情享乐身体因两种血液组成的血液而膨胀这远比我们要做的勇敢无数……突然而残忍地,你的指甲染上无辜的紫色血液而你却对此毫无知觉这个跳蚤究竟犯了什么罪孽无非是从你那吸取的一滴血液……在这首诗中,诗人将千古传诵的爱情比作跳蚤,男女双方通过一种特殊的方式结合在一起:“它先吮吸我的血液,然后是你,我们的血液在它体内融合在一起。
”《跳蚤》可以说是一首让人过目不忘的玄学派诗歌,尤其是对于我们这些对美好的东西有着偏爱的人来说,跳蚤的意象很难让人喜欢起来,相信在文艺复兴时期这样的意象是有些另类的,而这种效果正是邓恩所希望的。
将跳蚤的身体看作是可以提供隐居的场所也是有一定道理的,因为跳蚤既吸了“你”的血,也吸了“我”的血,在某种意义上说,“我们”已经融成一体,而这样的结合是外人看不到的,因此就不会被人们称做“罪恶和耻辱”。
但很可惜的是:女方最后杀死了跳蚤,也就断了双方的联系,爱情的坚贞不渝受到了置疑。
一个小小的跳蚤居然能引发诗人如此大胆而丰富的想象,让我们不得不佩服邓恩的想象力,从而也就明白了为什么邓恩会成为玄学派诗人的领军人物了。
二诗歌中的“圆规”意象在邓恩赠给妻子的诗《别离辞:节哀》中,他使用“圆规”意象来表达夫妻之间的感情,从而使该意象成为玄学派诗人著名的“奇思妙喻”。
邓恩在诗中这样写到:就还算两个吧,两个却这样和一副两脚规情况相同;你的灵魂是定脚,并不像移动,另一脚一移,它也动。
Antimony in the environment a review focused on natural waters Occurrence
0012-8252r02r$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 1 2 - 8 2 5 2 Ž 0 1 . 0 0 0 7 0 - 8
Table 1 Antimony abundance
Material
Cosmic abundance Chondrites
Earth-Science Reviews 57 Ž2002. 125–176
rlocaterearscirev
Antimony in the environment: a review focused on natural waters I. Occurrence
Montserrat Filella a,), Nelson Belzile b, Yu-Wei Chen b
126
M. Filella et al.r Earth-Science ReÕiews 57 (2002) 125–176Βιβλιοθήκη 1. Introduction
A good deal of research on geochemical and biogeochemical processes in natural waters has been, and continues to be, devoted to trace elements, particularly transition metals. Rather less attention has been focused on the so-called metalloid elements. Among them, antimony is the one that has received the scantiest attention.
Effect of Additives on the Activity of Tannase from Aspergillus awamori MTCC9299
Effect of Additives on the Activity of Tannasefrom Aspergillus awamori MTCC9299Vinod Chhokar &Meenakshi Sangwan &Vikas Beniwal &Kiran Nehra &Kaur S.NehraReceived:2April 2009/Accepted:4October 2009/Published online:21October 2009#Humana Press 2009Abstract Tannase from Aspergillus awamori MTCC 9299was purified using ammonium sulfate precipitation followed by ion-exchange chromatography.A purification fold of 19.5with 13.5%yield was obtained.Temperature of 30°C and pH of 5.5were found optimum for tannase activity.The effects of metals and organic solvents on the activity of tannase were also studied.Metal ions Mg +2,Mn +2,Ca +2,Na +,and K +stimulated the tannase activity,while Cu +2,Fe +3,and Co +2acted as inhibitors of the enzyme.The addition of organic solvents like acetic acid,isoamylalcohol,chloroform,isopropyl alcohol,and ethanol completely inhibited the enzyme activity.However,butanol and benzene increased the enzyme activity.Keywords Tannase .DEAE-cellulose .Organic solvents .Metal ions .Aspergillus awamori MTCC 9299IntroductionTannase (tannin acyl hydrolase,EC 3.1.1.20)is an inducible enzyme that catalyzes the hydrolysis of ester and depside bonds in hydrolyzable tannins by releasing glucose and gallic acid [1,2].Gallic acid finds application in many fields like dye making,pharmaceuticals,leather,and chemical industries.Besides gallic acid production,the enzyme is extensively used in the preparation of instant tea,wine,beer,and coffee-flavored soft drinks and also as additive for detannification of food.A potential use of tannase is in Appl Biochem Biotechnol (2010)160:2256–2264DOI 10.1007/s12010-009-8813-7V .Chhokar (*):V .BeniwalDepartment of Bio and Nano Technology,Guru Jambheshwar University of Science and Technology,Hisar 125001Haryana,Indiae-mail:vinodchhokar@M.Sangwan :K.NehraDepartment of Biotechnology,Choudhary Devilal University,Sirsa 125055Haryana,IndiaK.S.NehraDepartment of Biotechnology,t.College,Adampur 125052(Haryana,Indiathe treatment of waste water contaimination with polyphenolic compounds such as tannic acids and as an analytical probe for determining the structures of naturally occurring gallic acid esters[3,4].The Aspergillus species produces a large variety of extracellular enzymes,of which tannases are of significant industrial importance.As each industrial application may require specific properties of the biocatalysts,there is still an interest in finding new tannases that could find novel applications.There are several reports on the production of tannase[5],but there are only a few reports on the detailed characterization,i.e.,the effect of additives such as metal ions,cations,anions,surfactants,reducing agents,chelators,organic solvents,etc. on the enzyme activity[6].Organic solvents can be advantageous in various industrial enzymatic processes, e.g.,the reaction media used in biocatalytic esterification and transesterification contains less than1%water.The use of organic solvents can increase the solubility of nonpolar substrates,increase the thermal stability of enzymes,decrease water-dependent side reactions,or eliminate microbial contamination[7].Keeping this in view, the effect of additives such as metal ions,organic solvents,etc.on the activity of tannase from Aspergillus awamori MTCC9299was investigated.Materials and MethodsMicroorganism and Maintenance of CultureA tannase-producing fungus was isolated from the soil sample collected from Guru Jambheshwar University of Science and Technology campus.Soil sample(1g)was dissolved in10ml sterile distilled water.Of this,1ml was inoculated into potato dextrose broth containing0.5%tannic acid and incubated at30°C for72h.Aliquots from this were plated on agar plates containing0.2%tannic acid.Fungus colony capable of forming clear zone around the mycelium due to the hydrolysis of tannic acid was selected and purified. Selected strain was then morphologically identified as A.awamori MTCC9299by Microbial Type Culture Collection,Institute of Microbial Technology,Chandigarh,India.The strain was maintained on potato dextrose agar slants in a refrigerator at4°C by regular transfers.Preparation of Spore InoculumFungal spore inoculum was prepared by adding2.5ml of sterile distilled water containing 0.1%Tween80to a fully sporulated culture.The spores were dislodged using a sterile inoculation loop under strict aseptic conditions,and the number of spores in the suspension was determined using the Neubauer chamber.The volume of1ml of the prepared spore suspension was used as the inoculum with concentration of5×109spores. Fermentation MediumFor the fermentation process,a250-ml Erlenmeyer flask with50ml of Czapek Dox minimal medium containing(gram per liter):NaNO3,6;KH2PO4,1.52;KCl,0.52;MgSO4. 7H2O,0.52;FeSO4.7H2O,0.01;and ZnSO4.7H2O,0.01was employed[8].The medium was adjusted to pH5.0and then sterilized at121°C for15min.Tannic acid solution was prepared separately,and the solution was adjusted to pH5.0with0.1M NaOH,then sterilized by filtering through a sterile millipore membrane(pore size0.2µm)and added to the medium to have a final tannic acid concentration of1%.Tannase AssayTannase activity was determined colorimetrically using the method of Mondal[9].The reaction mixture contained0.3ml of tannic acid(0.5%in0.2M sodium acetate buffer,pH5.5)and 0.1ml of enzyme and was incubated at30°C for20min.The enzymatic reaction was stopped by addition of3ml of BSA solution,which precipitates the remaining tannic acid. The tubes were centrifuged(5,000×g10min),and the resultant precipitate was dissolved in a 3-ml SDS-triethanolamine solution.A1ml of FeCl3reagent was added to each tube and was kept for15min at room temperature for stabilization of the color.The absorbance was read at 530nm against the blank.One unit of enzyme activity is defined as the amount of enzyme required to hydrolyze1mM of tannic acid in1min under assay conditions.Assay of Protein ConcentrationThe protein concentration was determined by the Bradford method[10]using bovine serum albumin as the standard.Purification of TannaseSupernatants from batch cultures were concentrated using ammonium sulfate fractionate and dialyzed against acetate buffer(0.02M and pH5.5)at4°C.The resultant enzyme solution was loaded onto2.5×10cm DEAE-cellulose column equilibrated with0.02M acetate buffer(pH 5.5),and the proteins were eluted with a linear gradient of0.0–0.5M NaCl at a flow rate of5ml/h. The fractions of2ml each were collected and analyzed for enzyme activity.Fractions with high enzyme activity(fraction number4and5)were pooled together and used for further experiments.SDS-PAGE and Molecular Weight(Mr)DeterminationThe comparative mobility of partially purified and purified tannase was carried out on7.5% SDS-PAGE.Molecular weight markers were purchased from Sigma and were run parallel to the samples.Enzyme CharacterizationThe effect of different temperatures,pH,organic solvent,and metal ions on the enzyme fractions obtained after DEAE-cellulose chromatography was studied.Optimum pH and Temperature for Tannase ActivityThe optimum pH for tannase activity was determined at30°C by incubating the enzyme with substrate at different pH ranges from3to6.The pH of the reaction mixture was varied using different buffers(acetate buffer for pH3.5–5.5and phosphate buffer for pH6).The optimum temperature was determined by incubating the reaction mixture for20min at different temperatures ranging from20to70°C.Effect of Organic Solvents and Metals IonsThe enzyme solution containing different concentrations(20%,40%,and60%)of various organic solvents(acetone,toluene,benzene,ethanol,acetic acid,isoamylalcohol,chloroform,phenol,butanol,and glycerol)and1mM concentration of various metal ions like Ca+2,Na+,K+,Mn+2,Fe+3,Zn+1,Co+2,Cu+2,and Mg+2were incubated(acetate buffer 0.2M,pH5.5)at30°C for20min,and the effect of organic solvents and metal ions on tannase activity was studied.Results and DiscussionPurification of TannaseAmmonium sulfate fractionation was done at various concentrations(50–90%).Recovery of enzyme was maximum at80%fractionation.The elution profile of tannase from the DEAE-cellulose column filtration is shown in Fig.1.The elution profile of the enzyme showed two peaks.Maximum tannase activity was found at the first peak.The active fraction(fraction number4and5)were pooled.DEAE-cellulose column chromatography led to an overall purification of19.5-fold with a yield of13.5%(Table1).Mahendran et.al.[11]and Kasieczka-Burnecka et.al.[12]also obtained similar values after DEAE-cellulose column chromatography of tannase from Paecilomyces variotii and Verticillium sp.P9, respectively.However,a purification fold of135with91%yield of tannase from Penicillium variable has also been reported using gel-filtration chromatography[13].SDS-PAGE and Molecular Weight(Mr)DeterminationFigure2shows the molecular mass of purified tannase obtained from SDS-PAGE analysis, with a single band of101±2kDa indicating the homogeneity of the enzyme.Tannases reported so far are generally of high molecular weight ranging from80to310kDa[11–13]. Tannase from Aspergillus niger ATTC16620have been reported as a single monomer unit of149kDa[14].Tannase from Aspergillus flavus and A.niger N888has also been reported as single peptide of80–85and165kDa,respectively[14].However,the molecular weight of P.variable tannase has been reported to be310kDa with a dimer of two subunit of158kDa[13].Fig.1Elution graph ofion-exchange chromatographyEffect of pH and Temperature on the Activity of EnzymeEffect of initial pH (Fig.3)of the reaction mixture on the tannase activity showed that the activity is extremely low at pH 3.0(1.63U/ml).The activity of enzyme increased gradually with increase in pH peaking at pH 5.5(2.88U/ml).Further increase in pH resulted in decrease in the activity of tannase.To evaluate the effect of temperature on the activity of purified tannase,the temperature was varied from 25to 70°C.With an increase in temperature,the tannase activity increased,and optimum activity was recorded at 30°C (Fig.4).These results are in agreement with the previous reports of pH 5.5for Aspergillus ruber [15]and a pH range of 5–7for P .variotii [11].The optimum temperature for tannase activity was 30°C,which was similar to those obtained for Lactobacillus plantarum CECT748[16].However,optimum temperature and pH of tannase from A.awamori Nakazawa have been reported to be 35°C and pH 5.0,respectively [2].Effect of Organic Solvents on Enzyme ActivityIn nature,enzymes function in aqueous solutions.Therefore,it is not surprising that virtually all studies in enzymology so far have used water as the reaction medium.However,from the biotechnological standpoint,there are numerous advantages of conducting enzymatic Table 1Purification table of tannase from A.awamori MTCC 9299.Source Total activity Total protein (mg)Specific activity(µ/mg)Purification (fold)Yield (%)Crude 128261.00.4891100Ammonium sulfate purification 37.1241.70.891.8229Ion exchange17.28 3.769.5519.513.5Chromatography Lane1 Lane2 Lane3 Fig.2Molecular mass of puri-fied A.awamori MTCC 9299tannase estimated by electropho-ne 1shows markerproteins (kilodalton);lane 2shows purified tannase (101±2kDa molecular mass);and lane 3shows partially purified tannase(ammonium sulfate precipitation)conversions in organic solvents as opposed to water:(1)high solubility of most organic compounds in nonaqueous media;(2)ability to carry out new reactions impossible in water because of kinetic or thermodynamic restrictions;(3)greater stability of enzymes;(4)relative ease of product recovery from organic solvents as compared to water;and (5)the insolubility of enzymes in organic media,which permits their easy recovery and reuse and,thus,eliminates the need for immobilization [17].To determine the effect of organic solvents on the activity of tannase,various organic solvents (Table 2)were used at different concentrations (20%,40%,and 60%).It was found that acetic acid,isoamylalcohol,chloroform,and isopropyl alcohol completely inhibited the activity of tannase at all concentrations.However,ethanol inhibited the tannase activity by 48.84%initially;thereafter,complete loss in the enzyme activity was observed at 40%and 60%.A gradual decrease in the activity of tannase was observed with the increasing concentration of acetone and toluene,and finally,at 60%,the activity was reduced to 55.01%and 28.49%,respectively.With the initial inhibitory effect at 20%and 40%methanol,the original activity was regained at 60%.It was also observed thatthe Fig.3Effect of pH on tannaseactivity Fig.4Effect of temperature ontannase activitypresence of butanol and benzene increased the enzyme activity by twofold at 60%v /v concentration.Sharma et.al.[13]have also studied the effect of organic solvents on tannase from P .variable and reported more than 60%residual activity in 20%v /v of carbon tetrachloride,heptane,petroleum ether,and toluene after 60min.They also observed that the enzyme was stable more than 50%in 60%v /v of carbon tetrachloride,heptane,petroleum ether,and toluene for 5min.Saborowski et.al [7]studied the effect of organic solvents on endopeptidases and found that the chymotrypsin and protease activity were slightly elevated at 5%and 10%concentration of acetone,2-propanol,methanol,and ethanol,respectively.Trypsin activity,in contrast,was strongly elevated by organic solvents;the activity rose concomitantly to eightfold of initial value at a concentration of 40%of 2-propanol.Fridovichi [18]reported that in most of the cases,the organic solvents acted as competitive inhibitors at low concentrations and became increasingly noncompetitive as the concentration of the solvent was raised.Effect of Metal Ions on Enzyme ActivityVarious metal ions like ZnSO 4,MgSO 4,CaCl 2,CuSO 4,MnSO 4,Fe 2(SO 4)3,CoCl 2,NaCl,and KCl at 1mM concentration each were tested for their effect on tannase activity.Table 3Table 2Effect of organic solvents on tannase activity.Control100%Concentration (v /v ;%)20%40%60%Acetone78.51±0.9463.92±0.9455.01±0.84Butanol163.86±1.14203.74±2.07199.44±3.16Benzene138.76±0.48127.53±1.12199.44±1.21Toluene86.66±2.6982.67±1.5228.49±1.21Acetic acid−−−Methanol54.62±2.6076.68±5.94100.31±0.54Ethanol51.16±1.14−−Chloroform−−−Isopropyl alcohol−−−Isoamyl alcohol −−−AdditivesRelative activity (%)Control100ZnSO 496.52±0.2MgSO 4123.99±0.22CoCl28.86±0.85Cu SO 448.79±1.33MnSO4115.23±1.07Fe SO 423.11±0.44CaCl2116±0.57NaCl111.45±0.89KCl 109.89±1.13Table 3Effect of metal ions ontannase activity.shows that among all the metal ions studied Mg+2,Mn+2,Ca+2,Na+,and K+elevated the tannase activity by23.9%,15.23%,16%,11%,and9%,respectively.Zn+2did not show any significant effect on tannase.Cu+2,Fe+3,and Co+2were found to be strongly inhibiting the tannase activity by51.21%,76.89%,and71.14%,respectively.The effect of metal ions on tannase activity was studied by Kar et.al.[6].Mg+2or Hg+(1.0mM)activated tannase activity;on the other hand,Ba+2,Ca+2,Zn+2,Hg+2,Ag+,Fe+3,and Co+2inhibited tannase activity at1.0-mM concentration.Mukherjee and Banerjee[4]found that the presence of the divalent ion Mg+2at low concentration increases tannase activity, whereas,it was inhibited maximally by Hg++followed by Fe+3,Zn+2,and Ba+2.Sabu et.al.[14]also studied effect of metal ions on tannase from A.niger ATCC16620and found that the addition of metal ions like Zn+2,Mn+2,Cu+2,Ca+2,Mg+2,and Fe+2inhibited the enzyme activity.Kasieczka-Burnecka et.al.[12]have recently reported inhibitory effect of Zn+2,Cu+2,K+,Cd+2,Ag+,Fe+3,Mn+2,Co+2,Hg+2,Pb+2,and Sn+2on tannase from Verticillium sp.References1.Lekha,P.K.,&Lonsane,B.K.(1997).Production and application of tannin acyl hydralose:state of theart.Advances in Applied Microbiology,44,215–260.2.Mahapatra,K.,Nanda,R.K.,Bag,S.S.,Banerjee,R.,Pandey,A.,&Szakacs,G.(2005).Purification,characterization and some studies on secondary structure of tannase from Aspergillus awamori nakazawa.Process Biochemistry,40,3251–3254.3.Seth,M.,&Chand,S.(2000).Biosynthesis of tannase and hydrolysis of tannins to gallic acid byAspergillus awamori—optimisation of process parameters.Process Biochemistry,36,39–44.4.Mukherjee,G.,&Banerjee,R.(2006).Effects of temperature,pH and additives on the activity oftannase produced by a co-culture of Rhizopus oryzae and Aspergillus foetidus.World Journal of Microbiology&Biotechnology,22,207–211.5.Aguilar,C.N.,&Gutierrez-Sanchez,G.(2001).Review:sources properties,applications and potentialuses of tannin acyl hydrolase.International Journal of Food Science&Technology,7,373–382.6.Kar,B.,Banerjee,R.,&Bhattacharyya,B.C.(2003).Effect of additives on the behavioural properties oftannin acyl hydrolase.Process Biochemistry,38,1285–1293.7.Saborowski,R.,Sahling,G.,Navarette del Toro,M.A.,Walter,I.,&Garcia-Carreno,F.L.(2004).Stability and effects of organic solvents on endopeptidases from thegastric fluid of the marine crab Cancer pagurus.Journal of Molecular Catalysis.B,Enzymatic,30,109–118.8.Bradoo,S.,Gupta,R.,&Saxena,R.K.(1996).Screening for extracellular tannase producing fungi:development of a rapid and simple plate assay.Journal of General and Applied Microbiology,42,325–329.9.Mondal,K. C.,Banerjee, D.,Jana,M.,&Pati, B.R.(2001).Colorimetric assay method fordetermination of the tannase activity.Analytical Biochemistry,295,168–171.10.Bradford,M.M.(1976).A rapid and sensitive method for the quantitation of microgram quantities ofprotein utilizing the principle of protein-dye binding.Analytical Biochemistry,72,248–254.11.Mahendran,B.,Raman,N.,&Kim,D.J.(2006).Purification and characterization of tannase fromPaecilomyces variotii:hydrolysis of tannic acid using immobilized tannase.Applied Microbiology and Biotechnology,70,444–450.12.Kasieczka-Burnecka,M.,Karina,K.,Kalinowska,H.,Knap,M.,&Turkiewicz,M.(2007).Purificationand characterization of two cold-adapted extracellular tannin acyl hydrolases from an Antarctic strain Verticillium sp.P9.Applied Microbiology and Biotechnology,77,77–89.13.Sharma,S.,Agarwal,L.,&Saxena,R.K.(2008).Purification,immobilization and characterization oftannase from Penicillium variable.Biores Technology,99,2244–2251.14.Sabu,A.,Kiran,S.G.,&Pandey,A.(2005).Purification and characterization of tannin acyl hydrolosefrom Aspergillus niger ATCC16620.Journal of Food Technology and Biotechnology,2,133–138. 15.Kumar,R.,Sharma,J.,&Singh,R.(2007).Production of tannase from Aspergillus ruber under solid-state fermentation using jamun(Syzygium cumini)leaves.Microbiological Research,162,384–390.16.Rodriguez,H.,Rivas,B.,Gomez-Cordoves,C.,&Munoz,R.(2008).Characterization of tannaseactivity in cell free extracts of Lactobacillus plantarun CECT748.International Journal of Food Microbiology,121,92–98.17.Zaks,A.,&Klibnov,A.M.(1985).Enzyme-catalyzed processes in organic solvents.Proceedings of theNational Academy of Sciences of the United States of America,82,3192–3196.18.Fridovichi,I.(1996).Some effects of organic solvents on the reaction kinetics of milk xanthine oxidase.Journal of Biological Chemistry,241,3624–3629.。
胶体基本理论—胶体体系概述
现代胶体科学的研究特点
其中，两个根本的问题始终是胶体和界面科学工作者研究的中心
（1）分子间力和界面力的性质问题，主要是弱相互作用。在分散体系中， 分散相的相互作用，分散相与分散介质的相互作用，分散相与吸附物的相互 作用，分散介质与吸附物的相互作用，以及吸附层中吸附物的相互作用等都 受到这种力的作用。
《表面活性剂、胶体与界面化学基础》
考试考核
平时成绩：考勤+课堂表现 线上考核、互动、评价：50% 期末考试：50%
基本理论
界面和分散体系 胶体体系概述 胶体的基本性质 表面活性剂结构和定义 表面张力和表面特性 表面活性剂在界面的吸附 表面活性剂溶液性质 乳状液HLB值、PIT理论
在胶核同周围介质的界面区域就形成所谓双电层，内层是胶核固相的电位离子层， 外层是液相中的反离子层。
这些异号离子，其中紧靠电位离子的部分
胶核
被牢固的吸引着，当胶核运动时，它也随着
一起运动，形成固定的离子层，称为吸附层。
而其它的异号离子，距离电位离子较远，受
到的引力较弱，不随胶核一起运动，并有向
水中扩散的趋势，形成了扩散层。
胶体与界面化学的研究内容
宏观物质
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分 子 原 子 基本粒子
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胶体与界面化学主要是研究胶体分散体系和界面现象的一门科学，是 物理化学的重要分支。既要研究胶体化学的问题，有必然涉及表面化 学的问题，两者相互联系、相辅相成。
分散体系 纳米材料
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朱章志运用扶正祛邪法论治糖尿病经验
ʌ临证验案ɔ朱章志运用扶正祛邪法论治糖尿病经验❋曾绘域1,朱章志2ә,周㊀海3,陈㊀珺3,张文婧3(1.深圳市中西医结合医院,广东深圳㊀518104;2.广州中医药大学第一附属医院,广州㊀510405;3.广州中医药大学,广州㊀510405)㊀㊀摘要:糖尿病属于中医学 消渴病 范畴,以往医家多认为其病机为阴虚燥热,治疗以滋阴清热为法㊂朱章志教授通过长期的临床观察与实践,立足于张仲景 保胃气,扶阳气 的理论,认为糖尿病的病机为正虚邪滞,即太阴虚损㊁阳气不足㊁收敛不及,寒㊁水㊁湿之邪阻滞阳气运行通道㊂治疗上不囿陈法,以扶正祛邪为大法,通过固护太阴㊁扶助阳气㊁收敛阳气,祛除寒水湿之邪,恢复阳气运行之通畅,使阳气功能复常㊁运行有序,为糖尿病的治疗提供临床新思路㊂㊀㊀关键词:扶正祛邪;糖尿病;朱章志㊀㊀中图分类号:R587.1㊀㊀文献标识码:A㊀㊀文章编号:1006-3250(2021)01-0149-03Discussion on ZHU Zhang-zhi's Experience in Treating Diabetes Mellitus by Using The Method of Reinforcing The Healthy Qi and Eliminating The Pathogenic FactorsZENG Hui-yu 1,ZHU Zhang-zhi 2ә,ZHOU Hai 3,CHEN Jun 3,ZHANG Wen-jing 3(1.Shenzhen Hospital of Integrated traditional Chinese and Western Medicine,Guangdong,Shenzhen 518104,China;2.The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510405,China;3.Guangzhou University of Chinese Medicine,Guangzhou 510405,China)㊀㊀Abstract :Diabetes mellitus belongs to the category of "xiao ke"in traditional Chinese medicine.Doctors used to think that its pathogenesis was Yin deficiency and dryness heat ,and the treatment was nourishing Yin and clearing heat.Through long-term clinical observation and practice ,and based on ZHANG Zhong-jing's theory of protecting stomach Qi and supporting Yng Q ,professor ZHU Zhang-zhi believes that the pathogenesis of diabetes is deficiency of healthy Qi and stagnation of pathogen.Because of the deficiency of greater Yin and Yang Qi ,and the lack of convergence ,the cold ,water and dampness block the operational channel of Yang Qi.The treatment of diabetes mellitus should be based on reinforcing the healthy Qi and eliminating the pathogenic factors.By strengthening Taiyin ,supporting Yang Qi ,astringent Yang Qi ,dispelling the evil of cold ,water and dampness ,we can restore the smooth operation of Yang Qi ,restore the function of Yang Qi to normal and operate orderly ,which provides a new clinical method for the treatment of diabetes mellitus.㊀㊀Key words :Reinforcing the healthy Qi and eliminating the pathogenic factors ;Diabetes mellitus ;ZHU Zhang-zhi❋基金项目:国家自然科学基金资助项目(81873190)-降糖三黄片在糖脂毒性所致胰岛β细胞损伤的自噬调控作用作者简介:曾绘域(1990-),女,广东云浮人,住院医师,硕士研究生,从事六经辨治内分泌疾病的临床与研究㊂ә通讯作者:朱章志(1963-),男,湖南衡阳人,主任医师,博士研究生导师,从事六经辨治内分泌疾病的临床与研究,Tel :************,E-mail :zhuangi@ ㊂㊀㊀随着人口老龄化和生活方式的改变,我国糖尿病的患病率呈上升趋势,2013年我国18岁以上人群糖尿病患病率为10.4%[1]㊂中医药在延缓糖尿病的进展及防治其并发症方面具有一定优势[2-4]㊂糖尿病属于中医学 消渴病 范畴,以往医家多认为其病机为阴虚燥热,治疗以滋阴清热为法,但疗效尚不能令人满意㊂朱章志教授通过长期的临床观察与实践,认为正虚邪滞乃糖尿病病机之核心,采用扶正祛邪法治之屡获奇效㊂1㊀正虚邪滞之糖尿病病机‘素问㊃经脉别论篇“曰: 饮入于胃,游溢精气,上输于脾,脾气散精 水精四布,五经并行㊂食物入胃,经脾胃运化化生精气,然后输布全身㊂糖尿病患者常嗜食肥甘,起居无常,烦劳紧张,致太阴虚损,正气内虚,阳气戕伐,津液代谢异常,而生寒水湿之邪㊂寒㊁水㊁湿之邪气作为阴邪,又可阻滞阳气运行之通道㊂阳气运行通道不畅,不能敷布温煦四肢,可见手足逆冷;阳气运行受阻,又可出现郁而化热之象㊂因此朱章志认为,疗糖尿病的关键在于恢复阳气运行之通畅,根据糖尿病正虚邪滞的病机,治疗以扶正祛邪为法,顾护太阴㊁扶助阳气㊁收敛阳气,祛除寒水湿之邪,使阳气功能复常则行有序㊂2㊀运用扶正祛邪法治疗糖尿病2.1㊀扶正2.1.1㊀固护中气,扶助阳气㊀张仲景遣方用药常体现 保胃气 之思想[5],如桂枝汤中配伍生姜㊁大枣㊁炙甘草,发汗祛邪不忘顾护中气;又如白虎汤中加梗米㊁炙甘草以和中益胃,又可防止石膏㊁知母大寒伤中㊂ 有胃气则生,无胃气则死 ,故扶正之要以保胃气为先㊂朱章志认为,阳气在人体的生命活动中占主导9412021年1月第27卷第1期January 2021Vol.27.No.1㊀㊀㊀㊀㊀㊀中国中医基础医学杂志Journal of Basic Chinese Medicine地位㊂‘素问㊃生气通天论篇“曰: 阳气者若天与日,失其所则折寿而不彰 是故阳因而上,卫外者也㊂ ‘黄帝内经“把阳气比作太阳,阳气运行失常可致短寿㊂阳气具有抵御外邪㊁护卫生命㊁维持机体生命活动的作用,津液的气化㊁血液的运行均需阳气的温煦与推动㊂因此,在人体的阴阳平衡中阳气起着主导作用㊂朱章志认为,正气虚衰㊁太阴虚损㊁阳气不足是糖尿病发生发展之根本原因,因此扶正首当 固护中气,扶助阳气 ,故常以附子理中汤为底方,固护中宫㊂太阴脾土居中央,犹如足球比赛之中场,能联系前锋与后卫进可攻退可守,进可充养肺卫之气抵御外邪,退可顾护少阴以防寒邪内陷㊂‘四圣心源㊃卷二太阴湿土“提到: 湿者,太阴土气之所化也故胃家之燥,不敌脾家之湿,病则土燥者少而土湿者多也㊂[6] 阴脾土易挟寒湿,附子理中汤功善固护中气㊁温补脾阳而散寒湿,为治疗太阴阳虚寒湿之要方㊂方中附子辛温大热,补坎中真阳,又能散寒湿,荡去群阴;干姜去脏腑沉寒痼冷,温暖脾土,复兴火种;人参被誉为 百草之王 能大补元气,为扶正固本之极品;白术味苦性温,功善健脾燥湿,乃扶植太阴之要药;炙甘草善益气补中,调和药性,诸药合用以收培补中阳㊁散寒除湿之效㊂若其人神疲懒言,气虚较甚,在附子理中汤的基础上可重用红参㊁北芪以大补元气,健脾益气;若其人四肢不温㊁肢体困重㊁寒湿较重者,可加重附子㊁干姜之量,并加细辛㊁吴茱萸以散久寒;若其人口干口苦㊁舌苔黄腻㊁大便黏滞不爽兼夹湿热之象,可仿当归拈痛汤之意,加茵陈㊁当归㊁黄芩以利湿清热㊂2.1.2㊀收敛阳气,阳密乃固㊀朱章志认为, 阴 可理解为 阳气 的收敛㊁收藏状态,糖尿病 阴虚燥热 之象乃阳气不足㊁收敛不及㊁升发太过所致[7]㊂‘素问㊃生气通天论篇“提到: 阳气者,烦劳则张 ㊂现代人起居无节,以妄为常,阳气因而不能潜藏,常常浮越于外容易出现假热之象,医者不察,妄投清热泻火之品,实乃雪上加霜㊂ 凡阴阳之要,阳密乃固 ,收敛阳气即是扶正,犹如太极之能收能放,收敛是为了聚集能量,阳气固密,正气才能强盛,方能更好的制敌㊂朱章志常用砂仁㊁肉桂㊁白芍㊁山萸肉㊁泽泻等药物收敛阳气㊂砂仁辛温,既能宣太阴之寒湿,又能纳气归肾,使阳气收敛于少阴,少火生气㊂‘本草经疏“提到: 缩砂蜜,辛能散,又能润 辛以润肾,故使气下行 气下则气得归元㊂[8] 肉桂引火归原,导浮越之阳气归于命门,益火消阴㊂若患者出现咽痛㊁牙龈肿痛㊁痤疮等阳气不敛㊁虚火上冲之象,常用砂仁㊁肉桂以收敛阳气,纳气归肾,引火归原㊂白芍味酸能敛,敛降甲木胆火,使相火归位㊂‘本草求真“曰: 气之盛者,必赖酸为之收,故白芍号为敛肝之液,收肝之气,而令气不妄行也㊂[9] 朱章志常使用白芍以补肝之体㊁助肝之用,收敛肝气,肝平则郁气自除,火热自消㊂山萸肉秘精气㊁敛阳气,使龙雷之火归于水中㊂朱章志常用山萸肉收敛正气,遇汗出多者,常重用以固涩敛汗㊂泽泻能泻能降,能入肾泻浊,开气化之源,泻浊以利扶正,又能降气而引火下行㊂朱章志常用泽泻打通西方潜藏之要塞[10],在温阳之品中加入泽泻,利于阳气潜藏,使孤阳有归㊂2.1.3㊀填补阴精,以滋化源㊀‘素问㊃金匮真言论篇“提到: 夫精者,身之本也㊂ 精 是人体生命活动的物质基础,能化气生髓,濡养脏腑㊂人体之精禀受于父母,又由后天水谷之精不断充养,归藏于肾中㊂ 孤阴不生,独阳不长 ,无阳则阴无以生,无阴则阳无以化㊂肾乃水火之脏,阴精充足才能涵养坎中真火,使真阳固密于内,化生正气㊂朱章志常在秋冬之季嘱糖尿病患者进补阿胶等血肉有情之品填补肾精㊂肾主封藏,秋冬进补使肾精充养,以滋阳气化生之源㊂阿胶用黄酒烊化,既能祛除阿胶之腥,又能借黄酒通行之性解阿胶滋腻碍胃之弊,每日少量服用,以有形之精难以速生,填补肾精以缓补为要㊂除此之外,遣方用药时亦会注意顾护阴精,在使用温阳药的同时常常配伍山萸肉㊁白芍等养阴药,以防温燥伤阴之弊㊂2.2㊀祛邪2.2.1㊀外散寒水以运太阳㊀ 太阳为开 ,太阳乃三阳之表,巨阳也,其性开泄以应天,为祛邪之重要通道㊂在运气里,太阳在天为寒,在地为水,合而为太阳寒水㊂张仲景太阳病篇研究的是水循环过程,治太阳就是治水[11]㊂寒㊁水之邪闭郁在表,气血运行不畅,可见肌肤麻木不仁㊂邪气滞留太阳,阻碍阳气运行,当因势利导㊁开太阳之表以发汗,外散寒㊁水之邪㊂糖尿病患者正气亏虚为本,祛邪不能伤正,朱章志临床常用桂枝麻黄各半汤小发其汗,使玄府开张,邪有出路㊂桂枝麻黄各半汤乃发汗轻剂,为桂枝汤与麻黄汤相合而得,其中麻黄㊁桂枝㊁生姜㊁北杏发散宣肺以开皮毛,芍药㊁大枣㊁炙甘草酸甘化阴以益营,诸药相合,刚柔相济,祛邪而不伤正㊂邪去正安,阳气运行通畅,水液代谢复常则阳气自充,而无寒水之扰㊂若寒邪较重可用三拗汤,此为麻黄汤去桂枝而成,功善开宣肺气,疏散风寒,因去辛温之桂枝发汗力不及麻黄汤,祛邪而不伤正㊂2.2.2㊀下利水湿以健少阴㊀少阴乃水火交会之脏,元气之根,人身立命之本㊂‘医理真传“提到: 坎中真阳,一名龙雷火,发而为病,一名元阳外越,一名孤阳上浮,一名虚火上冲㊂此际之龙,乃初生之龙,不能飞腾而兴云布雨,惟潜于渊中,以水为家,以水为性,遂安其在下之位㊂水盛一分龙亦盛一分,水高一尺龙亦高一尺,是龙之因水盛而游 [12]㊂阴盛051中国中医基础医学杂志Journal of Basic Chinese Medicine㊀㊀㊀㊀㊀㊀2021年1月第27卷第1期January2021Vol.27.No.1则阳衰,水湿之邪泛滥,则龙雷之火因而飞越在外㊂叶天士深谙张仲景之理,提到 通阳不在温,而在利小便 [10,13],通过利小便的方法,使水湿之邪从下而解,阳气运行通道无水湿之邪阻碍,则阳气无需温养而自通,水盛得除则真龙亦安其位㊂朱章志常用五苓散㊁真武汤下利水湿,以复阳气之通达,少阴之健运㊂五苓散具有通阳化气利水之效,治疗膀胱气化不利形成的蓄水证㊂方中猪苓㊁茯苓㊁泽泻导水湿之邪下行;白术健脾燥湿,杜绝生湿之源;桂枝助膀胱气化,通阳化气行水又通气于表,使全身在表之湿邪皆得解,五药合用,膀胱气化复常,水道通调使小便得利,水湿得出㊂真武汤为治疗少阴阳虚㊁水气泛滥之主方,方中附子振奋少阴阳气,使水有所主;白术㊁茯苓健脾制水;生姜助附子敷布阳气,宣散水气;芍药利小便,制附㊁姜之燥,五味相合共奏温阳利水之功㊂2.2.3㊀开郁逐寒以畅厥阴㊀肝为将军之官,肝气主动主升发,能统帅兵马,捍卫君主㊂厥阴肝经,体阴用阳,内寄相火,相火敷布阳气,祛阴除寒,是祛邪的先锋主力军㊂朱章志常用吴茱萸汤祛除厥阴肝经之寒邪,恢复肝经阳气之运行㊂方中吴茱萸辛苦而温,芳香而燥,‘本草汇言“曰: 开郁化滞,逐冷降气之药 [14],能温胃暖肝,降浊阴止呕逆,为治疗肝寒之要药㊂配以生姜温胃散寒,佐以人参㊁大枣健脾益气补虚,全方散寒与降逆并施,共奏暖肝温胃㊁降逆止呕之效㊂‘素问㊃至真要大论篇“说: 帝曰:厥阴何也?岐伯曰:两阴交尽也㊂ 物极必反,重阴必阳㊂厥阴为阴尽阳生之脏,足厥阴肝经与足少阳胆经互为表里,若出现肝气不疏㊁枢机不利㊁气郁化火,朱章志常用小柴胡汤和畅枢机,开郁以复气机调达㊂方中柴胡疏泄肝胆之气;黄芩清泄胆火,一疏一清,气郁通达,火郁得发;生姜㊁半夏和胃降逆;人参㊁大枣㊁炙甘草固护中宫,全方寒温并用㊁补泻兼施,以复厥阴疏泄之职,使气机和畅㊁阳气运行有序㊂3㊀典型病案患者杨某,女,65岁,2017年3月10日初诊:2型糖尿病病史6年余,症见疲乏,双下肢轻度浮肿,下肢冰凉,背部易汗出,口苦口干,偶有腰膝酸软,纳眠可,二便调,舌淡暗,苔黄腻,脉沉细㊂辅助检查示糖化血红蛋白10.8%,空腹血糖14.59mmol/L,总胆固醇6.38mmol/L,甘油三酯3.66mmol/L,低密度脂蛋白胆固醇4.34mmol/L㊂西医诊断2型糖尿病㊁高脂血症,治疗给予门冬胰岛素30(早餐前22u晚餐前20u)控制血糖,阿托伐他汀钙片(20mg, qn)调脂㊂中医诊断消渴病,少阴阳虚寒湿证㊂患者少阴阳气衰微不足以养神,固见疲乏;腰为肾之府,少阴阳虚则见腰膝酸软,阳虚寒盛则见下肢冰凉;背部正中乃督脉运行之所,阳气虚衰无以固摄则见背部汗出;少阴阳虚不能主水,寒水泛滥则见双下肢浮肿;水湿内停有郁而化热之象,则见口苦口干㊁舌苔黄腻㊁舌淡暗,脉沉细为少阴阳虚寒湿之征,治以温阳散寒㊁利水除湿为法㊂方以扶正祛邪方合当归拈痛汤加减:炮附片10g(先煎1h),红参10g (另炖),干姜15g,白术30g,炙甘草15g,桂枝12 g,麻黄8g,生姜30g,猪苓10g,泽泻30g,茯苓30 g,白芍30g,酒萸肉45g,当归15g,茵陈10g,5剂水煎服,2d1剂,水煎至250ml,饭后分2次服用,次日复煎㊂方中以附子理中汤为底方温补中焦,散寒除湿;加桂枝㊁麻黄使寒湿之邪从皮毛而解;加五苓散通阳化气,使湿邪从下而出;生姜散寒除湿;白芍㊁酒萸肉收敛阳气,以助正气祛邪;当归活血利水;茵陈清热利湿㊂2017年3月24日二诊:患者双下肢浮肿减轻,疲乏较前好转,无口干口苦,无腰膝酸软,仍觉下肢冰凉,背部仍有汗出,动则尤甚,大便每日二行,质偏烂,舌淡暗,苔白腻,脉细㊂患者大便质烂,乃邪有出路,导水湿之邪从大便而解㊂患者无口干口苦,舌苔由黄腻转为白腻,知湿郁化热之象已除,遂去茵陈㊂仍觉下肢冰凉乃内有久寒,加制吴茱萸12g以散沉寒痼冷;上方加酒萸肉至60g以加强收敛阳气㊁固摄敛汗之效,加黄芪60g以健脾益气敛汗;加砂仁6g(后下)㊁肉桂3g(焗服)以加强收敛阳气㊁扶助正气之效,7剂水煎服,服法同前㊂2017年4月7日三诊:患者背部汗出减少,下肢转温,余症皆除,大便每日二行质软,舌淡红,苔薄白,脉细较前有力,继续服二诊方药5剂㊂后给予附子理中丸(每次8粒,每日3次)服用1个月巩固疗效㊂2017年11月17日复诊:患者上述症状皆除,纳眠可,二便调㊂复查糖化血红蛋白6.8%,空腹血糖6.5mmol/L,总胆固醇5.14mmol/L,甘油三酯1.65 mmol/L,低密度脂蛋白胆固醇2.43mmol/L㊂4㊀结语以往医家多以滋阴清热为法治疗糖尿病,通过长期的临床实践,朱章志不囿陈法,根据糖尿病患者当前之病因病机特点,运用扶正祛邪法治疗糖尿病,通过顾护太阴㊁扶助阳气㊁收敛阳气,祛除寒水湿之邪气,恢复阳气运行之通畅,为糖尿病的治疗提供新思路㊂参考文献:[1]㊀WANG L GAO-P-ZHANG-M,et al.Prevalence and EthnicPattern of Diabetes and Prediabetes in China in2013[J].JAMA,2017,317(24):2515-2523.[2]㊀谭宏韬,刘树林,朱章志,等. 首辨阴阳,再辨六经 论治惠州地区2型糖尿病的临床观察[J].中华中医药杂志,2018,33(9):4240-4244.(下转第181页)offspring of sleep-deprived mice[J].Psychoneuroendocrinology,2009,35(5):775-784.[9]㊀覃甘梅,覃骊兰.心肾不交型失眠动物模型研究进展[J].中华中医药杂志,2018,33(1):229-231.[10]㊀吕志平,刘承才.肝郁致瘀机理探讨[J].中医杂志,2000,41(6):367-368.[11]㊀游秋云,王平,田代志,等.老年肝郁失眠证候大鼠模型的建立和评价[J].中国实验方剂学杂志,2013,19(2):222-225. 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短板效应,瓦拉赫效应作文
短板效应,瓦拉赫效应作文英文回答：The concept of "short board effect" refers to the phenomenon where a person's weaknesses or limitations overshadow their strengths or talents. It is often used to describe situations where an individual's deficiencies hinder their overall performance or success. For example, a person who is highly intelligent but lacks social skills may struggle to build meaningful relationships or advancein their career.On the other hand, the "Valley of the Shadow of Death" effect, also known as the "Dunning-Kruger effect," describes a cognitive bias in which individuals with low ability or knowledge overestimate their competence. This effect occurs because people with limited skills or understanding often lack the ability to recognize their own incompetence. As a result, they may have an inflated sense of confidence and make poor decisions or judgments.Both the short board effect and the Valley of the Shadow of Death effect have significant impacts on individuals and their interactions with others. In the case of the short board effect, it can lead to frustration,self-doubt, and hinder personal growth. Individuals may become overly focused on their weaknesses, neglecting their strengths and potential. This can limit their opportunities and hinder their ability to reach their full potential.Similarly, the Valley of the Shadow of Death effect can have detrimental consequences. Individuals who overestimate their abilities may fail to seek feedback or improve their skills. This can lead to poor performance, strained relationships, and missed opportunities for growth. Moreover, their overconfidence may also hinder theirability to learn from their mistakes and adapt to new challenges.中文回答：“短板效应”是指一个人的弱点或限制超过了其优势或才能的现象。
小学上册B卷英语第1单元自测题
小学上册英语第1单元自测题英语试题一、综合题(本题有100小题，每小题1分，共100分.每小题不选、错误，均不给分)1.My friend is a _____ (经济学家) and studies money.2.What do you call a sweet, baked treat made with chocolate?A. CakeB. BrownieC. CookieD. All of the aboveD3.Which ocean is the smallest?A. AtlanticB. IndianC. ArcticD. PacificC4.What do we call a young eel?A. FryB. ElverC. KitD. PupB Elver5.The __________ is a popular tourist destination in Spain. (巴萨罗那)6. A __________ (生物化学反应) occurs within living organisms.7.What is the name of the famous landmark in Egypt with a lion's body and a human head?A. Great WallB. ColosseumC. Statue of LibertyD. SphinxD8.What do we call a historical document?A. ManuscriptB. ArtifactC. ArchiveD. All of the above9.My sister is learning to play the ____ (flute).10.The capital city of Comoros is __________.11.What do you wear on your feet?A. HatB. ShirtC. ShoesD. Belt12.The color of an object depends on the ______ (wavelength) of light it reflects.13.My mom enjoys __________ (参加) community events.14.What is the main purpose of a map?A. To tell timeB. To find directionsC. To play gamesD. To show picturesB15.The capital of Cuba is ________ (哈瓦那).16.What do we call a large area of land that is flat and has very few trees?A. PlainB. PlateauC. ValleyD. MountainA17.The __________ is known for its ancient ruins.18.The process of crystallization involves forming __________ from a solution.19.The ancient Egyptians used ________ to measure time.20.My sister enjoys __________ (参与公共事务).21. A ____ is a small reptile that basks in the sun.22.Which animal is known for building dams?A. BeaverB. RabbitC. SquirrelD. BearA23.________ (植物资源共享) enhances knowledge.24.I created a treasure hunt using my ____. (玩具名称)25.What is the name of the bear that lives in the Arctic?A. PandaB. GrizzlyC. PolarD. BlackC26.The antelope is known for its incredible ______ (跳跃).27.What is the process of water turning into vapor called?A. CondensationB. EvaporationC. PrecipitationD. SublimationB28.I like to ______ (参加) art exhibitions.29.Which planet is known as the Red Planet?A. VenusB. MarsC. MercuryD. NeptuneB30.The characteristics of a plant can reveal much about its ______ and adaptations. (植物的特征可以揭示其栖息地和适应性。
Preface
Man vet hvor en planet befinner seg om tolv˚ar,fire m˚aneder og ni dager.Men man vet ikke hvor en sommerfugl vil værefløyet hen om et minutt.Jens Bjørneboe,Krutt˚arnet,1969iiiPrefaceThis thesis is submitted to the Norwegian University of Science and Technol-ogy(NTNU)in partial fulfillment of the degree of Dr.ing.It contains a short summary and eight scientific papers.The work has partly been carried out in the group of theoretical physics at the Faculty of physics,informatics and mathematics at NTNU,and partly at the Department of Physiology at McGill University,Montreal.I wish to express my gratitude to the members of these groups,for giving many constructive comments regarding my work.It has not been easy for me to convince all the members of these groups,partly because some of the results are controversial,and partly because the results are interdisciplinary in nature.I wish to thank my supervisor Jan Myrheim for his patience,encouragement and kind assistance.I will also thank Johan S.Høye for much help regarding the controversial parts of the thesis.The help and comments from K˚are Olaussen has been of invaluable importance through all stages of the thesis work,from the interpretation of the energy equations to brilliant advise regarding politics of publishing.It has been a pleasure for me to work with Nils Skarland,his language and humor has been very important.Michael R.Guevara and Kevin Hall at McGill University deserves credit for constructive criticism and feedback.Financial support from NTNU is acknowledged.I have received much en-couragement from my parents,Randi and Endre Endresen,and from my parents in law,Sigrunn and Sverre Stensby.Finally I would like to express my deepest gratitude to my wife Mariane Cecilie Stensby for encouragement and support.Lars Petter EndresenJune23,2000iiiivContentsPreface iii Contents v Summary1Papers:I.A Possible Resolution of the Gating ParadoxII.Modeling the Electrical Activity of Pacemaker CellsIII.A Theory for the Membrane Potential of Living CellsIV.Chaos in Weakly Coupled Pacemaker CellsV.Limit Cycle Oscillations in Pacemaker CellsVI.Runge-Kutta Formulas for Cardiac OscillatorsVII.A Formula for Steplength Control in Numerical IntegrationVIII.An Efficient Step Size Selection for ODE Codesvvi1 SummaryThe subject of my thesis is mathematical models of the heartbeat and their basis in laws of physics and chemistry.In particular,it is concerned with models of the cells in the pacemaker region of the heart,the so called sinoatrial node. Even with this limitation there are many aspects of the problem[1],and I have chosen to concentrate on few rather specific topics.My work is presented here in eight research papers,of various length and importance,following this brief introduction.The main papers are I and III,both emphasizing the physical understanding of the topics under discussion.Paper I deals with a so called paradox concerning experimental data on the gating of ionic channels in the cell membrane.Paper III describes a complete model of an oscillating cell,and discusses how it is related to general principles like the conservation laws for electric charge and energy.The underlying assumption of all models in thisfield,going back to van der Pol in1926[2],is that biological oscillators can be described by differential equations. The van der Pol equation,v=0,(1)¨v−(α−3γv2)˙v+ω2describes an oscillatory electrical circuit.Here v is voltage,t is time,˙v and¨v are thefirst and second time derivatives of v,whileα,γ,andω0are parameters.A typical behavior resulting from this equation is a so called relaxation oscillation, characterized by a long rest period followed by a rapid rise and fall of the poten-tial,called an action potential.Thus,the equation provides an electrical analogy capturing one essential feature of the biological system,but is not intended as a completely realistic model.A realistic model of cardiac electrical activity wasfirst developed by Denis Noble in1962[3],based on the work of Hodgkin and Huxley[4].Since then many new models have been proposed,largely as a result of a bi–directional interaction between theory and experiment[5].The models in this thesis are the result of a bi–directional interaction between theory and simulation.This means that we have used simulation to determine what is possible using well–known principles from physics,and only afterwards compared with experiments.This approach is creative plagiarism,as described by Krauss[6]:“One sees the same concepts,the same formalism,the same tech-niques,the same pictures,being twisted and molded as far as possible to apply to a host of new situations,as long as they have worked before.”In this connection it is important to realize that model building may serve different and sometimes conflicting purposes.A very simple model,like the van der Pol equation,may give a useful qualitative understanding,from which it may be possible to predict qualitatively how the system responds to changes in2its environment.But if one needs more quantitative predictions,for example in order to understand arrhythmia and other pathological conditions of the heart, or the effect of drugs,one needs models that are much more detailed and realistic. The drawback of such elaborate models is that they tend to lose predictive power, because they become very complicated,and include a lot of parameters that have to be adjusted so that the modelfits experimental observations[7].All the models presented in the included papers are compromises between the two extremes.They are not realistic in every detail,but are sufficiently realistic to reproduce perfectly experimentally observed action potentials.At the same time,they do so at a rather small cost in terms of the number of parameters to befitted.The simplest of these models is the one used in paper IV,with only twofirst order ordinary differential equations describing one cell.Paper II is a more general discussion of the principles of model reduction.Note that the gain by the reduction in complexity of a model may be at least twofold.There is an obvious gain in computer time,which is sometimes of crucial importance if the model is to be useful in numerical simulations of large systems with many coupled cells.But no less important is the general principle that a complicated model with a large number of parameters mayfit observations within the range where it has been tested,without actually representing the physical reality.It may simply beflexible enough tofit anything.A simple model,on the other hand,is not so easily made tofit the observed data,unless it contains some grain of truth.Thus,if there is a choice between different models that all reproduce correctly the same set of data,and one needs to extrapolate into a region where no data exist,the simplest model is a reasonable choice.Simplicity is not the only criterion for choosing between competing models. An even more basic criterion is that a good model should be based on,or at least compatible with,the known laws of physics.The physicist,or scientist in general,should not be content with a phenomenological description of oscillating cells,no matter how successful,unless it has a sound basis in physics.The ambition should be to understand the behavior of the cells in terms of general laws,such as conservation laws for energy,electric charge and other quantities, and the laws of electromagnetism and statistical physics.This point of view is one main motivation for my work,and in particular for the papers I and III.Fortunately,these two ideals,that a model should be simple and have a sound physical basis,seem to be not only compatible,but often so closely related that they can be regarded as the two sides of the same coin.In fact,it is a rather general experience in physics that an improved understanding of some phenomenon also leads to a simpler description.I would like to point out two examples from paper III of increased understand-ing leading to simpler models.Thefirst example is the simple and well–known relation between the charge q,capacitance C and voltage v on a capacitor,q=Cv,(2)3 which is used in this paper to determine the membrane voltage for a living cell. It has been customary to use the time derivative of this equation,giving a rela-tion between current and voltage change,instead of using the equation directly. This is not difficult to understand,since the membrane currents are more easily observable than the correspondingfluctuations in membrane charge q.Second we found that the potential energy associated with transmembrane transport ofions can be writtenP=12Cv2−T s−Vπ.(3)Here C is capacitance,v voltage,T temperature,s entropy relative to equilibrium, V cell volume andπosmotic pressure.The meaning of this equation is that whenever ions move across the membrane of a cell,one will notice a change in:1.the transmembrane voltage difference,v;2.the cells entropy relative to equilibrium,s;and3.the transmembrane osmotic pressure difference,π.I have mostly considered models of one single cell.The exception is paper IV, in which a system of two coupled cells is investigated,from the point of view of the general theory of dynamical systems.In general,when two or more oscillators of different frequencies are coupled together,one may observe synchronization, also called phase locking,as in the normal state in the sinoatrial node.Another theoretical possibility is chaotic oscillations,as demonstrated in this paper for certain ranges of parameter values.In paper V it is shown,using the model of paper III,how one single cell can reach the same stable limit cycle from different initial conditions.As already mentioned,in computer simulations the computational efficiency of the model used is sometimes one of the most important factors.One way to improve the efficiency is to choose an efficient method for numerical integration. In the papers VI,VII and VIII this problem is investigated.From a medical point of view it would have been important and interesting to also focus on the effect of drugs.I regret that this topic is not discussed here, since it is most relevant for patients suffering from heart disease.For more extensive reviews for the topics discussed in this thesis I refer to Noble[1]and Wilders[7].4Bibliography[1]D.Noble.The initiation of the heartbeat.Oxford University Press(1979).[2]Van der Pol,Balthasar,et al.“On“Relaxation-Oscillations.””1922,Lon-don,Edinburgh and Dublin Philosophical Magazine and Journal of Science, pp.978-992.[3]D.Noble.A modification of the Hodgkin–Huxley equations applicable toPurkinjefibre action and pacemaker potentials,J.Physiol160:317–352 (1962).[4]Hodgkin,A.L.and Huxley,A.F.“A quantitative Description of MembraneCurrent and its Application to Conduction and Excitation in Nerve.”1952, J Physiol,pp.500-544.[5]D.Noble.The Development of Mathematical Models of the Heart,Chaossolitons&fractals,5:321–333(1995).[6]L.M.Krauss.Fear of Physics:A Guide for the Perplexed.Basic Books(1994).[7]R.Wilders.“From single channel kinetics to regular beating.A model studyof cardiac pacemaking activity.”PhD Thesis.pp17–40.Universiteit van Amsterdam.ISBN90–9006164–9(1993).5。
15组-凡勃伦效应
”
凡勃伦效应应用案例
中粮悦活：果汁的凡勃伦效应
商品价格越高，消费者反而越愿意购买的消费倾 向。其成立的原因在于，随着消费能力的提高，人们 消费的目的已经超越了产品的物理功能，更期望得到 的是一种被认同与自我认同的满足感。
--引自《营销解读》2010.10 P44-45
凡勃伦效应应用案例
Vertu
选择699元
[百分
比]
选择1699元
100% 实验组B
选择1699元
实验组A
凡勃伦效应
3、凡勃伦效应应用案例
Veblen effect
凡勃伦效应应用案例
“炫耀性消费”
Conspicuous Consumption
1990年，在纪念梵高逝世100周年的热潮中，梵高的 作品《加歇医生的肖像》在嘉士得（Christie’s）拍 卖公司以8250万美元的价格被日本纸业大王斋藤英 夺得，创下了当时艺术品拍卖的最高成交价。
情景实验
实验结果
本实验总共邀请到30名被试参与。当他们被问到：两只口红上唇后的颜色和质 感几乎没有差别，其中一支价格为355元，另一支的价格为46元，你会选择购买哪 一支时。其中25名同学选择购买355元的口红，而有5名同学选择购买46元的口红。
人数
选择46元 17% 选择355元
[百分比]
情景实验
实验结果
本次实验共邀请了30人参与，并将这30人随机的均分在A、B两组，分别就以上 问题对两组人员进行提问。最终得到如下结果：
实验组A:15人中有13人选择右边1699元的镯子，2人选择了左边699元的镯子。
实验组B:15人全部选择左边1699元的镯子。 选择699元 [百分 比]
人数
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Effects of the vanilloid agonist olvanil and antagonist capsazepineon rat behaviorsJohn W.Kasckow a,b,c,*,James J.Mulchahey b,d ,Thomas D.Geracioti Jr.a,b,caPsychiatry Service (116A),Cincinnati VAMC,3200Vine Street,Cincinnati,OH,USAbDepartment of Psychiatry,School of Medicine,University of Cincinnati,231Albert Sabin Way (ML559)Cincinnati,OH 45267-0559,USAcUniversity of Cincinnati Neurosciences Program,Cincinnati,OH,USA dPhase 2Discovery,Inc.,3130Highland Avenue,Cincinnati,OH,USAAccepted 17October 2003AbstractVanilloid receptors (VR)are molecular integrators of painful chemical and physical stimuli.Olvanil is an agonist of the vanilloid receptor;capsazepine is a competitive VR antagonist.The authors were interested in investigated the effects of these compounds on anxiety-like behaviors in rats using the elevated plus maze.In addition,the authors examined the effects of olvanil on the Porsolt swim test.Doses of 0,0.2,1.0and 5.0mg/kg olvanil,respectively,yielded percent open arm entries at 5min of 25F 10.1,19.3F 7.1,14.9F 5.9and 0F 0.We demonstrated a drug effect by showing that the mean of the 0.2,1and 5mg/kg doses was significantly lower than the 0mg/kg dose at P <.05.In addition,the authors examined the effect of olvanil on the ability of rats to perform in the Porsolt swim test.Float time for rats was tested with 0.1or 2mg/kg olvanil and differences between the float times for the lower and higher doses were significant at P <.05.In addition,the effects of various doses of the vanilloid antagonist capsazepine was examined on elevated plus maze behavior.Doses of 0,1,5and 10mg/kg yielded percent time in the open arms at 5min of 1.46F 1.38,15.05F 10.42,11.54F 10.57,and 14.56F 7.86.The mean of the 1,5and 10mg/kg doses was significantly greater than the percent time in the open arms for the vehicle,consistent with a drug effect.The results suggest that the vanilloid agonists and antagonists may impact on behaviors involving anxiety and affect.However,it cannot be ruled that the findings could be due to nonspecific motor effect.D 2003Elsevier Inc.All rights reserved.Keywords:Capsazepine;Elevated plus maze;Olvanil;Porsolt swim test;Rat1.IntroductionVanilloid receptors are molecular integrators of painful chemical and physical stimuli such as noxious heat (>48j C)and low pH.Heat is known to open the channel pore of the vanilloid receptor 1(VR1).After exposure to these stimuli,VR1receptors become permeable to Na +and Ca 2+ions causing the neurons to depolarize and fire action potentials.Capsaicin and protons lower the heat threshold of the receptor (Piomelli,2001;Szallasi and Blumberg,1999).A variety of agonists and antagonists of the VR1exist.Olvanil is one capsaicin analog,which acts as an agonist atthe vanilloid receptor.Capsazepine is a competitive VR1antagonist.Another capsaicin analogue is 3H-resinferatoxin,which binds to VR1receptors in the central nervous system (CNS).This compound binds to the preoptic area,locus ceruleus,medial hypothalamus,reticular formation and ventral thalamus (Acs et al.,1996).There is evidence that agonists and antagonists of the VR1evoke physiologic responses within the CNS.For instance,both capsaicin and olvanil evoke a concentra-tion-dependent release of calcitonin gene-related peptide;capsazepine inhibits this response (Wardle et al.,1997).Capsaicin has also been shown to stimulate glutamate release from hypothalamic slices and lumbar dorsal horn.This response is calcium dependent and is also inhibited by capsazepine (Sasamura et al.,1998).There are links between VR1and cannabinoid recep-tors.Anandamide transport is apparently inhibited by olvanil given that intracellular accumulation of 3H-anan-damide by human astrocytoma cells is observed following0278-5846/$–see front matter D 2003Elsevier Inc.All rights reserved.doi:10.1016/j.pnpbp.2003.10.007Abbreviations:Vanilloid receptor 1,VR1.*Corresponding author.Department of Psychiatry,School of Medi-cine,University of Cincinnati,231Albert Sabin Way (ML559)Cincinnati,OH 45267-0559,USA.Tel.:+1-513-558-2989;fax:+1-513-558-0264.E-mail address:jkasckow@ (J.W.Kasckow)/locate/pnpbpProgress in Neuro-Psychopharmacology &Biological Psychiatry 28(2004)291–295coincubation with olvanil(Mezey et al.,2000).In addi-tion,as per immunocytochemical and in situ hybridization studies,VR1expressing neurons are located in cortical areas(layers3and5),the limbic system(hippocampus, central amygdala,medial and lateral habenula),striatum, hypothalamus,substantia nigra,reticular formation,locus ceruleus and inferior olive.This would suggest that vanilloid receptors could play a role in modulating the CNS.The effects of vanilloids on behavior have not been studied well.There are studies indicating that motor activity can be suppressed by the activation of vanilloid receptors.For instance,capsaicin and various analogs such as N-linoleoyl-vanilyl-amine(livanil)and N-alpha-linole-noyl-vanilyl-amine(linvanil)inhibit ambulation,stereotyp-ic behavior and activity in the open field test(Di Marzo et al.,2001).The study at hand sought to determine if vanilloid receptor-mediated stimulation or inhibition results in behavioral effects in models of anxiety and depression.The objective of the current study was to evaluate olvanil and capsazepine for their anxiolytic or antidepressant potential utilizing the elevated plus maze and Porsolt swim test.2.Methods2.1.AnimalsSprague–Dawley rats weighing approximately200g were group housed on a12:12-h light–dark cycle(lights on at6:00h and off at18:00h)for7days with food and water available ad libitum.They were housed four per cage at240j C in a humidity-controlled room.3.Experimental procedures3.1.Drug administrationOn the day of experimentation with either the elevated plus maze or Porsolt swim test,rats were injected with olvanil,capsazepine or vehicle intraperitoneally30min before the behavioral tests.Vehicle consisted of sesame oil. Optimal doses of olvanil and capsazepine had been deter-mined based on the degree of sedation achieved;for instance, it was found that intraperitoneal administration of150–400 mg/kg of capsazepine lead to marked sedation and adminis-tration of50mg/kg of olvanil lead to mild sedation.Thus, lower doses were utilized as indicated below.3.2.Behavioral tests and apparatusWe utilized the elevated plus maze initially for our experiments to screen these agents for several reasons. The elevated plus maze has been used in the past to screen for anxiolytic as well as antidepressant medications;it is felt to be relevant to both anxiety and depressive behaviors.The elevated plus maze offers ease of data collection and requires minimal equipment in the form of the test field, behavior recording,and data interpretation.Furthermore, anxiety-like behaviors on the elevated plus-maze are pre-cisely defined in an operational manner.Essentially,all four feet of the rat are either in an open arm or in a closed arm.If a rat receiving some type of treatment spends a significantly greater amount of time in the closed arms of the maze relative to control rats,then the behavior of that rat may be interpreted as anxiety-like.Elevated plus maze testing was performed as follows: based on Lister(1987),a two feet–four arm radial maze consisting of two opposing enclosed arms[30Â30Â5cm (ÂlengthÂwide)]and two opposing exposed arms(30Â5 cm)was constructed and was elevated on a pedestal30cm above the surface of a table and situated in the center of a dimly lit room.Testing was conducted in a quiet,dedicated room that was dimmed to provide22–350lx of illumination on the exposed arms of the maze and less than1lx within the enclosed arms.Animals were placed facing the enclosed arm in the center of the plus maze.Testing took place for5 min following Heinrichs et al.(1992,1994).We assessed time in open arms,number of entries into the open and closed arm as per Windle et al.(1997).All observers were blind to treatment to remove investigator bias.The Porsolt swim test was performed based on Porsolt et al.(1977)and Lopez-Rubalcava and Lucki(2000).Swim sessions were conducted by placing rats in vertical Plexiglas cylinders(heightÂdiameter:40Â18cm)containing15cm of water maintained at25j C.Rats were not able to support themselves by touching the bottom with their feet.An initial pretest was performed in which rats were placed15min in the water,then dried with paper towels for15min and then returned to their home cages.Twenty-four hours later,they were placed in the cylinder again and the amount of swim and float time was determined for5min.Test sessions were videotaped from an overhead view for scoring later.A rat was judged immobile whenever it remained floating pas-sively in the water in a slightly hunched but upright position with its head just above the surface.3.3.Data analysisFor the analysis of elevated plus maze experiments,we expressed the data for each group of animals as percent open arm entries,percent amount of time spent in the open arms and number of closed arm entries.Percent open arm entries was calculated by dividing the number of open arm entries by the total number of entries(open arm entries F closed arm entries)and expressing this as a percentage.In addition, the percent open arm time was calculated by dividing the amount of time in the open arms divided by the total time in both arms(closed and open arm times)and expressed as a percentage.An entry into the closed or open arms wasJ.W.Kasckow et al./Progress in Neuro-Psychopharmacology&Biological Psychiatry28(2004)291–295 292defined as all four feet of the rat being in the respective arm. Data from the Porsolt swim test was expressed as percent float time.Statistical comparisons were performed using a two-way ANOV A followed by planned comparisons with SAS software.Factors analysed included DoseÂDrug effects or drug effects.4.ResultsThe effects of various doses of the vanilloid agonist olvanil on elevated plus maze performance was as follows, Doses of0(n=15),0.2(n=12for this and all subsequent doses), 1.0and 5.0mg/kg olvanil,respectively,yielded percent open arm entries at5min of25F10.1,19.3F7.1, 14.9F5.9and0F0(mean F S.E.;see Fig.1).The percent open arm times at5min were12.9F8.1for the 0mg/kg dose,8.9F4.2for the0.2mg/kg dose,15.2F7.9for the1mg/kg dose and0F0for the5mg/kg olvanil dose.Furthermore,the mean(F S.E.)number of entries into the closed arm at5min were1.7F0.3,3.3F0.8, 2.7F0.3and0.25F0.1for doses of0,0.2,1and5mg/ kg olvanil,respectively.For percent open arm entries,the mean of the0.2,1and5mg/kg doses was significantly lower than the0mg/kg dose at P<.05consistent with the hypothesis that olvanil caused a drug effect on the rat behavior.For this outcome measure,there were no statis-tical differences between the0.2,1and5mg/kg doses and thus a DoseÂDrug effect was not demonstrable.Fig.2represents float time for rats treated with0.1or2 mg/kg olvanil.The left portion of each pair of bars represents float time acquired on the pretest followed24h later by treatment with the indicated dose of olvanil.A dose of0.1 mg/kg olvanil yielded a pretest float time of123.3F12.3s and24h later,the float time was150.1F18.9s.A dose of 2mg/kg olvanil yielded a pretest float time of99.1F11.5s and24h later,the float time was180.7F18.4s.The differ-ences between the float times for the lower and higher doses were significant at P<.05(one-sided t test;n=12per group).The effects of various doses of the vanilloid antagonist capsazepine on elevated plus maze behavior was as follows. Doses of0,1,5and10A g/kg(n=9for each)yielded percent time in the open arms at5min of1.46F1.38, 15.05F10.42,11.54F10.57,and14.56F7.86(see Fig.3).The percent open arm entries at5min were4.2F3.7for the0A g/kg dose,20.7F11.4for the1A g/kg dose,13.9F11.1for the5A g/kg dose and15.7F7.1for the10A g/kg capsazepine dose.Furthermore,the number of entries into the closed arm at5min were3.4F0.5,2.9F0.5, 2.4F0.3and3.1F0.4for doses of0,1,5and10A g/kg capsazepine,respectively.Percent time in the open arms for the mean of the1,5and10A g/kg doses was significantly greater than the percent time in the open arms forthe Fig.1.This figure represents percent open arm entries of rats spent on theelevated plus maze at5min following acute injections of0,0.2,1.0and5.0mg/kg olvanil.The mean value of the percent open arm entries of the0.2,1.0and5.0mg/kg dose was significantly lower relative to the0mg/kg dosebased on P<.05(one-sided test based on planned comparisons;n=9pergroup).Fig.2.This figure represents the float time for rats treated with0.1or2.0mg/kg olvanil.The left portion of each pair of bars represents float timeacquired on the pretest followed24h later by treatment with the indicateddose of olvanil.The differences between the float times for the lower andhigher doses are significant(one-sided t test;n=12pergroup).Fig.3.This figure represents the percent amount of time rats spent in theopen arms at5min following acute administration of capsazepine,1,5or10A g/kg.The mean value of the percent time in the open arms of the threedoses was significantly lower than that obtained with the vehicle based onP<.05based on planned comparisons(two-sided test;n=9per group).J.W.Kasckow et al./Progress in Neuro-Psychopharmacology&Biological Psychiatry28(2004)291–295293vehicle,consistent with a drug effect.We were not,how-ever,able to demonstrate an effect of DoseÂDrug.5.DiscussionThe research literature on endovanilloids has focused predominantly on the role they play in pain perception (Caterina et al.,1997;Di Marzo et al.,2000).Vanilloid receptors have been found to be expressed in various rat brain nuclei,including limbic nuclei.As a result,investi-gators have more recently hypothesised that vanilloids play a role in mediating other behaviors.Recent reports have examined such a possible role.One report indicated that resiniferatoxin,an ultrapotent capsaicin analog can reduce emesis in the ferret(Andrew and Bhandaru,1993).Furthermore,intracerebroventricu-larly administered resiniferatoxin in the musk shrew induced emesis as well as genital grooming(Rudd and Wai,2001).In another report,capsaicin,an agonist of vanilloid receptors,was able to attenuate hyperkinetic activity in a rat model of Huntington’s disease induced by intrastriatal injection of3-nitropropionic acid.The authors in the latter study hypothesized that the mecha-nism of action involved the endovanilloid system interact-ing with either the dopamine or GABA system(Lastres-Becker et al.,2003).In the current study,we have assessed the role of vanilloids in behavioral tests which screen compounds for potential anxiolytic and antidepressant capabilities.Anxiety-like behaviors were measured on the elevated plus maze. There are many other behavioral tests for detecting anxiety-like behaviors(Willner,1991).Each of these have their advantages and limitations in terms of modelling the human condition.When testing olvanil on the elevated plus maze,we demonstrated that the mean of the0.2,1and5mg/kg doses was significantly lower than the0mg/kg dose,consistent with the hypothesis that olvanil may have caused an anxiogenic-like effect.The mean number of entries into the closed arm at5min for the5mg/kg dose of olvanil was low which suggests that a nonspecific effect on motor activity cannot be ruled out.The inability to distinguish between anxiolytic effects and nonspecific motor inhibition is a common challenge when using preclinical animal screening methodology.There are no animal models which can avoid these confounds(Wall and Messier,2001).Our finding that capsazepine was able to increase percent time in the open arms was consistent with our hypothesis that this compound potentially possesses anxiolytic poten-tial.Percent time in the open arms for the mean of the1,5 and10A g/kg doses was significantly greater than the percent time in the open arms for the vehicle.The effects on closed arm entry at all doses were not different suggest-ing that it was less likely that capsazepine had a nonspecific effect on motor performance.We also demonstrated that olvanil appeared to possess potential antidepressant potential given its ability to reduce float time at higher doses relative to lower doses. 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