History And Theory Leicester School Of Architecture

DE MONTFORT UNIVERSITY FACULTY OF ART DESIGN LEICESTER SCHOOL OF ARCHITECTURE ARCH1031 HISTORY THEORY 1 ESSAY In 1956, various people broke away from the Congres Internationaux d’Architecture Moderne (CIAM), founded in 1928, in order to set up an international splinter group of modern architects, Team 10. This led to the demise of CIAM. What were the goals of Team 10? How did they articulate their disagreements with the objectives of CIAM? Choose a specific building or project to show how one (or a pair) of the members of Team 10 attempted to put those goals into practice. Alison and Peter Smithson s: investigative duties. Experiment and Utopia in the House of the future Marco Fiorino P13214090 Session 2014/15 Architecture can be seen a tool for exploring the future; an instrument for questioning ourselves about the infinite possibilities that humankind has whenShow MoreRelatedQuestions On Online Regulation On The Code Of Cyberspace2001 Words   |  9 Pageschildren or adults. The problem of perspectives is one of cultural relativism in the sense that â€Å"we† limit access to information in an effort to defend important cultural values and social stability. The purpose of this essay is to ascertain which school of thought regulating the digital environment should be subscribed to. This essay will be consisting a brief historical overview of the cyberlibertarian, cyberpaternalist and network communitarian points of view on the freedom of the Internet communicationRead MoreThe First World War And The Reconstruction Of Britain2496 Words   |  10 Pagesreconstruction of Britain changed the direction of British architecture and which architects were most influential in this redevelopment process. Furthermore, it will explore the Modernist movement by evaluating key historical information which contributed to the progression of a new, mid-century style. Brutalism, a disputed architectural movement which developed during the 1950s and 1960s when there was a significant change in direction for British architecture. Brutalism descended from the Modernist architecturalRead MoreHistory And Theory : Ancient Egyptian Architecture3481 Words   |  14 Pages DE MONTFORT UNIVERSITY FACULTY OF ART, DESIGN HUMANITIES LEICESTER SCHOOL OF ARCHITECTURE ARCH1031 HISTORY THEORY 1 ESSAY Ancient Egyptian architecture had a number of well known generic building types (pyramids, mortuary temples and so on). Select one building and discuss is background and architectural characteristics, relating it where necessary to other examples. The Construction, Origin and Prominence of the Great Pyramids up to 4th Dynasty Egypt Harry George Keable P14148274 SessionRead More Impressionism bridge between past and future Essay2073 Words   |  9 Pagesdenunciation, friendship and animosity, the pastiche of artists were both a culmination of a an art period and a bridge to the next artistic discovery. The France that most of the Impressionist artists were born into had experienced a â€Å"recent history...as dramatic and changeable as the era the painters were about to live through† (The Impressionists Handbook 12). By 1851 Emperor Napoleon III was firmly entrenched as a ruler of France. As a sign of his power, Napoleon III began his reign withRead MoreOrganizational Behaviour Analysis28615 Words   |  115 PagesNovember 2007  © Dr. Lesley Prince 2007. Organisational Analysis: Notes and Essays Page i Page ii Please do not attempt to eat these notes. CONTENTS Introduction to the Workshop Topics And Themes The Nature and Scope of Organisation Theory Levels of Analysis The Metaphorical Approach Organising Processes Understanding Change Conflict, Negotiation, and the Politics of Change Group and Team Working Cultures and Leaders as Cultural Agents Trust Linking the Themes Introductory NotesRead MoreThe History and Structure of the Travel and Tourism Sector Essay9258 Words   |  38 PagesHnd Travel and Tourism 2012 The history and structure of the travel and tourism sector Assignment 1 Diane Quinn diane quinn THE HISTORY AND STRUCTURE OF THE TRAVEL AND TOURISM SECTOR Task one:- LO1 - Explain the key historical developments in the travel and tourism sector. You should provide a concise outline of key developments from the pilgrimages to the current day and conclude with future developments. You need to refer to the growth of the package holiday as a key development andRead MoreExploring Corporate Strategy - Case164366 Words   |  658 Pageswhich have been chosen to enlarge speciï ¬ c issues in the text and/or provide practical examples of how business and public sector organisations are managing strategic issues. The case studies which follow allow the reader to extend this linking of theory and practice further by analysing the strategic issues of speciï ¬ c organisations in much greater depth – and often providing ‘solutions’ to some of the problems or difï ¬ culties identiï ¬ ed in the case. There are also over 33 classic cases on the Companion

A Summary of Four Articles on Finance from the Internet Free Essays

This article furnishes its readers with relevant tips for parents who want to successfully send their children to school as they reach for some higher level of scholastic learning. It begins with the basic problematic most countries the world over is beset: government subsidies to defray the expensive cost of education for students (and parents at that) do not seem to cover that much. The case in point, at least specifically for this write-up, addresses how the government has stopped its subsidies for â€Å"student fees† which in turn makes it quite difficult for both parents and students to cope with. We will write a custom essay sample on A Summary of Four Articles on Finance from the Internet or any similar topic only for you Order Now The article submits certain proposals to help both parents and students address the mounting task of university education. Among the choices include availing of loan packages such as: Student Loans (managed by Student Finance Direct), which allows a student to borrow money at a modest 9% interest, to be subsequently paid after graduation; Student Grants† – the more â€Å"generous† type of grant given to financially challenged families, or to single parent students, as even to those whose financial income is below 17,000 per annum. The article ends with alternative proposals that touch on some more means to get this whole university education going. Whichever the readers choose though, the bottom line remains: sending one’s children to school may appear to be an insurmountable task, but it is not impossible nevertheless. 1.  Ã‚  Ã‚  Ã‚  Ã‚   Top tips for first time buyers[1] The central concern of this write-up is to guide first time homeowners on important issues, which can either make or break their whole experience of buying a house. True enough, the first premise of the article is telling enough to even dismiss or set aside – buying a house is a big commitment and entails having to shoulder a lot of responsibilities in the years to come. First up, it is by right of commonsense that buyers are given this Bible-piece of advice: do not buy what you cannot afford. The initial temptation to procure a property based on the impulse to acquire an ideal house can at times blur the fact that there are some financial considerations that cannot be left out – these include, among others, â€Å"duty, solicitor and/or estate agent fees, a valuation report†. To be sure, this does not even include transfer and renovation costs. The article also gives vital information on the remaining important things that should not be missed. Among others, buyers have to be fully aware of the stipulations of the contract, the mortgage deals that they are agreeing to put up with and payment methods. Still, some other concerns that include insurance policies, procurement of home appliances, the suitability of the house location vis-à  -vis one’s work or children’s school are to be considered. 2.  Ã‚  Ã‚  Ã‚  Ã‚   Savings and investments for your children[2] â€Å"Children don’t come cheap† is the statement that commences this short yet very insightful article which deals with an effective and forward-looking ways to invest for one’s children. In this times when managing one’s finances rightly becomes more and more difficult to do, it is certainly with a great sense of love and concern that one is called for to save for his/her children’s future and not compromise their wellbeing in the process. There are a few things that can be noted to help achieve this task. First up, the article proposes that parents should open a â€Å"bank account† for their children. It may seem like it is too early children to actually save. But the whole point of the exercise is to start saving regularly when one finds some time and resources to do it. As in a case of a habit, saving little pennies for one’s children can â€Å"accumulate quickly† without actually being noticed. Another proposal that the article gives is for parents to set aside some tax relief that the government provides for parents who raise children. But this can only happen if one is willing to actually avail of the tax allowance in the very first place. As it stands, tax reliefs for parents raising their children is one hefty source of cash, and it defrays the cost of the children’s living expenses in many ways. It may be wise to check on the availability of this type of resources, as the article would implicitly suggest. The article ends by elaborating how a parent can opt to open a trust fund for his/her children. This is a real investment for the children, yet it comes in a variety of choices. One may opt to simply save straightforwardly to a company for the children. Another option is to invest as though one does in stocks or shares. The third can be a combination of both. It really is up to the parents to choose the most viable alternatives to ensure that their children’s needs in the future will be secured and protected. [1] Top tips for first time buyers, retrieved 14 May 2008, http://www.financialarticles.info/article_50.html [2] Saving and investments for your children, retrieved 14 May 2008,   http://www.financialarticles.info/article_45.html How to cite A Summary of Four Articles on Finance from the Internet, Papers

Creon and Antigone as Tragic Heroes in Sophocles Essay Example For Students

Creon and Antigone as Tragic Heroes in Sophocles Essay Antigone Antigone essays Creon and Antigone as Tragic Heroes Creon and Antigone, main characters in the Greek tragedy Antigone by Sophocles share some of the same characteristics that make up a tragic hero, but to varying degrees. Antigone, daughter of her mother/grandmother, Jocasta, and father, Oedipus is head strong, proud, and stubborn. She had three siblings, Ismene her sister, and two brothers Eteocles and Polyneices who found there deaths at the end of each others sword in battle over which would become king of Thebes. Antigones pride fullness and loyalty is revealed when Polyneices is denied proper burial by her uncle and king Creon. The two buttheads in the political for Creon and personal for Antigone situation and bring about the downfall of the royal family. Aristotles view on a tragic hero is someone that would have to be held in high standards (royalty) in order to evoke compassion and anxiety in the audience. Creon and Antigone are royalty and share the most important aspect of a tragic hero, each have a tragic flaw. Both of the two characters have an inability to compromise or even reason with. Antigones tragic flaw was amplified by her loyalty for her brother; she acted irrational, in not taking preparation or thoroughness into consideration when burying her brother. Further more when confronted by Creon, himself she disrespected and basically told him to silence himself because his words were distasteful to her. So then sealing her death by becoming an immediate martyr for the wrong cause. .. anything against Creons will. Creon, in his paranoia was plagued with the feeling of incompetence and need to establish dominance. His decree that no one would bury Polyneices only provoked the people of Thebes into thinking of him as insensitive to their culture. When his ruling was disobeyed, only led him to him to believe that conspiracy was about and that no matter, family or not, he would punish Antigone, causing a chain reaction of events causing the loss of his entire family, except Ismene. Leaving the audience experiencing pity and fear for both characters. Neither Creon nor Antigone, were either all bad or all good. Creon while tyrant like only wanted Thebes to flourish, Antigone while showing honor to her brother never stopped to really consider the effect that her actions would have on others. The goodness and evil are represented in a yin yang (white semicircle containing black dot and black semicircle with a white dot in it making a complete circle. Yin exists in Yang and Yang exists in Yin, good in evil, evil in good. Suffering, tolerating or enduring evil, injury, pain, or death, Creon endured suffering on many levels, loss of two sons, wife, two nephews, niece, brother, and sister his own hands bringing to their demise, living with the fact of it was all his fault. The lament was his. Antigone suffered but to a lesser degree, loss of father, mother, and two brothers would no doubt cause pain but soon she was to be released into a high power, Creon left to suffer. I believe that both Creon and Antigone were tragic heroes both accomplished the goal of evoking fear and pity. While I do think that they reflected in each by varying degrees. Creon fit the profile but Antigone was the heroine of the story. .

Religion and Environmental Ethics free essay sample

In the paper he wrote Christianity bears a huge burden of guilt and concludes that Hence we shall continue to have a worsening ecologic crisis until we reject the Christian axiom that nature has no reason for existence save to serve man. White depicted Western Christianity as seeing the world existing primarily for the benefit of man, and man, bearing Gods image and sharing in great measure Gods transcendence of nature, exploit nature for his proper ends according to Gods will. This thesis of White shall be referred to as Dominion Hypothesis for ease of identification in this paper. But are the claims in his Dominion Hypothesis valid? Does Christianity bear a burden of guilt for the ecological crisis of the world? The purpose of this paper is to assess the strength of his thesis by firstly analysing what the biblical scriptures and theologians have to say with regard to the relationship of God, man and the environment. We will write a custom essay sample on Religion and Environmental Ethics or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Next the symptoms and origins of our ecological crisis are examined, after which their ties with Western Christianity are assessed to determine whether the later has causal relationship with the former. Finally, after arriving at the conclusion, some recommendations are presented. 1 Whites Thesis Whites thesis can briefly be summarized as: All forms of life modify their contexts, and the human race has in one sense simply done this more than others. However, the human impact on the environment, whilst frequently detrimental in the past, was given an added impetus by Christianity in its Westernized form. Western society, as a product of Westernized Christianity, inherits an exploitative attitude to the natural world which is the key to our present ecological crisis. (Richardson, 1998) . White depicted Western Christianity as seeing the world existing primarily for the benefit of man, and it is according to Gods will that man exploit nature for his proper ends. Biblical verses that align to the Dominion Hypothesis Arguably the following passages from the Bible are aligned to the Dominion Hypothesis and are most frequently cited by ecology critics of the Bible. Then God said, Let us make man in our image, after our likeness; and let them have dominion over the fish of the sea, and over the birds of trhe air, and over the the cattle, and over all the earth, and over every creeping thinng that creeps upon the earth So god created man in his own image, in the image of God he created him; male and female he created them. And God blessed them, and God said to them Be fruitful and multiply, and fill the earth and subdue it; and have dominion over the fish of the sea and over every living thing that moves upon the earth. And God said, Behold, I have given you every plant yielding seed which is upon the face of all the earth, and every tree with seed in its fruit; you shall have them for food. (Gen. 1:26-29) Yet thou has made him little less than God, and dost crown him with glory and honor. Thous hast given him dominion over the works of thy hands; thous hast put all things under his feet; all sheep and oxen, and also the beasts of the field, the birds of the air, and the fish of the sea, whatever passes along the paths of the sea. (Ps. 8:5-8) 2 And God blessed Noah and his sons, and said to them, Be fruitful and multiply, and fill the earth. The fear of you and the dread of you shall be upon every beast of the earth, and upon every bird of the air, upon everything that creeps on the ground and all the fish of the sea; into your hand they are delivered. Every moving thing that lives shall be food for you; and as I gave you the green plants, I give you everything. (Gen. 9:1-3) You have made them to be a kingdom and priests serving our God, and they will reign on earth (Rev. 5:10). According to exegeses by theology scholar (Hiebert, 1996), the term dominion, from the Hebrew verb radah, implies that it grants humans the right and responsibility to rule, to govern the rest of creation. It connotes a hierarchy of power and authority in which the human race is positioned above the rest of the natural world, although the verb radah does not itself define how this dominion is to be exercised, whether benevolently or malevolently. The laws of Leviticus, when they stipulate that household servants are not to be *ruled* harshly (Lev. 25:43, 46, 53), imply that this kind of dominion may be kind and humane. Yet the use of radah in the context of international relations, where it is more commonly employed, carries a decidedly more antagonistic tinge, since it signifies rule over one*s enemies. It occurs frequently in descriptions of military conquest, where it is paired with such verbs as *destroy* (Num. 24:19) and *strike down* (Lev. 26:17; Isa. 14:6). When used of the Israelite king, radah always refers to dominion over his enemies, not to rule over his own Israelite subjects, for which the verb malak, *reign,* is the usual term. Similar conclusions may be drawn about the phrase *subdue the earth* in Gen. :28. The verb *subdue,* from the Hebrew kavash, depicts a hierarchical relationship in which humans are positioned above the earth and are granted power and control over it. The verb kavash is even more forceful than radah, describing the actual act of subjugation, of forcing another into a subordinate position. It is used for military conquest, where the same phrase used in Gen. 1:28 , *subdue the earth/land,* can be employed to depict the destruction and occupation of conquered territory (Num. 32:22, 29). It is also used of the king*s forcing his people into slavery against God*s wishes (Jer. 4:11, 16), and of rape (Esther 7:8; Neh. 5:5). In many of these cases, the abuse {19} of power is patently obvious. 3 Biblical verses that align to the Eco-Friendly perspective On the other hand, the following verses can be interpreted as being aligned to an EcoFriendly view:Let the heavens be glad, and let the earth rejoice; let the sea roar, and all that fills it; let the field exult, and everything in it! Then shall all the trees of the forest sing for joy before the LORD, for he comes, for he comes to judge the earth. He will judge the world in righteousness, and the peoples in his faithfulness. (Psalm 96:11-13) Praise the LORD! Praise the LORD from the heavens; praise him in the heights! Praise him, all his angels; praise him, all his hosts! Praise him, sun and moon, praise him, all you shining stars! Praise him, you highest heavens, and you waters above the heavens! Let them praise the name of the LORD! For he commanded and they were created. And he established them forever and ever; he gave a decree, and it shall not pass away. a Praise the LORD from the earth, you great sea creatures and all deeps, fire and hail, snow and mist, stormy wind fulfilling his word! Mountains and all hills, fruit trees and all cedars! Beasts and all livestock, creeping things and flying birds! Kings of the earth and all peoples, princes and all rulers of the earth! Young men and maidens together, old men and children! Let them praise the name of the LORD, for his name alone is exalted; his majesty is above earth and heaven. (Psalm 148:1-13) *When you besiege a city a long time, to make war against it in order to capture it, you shall not destroy its trees by swinging an axe against them; for you may eat from them, and you shall not cut them down. For is the tree of the field a man, that it should [m]be besieged by you? Only the trees which you known are not fruit trees you shall destroy and cut down, that you may construct siegeworks against the city that is making war with you until it falls. (Deuteronomy 20:19-20) *When you enter the land and plant any kind of fruit tree, regard its fruit as forbidden. For three years you are to consider it forbidden; it must not be eaten. In the fourth year all its fruit will be holy, an offering of praise to the Lord. But in the fifth year you may eat its fruit. In this way your harvest will be increased. I am the Lord your God. (Leviticus 19:2325) You shall not let your cattle breed with a different kind; you shall not sow your field with two kinds of seed; nor shall there come upon you a garment of cloth made of two kinds of stuff. (Leviticus 19:19) For six years you shall sow your land and gather in its yield; but the seventh year you shall let it rest and lie fallow, that the poor of your people may eat; and what they leave the wild beasts may eat. (Exodus 23: 10-11) 5 The nations were angry, and your wrath has come. The time has come for judging the dead, and for rewarding your servants the prophets and your people who revere your name, both great and small * and for destroying those who destroy the earth. * (Rev 11:18) For true and righteous are his judgments: for he hath judged the great whore, which did corrupt the earth with her fornication, and hath avenged the blood of his servants at her hand. (Rev 19:2) They will neither harm nor destroy on all my holy mountain, for the earth will be filled with the knowledge of the Lord as the waters cover the sea. (Isaiah 11:9) The wolf and the lamb will feed together, and the lion will eat straw like the ox, but dust will be the serpents food. They will neither harm nor destroy on all my holy mountain, says the LORD. (Isaiah 65:25) Theology scholars commenting on this view of nature of the Old Testament wrote : It is therefore fair to conclude that nature is far from de-animated in Biblical thought. (Wybrow, 1990), The natural world may not be see n as sacred or divine in the Bible, but it is certainly not dead, lifeless, and outside the divine moral framework here are no scriptures suggesting that nature was viewed as dead matter to be manipulated by man.. (Kinsley, 1995). Referring to the theme of the kingdom of God running through the New Testament, Zerbe (1992) argues that the New Testament has significant ecological implications, he explained: Isaiah*s vision of restored humanity and nature climaxes with the statement that there will no longer be any hurt or destruction in creation (Isa. 11:9; 65:25). And John*s vision of judgment states that those who destroy the earth will themselves be destroyed (Rev. 11:18; 19:2). It is noteworthy that the prophetic critique of Rome in Rev. 17:1-19:4 closely connects greed and the earth*s destruction: the insatiable desire for consumption and wealth is what results in the destruction of people and the earth. The corresponding passages are as quoted above. 6 Alternative view: Dominion Theology in Genesis 1 vs. Dependence Theology in Genesis 2 And lastly, but most importantly, consider the following two verses, both from Genesis 2:Then the Lord God formed a man from the dust of the ground and breathed into his nostrils the breath of life, and the man became a living being. (Genesis 2:7) The Lord God took the man and put him in the Garden of Eden to work it and take care of it. (Genesis 2:15) What is very important to the discussion in this paper is that according to Hiebert (1996), as evident in the above verses, Genesis 2 presents an alternative to the dominion theology of Genesis 1, which he calls dependence theology. His thesis being that the first human is made of the same arable soil as are all of other forms of life; and the divine breath into which his nostrils blown is the same with which all the animals live and breathe (Gen. :7; 7:22). The role of the human in the earth described is not that of mastery but of servanthood. In this account of creation, the theology of the human place in creation is not a theology of dominion but a theology of dependence (Hiebert, 1996). This theology is evident in other parts of Scripture, examples including Psalm 104 and the Book of Job (McKibben,1994). According to Hiebert: In this tradition (Genesis 2), the human being is positioned very differently within the world of nature. Here the archetypal human is made not in the image of God but out of topsoil, out of the arable land that was cultivated by Israelite farmers (Gen. 2:7). As a result of this kind of creation, humans hold no distinctive position among living beings, since plants and animals also were produced from this same arable soil (2:9, 19). Moreover, the role assigned humans within creation in this story is not to rule (radah) and to subdue (kavash) but rather to {23} *serve* (avad; Gen. 2:15; 3:23). The Hebrew term avad is properly translated *till* in these verses (NRSV), since it clearly refers to the cultivation of arable land. But avad is in fact the ordinary Hebrew verb *serve,* used of slaves serving masters and of humans serving God (Gen. 12:16; Exod. 4:23). , the conflicts of Genesis I and Genesis 2 notwithstanding, there are lots of thesis arguing that there is no inconsistency between the two chapters and the ouvert differences are due to different ways in recapitulation only . (Young, 1960),(Archer, 1964),(Kitchen,1966) On another plane of our discussion, we shall now turn to a brief discussion of the historical origins of our ecological crisis. 7 The Historical Origins of our Ecological Crisis There is general consensus that the planet earth is heading towards environmental catastrophe due to alarming development at different fronts: the green house effect, acid rain, damage to ozone layer, deforestation, loss of biodiversity, chemical pollution, freshwater shortage, etc. , amongst others. (Magdoff Foster, 2011).. But how did all these pollutions started? according to Thorsheim (2006), in his book The Invention of Pollution, it all started with the use of fossil energy, which was conducive to the Industrial Revolution. The first largescale commercial use of fossil energy was coal in Britain in the 1800s, which he referred to as a Faustian bargain for Britain, since on the one hand it helped to bring tremendous wealth, advance and power to the country, whilst on the other coal also filled the air with immense smoke and acidic vapors, which was one of the origins of what we now call the green house effect and acid rain. Fossil oil as energy had also been popularized ever since Edwin L. Drake drilled the first oil well in 1853, but the impact on the environment is equally as detrimental as Coal, if not more so. The fossil energy application was conducive to the Industrial Revolution, and the Industrial Revolution had led to the advance in comfort, convenience and enjoyment, from dwelling comfort to transport convenience to material needs, leading to the abundance and later overabundance in supply of products. Consumerism in the past decades had eventually been invented in order to help us to recognize our needs, and due to the needs for growth of enterprises, some products have also began to be designed with built-in obsolescence. All these initiatives had contributed to the generation of ever more wastes than in the centuries before the industrial revolution, much more than can be sinked by the earth, which contributed to the chemical pollution of soil, water, which has also altered the bio-diversity of the Earth. 8 Ever since the Industrial Revolution, the consumption of energy has experienced exponential growth (see figure 1. 1). Concomitantly, different kind of detrimental impacts had been inflicted upon the ecology of the earth (see figure 1. 2). As an in-depth analysis of our ecological crisis is out of the scope of this paper, focus is now centred on the origin of the crisis, viz. the advent of fossil energy application, which shall be discussed below. Some key developments relating to fossil energy application:1665 Invention of the first modern industrial steam engine by English inventor Edward Somerset which can use wood or coal as fuel 1794 First produce of Coal Gas by William Murdoch 1853 First refinement of Kerosene by Abraham Gesner 1859 Drilling of first Oil Well by Edwin Drake 1859 Building of the first practical self-combustion engine by Etienne Lenoir Religious Background of the Inventors / Innovators Astonishingly, what the above key developments have in common, according to research by the author, is that all the inventors / innovators were Judeao-Christian in religious belief, as can be listed below according to extant data. Inventor/Innovator Place of Birth Religion Edward Somerset (1601-67) Monmouthshire, Bri tain Roman Catholic William Murdoch (1754 1839) Cumnock, Scotland Roman Catholic Abraham Gesner (1797-1864) Nova Scotia, Canada Protestant Christian Edwin Drake (1819-1880) New York, U. S. A. Jewish Jean-Joseph-Etienne Lenoir (1822-1900) Mussy-la-Ville, Belgium Roman Catholic However, just as one cannot say that the inventions or innovations in fossil energy application has been due to Western Christianity, as otherwise one will fall into the post-hoc ergo procter hoc fallacy, it is likewise not valid to attribute the ecological crisis directly to Western Christianity. However, If we put the question conversely by asking that if the inventors/innovators were pantheistic, believing that the nature is sacred in itself and should be reverred, then it is highly unlikely that the inventions/innnovations had been conjured and accomplished by them. Science and Christianity It has been argued that science and christianity are coherent to each other, A British Scientist, Robert Clark, once said we may interpret the fact scientific development has only occurred in a Christian culture. The ancients had brains as good as ours. In all civilizations, Babylonia, Egypt, Greece, India, Rome, Persia, China and so on, science developed to a certain point and then stopped. It is easy to argue speculatively that science might have been able to develop in the absence of Christianity, but in fact, it never did. And no wonder. For the non*Christian world felt there was something ethically wrong about science. In Greece, this conviction was enshrined in the legend of Prometheus, the fire*bearer and prototype scientist who stole fire from heaven thus incurring the wrath of the Gods. 10 Consider also these statements from renowned scientists; William Thomson: Do not be afraid to be free thinkers. If you think strongly enough, you will be forced by science to the belief in God. Isaac Newton: This most beautiful system of the sun, planets and comets could only proceed from the counsel and dominion of an intelligent and powerful Being , Stephen Hawking:In fact, if one considers the possible constants and laws that could have emerged, the odds against a universe that produced life like ours are immense. Conclusion This paper has attempted to examine the hypothesis of Lynn Whites that Christianity bears significant responsibility for the earths ecological crisis. The author has attempted to typologize and quote verses from the scriptures, exegeses and writings of theologians on the Biblical scriptures depicting the relationship of God, man and nature. Whilst according to the Dominion theological perspective as discussed above, the hierarchal relationship of God-gt;Man-gt;Nature (see figure 1. 3) is apparent, in the Dependence theological perspective, the hierarchal relationship of God-gt;Man ; God -gt; Nature (see figure 1. 4) is also evident. God God Man Man Nature Nature Figure 1. 3 The Dominion Perspective Figure 1. 4 The Dependence Perspective Other verses as listed under the section Passages that echo Eco-Friendly also act as a counter-argument for the Dominion hypothesis. It would seem therefore that Whites hypothesis that Western Christianity sees the world existing primarily for the benefit of man and therefore Christianity bears a huge burden of guilt is not grounded solidly, because as mentioned above, there are many verses which encourage man to be benign to our environment, and conversely, there is no single passage asking man to abuse nature for his primarily benefit only. However, if White argued that Christians bears a burden of guilt, then it is less reputable, as explained in the next paragraph. 11 If one concurs that scientific thinking is coherent to Christian belief, as discussed above, and like White argues in his paper, Western Christianity has been contributory in promoting modern science and technological advance, and from the standpoint of the analysing of advent of fossil energy as the origin of our ecological crisis, which does have tremendous detrimental impacts to our environment, it seems evident that Christians do have a direct linkage to the inventions and innovations leading to the mass scale use of fossil energy, the detrimental origin to our ecological system. Recommendations It can be said that with subtlety in the Biblical scriptures, interpretations are often contingent upon the context and the wisdom of the readers, as inspired at different times. What can be said is that given the state of development before the advent of sciences, man had been under the perpetual threats of nature, from attacks by animals, storms, sickness to famines and other disasters. The Dominion theological perspective no doubt inspired man to develop creative thinking about mastering the nature for the betterment of his lifelihood and survival, lacking which man might still be living rather primitively. The advent of sciences and most notably the Industrial Revolution can be depicted as the epitome of this mentality. As our civilization, technology and wisdom progresses, we should now be in a position to recognize that a Dominion mentality to the nature is detrimental to our environment and it is time that we revisit the scriptures to investigate whether we have overlooked an alternative theology in the Bible for seeing our relationship with nature-the Dependence approach, treating the nature as equals of ours, in which we serve god to ensure its goodness, and ensuring its long term sustainability to prepare for the Kingdom of God. 2 Bibliography Lynne White Jr (1967), The Historical Roots of Our Ecological Crisis, reproduced in John Barr (ed), The Environmental Handbook (London: Ballantine/Friends of the Earth, 1971) pp 3-16. David Kinsley, Ecology and Religion: Ecological Spirituality in Cross-Cultural Perspective (Englewood Cliffs, N. J. : Prentice Hall, 1995) Richard Cameron Wyb row The Bible, Baconism, and Mastery over Nature: The Old Testament and Its Moderrn Misreading (Ph. D disserrtation, McMaster University, Hamillton Ont. Canada, 1990) p. 206 Theodore Hiebert, Professor of Old Testament at McCormick Theological Seminary, Chicago, Illinois. , Direction (Winnipeg, MB), 1996 Gordon Zerbe, Assistant Professor of New Testament at Canadian Mennonite Bible College, Winnipeg, Manitoba. , Direction (Winnipeg, MB), 1992 Howard Snyder, Liberating the Church: The Ecology of Church and Kingdom (Downers Grove: Inter-Varsity Press, 1983) 45-51. Young, Edward J. (1960) An Introduction to the Old Testament (Grand Rapids: Eerdmans Publishing Co. ). Archer, Gleason (1964), A Survey of Old Testament Introduction (Chicago: Moody Press). Kitchen, Kenneth (1966), Ancient Orient and Old Testament (London: Tyndale Press). Thorsheim, Peter (2006), Inventing Pollution: Coal, Smoke and Culture in Britain since 1800 13

Ion Channel Disease Essays

Ion Channel Disease Essays Ion Channel Disease Essay Ion Channel Disease Essay MECH A NIS MS OF D IS EASE Review Article Mechanisms of Disease F R A N K L I N H . E P S T E I N , M. D. , Editor ION CHANNELS - BASIC SCIENCE AND CLINICAL DISEASE AND MICHAEL J. ACKERMAN, M. D. , PH. D. , DAVID E. CLAPHAM, M. D. , PH. D. I ON channels constitute a class of proteins that is ultimately responsible for generating and orchestrating the electrical signals passing through the thinking brain, the beating heart, and the contracting muscle. Using the methods of molecular biology and patch-clamp electrophysiology, investigators have recently cloned, expressed, and characterized the genes encoding many of these proteins. Ion-channel proteins are under intense scrutiny in an effort to determine their roles in pathophysiology and as potential targets for drugs. Defective ion-channel proteins are responsible for cystic fibrosis,1 the long-QT syndrome,2 heritable hypertension (Liddle’s syndrome),3,4 familial persistent hyperinsulinemic hypoglycemia of infancy,5,6 hereditary nephrolithiasis (Dent’s disease), and a variety of hereditary myopathies,7-9 including generalized myotonia (Becker’s disease), myotonia congenita (Thomsen’s disease), periodic paralyses, malignant hyperthermia, and central core storage disease (Table 1). Elucidating the mechanisms of these diseases will benefit medicine as a whole, not just patients with a particular disease. For instance, although the inherited long-QT syndrome is not common, identifying the underlying defects in the KVLQT1 and HERG potassium channels and the SCN5A sodium channels may benefit the study of ventricular arrhythmias, which are responsible for 50,000 sudden deaths each year in the United States. Likewise, al- hough a defect in the recently cloned epithelial sodium channel (ENaC) is the basis of a very rare form of inherited hypertension (Liddle’s syndrome, or pseudoaldosteronism), normal ENaC may serve as an alternative target in attempts to correct the physiologic defects created by the cystic fibrosis transmembrane regulator (CFTR), which is mutated in patients with cystic fibrosis, and work with ENaC may provide insight into the mechanism of essential hypertension. This review focuses on ion channels as functioning physiologic proteins, sources of disease, and targets for therapy. We will discuss two prominent diseases caused by defects in ion-channel proteins, as well as two specific ion channels whose recent molecular identification raises new prospects for pharmacologic manipulation. PHYSIOLOGY OF ION CHANNELS From the Department of Pediatrics and Adolescent Medicine, Mayo Foundation, Rochester, Minn. (M. J. A. ); and the Department of Cardiology, Children’s Hospital Medical Center, Department of Neurobiology, Harvard Medical School, Boston (D. E. C. ). Address reprint requests to Dr. Ackerman at the Department of Pediatrics and Adolescent Medicine, Mayo Eugenio Litta Children’s Hospital, Mayo Foundation, Rochester, MN 55905.  ©1997, Massachusetts Medical Society. Ion channels are macromolecular protein tunnels that span the lipid bilayer of the cell membrane. Approximately 30 percent of the energy expended by cells is used to maintain the gradient of sodium and potassium ions across the cell membrane. Ion channels use this stored energy much as a switch releases the electrical energy of a battery. They are more efficient than enzymes; small conformational changes change (gate) a single channel from closed to open, allowing up to 10 million ions to flow into or out of the cell each second. A few picoamps (10 12 A) of current are generated by the flow of highly selected ions each time the channel opens. Since ion channels are efficient, their numbers per cell are relatively low; a few thousand of a given type are usually sufficient. Ion channels are usually classified according to the type of ion they allow to pass - sodium, potassium, calcium, or chloride - although some are less selective. They may be gated by extracellular ligands, changes in transmembrane voltage, or intracellular second messengers. Conductance is a measure of the ease with which ions flow through a material and is expressed as the charge per second per volt. The conductance of a single channel, g, as distinguished from the membrane conductance (G) of all the channels in the cell, is defined as the ratio of the amplitude of current in a single channel (i ) to the electromotive force, or voltage (V): g i . V The direction in which ions move through a channel is governed by electrical and chemical concentraVol ume 336 Numbe r 22 575 The New Engla nd Journa l of Medicine TABLE 1. HERITABLE DISEASES MODE OF INHERITANCE* OF ION CHANNELS. NO. OF AMINO ACIDS DISEASE ION-CHANNEL GENE (TYPE) CHROMOSOME LOCATION COMMON MUTATIONS†  Cystic fibrosis Familial persistent hyperinsulinemic hypoglycemia of infancy Hypercalciuric nephrolithiasis (Dent’s disease) Liddle’s syndrome (hereditary hyperten sion; pseudoaldosteronism) AR AR X-linked CFTR (epithelial chloride channel) SUR1 (subunit of ATP-sensitive pancreatic potassium channel) CLCN5 (renal chloride channel) 7q 11p15. 1 Xp11. 22 480 1582 746 AR ENaC (epithelial sodium channel) a subunit b subunit g subunit 12p 16p 16p 1420 640 649 F508 (70 percent of cases) and 450 other defined mutations Truncation of NBD2 (nucleotidebinding domain 2) 1 intragenic deletion, 3 nonsense, 4 missense, 2 donor slice, 1 microdeletion R564stop, P616L, Y618H (all in b subunit); premature stop codon in b and g subunits; C-terminal truncation Long-QT syndrome (cardiac arrhythmia) LQT1 LQT2 LQT3 Myopathies Becker’s generalized myotonia Central core storage disease Congenital myasthenic syndrome AD KVLQT1 (cardiac potassium channel) HERG (cardiac potassium channel) SCN5A (cardiac sodium channel) 11p15. 5 7q35–36 3p21–24 581 1159 2016 1 intragenic deletion, 10 missense 2 intragenic deletions, 5 missense KPQ1505–1507, N1325S, R1644H D136G, F413C, R496S R163C, I403M, Y522S, R2434H T264P L269F , G153S T698M, T704M, M1585V, M1592V R528H, R1239H G341R, G2433R G1306A Q552R V1293I, G1306V, T1313M, L1433R, R1448C, R1448H, V1589M S804F, G1306A, G1306E, I1160V D136G, G230E, I290M, P480L AR ? ? Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Malignant yperthermia Masseter-muscle rigidity (succinylcholine-induced) Myotonia levior Paramyotonia congenita Pure myotonias (fluctuations, permanins, acetazolamideresponsive) Thomsen’s myotonia congenita AD AD AD ? AD AD AD AD CLCN1 (skeletal-muscle chloride channel) RYR1 (ryanodine calcium channel) nAChR (nicotinic acetylcholine receptor) e subunit a subunit (slow channel) SCN4A (skeletal-muscle sodium channel) CACNL1A3 (dihydropine-sensitive calcium channel) RYR1 SCN4A CLCN1 SCN4A SCN4A CLCN1 7q35 19q13. 1 17p 2q 17q23–25 1q31–32 19q13. 1 17q23–25 7q35 17q23–25 17q23–25 7q35 988 5032 473 457 1836 1873 5032 1836 988 1836 1836 988 AR denotes autosomal recessive, and AD autosomal dominant. † Missense mutations are represented by the standard nomenclature (AxxxB, meaning that at amino acid position xxx, amino acid A has been replaced by amino acid B). tion gradients. Ions flow passively through ion channels down a chemical gradient. Electrically charged ions also move in an electrical field, just as ions in solution flow to one of the poles of a battery connected to the solution. The point at which the chemical driving force and the electrical driving force are exactly balanced is called the Nernst potential (or reversal potential [Erev]). Above or below this point of equilibrium, a particular species of ion flows in the direction of the dominant force. The net flow of electricity across a cell membrane is predictable given the concentrations of ions and the number, conductances, selectivities, and gating properties of the various ion channels. Electrophysiologic concepts are simplified by recalling the Nernst potentials of the four major ions 1576 May 2 9 , 1 9 9 7 across the plasma membrane of cells. These are approximated as follows: sodium, 70 mV; potassium, 98 mV; calcium, 150 mV; and chloride, 30 to 65 mV (Fig. 1). The positive and negative signs reflect the intracellular potential relative to a ground reference electrode. When only one type of ion channel opens, it drives the membrane potential of the entire cell toward the Nernst potential of that channel. Thus, if a single sodium-selective channel opens in a cell in which all other types of channels are closed, the transmembrane potential of the cell will become ENa ( 70 mV). If a single potassium channel opens, the cell’s transmembrane potential will become EK ( 98 mV). Because cells have an abundance of open potassium channels, most cells’ transmembrane potentials (at rest) are approximately MEC H A NIS MS OF D IS EASE Extracellular Cell membrane Intracellular Ca2 Ion channels 2. 5 mM Depolarization 0. 0001 mM Nernst potential (Erev) 150 mV Control mechanisms 142 mM Depolarization 10 mM Na 70 mV Gating Voltage Time Direct agonist G protein Calcium Depolarization Nonselective Repolarization 0 mV Modulation Increases in phosphorylation   Oxidation–reduction Cytoskeleton Calcium ATP 101 mM Repolarization Cl Depolarization 5–30 mM Cl 30 to 65 mV 4 mM Repolarization 155 mM K 98 mV Figure 1. Physiology of Ion Channels. Five major types of ion channels determine the transmembrane potential of a cell. The concentrations of the primary species of ions (sodium, calcium, chloride, and potassium) are millimolar. The ionic gradients across the membrane establish the Nernst potentials of the ion-selective channels (approximate values are shown). Under physiologic conditions, calcium and sodium ions flow into the cells and depolarize the membrane potential (that is, they drive the potential toward the values shown for ECa and ENa), whereas potassium ions flow outward to repolarize the cell toward EK. Nonselective channels and chloride channels drive the potential to intermediate voltages (0 mV and 30 to 65 mV, respectively). 0 mV, near EK. When more than one type of ion channel opens, each type â€Å"pulls† the transmembrane potential of the cell toward the Nernst potential of that channel. The overall transmembrane potential at a given moment is therefore determined by which channels are open and which are closed, and by the strength and numbers of the channels. A cell with one o pen sodium channel and one open potassium channel, each with the same conductance, will have a transmembrane potential halfway between ENa ( 70 mV) and EK ( 98 mV), or 14 mV. The result is the same when there are 1000 equal-conductance, open sodium and potassium channels. Ion channels are both potent and fast, and they are tightly controlled by the gating mechanisms of the cell (Fig. 1). The modern way to see an ion channel in action is to use the patch-clamp technique. With this method,10 a pipette containing a small electrode is pressed against the cell membrane so that there is a tight seal between the pipette and the membrane (Fig. 2). In essence, the electrode isolates and captures all the ions flowing through the 1 to 3 mm2 of membrane that is defined by the circular border of the pipette. In this fashion, the ionic current passing through a single ion channel can be collected and measured. Several geometric configurations can be used if a mechanically stable seal is formed. The current passing through the attached patch (cell-attached configuration), a detached patch (inside-out or outside-out configuration), or the whole cell can be measured, providing information about ion channels within the Vol ume 336 Numbe r 22 1577 The New Engla nd Journa l of Medicine A Cellattached mode B Electrode Pipette Insideout mode C Wholecell mode Acetylcholine Acetylcholine Cell membrane IK. ACh g 40 pS to 1 msec Closed pA Closed Gbg protein pA msec Open Open msec msec Figure 2. Patch. In the â€Å"cell-attached† mode (Panel A), a pipette is pressed tightly against the cell membrane, suction is applied, and a tight seal is formed between the pipette and the membrane. The seal ensures that the pipette captures the current flowing through the channel. In the cell-attached membrane patch, the intracellular contents remain undisturbed. Here, acetylcholine in the pipette activates the IK. ACh, which has a characteristic open time (tO) of 1 msec and a conductance (g) of 40 picosiemens. In the inside-out mode (Panel B), after a cell-attached patch has been formed, the pipette is pulled away from the cell, ripping off a patch of membrane that forms an enclosed vesicle. The brief exposure to air disrupts only the free hemisphere of the membrane, leaving the formerly intracellular surface of the membrane exposed to the bath. Now the milieu of the intracellular surface of the channels can be altered. In this figure, adding purified Gbg protein to the exposed cytoplasmic surface activates the IK. ACh. In the whole-cell mode (Panel C), after a cell-attached patch has been formed, a pulse of suction disrupts the membrane circumscribed by the pipette, making the entire intracellular space accessible to the pipette. Instead of disrupting the patch by suction, a pore-forming molecule, such as amphotericin B or nystatin, can be incorporated into the intact patch, allowing ions access to the interior of the cell but maintaining a barrier to larger molecules. In this figure, the net current (IK. ACh) after the application of acetylcholine is shown. environment of the cell, in isolation from the rest of the cell, or over the entire cell, respectively. MOLECULAR BLUEPRINTS OF ION CHANNELS Many ion channels have been cloned by assaying their function directly with the use of oocytes from South African clawed toads (Xenopus laevis). 11 These oocytes are large enough to be injected with exogenous messenger RNA (mRNA) and are capable of synthesizing the resulting foreign proteins. In â€Å"expression cloning,† in vitro transcripts of mRNA from a complementary DNA (cDNA) library derived from a tissue known to be rich in a particular ion channel are injected into individual oocytes. Subsequently, the currents in the oocytes are meas1578 May 2 9 , 1 9 9 7 ured by two-electrode voltage clamp techniques. The cDNA library is serially subdivided until injected mRNA from a single cDNA clone is isolated that confers the desired ion-channel activity. Moreover, mutant cDNA clones with engineered alterations in the primary structure of the protein can be expressed and the properties of the ion channel can be studied to determine which regions of the protein are critical for channel activation and inactivation, ion permeation, or drug interaction. Most ion-channel proteins are composed of individual subunits or groups of subunits, with each subunit containing six hydrophobic transmembrane regions, S1 through S6 (Fig. 3A). 13 The sodium and calcium channels comprise a single (a) subunit containing four repeats of the six transmembrane-span- A M ECH A NIS MS OF D IS EASE A C-type slow inactivation B K Extracellular S4 S1 S2 S3 S4 S5 H5 S6 S4 S4 S4 Cell membrane †Ball and chain† N-type fast inactivation P N S4 voltage sensor H5 channel pore C K Intracellular P P K Figure 3. Structure of Ion Channels. Panel A shows a subunit containing six transmembrane-spanning motifs, S1 through S6, that forms the core structure of sodium, calcium, and potassium channels. The â€Å"ball and chain† structure at the N-terminal of the protein is the region that participates in N-type â€Å"fast inactivation,† occluding the permeation pathway. The circles containing plus signs in S4, the voltage sensor, are positively charged lysine and arginine residues. Key residues lining the channel pore (H5) are found between S5 and S6. The genes for sodium and calcium channels encode a protein containing four repeats of this basic subunit, whereas the genes for voltageactivated potassium channels (Kv) encode a protein with only a single subunit. The genes for Kir channels encode a simple subunit structure containing only an H5 (pore) loop between two transmembrane-spanning segments. P denotes phosphorylation. Panel B shows four such subunits assembled to form a potassium channel. Although no mammalian voltage-dependent ion-channel structure has been revealed at high resolution by x-ray crystallography, the dimensions of the pore region shown here were derived by using high-affinity scorpion toxins and their structures (as determined by nuclear magnetic resonance imaging) as molecular calipers. 12 The pore region appears to have wide intracellular and extracellular vestibules (approximately 2. 8 to 3. 4 nm wide and 0. 4 to 0. 8 nm deep) that lead to a constricted pore 0. 9 to 1. 4 nm in diameter at its entrance, tapering to a diameter of 0. 4 to 0. 5 nm at a depth of 0. 5 to 0. nm from the vestibule. ning motifs. Voltage-gated potassium channels (Kv; this nomenclature refers to K channel, voltagedependent) are composed of four separate subunits, each containing a single six-transmembrane–spanning motif (Fig. 3B). 14 The subunits are assembled to form the central pore in a process that also determines the basic properties of gating and permeation charact eristic of the channel type. The peptide chain (H5 or P loop) between the membrane-spanning segments S5 and S6 projects into and lines the water-filled channel pore. Mutations in this region alter the permeation properties of the channel. S4 contains a cluster of positively charged amino acids (lysines and arginines) and is the major voltage sensor of the ion channel. Voltage-dependent â€Å"fast inactivation† of the channel is mediated by a tethered amino-terminal– blocking particle (the â€Å"ball and chain†) that swings in to occlude the permeation pathway. 15 The most recently discovered family of ion-channel proteins is that containing the inwardly rectifying potassium-selective channels (Kir, for K channel, inward rectifier). These channels determine the transmembrane potential of most cells at rest, because hey are open in the steady state. Kir channels are known as inward rectifiers because they conduct current much more effectively into the cell than out of it. Despite this biophysical property of the Kir channels, the physiologically important current is the outward one that accompanies the efflux of potassium ions. The topography of Kir channels resembles that of Kv channels, but the su bunits in Kir channels lack the S1 to S4 segments present in Kv channels. 16 With only two transmembrane-spanning segments, Kir channels have a deceptively simple domain surrounding the conserved H5 pore. However, pore formation by different combinations of subunits, direct gating of G proteins, and interactions with other proteins adds considerable complexity to the behavior of the Kir channels. HERITABLE DISEASES ASSOCIATED WITH ION-CHANNEL MUTATIONS Cystic Fibrosis One in 27 white persons carries a mutant CFTR gene, and 1 in 2500 to 3000 is born with cystic fiVol ume 336 Numbe r 22 1579 The New Engla nd Journa l of Medicine A B Cell membrane TM1 TM6 TM7 Extracellular TM12 Skin Cl , 60 mmol/liter Lungs Bronchiectasis Pneumothorax Hemoptysis Cor pulmonale N F508 NBD1 ATP ADP Pi NBD2 ATP ADP Pi Liver Obstructive biliary tract disease Pancreas Enzyme insufficiency Insulin-dependent diabetes mellitus Regulatory domain S I P Reproductive tract Male infertility Congenital absence of vas deferens PKA PP2A C 1 Gene therapy to replace CFTR gene (phase 1) Extracellular Cell membrane 3 Activate mutant CFTR with NS004 (experimental) 2 Direct CFTRprotein delivery (in vitro) 5 Activate non-CFTR chloride channels with aerosolized UTP (phase 3) 6 Decrease sodium uptake by blocking ENaC with aerosolized amiloride (phase 3) Na CFTR P2R R P lCI. ATP Cl P Intracellular I Meconium ileus S Small intestine P ENaC P ATP Intracellular Cl 4 Chaperonins (none tested yet) 1580 May 2 9 , 1 9 9 7 P S I P Endoplasmic reticulum S I P S I P P M EC H A NIS MS OF D IS EASE Figure 4. Cystic Fibrosis and CFTR. In cystic fibrosis, defective apically located membrane chloride channels (CFTR) in a variety of epithelial cells do not allow the egress of chloride ions into the lumen. Control over epithelial sodium channels is also lost, increasing the reabsorption of sodium from the lumen. Thick, desiccated mucus results, which accounts for the primary clinical manifestations of the disease (Panel A). 7 CFTR contains 12 transmembrane segments (TM1 through TM12, Panel B), several of which (TM1, TM6, and TM12) contribute to the chloride-channel pore. There are also two nucleotide-binding domains (NBD1 and NBD2) and a regulatory domain. The chloride channel is regulated by ATP binding and hydrolysis at the nucleotide-binding domains and by the phosphorylation (P) of serine residues (S) in the regulatory domain. The most common mutation in cystic fibrosis, found in more than 70 percent of cases, involves a deletion of a single amino acid (phenylalanine) in NBD1 ( F508). PKA denotes protein kinase A, PP2A protein phosphatase 2A, and Pi inorganic phosphorus. Molecular strategies to treat cystic fibrosis (Panel C) include replacing the mutant chloride channel by gene therapy (1) or protein delivery (2); improving the secretion from the existing mutant CFTR protein with CFTR-channel openers, such as NS004 (3) or â€Å"chaperonins† for F508 in the endoplasmic reticulum (4); bypassing the CFTR defect by activating other chloride channels with aerosolized uridine triphosphate (UTP) (5); and blocking the increased reabsorption of sodium through epithelial sodium channels (ENaC) with aerosolized amiloride (6). The investigational stages of these strategies are given in parentheses. P2R denotes type-2 purinergic receptor, and R regulatory domain. brosis (among blacks the incidence is 1 in 14,000, and among Asians it is 1 in 90,000). The manifestations of cystic fibrosis stem from a defect in a chloride-channel protein, CFTR, that does not allow chloride to cross the cell membrane (Fig. 4A). 7 The CFTR gene encodes a chloride channel that is activated by the binding of ATP to its nucleotide-binding domains and by the phosphorylation of key serine residues in its regulatory domain; the phosphorylation is mediated by cyclic AMP and protein kinase A (Fig. 4B). 18-21 CFTR also appears to regulate the absorption of sodium through ENaC, the epithelial sodium channel, and to activate other â€Å"outwardly rectifying† chloride channels. More than 450 mutations have been identified in CFTR, which contains 1480 amino acids. A deletion of phenylalanine at position 508 ( F508) accounts for more than 70 percent of cases of cystic fibrosis and is associated with severe pancreatic insufficiency and pulmonary disease. The F508 CFTR channel conducts chloride reasonably well when it is incorporated into a cell membrane, but because of improper folding the mutant protein becomes stuck in intracellular organelles and is not inserted into the cell membrane. 2 The majority of mutant CFTR proteins are processed abnormally, like the F508 mutant, but some mutations cause either defects in regulation or defective conduction through the CFTR channel. 23 Different CFTR genotypes may provide opportunities to develop unique therapeutic strategies. For instance, misfolded mutants could be escorted to the membrane by yet-to-be-invented â€Å"chaperonins,† whereas the action of poorly conducting mutant proteins may be enhanced by CFT R-specific channel openers. Molecular genotypes are correlated with the severity of pancreatic insufficiency, but not with the severity of pulmonary disease. 24 An exception is the A455E CFTR mutant (in which alanine is changed to glutamic acid at position 455), which has been associated with mild lung disease and accounts for 3 per- cent of cases of cystic fibrosis in the Netherlands. 25 In addition, a primarily genital phenotype of cystic fibrosis that involves the congenital bilateral absence of the vas deferens has been described in otherwise healthy males who are heterozygous for the F508 CFTR mutation. 6 Pulmonary disease accounts for over 90 percent of mortality from cystic fibrosis, and therefore treatment is mostly directed at ameliorating lung disease. Therapy includes antibiotics to eliminate common respiratory pathogens (Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Staphylococcus aureus), recombinant human DNase to decrease the viscosity of secretions, and antiinfl ammatory drugs to reduce the inflammatory response. 7 The recognition of the ion-channel defect in cystic fibrosis has led to novel approaches, such as replacing the defective channel gene by gene transfer with either viral carriers such as adeno-associated virus or nonviral carriers such as cationic liposomes (now in phase 1 trials)28; stimulating the activation of reduced numbers of functional ion channels with a CFTR-channel opener (NS004, a substituted benzimidazolone)29; mobilizing mutant CFTR proteins to the cell surface30,31; counteracting the defect in chloride efflux by blocking the influx of sodium with amiloride32,33; and bypassing CFTR-mediated conductance of chloride by activating other chloride channels, such as ICl. Swell, ICl. Ca, and ICl. ATP34 (Fig. 4C). Long-QT Syndrome A more detailed understanding of cardiac arrhythmogenesis is emerging as the workings of most of the types of ion channels underlying cardiac action potentials are elucidated. 35,36 The various long-QT syndromes are the first genetically determined arrhythmias known to be caused at the molecular level by defects in myocardial ion channels (Fig. 5). The congenital long-QT syndrome has an estimated incidence of 1 in 10,000 to 1 in 15,000. It is characterized by prolongation of the QT interval Vol ume 336 Numbe r 22 1581 The New Engla nd Journa l of Medicine A C LQT1 (11q15. 5) KvLQT1 IKs C Long-QT Syndrome Prolongation of QT (QTc 460 msec1/2) Syncope Sudden death N 1 581 Cell membrane LQT2 (7q35–36) HERG IKr Prolonged QT N 1 C 1159 LQT3 (3q21–24) Torsade de pointes II III IV SCN5A INa C P N 1 2016 KPQ P P P P B 47 mV 1 0 Current clamp 85 mV 0 100 2 Prolonged cardiac action potential 3 LQT4 (4q25–27) 4 ? 200 300 400 M illiseconds 500 corrected for heart rate (QTc) to more than 460 msec1/2, and it is an important but relatively rare cause of sudden death in children and young adults (Fig. 5A). The majority (two thirds) of persons with the long-QT syndrome are identified during routine electrocardiographic screening or after the evaluation of a primary relative who is affected. Approximately one third of subjects are identified during a clinical evaluation for unexplained syncope or cardiac or respiratory arrest. These subjects are at an annual risk of 5 percent for an abrupt syncopal episode. Without treatment, symptomatic subjects have 1582 May 2 9 , 1 9 9 7 a 10-year mortality rate approaching 50 percent. Often the arrhythmia is a torsade de pointes polymorphic ventricular tachycardia, typically triggered by adrenergic arousal. 37 Genetic origins were suggested for this syndrome by descriptions both of the autosomal recessive form associated with congenital deafness (Jervell and Lange-Nielsen syndrome)38 and of an isolated autosomal dominant form (Romano– Ward syndrome). 9,40 Substantial progress has been made toward elucidating the molecular basis of the most common inherited subtypes of the long-QT syndrome (Fig. M EC H A NIS MS OF D IS EASE Figure 5. The Long-QT Syndrome. A person with the long-QT syndrome may have unexplained syncope, seizures , or sudden death (Panel A). More likely, the person will be asymptomatic and identified by electrocardiographic screening during a routine evaluation or the screening of a primary relative who is symptomatic. The strict electrocardiographic definition of a prolonged QT interval varies according to age and sex, but generally a QT interval corrected for heart rate (QTc) greater than 460 msec1 ? 2 is considered abnormal. According to Bazett’s formula, the QTc is calculated by dividing the QT interval by the square root of the R-R interval. In patients with the long-QT syndrome, the T-wave morphology is often abnormal. This base-line rhythm can degenerate into a polymorphic ventricular tachycardia, classically a torsade de pointes, as shown here, after a stimulus that is not precisely understood but that often takes the form of adrenergic arousal. The prolonged QT interval as measured on the electrocardiogram results from an increased duration of the cardiac action potential (Panel B). The ventricular action potential is maintained at a resting membrane potential (approximately 85 mV) by inwardly rectifying potassium currents (IK1, phase 4). Once an excitatory stimulus depolarizes the cell beyond a threshold voltage (for example, 60 mV), sodium currents are activated that quickly depolarize the cell (INa, phase 0). These sodium channels are rapidly inactivated, allowing transient potassium currents to return the action potential to the plateau voltage (phase 1). The plateau lasts about 300 msec and provides time for the heart to contract. The plateau is maintained by the competition between outward-moving potassium currents and inward-moving calcium currents (phase 2). Progressive inactivation of calcium currents and increasing activation of potassium currents repolarize the cell to the resting membrane potential (phase 3). On a molecular basis, the autosomal dominant LQT1 and LQT2 are caused by defects in potassium-channel genes (KvLQT1 and HERG) involved in phase 3 repolarization (Panel C). LQT3 is caused by a defective sodium-channel gene, SCN5A. A common SCN5A mutation in families with LQT3 involves a deletion of three amino acids ( KPQ) in the III–IV cytoplasmic linker loop, which is known to regulate inactivation. The mutant sodium channel fails to become completely inactivated, resulting in sustained depolarization and prolonging the cardiac action potential. The linear topology of the proteins responsible for LQT1, LQT2, and LQT3 is shown, with the amino acids numbered beginning with the N-terminal - a total of 581, 1159, and 2016 amino acids, respectively. The chromosomal locations for these genes are shown in parentheses. 5C). 2,36 Recent studies of 16 families with chromosome-II–linked long-QT syndrome type 1 (LQT1) implicated KvLQT1, a 581-amino-acid protein with sequence homology to voltage-activated potassium channels. 41 One intragenic deletion and 10 missense mutations were identified. The combination of the KvLQT1 and ISK subunits (the latter of which contains 130 amino acids, also known as minK) appears to reconstitute the cardiac IKs current. 42,43 IKs (â€Å"s† denotes â€Å"slow†) is one of the principal delayed-rectifying potassium currents responsible for phase 3 repolarization in the heart (Fig. 5B). LQT1 may account for half the incidence of the long-QT syndrome in its autosomal dominant forms. Mutations in a second potassium channel, the human ether-a-go-go–related gene (HERG), have been identified in subjects with the long-QT syndrome type 2 (LQT2), which has been linked44,45 to chromosome 7q35–36. HERG is responsible for the other major potassium current (IKr [â€Å"r† denotes â€Å"rapid†]) that participates in phase 3 repolarization. It is a unique voltage-gated potassium channel; its secondary structure is that of a typical voltage-activated (Kv) potassium channel (Fig. 3A), but it behaves more like an inwardly rectifying (Kir) potassium channel. 6 The role of HERG in normal cardiac physiology appears to be to suppress depolarizations that lead to premature firing. Subjects with LQT2 may therefore be prone to sudden cardiac death, because they lack protection from arrhythmogenic afterbeats. Class III antiarrhythmic drugs block HERG channels. In addition, antihistamines such as terfenadine and antifungal drugs such as ketoconazole have been implicated in acquired cases of the long-QT syn- drome because of their ability to block IKr (HERGmediated) current. The third subtype of the long-QT syndrome (LQT3) has been linked to the gene for the cardiac sodium channel (SCN5A) on chromosome 3p21– 24. 47 This channel is responsible for the fast upstroke of the cardiac action potential (phase 0, Fig. B), which ensures contractile synchrony by causing the potential to spread rapidly throughout the heart muscle. A deletion of three amino acids, KPQ1505– 1507, in a region thought to control rapid inactivation has been demonstrated in LQT3-linked families. The mutant sodium channel fails to inactivate completely, resulting in reopenings of the channel and long-lasting bursts of channel activity. 48,49 The resulting prolonged inward current lengthens the action potential (and thus the QT interval). Finally, a fourth heritabl e type of long-QT syndrome (LQT4) has been linked to chromosome 4q25–27. Its causative gene has not been identified, although a gene encoding a calcium–calmodulin kinase has been proposed. 0 Current therapies for the long-QT syndrome include b-adrenergic–antagonist drugs, cardiac pacing, and left cervicothoracic sympathectomy. The majority of families with heritable long-QT syndrome have type 1, 2, or 3, offering the prospect of genetic screening and directed antiarrhythmic therapy. Theoretically, therapies that augment potassium-channel activity may be used in subjects with potassiumchannel defects (LQT1 and LQT2),51 and those with sodium channel–linked defects (LQT3) may benefit from drugs that decrease sodium-channel activation (such as mexiletine). 52 Vol ume 336 Numbe r 22 1583 The New Engla nd Journa l of Medicine TABLE 2. ION CHANNELS AND DRUGS THAT AFFECT THEM. Calcium channels Antianginal drugs (amlodipine, diltiazem, felodipine, nifedipine, verapamil) Antihypertensive drugs (amlodipine, diltiazem, felodipine, isradipine, nifedipine, verapamil) Class IV antiarrhythmic drugs (diltiazem, verapamil) Sodium channels Anticonvulsant drugs (carbamazepine, phenytoin, valproic acid) Class I antiarrhythmic drugs IA (disopyramide, procainamide, quinidine) IB (lidocaine, mexiletine, phenytoin, tocainide) IC (encainide, flecainide, propafenone) Diuretic drugs (amiloride) Local anesthetic drugs (bupivacaine, cocaine, lidocaine, mepivacaine, tetracaine) Chloride channels Anticonvulsant drugs (clonazepam, phenobarbital) Hypnotic or anxiolytic drugs (clonazepam, diazepam, lorazepam) Muscle-relaxant drugs (diazepam) Potassium channels Antidiabetic drugs (glipizide, glyburide, tolazamide) Antihypertensive drugs (diazoxide, minoxidil) Class III antiarrhythmic drugs (amiodarone, clofilium, dofetilide, N-acetylprocainamide, sotalol) Drugs that open potassium ch annels (adenosine, aprikalim, levcromakalim, nicorandil, pinacidil) TARGETING ION CHANNELS Drugs that target ion channels include calciumchannel blockers (used in patients with hypertension), potassium-channel blockers (used in patients with non-insulin-dependent diabetes mellitus), some diuretics and antiseizure medications, and essentially all antiarrhythmic drugs (Table 2). Recent progress in the basic understanding of the ATP-sensitive potassium channel (IK. ATP) and the G-protein–activated potassium channel (IK. ACh) shows the opportunities for drug design. The ATP-Sensitive Potassium Channel The IK. ATP current has been characterized in heart, skeletal muscle, pituitary, brain, smooth muscle, and pancreas. 55 In the pancreas, it plays a major part in regulating glucose homeostasis and the secretion of insulin. 56 Rising plasma glucose concentrations increase intracellular concentrations of ATP in islet beta cells, which in turn inhibit IK. ATP channels. As these potassium channels close, the cell’s membrane potential depolarizes away from EK and enters the range in which voltage-dependent calcium channels are activated. The resulting influx of calcium triggers insulin secretion. As plasma glucose concentrations decline, intracellular concentrations of ATP decrease and IK. ATP channels become more active, hyperpolarizing the cell, closing the calcium channels, and terminating the secretion of insulin. Oral hypoglycemic drugs (such as glyburide) bind to the sulfonylurea receptor to inhibit the activity of IK. ATP and promote the secretion of insulin. 57 Drugs that open potassium channels include nicorandil, pinacidil, aprikalim, levcromakalim, and diazoxide. In vascular smooth muscle these drugs open IK. ATP channels, hyperpolarize cell membranes, and reduce calcium-channel activity, thus decreasing vascular tone. The drugs are therefore potentially cardioprotective and may provide novel therapeutic approaches in patients with cardiac disease or hypertension. 58-60 The subtype specificity of sulfonylurea receptors (SUR1 in the pancreas and SUR2 in the heart) may be exploited to develop more specific drugs. The G-Protein–Activated Potassium Channel The ATP-sensitive potassium channel IK. ATP is a multimeric complex of inwardly rectifying potassiumchannel subunits (Kir 6. 2 K. ATP-a) and the sulfonylurea receptor (SUR1 K. ATP-b). 53,54 The genes for both are located on chromosome 11p15. 1. SUR1 binds sulfonylurea drugs. Mutations in the SUR1 gene are responsible for persistent hyperinsulinemic hypoglycemia of infancy. 5,6 Kir 6. 2 is an inwardly rectifying potassium channel. Like other such channels, it has two transmembrane-spanning segments surrounding a pore domain. Expression of both SUR1 and Kir 6. 2 results in a potassium channel that is sensitive to intracellular ATP inhibited by sulfonylurea , drugs, and activated by diazoxide, as is consistent with the known properties of IK. ATP channels in pancreatic beta cells. The cardiac sulfonylurea receptor, SUR2, has a lower affinity for sulfonylurea drugs than does SUR1, and it may form the cardiac IK. ATP channel by combining with a homologue in the Kir 6 family. 1584 May 2 9 , 1 9 9 7 Vagally secreted acetylcholine binds to cardiac muscarinic type 2 receptors. Activating these G-protein– linked receptors slows the heart rate by opening a potassium-selective ion channel (IK. ACh) composed of G-protein–activated inwardly rectifying Kir subunits. In turn, IK. ACh decreases spontaneous depolarization (pacemaker activity) in the sinus node and slows the velocity of conduction in the atrioventricular node. 61,62 Muscarinic stimulation of IK. ACh can terminate arrhythmias, particularly supraventricular tachycardias, providing the basis for carotid massage and other vagotonic maneuvers. 5 Another G-protein–linked receptor agonist, adenosine, activates the same cascade in atria and pacemaking cells through type 1 purinergic receptors. Because muscarinic stimulation has many systemic effects, adenosine has become a favored treatment for supraventricular tachycardia; it is also useful in determining the underlying arrhythmic mechanism (usually a reentrant one). 63 The molecular mechanism of the activation of IK. ACh (IK. G) is known. 64 Cardiac IK. ACh is a heteromultimer of two inwardly rectifying potassium-channel subunits, GIRK1 (Kir 3. 1) and GIRK4 (CIR or Kir 3. 4),65 and it is activated after the direct binding of the bg subunits of G protein (Gbg). 66 Similar IK. ACh currents and GIRK proteins are present in the brain. M EC H A NIS MS OF D IS EASE Neuronal GIRK channel proteins are formed by heteromultimers of GIRK1 and GIRK2 in the cerebellum, midbrain, and cortex. In homozygous weaver mice that have profound ataxia due to the loss of granule-cell neurons during cerebellar development, a single point mutation in the highly conserved pore region of GIRK2 results in granule-cell death and failure of migration. The mutated weaver-mouse channel loses its potassium-ion selectivity and sensitivity to Gbg, converting a regulated repolarizing potassium channel into a constitutively active, nonselective depolarizing channel and resulting in increased excitotoxic cell death. 67 CONCLUSIONS A growing number of heritable diseases are known to be caused by ion-channel mutations. Chloridechannel defects underlie cystic fibrosis, certain myotonias, and heritable nephrolithiasis. Mutant sodium channels give rise to the long-QT syndrome and other myotonias, potassium-channel malfunction increases susceptibility to arrhythmias, and calciumchannel mutations can result in hypokalemic periodic paralysis, malignant hyperthermia, and central core storage disease. Identifying the structural framework of the major ion-channel proteins and resolving the precise relations between structure and function should make it possible to develop new therapies for patients with these disorders. We are indebted to David A. Factor for his assistance with the figures. REFERENCES 1. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996;154:1229-56. 2. Keating MT. The long QT syndrome: a review of recent molecular genetic and physiologic discoveries. Medicine (Baltimore) 1996;75:1-5. 3. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the b subunit of the epithelial sodium channel. Cell 1994;79:407-14. 4. Snyder PM, Price MP McDonald FJ, et al. Mechanism by which Lid, dle’s syndrome mutations increase activity of a human epithelial Na channel. Cell 1995;83:969-78. 5. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426-9. 6. Dunne MJ, Kane C, Shepherd RM, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703-6. 7. 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Cheng SH, Gregory RJ, Marshall J, et al. Defective intracellular transport and processing of CFTR is the molecular basis for most cystic fibrosis. Cell 1990;63:827-34. 23. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73:1251-4. 24. Dean M, Santis G. Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Hum Genet 1994;93:364-8. 25. Gan K-H, Veeze HJ, van den Ouweland AMW, et al. A cystic fibrosis mutation associated with mild lung disease. N Engl J Med 1995;333:959. 26. Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA 1992; 267:1794-7. 27. Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996;335:179-88. 28. Alton EW, Geddes DM. Gene therapy for cystic fibrosis: a clinical perspective. Gene Ther 1995;2:88-95. , 29. 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Role of Emotional Intelligence Essay Summary: This article discusses the correlation of a leaders Emotional Intelligence (â€Å"the ability to understand and manage moods and emotions in the self and others†) (George) and how it plays a role in how effective that manager is. The author first relates how emotions, moods and feelings play a part in how humans deal with each other on a day to day basis. Ms. George points out that positive moods and emotions can have a positive effect on how we deal with life, and on the flip side how negative moods and emotions can have the opposite effect in our social and work lives. She states that â€Å"Feelings are intimately connected to the human experience. Feelings are intricately bound up in the ways that people think, behave, and make decisions.† Many people with the inability to show emotion find life difficult as even the smallest decisions are hard to make with no gage of how others may react or â€Å"feel† about your choices. The article is not so much about how leaders behave but more so how effective that behavior is in understanding their own and others emotions and moods. The author states there are four different attributes of one’s emotional intelligence; the appraisal and expression of emotion; the use of emotion to enhance cognitive processes an decision making; knowledge about emotions; and the management of emotions. The article explores each of these attributes and how having these skills can be useful to a leader in dealing with their peers and subordinates. In all the article points to evidence that good leaders also have a higher emotional intelligence (whether they are born with it or whether they learn it). It does not state that EI is the only determining factor when comparing a good leader only that studies show that there is a correlation. Behavioral Issue: The behavioral issue is how one can use their knowledge of moods and emotions to shape the way they and others react to any given situation. Emotional intelligence in leaders can therefore bring forth the desired results of the organization that they work for. The four different attributes of EI can be used to utilize leaders and those that they lead.  Leaders with EI can use the attribute of appraisal and expression of emotion, which â€Å"ensures that people are able to effectively communicate with others to meet their needs and accomplish their goals or objectives.† A leader who uses the knowledge of emotion, will understand what determines what a person’s mood might be (such as knowing that delivering bad news will probably bring on a bad mood) and what the consequences of these moods might be (moods may linger for some time increasing negative attitudes and poor results of the sought after goal). A manager with good EI skills can help enhance â€Å"cognitive processes and decision making† skills of others. If a leader can predict or imagine what the reaction of someone else could be given two different actions will have the ability to make a decision as to which action to go with to bring out the desired result for his company. A leader who can manage his own feelings may well be able to manage or evoke desired emotions from others (getting his team motivated and excited about a new project) and this can be instrumental in meeting deadlines and the projected goals of his team. In short, emotional intelligence can be very useful to a manager who is trying to be an effective leader. Opinion: In my opinion I think the article touches on a very interesting subject. I believe the idea of emotional intelligence is integral to one being an effective manager. This article states many instances when the ability to determine and understand your own feelings, emotions and moods as well as that of others can in effect shape the mood and actions of others. â€Å"Truly effective leaders are also distinguished by a high degree of emotional intelligence, which includes self-awareness, self-regulation, motivation, empathy, and social skill.† (Goleman, 2004) I have personally known managers who display good EI (one who seemed to know how to always motivate me to do the best job possible no matter how lowly the task) and those who are most definitely lacking in the same skills (one who would berate me in front of customers and co-workers). â€Å"Every businessperson knows a story about a highly intelligent, highly skilled executive who was promoted into a leadership position only to fail at the job. And they also know a story about someone with solid—but not extraordinary—intellectual abilities and technical skills who was promoted into a similar position and then soared†. (Goleman, 2004) I am finding that I am firm believer in the  use of EI tests prior to hiring is a solid business decision. That way, when social skills are needed for the open position, you are getting an employee that matches all of your needs not just the technical ones. Relevance to the Study of Organizational Behavior: All businesses or organizations need managers to help shape their employees attitudes and behavior to ensure their desired outcomes. Managers who possess emotional intelligence help to make this possible in the most effective way possible. This is relevant because it deals with employees and with that, employee emotions and how they will react to a manager with good emotional intelligence. Managers who can motivate, or actively manage the workforce by using EI whether natural or learned will ultimately make the company money. Although EI is not required for some types of jobs (jobs that require little to no human contact) there are still many jobs where a manager’s emotional intelligence can be utilized and can make a difference to the bottom line of the company, which is usually the desired outcome. References George, J. M. (n.d.). Emotions and Leadership: The Role of Emotional Intelligence. Goleman, D. (2004). What Makes a Leader? Retrieved from Harvard Business Review: http://hbr.org/2004/01/what-makes-a-leader