My Brother Mitchell Handles The Athletics Scene Better...

Before we start this final chapter, can you believe we’ve made it? Twenty chapters at twenty years old, and here comes number twenty-one. I believe there’s no better way to end this book than to declare, with boundless joy, the glory of God. When life gets good, glory can get in the way of things. Even as I finish this book, I wonder whom I will meet and help because of this. However, God’s Will for the last twenty-one chapters has everything to do with Him and little to do with me. It’s a battle we face every day, especially for young men. Whenever we do things people value or applaud, we think it’s us who they cheer for. My brother Mitchell handles the athletics scene better than anyone I know. After pitching against Texas AM in the†¦show more content†¦Every time he thought he would be ready to make his comeback, another setback occurred. It reached the point where he began to feel dead inside. God lovingly restored Mitchell’s health, but more importantly, his heart, when He brought him out on the mound this year. He stopped trying to light up radar guns and started trying to become an effective pitcher – to perfect the craft God gifted him with. At this moment, he became what Kirk Saarloos, his pitching coach, would probably call a â€Å"pitcher† not a â€Å"thrower.† In one season of collegiate baseball, Mitchell became nominated as a top-60 player finalist for the Golden Spikes Award, which goes to the best player in all of college baseball. He received all-Big 12 honors at the end of the season. He put his team in a position to send them to Omaha, and eventually helped eliminate LSU, while competing in the College World Series. That’s quite the resume for one year of collegiate baseball. The day after we beat Texas AM, Mitchell and I drove home for the 2015 MLB Draft. While he received the chance to become a professional baseball player at this time, Mitchell declined the opportunity. It’s not as crazy as it sounds. As he sat in our living room under pressure with phone calls coming in, he continued to say the decision needed to be made out of faith, not fear. So, he decided to return to TCU for another season, where God will use Mitchell mightily as a

The Social Class Structure Of Victorian England Essay

All throughout Sir Arthur Conan Doyle’s prominent Sherlock Holmes fiction, there seems to be a lot of themes concerning the social class structure of Victorian England. I do not believe that Doyle’s true objective was to depict Holmes as upholding the traditional state of affairs of that time, as class inequality was a very prominent thing. Women were regularly thought of as having less intelligence than males and there was a seething, developing tension building up between the three categorized classes; those being the upper, middle, and lower. Doyle also depicts and writes frequently about a kind of â€Å"criminal class† who seem to be predestined to a life of crime and are often the people of the lower and working classes. This, to many people, might suggest that Doyle believed that the lower class working people were doomed to a life of crime. However, I postulate that it’s much more sophisticated than just that. There happen to be quite a few tongue-i n-cheek comments all throughout the Holmes canon and Doyle was simply using his characters to challenge the issues of social inequality and gender roles, rather than to conclusively solve them. I believe that Doyle’s Sherlock Holmes is the embodiment of critique of class and gender roles, criticizing the status quo by introducing multiple villains that don’t mesh with the stereotypical â€Å"criminal class†, by depicting those of the upper class as irrational, silly and mean-spirited; while at same time, Doyle was headlining women inShow MoreRelatedClass Structure Of Victorian England1130 Words   |  5 PagesThe difference in class structures of Victorian England was dependent on the lifestyles and jobs of individuals. The Victorian era of England lasted from 1837 to 1901. The Victorian England hierarchy was divided into three different classes; the upper, middle, and lower class and was reliant of occupational differences. The hierarchy was very rigid and t here was little social mobility, because of the fact that normally a person was born into their class and even their future career. In Great ExpectationsRead MoreSatirical Comments in The Importance of Being Earnest by Oscar Wilde999 Words   |  4 PagesThe class system during the Victorian Period played a significant role on people’s lives. The class a person belonged to played an important role in that individual’s future. In Victorian England, class diversity and class placement either hindered or enhanced people’s lives. One work of literature that comments on class distinctions in Victorian England is â€Å"The Importance of Being Earnest†, by Oscar Wilde. In â€Å"The Importance of Being Earnest†, Wilde expresses the concern with the Victorian peopleRead MoreEssay on Servants in Victorian England850 Words   |  4 PagesServants in Victorian England Servants were imperative to the functioning of middle and upper class homes in Victorian England. 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The three social classes included the working, middle, and upper leisure class. As the Industrial Revolution advanced, the working class became very isolated from the leisure class and often had low paying jobs such as a blacksmith, tradesman, and farmer. The wealthy ladies and gentlemen of the leisure class lacked awareness that their frivolous lifestyle was built on the laborious work of the working class. Charles DickensRead MoreThe Romantic Period Of The Victorian Era1715 Words   |  7 PagesThroughout history, many time periods have been similar and different from each other. People from each time period decide what they want to continue incorporating and what they would like to disregard. The Victorian Era was brought about upon to show rebellion from the Romantic period. The Victorian Era is a reaction against the Romantic Period due to differences in terms of historical influences, effects of science, crises of faith, and women’s desire for change. 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How Toppan Is Not Guilty For Insanity - 1290 Words

In 1902, people from New England descended Barnstable County Courthouse for her trial. After emerging of the jury from the deliberations, they ruled her as not guilty for insanity. As a result, she remained totally unmoved. In her final confession that was printed in New York Journal, Toppan boasted on fooling many doctors for years (Stedman, 1904). On the other hand, she regretted that she tipped her hand in poisoning four persons in a single at once. In her statement, he said that was the greatest mistake of my life. One person that Toppan consistently expressed a lot of sorrow was herself. She blamed her crimes on the lover who jilted her in early times. Toppan wrote that she still laughed and was jolly, but she learned how to hate too (Ramsland, 2006). She added by saying that if she had been a married lady, she probably would not have murdered any person people. She stayed the rest of her life in Taunton Lunatic Asylum. In the facility, she increasingly deranged and paranoi d by time. In an attempt to search for her justice, she wrote letters to several lawyers as well as doctors by repeatedly accusing hospital staff of attempting to poison her. How Different Entities Perceived Jane Toppan Many unsuspecting patients, as well as associates, perceived her as a well-respected nurse apart from being a gregarious caretaker after earning the nickname Jolly Jane. On the other hand, her prosecutors perceived her as mentally deranged murderers who injected over 30Show MoreRelatedHonora Kelly, Also, And Most Famously Known As, Jane Toppan1724 Words   |  7 PagesHonora Kelly, also, and most famously known as, Jane Toppan is one of America’s most famous serial killers. She was a woman who confessed to killing over thirty-three people, but experts say she killed around seventy more undocumented. She lived from the years 1857 to 1938. Honora’s mother died when she was very young from tuberculosis and her father was very abusive and known as the town’s alcoholic, he also was noted as a crack smoker. Her dad, Peter Kelley, died from being insane and supposedlyRead MoreMentally Ill Prisons And The Death Sentence2084 Words   |  9 Pagespleading guilty is seen as a loop hole or a way to shorten your sentence and make the jury feel bad for the defendant. Take Jane Toppan for example. A nurse at a private practice, she racked up dozens of victims between 1885 and 1901. She would experiment different medicine and different dosages to patients. When they were about die she got into bed with them and held them close, feeling their lives slip from them. She got sexual satisfaction out of this, so she pled guilty by reason of insanity. SheRead MoreFemale Serial Killers Essay2409 Words   |  10 Pagesmurder in the United States alone makes up more than three-quarters of the estimated world total† (Innes 5). Although women serial killers are not very common, they still have a huge impact on the death toll of innocent victims. In order to understand how woman serial killers operate, it is important to understand their motives, the different classifications of woman killers, society’s resp onse, and the consequences they face for their actions. There are many differences between the traits of men and

Process of Leadership Innovation and Change

Question: Discuss about the Process of Leadership Innovation and Change. Answer: Leadership and Change Concept The term leadership refers to the process of managing a group of people. In order to lead a group of people, an individual should have the ability to communicate with the followers. On the other hand, change refers to the management tool through which an organization implements new strategies. In order to implement a new business strategy, a leader must have the ability to lead the change management. Here, it is highly important to communicate with the employees in order to create urgency of the change (Sheldon 2016). Therefore, it can be said that in order to bring change within organization, it is essential to implement appropriate leadership approach. Importance of Locus Control There are two types of locus control such as internal and external. A person with internal locus control believes in taking responsibility for everything. These kinds of people believe in taking action in order to influence the followers. On the other hand, people with external locus control believe in blaming people for outcome. These kinds of people are more reluctant to take responsibilities of the followers (Benzie, Pryce and Smith 2016). There is certain difference between these types, which influences the leadership approach of individuals. The major difference between these two categories is leadership approach. An individual with internal locus control communicates with the followers in order to achieve objectives. On the other hand, people with external locus gove instruction for achieving objectives. Self-esteem and Leadership In order to influence a group of people, a leader should set examples among the employees. Therefore, it is highly important to be self-esteemed while leading a group of people. It helps to influence the followers as a role model. Therefore, self-esteem is the most important thing than a leader should have. In order to influence the followers, a leader must have adequate confidence on decision-making. The leader should reach the ultimate level of Maslows hierarchy, which is self-actualized (Martin and McCarthy 2016). In this phase, people are allowed to influence others with their decision-making ability. Therefore, it can be said that there is huge relationship between leadership and self-esteem. Contingency Theory, leader behavior and situational leadership The behavior of a leader depends on the leadership approach. There are several leadership approaches such as transformational, transactional, situational and autocratic. In transformational approach, an individual can communicate with the followers in order to implement innovation. On the other hand, in autocratic leadership approach, leaders force the followers to achieve a specific objective (Johnson and McKenzie 2016). The situational leaders are able to change their approach in accordance with the situational demand. The great man theory of leadership emphasize that a leader is not created, but can be trained. Therefore, it can be said that leadership approach of an individual depends on their learning and development. Values, Ethics and leadership In leadership, values and ethics are the most important factor that influences leadership approach of an individual. A leader should maintain ethical practice in order to improve organizational culture. A leader should not be discriminative while dealing with their followers. In order to influence the followers in an efficient manner, a leader should not discriminate the followers based on age, sex and abilities (Dimitriadis and Psychogios 2016). The leader should only evaluate the followers based on their performance. It would help to improve both organization culture and performance in an efficient manner. In order to achieve organizational objectives, a leader should earn trust from their followers. Implementing and maintaining ethical practices help to earn trust from the followers in an efficient manner. Knowledge Management and Leadership Knowledge management is a tool, which helps organizations to gather and evaluate stakeholders data. In order to conduct appropriate evaluation of stakeholders data, it is highly important to build efficient communication. Therefore, leadership is the major requirement through which it is possible to enrich communication with the internal and external stakeholders. Apart from that, innovative technology is required in order to improve knowledge management process of an organization (DeMatthews 2016). On the other hand, a leader is the person who can bring innovation with participative decision-making process. Therefore, it can be said a transformational leadership approach is required in order to improve knowledge management system. Vision and the duty cycle A leader should a long-term vision through which it is possible to handle sudden situation. Long-term vision helps the leaders to implement innovative strategies through which sustainability can be maintained. The leaders should gather feedbacks from the employees in order to improve the decision-making process (Johnson and McKenzie 2016). Moreover, the leader should promote the vision and mission among the followers in order to achieve overall goals. In this manner, it is possible to simplify the overall organizational objectives among the followers in an efficient manner. Reference list Benzie, H.J., Pryce, A. and Smith, K., 2016. The wicked problem of embedding academic literacies: exploring rhizomatic ways of working through an adaptive leadership approach.Higher Education Research Development, pp.1-14 DeMatthews, D.E., 2016. Competing Priorities and Challenges: Principal Leadership for Social Justice along the US-Mexico Border.Teachers College Record,118(8), p.n8 Dimitriadis, N. and Psychogios, A., 2016.Neuroscience for Leaders: A Brain Adaptive Leadership Approach. Kogan Page Publishers Johnson, G. and McKenzie, L., 2016. Capacity Building for Parental Engagement in Reading: A Distributed Leadership Approach Between Schools and Indigenous Communities. InLeadership in Diverse Learning Contexts(pp. 365-387). Springer International Publishing Martin, A.J. and McCarthy, L., 2016. Developing Sport Team Culture and Collective Leadership.Research Quarterly for Exercise and Sport,87(S1), p.S93 Sheldon, S.B., 2016. Moving beyond monitoring: A district leadership approach to school, family, and community partnerships. InFamily-School Partnerships in Context(pp. 45-63). Springer International Publishing

Marketing Mix for Sri Lankan Tea Essay Example For Students

Marketing Mix for Sri Lankan Tea Essay Table of Contents 1. Introduction02 2. Applying the Marketing Mix†¦Ã¢â‚¬ ¦. 04 2. 1 Product†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦.. †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦ †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦.. 05 2. 2 Place †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. 06 2. 3 Price †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦.. 08 2. 4 Promotion †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. 09 3. Conclusion 12 4. References †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. 13 1. Introduction Since the discovery of Tea in 2737 B. C in China, and after the Europeans learnt about tea in 1589, drinking tea has spread throughout the world and today it is a widely consumed beverage. Tea production in Sri Lanka is of high importance to the Sri Lankan economy and the world market. Sri Lanka is the worlds fourth largest producer of tea and the industry is one of the countrys main sources of foreign exchange and a significant source of income for labourers, with tea accounting for 15% of the GDP, generating roughly $700 million annually. Ceylon tea is divided into three groups: High or Upcountry (Udarata), Mid country (Medarata), and Low country (Pahatha rata) tea, based on the geography of the land on which it is grown. Tea produced in Sri Lanka carries the Lion Logo† on its packages, which indicates that that the tea was produced in Sri Lanka. The most important foreign markets for Sri Lankan tea are the former Soviet bloc countries of the CIS, the United Arab Emirates, Turkey, Iraq, Iran, UK, Japan, Saudi Arabia, Syria and Libya. Ceylon tea was renowned for its quality, but supplies exceeding demand, higher cost of production and intermediary’s margins have forced the tea industry to compete on price rather than on quality. Consumers preferring flavoured and instant teas are also not helping the local tea industry that produces old style orthodox teas. If you take the trend world over convenience and fast food are popular. People now do not have the time to brew tea and make tea in the traditional way. At present, instant tea is one of the fastest growing segments in the beverages market. Instant teas and green tea demand is growing in Europe, USA and Japan. Instant tea has created a lot of excitement and modernized the image of conventional tea. About 50% of instant tea consumers are newcomers to the tea market. Instant tea has not replaced the traditional tea bag, however, instant tea covers a very wide product range, usually depending not on the tea, but the flavouring used. The tea is usually a relatively a minor component, with sugar typically the primary ingredient, then flavourings, colouring agents, anti-caking agents, etc. Most instant teas do not contain real tea, rather tea extract. This artificial addition further separates instant teas from their parent leaves. However, one must not fail to appreciate the success of instant tea and recognize that it is a product, which has its roots in tea. The most instant of instant teas is called ‘Ready to Drink (RTD)’. Also known as bottled tea there used to be a strong stigma in the tea community about this relative of the leaf. Viewed largely as the stepchild of the big cola companies, RTD teas were thoroughly infused with their mass-production ethos: make it cheap, stack it high, move it fast. However, a new trend is beginning to emerge from the creative folks of the tea industry. Fighting to erase the image that Goliath cola companies have painted for tea, some true tea-loving companies are introducing innovative bottling methods. They are making great teas available without the addition of unnecessary preservatives, and without covering the lack of quality tea with an overabundance of sugar. The instant tea manufacturers are hoping to challenge beverage marketers outside the tea industry with their new products. The attempt to attract younger consumers is an effort to compete with the cold-drink market, which has grown by four times in the last ten years, according to market-research firm A. C. Nielsen. Nielsens statistics show a slow decline in the tea market over the past 10 years. Hence, instant tea manufacturers are targeting a younger market, hoping the product innovation will cultivate a new niche of tea drinkers in the declining market for tea. Young people are looking for convenience and variety and more countries are setting up instant tea factories to capture the growing demand. Applying the Marketing Mix Marketing mix is a general phrase used to describe the different kinds of choices organizations have to make in the whole process of bringing a product or service to market. The 4 Ps, first expressed in 1960 by E J McCarthy, is one way probably the best-known way of defining the marketing mix. The 4Ps are: In layman terms the Marketing Mix is the creation of a product that a particularly group of people want, put it on sale some place that those same people visit regularly, and price it at a level which matches the value they feel they get out of it; and do all that at a time they want to buy. However, a lot of hard work needs to go into finding out what customers want and how the product can meet such wants. Thereafter the company needs to figure out how to produce the item at a price that represents value to them, and get it all to come together at the critical moment. Getting even one element wrong can be disastrous for the product as well as for the company. However, when entering a foreign market in addition to the mix the company should focus its attention on the cultural aspects as well. For example, McDonald’s fast food giant was very successful in the entire world, but it failed in the Indian market, as it did not change its menu that included beef, which is not consumed in India. This report will discuss marketing an Instant Tea in America, UK, Japan and Australia, with regard to the marketing mix while considering the cultural aspects in each of these markets as well. 2. Product/Service As mentioned in the introduction tea as a beverage has been in existence for centuries. Therefore identifying the need for tea is not what we need to do. The problem many consumers face is the time they need to set aside from their fast pace life to brew a cup of tea. Hence, the objective should be to make sure this need is satisfied. With the fast p ace life and the trend of consumers looking more and more for convenience, it is very important that instant tea cater to this need. Instant tea should be easy to prepare where the consumer spends less time in preparing a quality product faster so they ave more time to enjoy it. Therefore, adding water (cold or hot) to powder to get the same effect and taste as a brewed a cup of tea should be a key feature of an instant tea. Further, this product should be able to prepare at anytime and at any given place when needed. This should also be nutritious by adding no artificial ingredients as the consumers of this product will buy this as they like consuming it rather than a drink or water or a cola. If the consumer is guaranteed of these features, they will go for this product. In the US market, this product will mainly be consumed by the Asian population who has a liking for tea. Hence the product should appeal to the Asian consumers and it should concentrate on captivating the younger generation where they feel accepted by their associates in having this tea. Culturally, tea is enjoyed by the older generation. Therefore, instant tea should meet the expectation of the younger generation. Globalisation requires a company to consider all aspects of a product, both domestically and internationally, at the creation stage itself. Doing so prevents expensive faux pas, such as the case of the Chevy Nova. Its name in Spanish can be said as â€Å"No va,† which means, â€Å"It doesn’t go,† not a particularly reassuring or marketable name for a car (Semenik and Bamossy 1995). The brand, its name, its feature emphasis, and the like must be developed with consideration for all its major markets worldwide. In areas where conflict is apparent, it is vital the company adapt to the local market. Therefore the brand name of an instant tea drink should be something which is accepted globally and not have any undesirable meaning in any language. Critical Thinking Vs. Systematic Thinking EssayHowever, in Japan a higher price product will not fetch consumers who are only looking to quench their thirst and in the US more than price, availability and health facts (new trend) will have a stronger impact in purchasing the product. Therefore each country will need to have separate pricing strategies. In any situation, the pricing among each country should not create a situation where the buyer buys from one country and sells it in another country to achieve a profit. This could occur especially when operating through distributors and where a discount scheme is offered to increase it by the number of products sold. Having price regulations in the contract with distributors will help minimize/control such a situation. 4. Promotion Promotion is another important ingredient in the marketing mix where this helps to build the perception and the want for the product. Promotion is the most localized component of the marketing mix. â€Å"The consumer, not the company, must decide what can be the same across borders,† and usually promotion is the most variable (Mazur 2004, 18). For example, McDonalds used sports figures in its promotional materials, ads, and television commercials several years ago. Rather than choose one known international sports figure, such as a Tiger Woods, the company picked figures recognized in each respective market, with a basketball star used in the United States, a footballer in the UK, and so on (Vignali 2001). This allowed McDonalds to project a locally appropriate image, one that identified the restaurant with local concerns and presented it as native to the region, rather than the United States. This in other words bridges the gap between culture and the product that is being offered. In the case of instant tea, having film stars promote this will be a good strategy as this will portray a message of having a healthy beverage in their busy life style. In US, UK, Australia and Japan, film stars are treated as idols and many follow what they do, eat, wear and hang out in places where their favorite film star goes regardless of cost. Having such celebrities use a brand will make the brand popular among young as well as old people. Displaying billboards in busy city areas where celebrities consume instant tea will help to capture a wider target market. Another way that the product can be promoted is through help from the supermarkets that will sell this product. The supermarket pamphlets, brochures and other advertising material can promote the product. Advertising plays a critical role when entering foreign markets as it all depends on how the target customers are approached. The same promotional campaign cannot be used in US as well as Japan. The reason being, American life is faster paced, while Australia has a more laid back life style, while in Japan cultural influence is still very strong. Further, Japanese will have an ego problem if the same advertisement that was targeted for the US market is used in Japan. UK will have the same effect if a Japanese advertisement is played or used in UK. Therefore each promotional method will need to be tailor made to suite each country’s culture and the target customer base. For example, Nisan Car Company has the same car in the US and in Australia with a different name. This is purely to make sure its accepted by the each market. In any such instance, the product should have its own brand name and image irrespective of how the message is sent across in each country. For example, Nike has its own name and its logo (Swooch) which makes it distinct in any country the product is marketed. However, the way its marketed is localized to suite its local customer base. Therefore establishing the brand name to image quality, convenience, health and affordability in the instant tea product should be key focus points in all its advertising campaigns though execution is different in each country. The method of advertising should be via media and having billboards in each major city that is being concentrated. Having advertising boards in major air ports and informing in them the availability in the air port itself will be a good strategy. Making sure the packaging is also done as per each country’s guidelines is another important factor. For example, US is very strict about the phthalate in products as this will harm children. Therefore suppliers need to make sure the required tests are done to avoid this chemical. Further, information on the pack will differ from one country to another. Having distributors giving authority to market the product in each country should be done in a way that the brand name is not tarnished and is ithin the criteria mentioned above that materializes from the brand. Further, promotions should be handled focusing on the manufacturing company and not the intermediary company name. Making sure the product is available in the right places and making sure product is moving will be the responsibility of the distributor. Conclusion The first thing that should be done when introducing a new product is to have a market research done in each market to identify the target market. This will help to gain a better insight of each market, gaining knowledge about its competitors and most of all the customers. Many large players have entered markets without proper research and ended up loosing their overall market share in other markets as well. A good example is the medicine Insulene which is used by diabetic patients. When this was marketed in the United Arab Emirates (UAE), this had adverse reactions as this included one ingredient from the pig, an animal banned in UAE. Therefore, the company had to re-launch the product making the product specialised for that UAE market. Further, it had to issue a press release apologising to the people of UAE and recall all the goods that were in stores at their cost. Going into a market with the attitude of â€Å"here is our product, take it or leave it† will not gain much acceptance among the customers. Therefore having researched the market and tailoring the marketing mix to capture all such aspects will be the key in succeeding in a foreign market. In conclusion it can be said that organisations must examine the purity of their global marketing plan rather than simply taking the national marketing plan and tweaking it to hopefully fit an international market. Businesses should begin a global marketing plan from scratch, making it truly in tune with each different market segment. Beginning from a global perspective will allow an international business to decide which products to offer where and to better position and promote its products worldwide. While a 100% global marketing mix is not attainable, many companies can move successfully onto a global scale by branding globally but acting locally. Creating an adaptable marketing strategy and component mix will allow the business to successfully negotiate the regional and cultural differences it will face, and increase both markets and profitability on the global market. References †¢ Semenik, R. , and Bamossy, G. 1995. Principles of Marketing, a Global Perspective. South Western, Cincinnati, USA. †¢ Vignali, C. 2001. McDonald’s: â€Å"think global, act local† – the marketing mix. British Food Journal, Bradford, vol. 103, issue 2, p. 97. †¢ Mazur, L. 2004. Globalisation is still tethered to local variations. Marketing, London, 22 January 2004, p. 18. †¢ Product (or Service) †¢ Place †¢ Price †¢ Promotion

Why Are the Homeless Homeless a satire Essay Example For Students

Why Are the Homeless Homeless a satire Essay Jason Garoutte December 3, 1996 English / Mr. Lunt Why Are the Homeless Homeless? There are many homeless people out on the streets of the large cities in this great nation. When unemployment still hasnt gotten near zero and new jobs are being created every day, people are starting to ask why there are still homeless people in the alleys and on the sidewalks of this country. This seems to be an ever haunting problem even though it would be so easy for homeless people to just get a job. Lets look at the general requirements for applying for and keeping a job. We will write a custom essay on Why Are the Homeless Homeless a satire specifically for you for only $16.38 $13.9/page Order now All you have to do is have nice clothes to make a decent impression, a home address and some way to be reached in tight situations, and a way of getting to work in the morning or nightwhichever the case may be. Thats it. And I, for one, have reached a solution to this widespread laziness. First of all, most homeless people spend their days hunting through trash cans and dumpsters for a piece of sustenance or at least something of value. If theyre not doing that, theyre begging for spare change on street corners. Eventually, one would think that they should be able to afford a couple of respectable suits or other outfits to wear while applying and even working for this job of theirs. All they have to do is poke around a little longer or beg a little more, and that job would be theirs to enjoy. Keeping these articles of clothing clean would be difficult, but manageable. If you cant afford a coin operated laundromat (Im sure thered be plenty of left over change from begging), just find some large, clean puddle of water in the street to wash things in. As for cleanliness, Im sure people throw away left over deodorant or antiperspirant, soap, and other such toiletries to where you can care of the bathing problem. You dont need to clean your hair, in fact, doing so would rid yourself of the natural oils that build up over time and actually hold your hair style in place. Second, with all the left over money and such, they could go to one of those Mailbox Etcetera stores and buy themselves a mailing address. That just means theyll have to cope with eating only what they find in the garbage, and not spending any of that extra cash on that frivolous fast food, or that healthy vegetable stuff. Suppose they absolutely need a phone number also. Whats stopping any of these people from sleeping close to a pay phone? Just record the number on the back of your hand (unless you have some nice paper on you) before you head out to the job interview. And if you really want to impress the boss, give him the number of the pay phone nearest your favorite begging corner or alley, just in case they cant get a hold of you at the first number. None would be the wiser. As for the commuting, all one would have to do is make sure the pay phone isnt too far from business. Better yet, sleep in front of the business, near a pay phone, so you can also respond to any requests promptly and efficiently. It would also give you much more time to sleep while waiting for that first paycheck. Now that you must take care of the job and the finding food and drink in the same twenty-four hour time period, you need all the sleep you can get. Having to commute through miles of busy sidewalk would make you wish you hadnt opted for a home away from work. All this being on-time and showing up so early would be sure impress the boss, especially if he already wasnt impressed with your feat of scrounging up the resources to hold this special occupation. Now if all this doesnt impress your supervisor, I dont know what will. .ue0051c695a2767c7e4f101b4de728fc8 , .ue0051c695a2767c7e4f101b4de728fc8 .postImageUrl , .ue0051c695a2767c7e4f101b4de728fc8 .centered-text-area { min-height: 80px; position: relative; } .ue0051c695a2767c7e4f101b4de728fc8 , .ue0051c695a2767c7e4f101b4de728fc8:hover , .ue0051c695a2767c7e4f101b4de728fc8:visited , .ue0051c695a2767c7e4f101b4de728fc8:active { border:0!important; } .ue0051c695a2767c7e4f101b4de728fc8 .clearfix:after { content: ""; display: table; clear: both; } .ue0051c695a2767c7e4f101b4de728fc8 { display: block; transition: background-color 250ms; webkit-transition: background-color 250ms; width: 100%; opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #95A5A6; } .ue0051c695a2767c7e4f101b4de728fc8:active , .ue0051c695a2767c7e4f101b4de728fc8:hover { opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #2C3E50; } .ue0051c695a2767c7e4f101b4de728fc8 .centered-text-area { width: 100%; position: relative ; } .ue0051c695a2767c7e4f101b4de728fc8 .ctaText { border-bottom: 0 solid #fff; color: #2980B9; font-size: 16px; font-weight: bold; margin: 0; padding: 0; text-decoration: underline; } .ue0051c695a2767c7e4f101b4de728fc8 .postTitle { color: #FFFFFF; font-size: 16px; font-weight: 600; margin: 0; padding: 0; width: 100%; } .ue0051c695a2767c7e4f101b4de728fc8 .ctaButton { background-color: #7F8C8D!important; color: #2980B9; border: none; border-radius: 3px; box-shadow: none; font-size: 14px; font-weight: bold; line-height: 26px; moz-border-radius: 3px; text-align: center; text-decoration: none; text-shadow: none; width: 80px; min-height: 80px; background: url(https://artscolumbia.org/wp-content/plugins/intelly-related-posts/assets/images/simple-arrow.png)no-repeat; position: absolute; right: 0; top: 0; } .ue0051c695a2767c7e4f101b4de728fc8:hover .ctaButton { background-color: #34495E!important; } .ue0051c695a2767c7e4f101b4de728fc8 .centered-text { display: table; height: 80px; padding-left : 18px; top: 0; } .ue0051c695a2767c7e4f101b4de728fc8 .ue0051c695a2767c7e4f101b4de728fc8-content { display: table-cell; margin: 0; padding: 0; padding-right: 108px; position: relative; vertical-align: middle; width: 100%; } .ue0051c695a2767c7e4f101b4de728fc8:after { content: ""; display: block; clear: both; } READ: Alexander the Great Essay I know Id be impressed after learning the amount of time this homeless person took just to get a reasonable outfit to show up to work with, the hours of begging just to get bus fare to another part of the city, and the humility endured to actually work up the nerve to ask someone fortunate enough to have some spare change in their pocket if they can spare some so that person can get a bite too eat. 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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. 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