The 9 Worst Pieces of Advice for College Graduates

The 9 Worst Pieces of Advice for College Graduates When you’re a new graduate, everybody and their uncle has advice for you. And everyone you talk to will assure you that their advice is the key. They can’t all be right. Avoid getting advice fatigue by keeping a keen ear out for some of these clunkers. They’re usually well-meaning, but can often knock you off your path. Here are  9 of the worst (and yet very common) bits of advice to  college graduates.1. â€Å"Go to grad school†Do not pass â€Å"go.† Do not collect $200. Delay the inevitable. Stay in school and get more degrees and be guaranteed more money when you graduate the next time. Sound good? For some, it is. For some fields, a Master’s or even PhD will be required. But for others, it’s just an expensive place to hide out from the real world. Unless you’re truly passionate about a career or field of study that requires advanced degrees, do a bit of soul searching to make sure grad school is right for you before you decide to apply automatically and end up wasting years and thousands upon thousands of dollars on something you won’t use in your future career.2. â€Å"Just show up and ask for a job!†You’ve got a dream job or a dream company. Right? Everybody has a goal. But sometimes the well-meaning grandparent or drunk uncle will tell you just to go on into that office and show them what you’ve got! They’ll have to reward your gumption and enthusiasm with a job! Right? Wrong. This is a rookie move which will betray your lack of experience and knowledge of how the work world works. The more conventional job search route, albeit slow and sometimes frustrating, will work out better for you.  3. â€Å"Hide your tattoos†It probably used to be true that tattoos could disqualify an applicant. But that’s not necessarily the truth now. There are plenty of industries and more creative fields where your individual style could be an asset in showing how we ll you’d fit into a company culture. Use your discretion, obviously. But on occasion, it’s okay to bare your ink.4. â€Å"You need to get a job in your industry right away†In other words: if you get an interim job that doesn’t have anything to do with your chosen profession, you’ll have killed your chances before you’ve even begun. Not true. If you can’t find a job in your dream field right away, then you can and should look for jobs in other industries or fields that will give you a boost in skills or experience that can easily translate into the job you ultimately want. Learn as much as you can, realize that diversifying your talents and experience might even make you an asset someday, and keep an open mind.5. â€Å"You should teach†Did you study humanities in undergrad? Does no one understand why? Think you have no viable career prospects? Write you off before you’ve even begun your professional life with the assumpti on that teaching is the only job available to you? Unless teaching is actually your calling, smile and nod and walk away.6. The Get Rich Quick SchemeAgain with the drunk uncle. Or the corner-cutting acquaintance who tells you about that opportunity just too amazing to pass up. Avoid any shortcuts that people dangle under your nose. There is no instant wealth or renown to be had without hard work and perseverance. Don’t stop chipping steadily away at your goals, and don’t put all (or even most) of your savings into an investment opportunity, no matter how enthusiastic your bro is that it’s the next big thing.  7. â€Å"You have to give it your all all the time†100% or 110% all day every day for the rest of your career is actually impossible. Certainly there are times when you’ll need to go all out, and times when you’ll have to work even harder than that in pursuit of a particular project or goal. But there are other times when you’l l need to take your foot off the gas and catch your breath. It’s okay to slow your pace now and again to avoid burnout. Just choose your moments carefully so as not to interfere with your goals and progress toward meeting them.8. â€Å"Follow your bliss†Do what you love and love what you do, right? Well†¦ sometimes it’s not quite so easy as that. While following your dreams is always a good idea, don’t just expect that everything will fall magically into place because you’re pursuing something you care deeply about. You still have to be smart. Save money. Strategize how to be on solid financial footing and don’t get lazy. Risks are one thing. Being stupid and expecting the money will just fall out of the sky is another†¦\9. â€Å"Get a stable job and stay there†This is the advice of a dying generation. A stable job is great. Job security, benefits, good money. All great. But settling isn’t. If you get stuck in a job y ou don’t really enjoy and which doesn’t challenge you too soon in your career, it could really hurt both your productivity and your earning potential. Not to mention your qi. Find a balance between following your bliss and providing for yourself and your future. If you hit that sweet spot, then you’re good to go. Steady sailing from here on out.

Perfect Cocktail Attire for Men and Women With 10 Stylish Outfits

Perfect Cocktail Attire for Men and Women With 10 Stylish Outfits SAT / ACT Prep Online Guides and Tips So you've gotten an invitation to a fabulous party and can't wait to go, but one line strikes terror into your heart: cocktail attire requested. What is cocktail attire, even? Never fear, I'll walk you through the guidelines of this dress code for both men and women and provide images of cocktail outfits you can easily recreate on your own. What Is Cocktail Attire? Cocktail attire is a dress code that is often adopted for parties and events that are somewhat fancy but not to the point of requiring full formal outfits. It’s popular for weddings and other special celebrations. There is some variation in what cocktail attire means based on the type of event, but it's generally meant to be fancy without being black tie. Cocktail attire is for fun but formal social events, so you can throw in a little more personality. The point is not to look like you’re going to work. What is cocktail attire for men? It can range from a more casual ensemble of dark jeans, a button up, and a sport coat to a more formal dark suit and tie. Sweaters and sweater-vests over button-up shirts are also acceptable in most cases. What is cocktail attire for women? Options include dresses and skirts with hemlines that fall slightly above the knee, dressy blouses, and pants. Suits for women are also acceptable. Cocktail Attire: Essential Guidelines Follow these guidelines to create a cocktail outfit that's fashionable, comfortable, and perfectly suited for the occasion. Cocktail Attire Rules For Everyone In crafting your outfit for a fancy occasion, you can't go wrong following the following guidelines. When in Doubt, Be More Formal It’s often best to err on the side of more formal if you’re unsure of the exact level of dressiness the event requires. Cocktail attire can be dressed up or down slightly depending on what sort of function you’re attending. If you’re not in a position where you can be assured that slightly less formal cocktail attire is acceptable, dress more formally. It’s more acceptable to be overdressed than underdressed in these situations. Find What’s Comfortable for You Don’t wear something that you think someone else would wear but that feels awkward or uncomfortable to you. For example, if you hate wearing dresses, don’t force yourself to put on a cocktail dress for this event. You can just as easily wear a nice pair of pants with a dressy blouse. Same goes for footwear - if you don’t like heels, wear flats or booties instead. 4 Rules to Know About Cocktail Attire for Men Dressing for formal occasions is generally simpler for men than women, but there are still some rules you should follow in picking out your outfit. Keep It Simple There are certain simple outfits that will always work for cocktail attire, like a well-tailored suit and tie with dress shoes. If you feel a bit lost when dressing for these types of events, stick to the basics. You can’t go wrong with a classic look (which you'll see examples of further on in this guide). No Sneakers or White Socks Don’t wear sneakers to an event that requires cocktail attire. Instead, go for loafers or other types of dress shoes or boots. Also avoid wearing white socks - they’ll stick out like a sore thumb and detract from the neatness of your outfit. It’s best to wear dark socks, ideally ones that match the color of your pants. If you’re feeling more adventurous, you can try some brightly colored argyle socks, but it’s best not to take too many risks if you don’t consider yourself a fashion expert. Prepare for Increased Formality If you think the event falls on the less formal side of things, you can try wearing just a pair of nice pants with a button-up, but you should be prepared to dress more formally if you find yourself feeling out of place. Bring a jacket and tie with you just in case you need to make yourself look a bit more dressed up. Jeans Require a Jacket Sometimes you can wear jeans to events that require cocktail attire, but they should be a dark wash with no rips or other wear marks. If you do opt for jeans, make sure you dress up your outfit by including a jacket. A more informal choice in pants should be balanced out with more formal clothing choices for your upper body. 4 Simple Guidelines to Navigating Cocktail Attire for Women Of course, the standard cocktail attire for women is the cocktail dress, but it can still be hard to know how to accessorize or what to wear if you prefer pants. Check out the rules below to help you pick a fashionable but appropriate cocktail outfit. Accessorize Responsibly It’s best to have just one stand-out accessory rather than going overboard and creating five different focal points within your outfit. If you have a piece of bold statement jewelry that you plan on wearing, keep any other accessories very minimalist. Cocktail attire outfits are supposed to have personality and convey a sense of fun, but they should still make you look classy and put together. Too many loud accessories can make you look a bit tacky. Choose Shoes That Are Fancy, but Not Flashy Dressy sandals, ballet flats, and heels are all acceptable as footwear to go along with cocktail attire. Try not to go overboard with super high heels or shoes that clash with the rest of your outfit and compete too much with other accessories. You also need to be practical - make sure you can move around easily and stand for a long time without feeling like your feet are going to fall off. On the flip side, you should avoid wearing sneakers or flip flops because footwear that is too casual can really mess up the sophistication of your outfit as a whole. More Revealing = Less Loud Short dresses are commonly worn as cocktail attire, but you shouldn’t take this to the extreme. Slightly above the knee is the best place for the hemline to fall, though you can go a bit shorter as long as the dress isn’t excessively revealing overall. Even dresses with cutouts can be acceptable as cocktail attire, but in that case it’s best to stick with solid colors and lengths that don’t make it risky for you to bend over and pick up that hors d'oeuvre you just dropped (five second rule guys, let’s not be wasteful). If you wear a dress with a really out there pattern, that’s fine, but if it’s also skin tight and short, it might not be appropriate for a more formal event. Dress Practically Finally, don’t squeeze yourself into an outfit that makes you feel uncomfortable or that’s totally irrelevant to your personal style. Keep in mind the length of the event and the activities that you’ll be doing throughout. If it’s a wedding, you’re probably going to want to dance. In that case, wear an outfit that allows room for movement and shoes that won’t lead to a broken ankle as soon as the beat drops. Cocktail Attire for Men: Example Outfits Below are pictures of some of the best and easiest to recreate cocktail attire outfits for men. If you're wondering which items you need to purchase for your own cocktail attire, the last section in this guide has a list of cocktail attire staples you should have in your closet. Cocktail Attire for Women: Example Outfits Below are photos of the three most popular cocktail attire outfit combinations for women. Use these photos as inspiration when searching your closet or thinking about which new pieces to buy. Combo 1: Classic Cocktail Dress Combo 2: Pants/Blouse or Jumpsuit Combo 3: Skirt/Blouse Cocktail Attire Basics: Must-Haves for Men and Women Now you have a better idea of what to wear to cocktail party or other formal occasion. The next step is to begin assembling your own cocktail attire. Below are essential pieces you should always have on hand for events that require cocktail attire. For Men Dark or light suit Tie (optional) Button-down shirts (neutral colors are the most versatile) Solid-color sweaters or those with a simple pattern Slacks Blazer Dark socks Loafers or similar shoes For Women Knee-length or slightly above the knee dress Mid-length skirt Button-down shirt or blouse Blazer Flats, heels or sandals

Communication journal article Example | Topics and Well Written Essays - 500 words

Communication journal - Article Example For effective implementation of change, communication both verbal and written has to be effected. Once communication has occurred, the next step is verification of the information passed and finally improvement of the systems previously in place. Communication, both verbal and written serves to relay information and create a vision for the free flow of information. It is noted that motivation works best in the implementation of change as opposed to intimidation and threats. People are more inclined to accept change when their opinion is sort regarding the matter at hand. Change occurs in stages and it’s thus paramount for the change agents to emphasize the need for communication in every stage by following a well organized communication plan. Managers can opt to use informal networks such as grapevines in the organization to enhance their subordinates’ participation in the change process. Authors come up with trends regarding communication and change in order to enhance the sale of their books. It is therefore the readers’ decision whether to follow these trends or draw their own

Business information system Essay Example | Topics and Well Written Essays - 500 words - 1

Business information system - Essay Example of data that would be captured; date of birth, the year that the student commenced and completed their high school education, the units and courses that were taken by the student, the co-curriculum activities that the students engaged in, sex of the student, academic performance, and their career goals. As stated earlier, the recruiters have set the parameters defining the qualities, which they require from the students. After gathering the above information from the recruits, they will process the data and come up with tangible information that would aid in the recruiting process (Arthur 27). The following are examples of information, which would be processed from the above data; the average age that students start their high school education, the average number of years that students attend high school, the common and least common units and courses that the students take, the common and least common co-curriculum activities that the students engaged in, the sex composition of students in high school, and the average academic performance of the students. In particular, the processed information is an advantage to the recruiters in that, it brings to the light, the features exhibited by the student recruits. The two initial processes; data collection and data processing, gives way to a third imperative process; inference by the recruiters. Before the data collection process, the recruiters had defined the threshold that the recruits had to surpass. However, after processing the information and making some inferences, the recruiters can come to the realization that the threshold was either too high or too low. For instance, the recruiters would infer that, either the students spend more or fewer years in high school contrary to what they had thought. In this regard, they will have to raise or lower the minimum age of admitting students to the university. Secondly, the recruiters may infer that, the units and courses that the students have taken in high school

The Darkness out there Essay Example for Free

The Darkness out there Essay Changing the mood during a story makes it more exciting and less predictable which captivates the readers interest. Both stories show evidence of significant mood change, which created a successful amount of suspense when I read them. The endings of the three stories are all quite similar because the characters die at the end because of what they have been through. Frankenstein ends as it began with letters written from Walton to his sister. Frankenstein has journeyed to the Arctic in pursuit of his creation and has lived to tell the extraordinary tale of his life. The reader finds out that the end of Frankensteins story was in the prologue and everything is pieced together, for example, the sighting of the gigantic stature in the beginning. After completing his story, Frankenstein dies on the boat and his monster finds him. The compassion he once felt for his creator returns to him as he confesses he wants to die too. The morals used throughout the story are summed up here in part of the monsters speech. I, the miserable and the abandoned, am an abortion, to be spurned at, and kicked, and trampled on Here, Shelley communicates the idea that everyone should be loved no matter how they look. This could be related to many modern issues, for example, a mother abandoning her baby. The ending matched the theme of the story, e. g. death and bereavement, and was very detailed. I liked the way the letters at the beginning and the end made the story very complete, and gave the story more of a purpose to be told. Walton wanted to hear it; Frankenstein wanted to tell it. Many of the ideas Shelley used in the novel were talked about by the monster at the end which also made the story educational because it talked about very realistic issues. In The Raven Poe leaves you unsure about the ending he has written. It is quite evident that the man is dead and the raven has frightened the man to death because his soul from out that shadow lies floating on the floor, which seems as if he has left his body but we are never sure why. The only evidence we have is that the man was a firm believer of superstition and maybe he was so scared of the thought of dying that it killed him. This is like the ending in The Tell Tale Heart, also by Edgar Allan Poe. At the end you know that the younger man has killed the older man but you cant figure out why. Poe lets the readers decide for themselves what has truly happened which involves their imaginations, which makes it a more memorable ending because the reader has had to think about it more. In Man Overboard it is safe to assume that a shark killed the man because he was praying to die and suddenly His last appeal had been heard and a fin approached him slowly. In Frankenstein and Man Overboard the men wanted to die so the ending is satisfactory to the character and reader because it was what was expected. In one of the stories it might have been better to keep the character alive for longer to create more fear in the characters mind which would have built up more suspense in the story if the character had to keep going through more horror. The ending of The Raven was good because the man didnt want to die but he did. This made the story more horrific because the character didnt want what happened in the end, making him more frightened and adding more fear and tension to the story for the reader because they could be so involved in the story that they would feel what the character is feeling. Linking ideas throughout a story is an effective way of keeping a reader interested. It keeps the story exciting if the reader is able to piece parts of different plots together. However, if the writer continually keeps inventing new plots that have no relevance to any of the current ones and make up a new story on their own, the reader may start to lose interest because it may confuse them. In Frankenstein, Shelley links many plots to one another as the novel progresses. This helps the reader to develop a clearer understanding of what is happening because each plot supports another one. The letters in Frankenstein are a good example of the way Shelley links different characters ideas together in the story. The letters Frankenstein received when he was away at Ingolstadt were about what was happening at his home. These letters made it easier for me to understand the story when Frankenstein returned home because all of the information had already been supplied about the environment and characters. I didnt have to concentrate on figuring out things about the story, which made it easier to read. The letters acting as the prologue and epilogue from Walton to his sister also linked the story together very well. When I had finished the story I realised what everything meant at the beginning, for example when Frankenstein said to Walton I have lost everything and cannot begin life anew. Reading statements like that at the beginning built up a lot of suspense and made me want to keep reading to find out more. This helped me enjoy the story more because I was always searching for something to find out about in the text. In The Raven, Poe links ideas with words, rhyme and verse structure. The way he wrote about the raven saying Nevermore at the end of each verse gave the plot more continuation because it provided a reason for man to keep reacting to in the next verse. It made me wonder whether the raven would say anything else so it kept me interested. The verses and the rhyming patterns are very structured, which linked each verse of the story together because they were of similar length and sound. The way the rhyming of the ore sound kept appearing in the same places in each verse gave the poem more rhythm and familiarity and linked the verses together even more because I was able to tell when the next rhyme would be. In Man Overboard, Churchill links the song with the setting very well. This is very important because the song is the cause of the ending of the story. Rowdy Dowdy Boys is a sea song and as the story is set on a ship, this makes it very appropriate and makes the atmosphere feel more realistic. It makes it easier to imagine the song being sung in its surroundings and puts the story into context more effectively. The main difference between these two stories is the type of language they contain because of the different periods they were written in, and the effect the language has on the style of the story. The Old Nurses Story and The Darkness Out There were written in different periods of history. The Old Nurses Story uses a more formal style of English.. The style of writing in The Darkness Out There may still be used in writing today. The style of language used in each story makes them very different from each other and we can identify the period in which they were written in very easily by looking at some of the words used and things written about that were popular at that time. I found that both stories contain many realistic and relevant ideas about morals and the contrasting behaviour of adults and children. Mukwinda Phiri 10Wn English 7 Show preview only The above preview is unformatted text This student written piece of work is one of many that can be found in our GCSE Mary Shelley section.

The Natural and Perceval, The Story of the Holy Grail Essay -- Literar

The novel The Natural is written by Bernard Malamud. Bernard was a famous author mainly known for writing short stories and novels. He was considered one of the great American Jewish authors of the 20th century. Bernard was born in Brooklyn, New York. His parents were Russian Jewish immigrants and he had a brother named Eugene. Unfortunately, Malamud entered his adolescence when the Great Depression began. The Natural is one of his more famous books, which was written in 1952. This novel is about a baseball prodigy named Roy Hobbs. He has a bat that he made himself, which he calls Wonderboy. Roy plans to join the major leagues and break all the records. However, his plans are put on hold when a woman he meets shoots. After fifteen years after the tragedy Roy goes back to baseball and is drafted to the New York Knights. Along his journey to becoming a superstar he is distracted from his goal by the women in his life. The Natural is very much similar to the mythological story of Percev al, the Story of the Holy Grail. Roy Hobbs is comparable to Perceval, Pop Fisher to the Fisher King and the pennant to the Holy Grail. Roy Hobbs and Perceval are similar because they are both the main characters of their own stories. Both their parents had some sort of natural talent. Perceval’s father was a great knight and Roy’s father was a baseball player. They then passed their gifts on to their children, which are Roy and Perceval. â€Å"Roy Hobbs is the Perceval figure of the Natural. Hobbs is a â€Å"natural† both in his ability to play baseball and in his simple and naà ¯ve manner.† (Source 4 Page 1) Perceval and Roy have special talents and are good at what they do. Perceval can fight and he leads his army to victory. â€Å"Perceval does battle with 20 of ... ... back to life again. Roy’s team was losing countless games in a row and Perceval’s kingdom has been suffering for numerous years. Nevertheless, Roy ends up not obtaining his goal and fails many people while Perceval finds the Holy Grail and is a hero among his kingdom. In conclusion, there are many characters, items and symbols in The Natural that are similar and related to the ones in Perceval, the story of the Holy Grail. Roy and Perceval are related because of their natural talents in baseball and fighting, the type of parents they come from and the same goals that they share. Pop Fisher and the Fisher King are parallel due to the related kind of illness they both have and the type of situation they are in. The pennant and the Holy Grail are comparable because they are the important treasures and goals that each of the main characters seek and hope to obtain.

How Does SHRM Influence Organizational Outcomes? Essay

Introduction In modern business environment, †Strategy† is always applied in each business area. As strategic management discipline originated in the 1950s and 1960s, strategic human resource management emerged as following. At the beginning, HR department is not viewed as an important division and in many multinational companies (Vymys.P 2014), only marketing, R&D and finance which are direct associated with the competition and revenue could get enough attention from general manager, stockholders and professors in management area. However, nowadays, strategic human resource management (SHRM) is considered to be a source of competitive advantage for a firm (Wright, Dunford, & Snell, 2001). An increasing number of senior managers or professors have begun to focus on human capital. Actually, the core competition ability of an enterprise is accumulated value of employees. During the process of promoting and implementing all the business in an enterprise, the initiative of the people, the guaranteed skills and the team cooperation is the key factor for it to work effectively; SHRM is, in fact, the management of power development and the core of management behavior includes the acquisition, motivation, organization and development of human resource management. These four parts form a unified whole and none is dispensable. The circulation of the â€Å"unified whole† promotes human resources management and enterprise management constantly, thus enhances the enterprise’s core competitiveness and profitability. In Google, the Human Resource department is called People Operations. They emphasize on the process which employees create value for the company and presents strategic modes in HR management. For example,each employee in Google has material packages in HR department with at least dozens of pages, on which record their abundant personal information,like SAT scores,rankings,GPA,resume, papers published,referees and even message in BBS and blog (Wei,J. 2013). In terms of recruitment,the questions candidates received are various and strange. Google devotes into seeking the smart to compete rivals and indeed,  this strategic recruitment method does work and provides countless value for the enterprise (Poundstone,W. 2012). In total, SHRM plays a crucial role in enterprise management and affects the success and failure in an organization. Strategic Human Resource Management and 8P Model Strategic human resource management (SHRM) is different from the concept â€Å"human resources management†. Put it in detail,SHRM refers that the essence of SHRM is to adopt a flexible but strategic perspective that accurately analyses both the internal and external environments of organizations to assure ’fit’ between HR strategies and practices, and between these and business strategiesï ¼Ë†Redman,T. and Wilkinson, A. 2013,p.50). The main characteristic of SHRM is to emphasize matching up between human resource management and enterprise strategies, to establish relevant human resource management activities and deployment according to organizational strategic objectives and to provide services and support for the implementation of enterprise strategy(Strategic Human Resource Management And 8P Model 2012) . Therefore, if an organization wants to achieve the goals, the first thing is to successfully manage human capital. However, how to motivate human talent to create a network and make the company successful? According to Adam Smithï ¼Ë†1776ï ¼â€°, economic activity was fulled not by workers as a collective mass but by †the acquired and useful ability of all the inhabitants and members of the society†. With the development of strategic human resource management, there is an increasing number of people focusing on capitalize the intangible asset. Many practices and strategies are applied in promoting the †best fit† and encouraging the network. Theodore Schultz(1960), American economist and the creator of human capital theory, in his report †Human Capital Investment and Urban Competitiveness† said, the source of economic growth can not increase only depending on the material input of the Labor force, but the more important is to rely on improved peopl e’s ability. According to the American economists estimates, from 1900 to 1957, the material capital investment increased by 4.5 times, profits increased by 3.55 times,while human capital investment increased by 3.5 times, profits increased by 17.55 times. During the 38 years from 1919 to 1957, 49% of  gross national product is the result of human capital(What Is Strategic Human Resource Management In An Organization 2008). Obviously, the contribution rate of human capital in the era of knowledge economy is far greater than that of material capital. Therefore, paying attention to the importance of human capital on economic growth is particularly urgent. Under the background of modern social economy, the enterprise must carry out strategic management of human capital and strengthen the competition and development of the enterprise. As I mentioned, SHRM is power management and its core function and soul is acquisition,motivation,organization and development. In terms of behavior and responsibilities of strategic human resource management, to conclude, there are eight essential abilities: Table1.Strategic Human Resource Management and 8P model (MBA Lib,2012) These eight abilities are specifiedï ¼Å¡ ——HRM project system based on strategy(Project) Understanding organizational strategic decision and management environment is the precondition of human resource planning. According to the enterprise development strategy, combining with the enterprise human resource current situation and making enterprise human resources plans enable the enterprise’s human resources to support enterprise strategic development needs and to contribute to the realization of enterprise strategy. The main activities of enterprise human resources planning encompass the analysis of supply and demand of human resources, the planning of amount of human resource planning, human resources structure optimization planning and human resource qualification promotion planning, and the concrete measures to realize the objective of human resource planning, namely, the various business plans. ——Job analysis system based on strategy(position) Job analysis is a basic work in an enterprise’s SHRM. Enterprises select the appropriate organization mode according to their own strategic and on the basis of this, set up departments including management processes and business processes and clear the responsibility and authority of the various functional departments. HR department should clear the responsibilities and  content of each department and analyze the necessary knowledge, skills, experience and personal quality as an employee. ——Employee’s qualification analysis system based on strategy and position (personnel) Enterprises should proceed based on strategic objectives and customer demand, on the basis of job analysis, analyze and conclude the staff with high performance and then set up â€Å"Staff Quality Model† in order to optimize human resource and motivate the staff’s potentials. ——recruitment system based on strategy and competence(provide) Recruitment based on strategy is no longer to simply hire people to fill the vacancies and what they acquire is the resource with which an enterprise can survive and win the competition. A company not only care about if the candidate is qualified in the position, but also care about if the candidate could provide support for the company to achieve the enterprise strategic objectives. Therefore, an enterprise should take human resource planning and â€Å"Staff Quality Model† into account, when recruiting. ——training system based on strategy and employee’s career(plant) The training system based on strategy and staff’s career development should encompass training demands assessment, drawing up a training plan and training results transformation. Training needs assessment should consider about strategic requirements, staff qualities and training needs by which employees want to achieve professional development in their career. ——career management based on strategy(profession) Career management based on strategy requires an enterprise to set up job positions and job classification based on the organizational strategies. Enterprises should establish different levels of qualification standards according to different employee’s classification, drive the employees to study and improve professional skills. In addition to this, HR division should set up promotion system by which employees have more motivation to do the work and improve themselves. Besides, an enterprise should build a good environment for employees to grow up and positively provide consultancy for  employees about promotion and skill improvement. By that, realize that the enterprise leads employees to grow up and employees promote the enterprise to develop. ——appraisal performance system based on strategy and key performance indicator (performance) Performance is an effective output in order to achieve strategic objectives including organizational performance, department(team) performance and personal performance. SHRM focuses on organizational overall performance whose goal is to survive and develop in the competition. Appraisal performance system based on strategy and key performance indicator requires an enterprise to develop relying on organizational strategic objectives and to determine the enterprise key results areas and key performance indicators through the analysis of the value chain of enterprises. Organizational performance is based on individual performance and team performance. When the organization performance targets are allocated to every employee and every job, and as long as each employee meets the organizational requirements, the realization of organizational performance is guaranteed. Standard procedure of performance appraisal comprises five links, namely, planing assessment, performance management(e,g, performance coaching, counseling and performance tracking), performance appraisal, performance feedback such as performance interview, and the use of performance appraisal(e.g. reward, promotion, elimination and improving the performance appraisal mode). ——payment management based on ability and achievement(payment) There are three ways measuring the value that employees create for the enterprise. So on the basis of it, there are emerging three compensation modes. The first mode is based on job duties which is determined by the importance of job and relative value of job in the enterprise. The second is based on performance evaluation. In this way, an employee’s salary is related to his performance. Evaluating the salary level by employee personal performance or team performance is a result oriented value distribution way. The third is to pay the employees according to employee’s ability, capacity, professional skills, experience internal quality and so on. Under the framework of strategic human resource management, the enterprise’s salary incentive  system should focus on the short-term performance improvement and long-term development of the enterprise. Therefore, compensation management must link to performance and ability appraisal by which each employee’s income and performance is related to the realization of organizational strategies. Payroll management based on performance and ability not only emphasize the value created by individuals and teamwork but also emphasize potential value that individuals and teams could bring about for the enterprise. Conclusion To conclude, SHRM to a large extent influences the organizational outcome. I have explained each function separately and each one is closely associated to the organizational strategy. Actually, the core management of an enterprise is human management and each department in the enterprise is operated by people. Therefore, what extent to capitalize the human resource and how to match the human resources with the organizational strategies is critical issue. More importantly,this also requires the HR division to understand the organizational strategies on which manage employees effectively and plan and execute SHRM strategies to help the enterprise to survive and win the global competition. To sum up, SHRM is to explore and motivate the value of people. A good HR division knows exactly which division need which talents and understand how to motivate the employee potential. However, to what extent to motive and explore these potentials to be the â€Å"Best Fit† and how to manage the talents from motivating personalities to forming a standard is another important issue. This would be discussed more deeply. References 1. Vymys,p.2014,Introduction to Human Resource Strategy(WORK6017), The university of Sydney,Sydney, 29 July, viewed 10 September 2014, 2. Mayhew,R. and Demand 2014, Chron,Small Business,10 September 2014, 3. Strategic Human Resource Management And 8P Model 2012, MBA Lib, viewed 10 September 2014, 4. Schultz,T. 1960,Human Capital Investment and Urban Competitiveness,social Sciences Academic Press, China. 5.What is Strategic Human Resource Management In An Organization 2008, MBA Lib, viewed 10 September 2014, 6. Redman,T. and Wilkinson,A. 2013, Contemporary Human Resource Management,Pearson,UK 7.Human Resource 2014,MBA Lib, Viewed 10 September 2014, 8.Wei,J. 2013,demystify the recruitment of Google:lengthy and picky five rounds of interviews,Sina ChuangShiJi, viewed 17 September 2014, 9. Manjoo,F. 2013,The Happiness Machine:How Google became such a great place to work, Slate, viewed 17 September 2014, 10. Google,2014,Google Career, viewed 17 September 2014, 11.Pounderstone,W.2012,Are You Smart Enough To Work At Google,Little,Brown and Company Press,United States of America.

Essay on Act III of the Crucible Essay

In the play â€Å"The Crucible† Arthur Miller creates a successful dramatic climax at the end of Act III. Integral to this success is Miller’s continued engagement with the audience. The principal reason why the climax is so dramatic and suspenseful is because the audience is involved with what is happening on stage. Throughout â€Å"The Crucible† Miller has achieved a powerful relationship with the audience both on an emotional and intellectual level. The audience in Act III continue to have an understanding of the personalities of the characters and an insight into their behaviour and how they react in different circumstances. In Act III the audience maintains a deep emotional relationship with the characters. They persist to despise certain characters such as Abigail who is exemplified as remorseful, untruthful and vengeful. In contrast the audience develops a more empathic relationship with some characters such as Elizabeth Proctor and Mary Warren. The context of Act III within the play lies just after the incarceration of several villagers on the alleged charges of witchcraft including the wives of three esteemed men within the village John Proctor, Francis Nurse and Giles Corey. The driving plot line of Act III is these three men’s attempt to redeem their wives a particular focus is on Proctor’s struggle. Part of Miller’s dramatic success is attributed to the way he is able to manipulate the historic and social context. The historical setting of the play is a theocratic Puritan settlement in 1692 in the Massachusetts. The theocracy is a significant part of the play as it leads to mounting frustration for the audience and it is the basis to the plot; Miller also uses the theocracy in Salem to convey an important message about Miller’s own social setting in 1950s America. When Miller was writing the play he was living in a society where McCarthyism was prevalent. The playwright in â€Å"The Crucible† particularly in Act III is conveying how McCarthyism is using communism as a false pretence to ‘hunt down’ McCarthy’s enemies in the same way that Salem is using the guise of witchcraft to rid themselves of threats or adversaries. Perhaps Miller is illustrating to the contemporary audience that the hysteria and difficulties of theocracy are strikingly similar to McCarthyism. An important part of the success towards the end of Act III are Miller’s stage directions they give a vivid instruction to the actors of how to portray to the audience the emotions felt by the characters. Miller begins the scene on a remarkably dramatic moment; Proctor becomes enraged when Abigail attempts to call Heaven. Proctor cries â€Å"How dare you call Heaven! Whore! Whore!† in this historical context the word â€Å"whore† has significantly powerful connotations with what the society would see as â€Å"evil† and â€Å"sin†. The characters on stage react to this in an expected way; Danforth appears to be confused and horrified and is shouting at Proctor â€Å"Man! Man, what do you-â€Å"we can see how severe the potential charge of â€Å"whore† could be. When Proctor attempts to justify this charge he is shown on stage as trembling and petrified he shouts â€Å"I have known her, sir, I have known her† this echo of biblical terminology shows the absolute control theocracy has upon Salem and how language from the Bible has managed to integrate into everyday language. The audience can see the impact and power of this scene by the emotion and bewildered reactions of others. Following this scene of commotion Miller creates a relatively calm scene, Proctor’s anxiety turns into confidence as he is sure his wife is able to verify his claims ,†my wife cannot lie†. Abigail, although not revealing much with speech, she is portrayed in contrast as enraged to the audience. Upon Elizabeth Proctor’s entry, there is a situation of suspense and importance, the audience can tell this because Elizabeth sees Proctor with his back turned which conveys to the audience it is a suspenseful moment and she is ordered by the Deputy-Governor to â€Å"Look at me only†. The audience can see the initial impact this has upon her as she appears weak and confused. The scene escalates in tension and a tremendous amount of pressure is being put upon her. Elizabeth is clearly fearful of the situation and the substantial implications of her testimony as she uses vague descriptions such as â€Å"dissatisfied† and she repeatedly states her husband is a â€Å"good and righteous man†. Elizabeth is intimidated by Danforth, at several times during her interrogation Goody Proctor attempts to look at her husband and he shouts at her â€Å"woman, look at me!† The use of this phrase shows a derogatory attitude towards women that was prevalent during this period of history. During Elizabeth’s questioning Danforth uses violence against her he holds her face and she is portrayed to the audience as full of agony and the clear impacts of the stress being put upon her. When Elizabeth is eventually shouted at â€Å"Is your husband a lecher?† she replies â€Å"no† and she is removed from the courtroom. This enrages the audience how Elizabeth’s answer which has essentially been forced out of her after being interrogated and not for a second been reconsidered. Empathy is also felt for Elizabeth because of the difficulty of the situation that has been forced upon her. The passion felt between the Proctors is evident here Elizabeth has lied putting her life at risk in order to save her husband’s name, Proctor then shouts, â€Å"she only thought to save my name† in desperation to save his wife. This devotion towards each other contrasts with the beginning of Act II where there was a sense of awkwardness between the couple. Following Good Wife Proctor’s ejection from the court-room, The Reverend Hale makes a passionate speech declaring his objection to the situation, â€Å"I may shut my conscience to this no more- private vengeance is working through this testimony†. Miller perhaps uses Hale in this situation to represent the audience’s opinion on stage, Hale is finally able to see clearly what is going on, and the audience is relieved that the lies of Abigail may be exposed. Furthermore there is a prospect of hope as Hale could possibly lead the demise of Abigail; he cries â€Å"This girl has always struck me as false†. Once Abigail is under pressure and she is at risk of being undermined she is able to control the situation by creating an ‘imaginary’ scene. Abigail lets out a loud chilling cry, which would have tremendous impact on the audience and stunned both the other characters and perhaps the audience also into silence. Abigail and the rest of the girls pretend that Mary Warren has shape shifted into a â€Å"yellow bird† which would have bewildered an audience. The girls are described as â€Å"transfixed† and â€Å"hypnotized† (upon the bird) showing how convincing their performance must have been. During Abigail’s â€Å"genuine conservation† with the bird she says â€Å"But God made my face Mary†¦envy is a deadly sin† Miller’s use of the word â€Å"sin† perhaps implies that Abigail is appealing to Danforth by making her language correspond to the Bible also by using the term â€Å"sin† Abigail makes Mary appear more sinister to the rest of the characters on stage and make her appear to be associated to the ‘devil’. The girls’ mimicking of Mary has a remarkable impact upon the atmosphere and pace of the scene, all the shouting between Mary and the girls adds to the drama and builds up excitement in the scene . The audience becomes horrified at the situation, with Abigail’s power and dominance she is able to shift the accusations from her to an innocent which must disgust the audience. Compassion is felt towards Mary because of the horrendous situation she is put in. It seems Miller’s original impression of the girls as ruthless appears to be fulfilled during these scenes.

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. 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