Economics Problems

Homework #3: Question 1. Problem and Application 4 on page 285. Please work on a, b, c, d, and e only. That is, ignore f. When you reconstruct the table in your work, please lower the space for Marginal Product and Marginal Cost by a half step. In other words, the first entries of Marginal Product and Marginal Cost should be aligned with the second entries of other columns. (50 points) Table of Costs: WorkerOutputMarginal Product Total CostAverage Total CostMarginal Cost 00–$200———– 12020 300$15. 00$5. 00 25030 400 8 3. 33 39040 500 5. 6 2. 50 412030 600 5 3. 33 514020 700 5 5 615010 800 5. 33 10 71555 900 5. 81 20 A. The table shows the marginal product; marginal product rises at first, but then starts to decline because of diminishing marginal product. B. The table shows the total costs for this scenario. C. Again, the table shows the average total cost. The average total cost will be shaped like a â€Å"U. † The average total cost declines as quantity rises when the quantity is low. When the quantity is high, the average total cost rises. D. The table shows the marginal cost. The marginal cost, like the average total cost, is also â€Å"U† shaped, but unlike the average total cost it rises steeply as the output increases. This is because of diminishing marginal product. E. When the marginal cost is falling, the marginal product is rising and vice versa. Question 2. (20 points) The licorice industry is competitive. Each firm produces 2 million strings of licorice per year. The strings have an average total cost of $0. 20 each, and they sell for $0. 30. a. What is the marginal cost of a string? Marginal cost = Change in total cost/change in quantity .30-. 20=. 0=Change in total cost .10/1=. 10 The marginal cost of one string is $0. 10. b. Is this industry in long-run equilibrium? Why or why not? No. In a long run quilibirum all firms are maximizing profits. No firms have incentive to enter or exit because all firms are earning zero economic profit. The firms in this competitive market are making a profit of $0. 10 on each string of licorice. At this rate there is no long-run equilibrium, but if more firms join this market to get in on some of the profit then there will be a long-run equilibrium; when too many firms join the market the demand goes down. This can cause firms to make zero profit. Question 3. (30 points) Consider the following table. The price of the product is $8. Quatitity Total cost 0. $8 1. 9 2. 10 3. 11 4. 13 5. 19 6. 27 7. 37 a. Calculate profit for each quantity. How much should the firm produce to maximize profit? b. Calculate marginal revenue and marginal cost for each quantity. Graph them. At what quantity do these curves cross? How does this relate to your answer to part (a)? c. Can you tell whether this firm is in a competitive industry? If so, can you tell whether the industry is in a long-run equilibrium?

A Medium of Exchange and a Unit of Account Versus Money

These Short Essays are partial fulfillment of Paper IE1001 of Part 1 of Certified Islamic Finance Professional (CIFP) [DRAFT V0. 5] INCEIF Student Name: Mustafa Aydemir Student ID: 1200279 IE1001 Assignment in Islamic Economics – Short Essay No 3 by Mustafa Aydemir – DRAFT Version 0. 5. doc -1- Bismillahirrahmanirrahim Essay No. (3) Money and Islam – A Medium of Exchange and a Unit of Account versus Money as a Commodity Everybody is using money. Most of us want it; we work for it and think how to get more of it. Therefore, it is vital to ask what money is, where it comes from, and what money is worth.Economics is an academic discipline that tries to answer those questions. It would be to long and lengthy to discuss about money creation and growth from A-Z but in the following paragraphs the subject matter is elaborated from the conventional as well as the Islamic worldviews. Money in the conventional sense is a commodity people use in exchange for goods and servi ces. Before money was used as a medium of exchange, barter trade was practiced whereby people trade goods and services in exchange for other goods and services.However, barter trade was considered not so practical as weighing, transporting and dividing goods was difficult. It was the lack of transferability and inefficiencies that created the need for better ways of exchange. The concept of money was born. There are different types of money that developed over time, which should be presented briefly. Commodity money is defined as valuable goods, which were used as an underlying for a currency, such as gold, silver, coffee or even tobacco. The biggest advantage of this kind of currency was its portability and easy storage.Another example of commodity money is the U. S. currency before 1971, which was backed by gold (Investopia). Fiat money is the paper money currently circulating in our world that is not convertible in any other type of money. It is used in our daily life where we bu y and sell goods and services. Fiat money is basically not backed by any commodity but by a government that guarantees its value and creates a perception and faith in people that it is worth it. It is simply needed because gold is IE1001 Assignment in Islamic Economics – Short Essay No 3 by Mustafa Aydemir – DRAFT Version 0. . doc -2- rare on this planet. The perception created is, that the stronger the economy, the stronger is the value of its money. It is important to understand, that money is valuable because we want it, but we want it only because it can get us a desired product or service. Money is generated by a kind of an uninterrupted collaboration between physical things, our elusive desire for them, and our theoretical trust in what has value. That is why printing fresh money will not enrich a nation. Another type of money is named credit money.Investopia defines credit money as â€Å"Any future monetary claim against an individual that can be used to buy go ods and services†. There are many forms of credit money, such as IOUs, bonds and money market accounts. Virtually any form of financial instrument that cannot be repaid immediately is considered credit money. Economists measure money in M1, M2 and M3 defined as follows. M1 money includes all coins and currency that is physically available, travellers checks, demand deposits, checking accounts that is used to make payments.M2 money is all the money in M1 plus saving accounts, timelinked deposits and non-institutional money-market funds. M3 money is all the money in M2 plus all large time-deposits, liquid assets, institutional money-market funds, and short-term repurchase agreements. M1+M2+M3 together is the total supply of money in an economy, the â€Å"broad money† Money fulfills the three main functions. It is used as a medium of exchange. Furthermore, money is a unit of account that is a numerical unit of measurement for transactions, goods and services.IE1001 Assignm ent in Islamic Economics – Short Essay No 3 by Mustafa Aydemir – DRAFT Version 0. 5. doc -3- Lastly, money is used to store value that can be retrieved and used again. In Islam money is not a commodity, which makes all the difference. It is not considered as a commodity that should be used for a price, but rather as a medium of exchange in business transactions Money as a commodity concept is prohibited, because it contradicts Islamic principles that does not recognize money as a tool to make profit. Money is only a medium of exchange, a way of defining the value of a thing; it has no value in itself, and therefore should not be allowed to give rise to more money, via fixed interest payments, simply by being put in a bank or lent to someone else. † (INCEIF Lecture Notes p. 81). Money used as a commodity would presumably divide the society into the poor and the rich, even countries into categories rich and poor economies neglecting their national debt levels. Peop le or nations in need for cash, deficit units, borrow money from people or nations with additional cash, surplus units.They are required to pay a fixed interest payment for their loans. This is riba and is clearly illegal according to Shariah law because it enriches surplus units without any contribution to the real economy. Consequently, people in need for money would take a high risk of becoming even poorer. Compound interest is the big problem that creates money out of thin air. Moreover, the so-called fractional banking system that creates 100. 000 USD out of a 10. 000 USD deposit, 90. 000 USD can be considered fictional money. 1Title: Concept of Money from Islamic Perspective; Class: Islamic Economics [IE1001]; Prof: Dr. Magda Ismail Abdel Mohsin; Institution: INCEIF; Date: 8/16/2006 # Of Pages: 44 IE1001 Assignment in Islamic Economics – Short Essay No 3 by Mustafa Aydemir – DRAFT Version 0. 5. doc -4- The rich is getting richer relatively faster than involvement into the real economy, because money creates more money without work required and Many countries fall into the trap of borrowing money from the International Monetary Funds, in particular Muslim states.The weaknesses of money as a commodity, hit those countries with all its evil as borrowed money doubles, multiplies and compounds. Consequently future generations are affected. The current generation is living in exaggerated prosperity on the cost of many future generations. Money is Islam should not be hoarded and kept in the bank savings account. Instead, money is required to circulate within the economy freely to benefit frequently, continuously, proactively and directly the society at large. This leads to the basic principle of interest prohibition and replaces this Riba system with that of Al-Bay.A system that is very different from Riba. The principle paradigm is risk sharing to allow borrowers and lenders to share rewards. The process of wealth accumulation and distribution in the economy is fair and just and fits the spending (infaq) criteria of Al-Bay suggested by the following verses. â€Å"Those who eat Riba (usury) will not stand on the Day of Resurrection except like the standing of a person beaten by Satan leading him to insanity. That is because they say: â€Å"Al-Bay is only like Riba,† whereas Allah has permitted Al-Bay’ and forbidden Riba.So whosoever receives an admonition from his Lord and stops eating Riba shall not be punished for the past; his case is for Allah (to judge); but whoever returns [to Riba], such are the dwellers of the Fire – they will abide therein. † (2-275) The verse (2-261) states the incentive of spending in the way of Allah swt by counting the great reward and the blessing that an individual get from one single transaction: Then the following verse (2-262) puts the conditions for infaq to be accepted, and that is for Infaq not to be followedIE1001 Assignment in Islamic Economics – Shor t Essay No 3 by Mustafa Aydemir – DRAFT Version 0. 5. doc -5- by Riya (show-off) or by harming anyone or harming the society as a whole. Even if the spending is based on charitable purposes mentioned in verse (2-263), no reminding of it and no harm should be resulted from spending process. Indeed, a kind speech and asking for forgiveness would have better impact. So infaq has to be fully for the sake of Allah swt. (2-264). The consequences of Infaq being not for the sake of Allah are serious as there would be neither Baraka nor growth.Verse (2-265) shapes the objective of spending and is to be for the sake of Allah and his reward so the profile of gain and loss in Infaq is different from the ordinary thinking. In conclusion, the definition of money and the way wealth is accumulated and spend draw a fine line in the distinction of both the conventional versus the Islamic economic system. As money is a medium of exchange, savings does not yield interest income but instead requi re business transactions.Al-Bay as the system of exchange that is based on the concept of spending (Infaq) and risk sharing for any single transaction between parties of exchange. It is notable that Tijarah and Bay are of two different meanings. Tijarah is for the individuals that are setting up the business that has the aspect of long term. It becomes clear that lots of efforts have to be spending in education, elucidation and clarification of the consequences by a simple definition of money. 2 2 This meaning can be clarified by looking verse: (2-282) â€Å"And do not be too weary to write it, whether it is small or arge, for its specified term. That is more just in the sight of Allah and stronger as evidence and more likely to prevent doubt between you, except when it is a Tijarah which you conduct among yourselves. †So we can understand from this verse that Tijarah is among some people that the conduct it among themselves. (61-10) â€Å"O you who have believed, shall I gu ide you to a Tijarah that will save you from a painful punishment? † So, we can sense the longterm involvement in this transaction as Allah swt stated that for in the following 3 verses 11,12 &13. 1 â€Å"It is that you believe in Allah and His Messenger and strive in the cause of Allah with your wealth and your lives. That is best for you, if you should know. †12 â€Å"He will forgive for you your sins and admit you to gardens beneath which rivers flow and pleasant dwellings in gardens of perpetual residence. That is the great attainment. † 13 â€Å"And you will obtain another favor that you love – victory from Allah and an imminent conquest; and give good tidings to the believers. † IE1001 Assignment in Islamic Economics – Short Essay No 3 by Mustafa Aydemir – DRAFT Version 0. 5. doc -6-

Strategy management Essay Example | Topics and Well Written Essays - 1500 words

Strategy management - Essay Example RyanAir is recognized for its rapid expansion due to deregulation of the aviation industry in 1997 in Europe and the notable success of its model, which is the low-cost business model (Palepu, 2007, p. 350). It was established in 1985, and it is the most successful and oldest low-cost airline in Europe. RyanAir was the first European budget airline having modeled itself after the success of Southwest Airlines, which is a low cost carrier in the US (Johnson, Whittington and Scholes, 2011, p. 47). The Porter’s five Forces at RyanAir Competitive Rivalry According to Johnson, Whittington and Scholes (2011, p. 89), due to deregulation, an increase in rivalry and competition on most routes create an overcapacity of various airlines from different competitors. This ultimately leads to an increase of the buyers’ power. As a result, the airlines ultimately try to counter increasing rivalry by forming various acquisitions and mergers as well as periodical and different strategic alliances. A number of airlines maintain a database of frequent flyer program so that they can increase the number of passengers. Airlines also offer discounts and unique offers to frequent flyers to increase customer loyalty. The recession and the US economic downturn combined with overcapacity among different competitors on the North Atlantic routes have forced carriers to concentrate their rivalry on the European countries. This is a significant threat to RyanAir. However, RyanAir has taken advantage over this challenge and has continued to offer low cost flights through an ambitious strategy aimed at reducing the fares further down. This inevitably gives the airline a competitive edge above its competitors (Albers, S., Auerbach, S., Baum, H., and Delfmann, 2005, p. 166). Threat of Entry of New Firms According to Boesch (2007, p. 124), a regulation was passed in the European countries that removed barriers for different and new competitors in the Airline industry. This led to a f ierce completion between newly based competitive airways and existing European based airlines. Landing slots in many European countries were used or reserved by national carriers and this led to scarcity of landing slots to new airlines. Despite the looming threat, the RyanAir has continued to attract more passengers and is opening up more routes to diversify its market share. This is at a time when other competitors are closing shop on some routes. Supplier Power There has always been, a high supplier power in the airline industry since there are only two suppliers of aircrafts, these are Airbus and Boeing. This has led to the high influence of the suppliers playing the dominant role in the industry. The cost of switching from one supplier to another has led to RyanAir retaining pilots and mechanics for usage of other supplier’s products. Fuel price has a direct proportion to the cost of oil and therefore the cost of fuel for RyanAir has been varying because of oil cost fluc tuation. Airport charges are also high therefore, being a significant concern for RyanAir (Johnson, Whittington and Scholes, 2011, p. 71). Buyer Power The buyers can be in charge of the acquiring authority and have additional choices to choose better services from the various airlines. RyanAir is fully aware of this major factor. It is the main reason it has come up with numerous promotions and offers for its customers in order to stay afloat and retain its renowned reputation in the airline in

Collective Security Essay Example | Topics and Well Written Essays - 1500 words

Collective Security - Essay Example It was to be an organization that would use peaceful negotiation to maintain international peace and security. Moreover, it would be an organization where all member states would be bound by the belief that all acts of "aggression and war are crimes against humanity" (Harney), and nations would therefore consider it their duty to desist from and prevent aggression. After any major conflict, prevention of future conflicts is always high on the agenda. To this end, the "favorite technique is to institute measures of co-operation and consultationwith a view to preventing war by moderating and restraining the free-for-all operation of the international anarchy" (Buzan, 163). Thus the setting up of the League of Nations, [and later the United Nations] was a paradigm shift from a policy of national defence to one of collective security. However, the League of Nations failed to achieve its goal of securing international peace and security, amply proven by the fact that the world was at war again within twenty years of its formation. Nevertheless, the failure of League of Nations cannot be called a failure of the idea of collective security. It was more a failure of political will amongst nations to look beyond their own short-term gains in order to make collective security a workable proposition. According to Meg Harney, "While an excellent idea in theory, the League met with repeated problems simply because the nations had not adapted their foreign policy to change to look after, instead of looking after the interests of the League as a whole working unit". The lack of political will among the bigger nations to implement collective security is evident in the stand taken by the big powers vis--vis the League of Nations. The rejection of the Treaty of Versailles by the US and by extension to the League was almost a 'death blow' to the fledging organization. As a result of domestic political compulsions, US President Woodrow Wilson failed to garner the support of the Senate, which according to the US Constitution is the body responsible for ratification of any treaty. The Senate voted against the Treaty and as a result the US did not become a member of the League of Nations. This left Great Britain, France, Italy and Japan as the main powers in the League of Nations. According to Karl Schmidt, "The majority of the British public supported the ideals of the League, but the British government viewed the League largely with indifference". This was largely due to the fact that men like Lloyd George, Stanley Baldwin and Curzon who dominated the government of the day believed in the 'old diplomacy'. Lloyd George preferred, as per Karl Schmidt, "Diplomacy by conference - where the great powers would meet in a less formal setting to discuss problems - to any such system as the League". Apart from this, the British were also affected by the US defection, as they did not want to shoulder the responsibility of single handedly securing the peace in Europe. France supported the League of Nations less for its idealism and more as a tool for securing its own protection. Ever fearful of an attack from Germany, the French leaders saw no difference between its own national security concerns and the League's collective security elements. Italy on the other hand, viewed the League with a certain amount of skepticism, which turned to dislike once Mussolini came to power,

Methodology of a research paper Example | Topics and Well Written Essays - 2000 words

Methodology of a - Research Paper Example basis for drawing the research methodology for the current study is the research onion model, which has been developed and proposed by Saunders as depicted below which reflects that highlights considerations for planning and implementing a particular research methodology initiating from review of possible philosophies supporting different course of research approaches, strategies, and data collection and interpretation methods available for business researches. Furthermore, the chapter also discusses the limitations of the adopted methodology along with the indication of the steps undertaken by the researcher to overcome them. Considering the objective of the study that is to present and discuss the planning carried by event management companies in Bahrain and challenges faced by them in the planning process in relation to the existing literature on the research topic it could be inferred that the outcome of the present study is of qualitative nature and would result in recommendations for event management industry participants of Bahrain. On the basis of this understanding, the research design drawn for the present study is based on a research philosophy referred to as the interpretivist paradigm (Smith, et al., 2009). This research theory supports examination of human experiences, exploring individuals’ perspectives or motivations, and interpreting the outcome of their actions or views. This therefore requires the researcher to understand and interpret the subjectivity and interaction of individuals which affect the behavior of individuals and their motives to take certain actions (Saunders, et a l., 2007). This implies that the present study examines the experiences of individuals involved in planning process in the event management companies operating in Bahrain and evaluating different aspects of planning as discussed in the literature review chapter of this report. The methodology associated with the interpretivist paradigm is of qualitative nature. The

Breaking the Glass Ceiling in Corporate America Research Paper

Breaking the Glass Ceiling in Corporate America - Research Paper Example Also, in Fortune 500 companies only 15 women are present in leadership positions. Black CEOs are even fewer in number, while Hispanics and Blacks constitute 5 to 10% of a renowned law firm’s associates of first year. They also account for only 2% of such firms as partners (Gilgoff 2009). A lot of employers are working to alter these statistics. They are working together with retirement specialists of minority groups who offer help in improving minority professionals to hold leadership positions. Also, prominent business schools are doing the same by including more minorities in leadership positions. A lot more employers in the private and public sectors are coming up with internal strategies to get minorities into senior positions. Within four years, the number of companies that apply to be in the annual magazine, Diversity Inc. ‘Top 50 Companies for Diversity’ column has tripled to over 400. This magazine requires that the minority groups are represented; in orde r, for a company to be considered in the rankings. Also, a lot of companies have come to the realization that minority representation is necessary for any profit making organization. This means that companies working to narrow the gap of minority leaders are not doing so as an act of social justice; rather, they want to improve their rankings (Gilgoff, 2009). It is a challenge to any company to try and maintain a workforce that is diverse. A report compiled recently by the Korn/Ferry International recruiting firm established that U.S. companies are losing $64 billion annually by replacing employees that they lose due to diversity management failing. Also, shortage of leaders in minority groups is presenting... A lot of employers are working to alter these statistics. They are working together with retirement specialists of minority groups who offer help in improving minority professionals to hold leadership positions. Also, prominent business schools are doing the same by including more minorities in leadership positions.   A lot more employers in the private and public sectors are coming up with internal strategies to get minorities into senior positions.   Within four years, the number of companies that apply to be in the annual magazine, Diversity Inc. ‘Top 50 Companies for Diversity’ column has tripled to over 400. This magazine requires that the minority groups are represented; in order, for a company to be considered in the rankings. Also, a lot of companies have come to the realization that minority representation is necessary for any profit making organization. This means that companies working to narrow the gap of minority leaders are not doing so as an act of soc ial justice; rather, they want to improve their rankings (Gilgoff, 2009).It is a challenge to any company to try and maintain a workforce that is diverse. A report compiled recently by the Korn/Ferry International recruiting firm established that U.S. companies are losing $64 billion annually by replacing employees that they lose due to diversity management failing. Also, shortage of leaders in minority groups is presenting great challenges. Minority employees are against working in companies that top jobs seen to be off limits (Gilgoff, 2009).

Customer Relationship Management For The Birmingham New Library Essay

Customer Relationship Management For The Birmingham New Library - Essay Example These strategies are vital for assessing both the internal and external environments, which are favourable or unfavourable to the successful business activities. The researcher incorporated varied marketing strategies vital for enabling the Birmingham Library to accomplish their goals successfully. The researcher provided varied recommendations which the company should take into considerations in order to achieve successful business performance. The action plan was formulated that attempted to reveal the way the objectives of the company will be achieved. Lastly, the conclusion was included that provided a concise summary of the market report. Customer Relationship Management for the Birmingham New Library Introduction The customer relationship management (CRM) has evolved as an effective approach for enabling companies to interact with their customers effectively in order to achieve their business goals successfully. CRM is a business strategy that enables the company to understand the needs of the clients, retain customers through customer experience, reduce management costs and increase profitability (Kangal, 201, p. 45). Senn, Thoma andYip (2013, p.28) defines CRM strategy as the management process accountable for predicting, identifying customers and satisfying their demanding needs for shared benefit. The CRM strategy integrates sales, services, technology solutions; thus it attempts to bring together every part of the business, which touches the client in order to achieve effective business organizational performance. The Birmingham Library is a new library, which is under construction in the Birmingham centre in England; thus employing effective strategy will enable the company to achieve their intended goals. Therefore, employing CRM strategy will be an effective means that will enable the company to assign, create and manage customer requests; thus contributing to effective business performance. The Birmingham Library will employ CRM strategy because this approach often integrates social media services in order to communicate, share customer opinions and experiences; thereby, building up successful customer relationship. Key Objectives The market report aims to examine the marketing strategies vital for increasing performance in the Birmingham Library. It analyses the internal and external factors that may

Business Law - Questions Assignment Example | Topics and Well Written Essays - 750 words - 1

Business Law - Questions - Assignment Example Mostly in the case of online business, an advertisement on a site suffices as â€Å"a formal offer to contract† and it becomes effective once a customer places â€Å"an order and the supplier accepts this† (Trading Online Understanding e-Commerce Contracts 2005). An online contract is enforceable in a court of law provided its terms can be confirmed through the documentation on the website and it explicitly defines the conditions for the sale. The terms and conditions of the contract should be clear, specific and unequivocally stating the jurisdiction. Such an agreement must state: 1. Obligations of both buyer or seller or in other words, the parties to the contract. 2. The amount of payment, the time of payment and the options for the mode of payment. 3. The exact details of the services to be rendered or the commodities to be sold and the dates and modes of delivery or approximate time. Two document used in this study are purchase order and sales order in Online selli ng are:. Standard Purchase Orders: Standard Purchase Order is also a form of contract, which is used to make requisitions for the purchase of goods. The terms and conditions of purchase, price, payment terms, quality specifications, terms of the warranty, location of delivery, delivery date or time etc are usually indicated on the same. Both the seller and buyer are bound to adhere to the conditions and specifications stated in the purchase and these are enforceable in a court of law. The following is a sample of the purchase order: (Picture Courtesy: http://www.ljmu.ac.uk/fin/fin_images/ai_app1.jpg) Element of contract in Purchase order in UK Online Selling are: 1) Acceptance: Seller's beginning of work on the services or goods subject to this purchase order or consignment of such goods, whichever takes place first, shall be deemed as a successful manner of acceptance of the purchase order. 2) Mutual Consent: In order for the contract to become valid, the parties to a particular co ntract

Planning For Clarity (Language Learning) Essay Example | Topics and Well Written Essays - 750 words

Planning For Clarity (Language Learning) - Essay Example The second step has the students interacting with each other while the tutor monitors this session like a referee. The first step when the tutor engages in teaching and interacting the students find an opportunity to loosen their guards from inhibitive apprehensions and become responsive. This is the time when the tutor holds the fort teaching and instructing, questioning and gingerly allowing students to respond to queries. The tutor/students interactions may begin with the tutor allowing students 10% of the time to answer questions. The tutor may then increase the number of questions and gradually extend the question/answers hour to 90%, transferring the session to the second step when the students begin interacting with each other using study material and discussions. It is crucially important to organize the interaction sessions with content rich and well designed study material so that the students get exposure to language learning resources. These study material must be condensed and balanced so that the contents appear neither inadequate nor cluttered. The class must be divided into 3 or 4 groups to allow for group discussions and preparation before the final competition. (Judy Haynes) The SIOP strategy invokes use of first language in the learning process of the second language. This bilingual approach puts the students at ease as they are materially prepared to grasp the second language more easily being acquainted with the lesson contents having understood them from their presentation in their own language. Since the study material are also biliteral, that is, scripted in the first and second languages, all the students have to do is grasp the text and grammar of the second language. The process of application is a workshop involving reading, writing, listening and speaking. The study material must adequately cover all of these. The tutor must allow time for students to learn on trial and error rote. The exercise must allow ample time for students to stir their mental aptitudes with language learning. (Bilingual/ESL Education Program, p7) Conclusion The SIOP strategy makes learning simple and user-friendly. Being connected to the mother tongue, its approach is that of a friendly neighbor. The tutor must adorn the role of the friendly neighbor. It goes without saying that the tutor must be thoroughly conversant with the first and second languages. The students' success totally depends on the tutor's approach with the curriculum and study material providing the vital links in the process. One learns the first language in an informal atmosphere of abandon and care. The process is much the same for the second language. Sources: Bilingual/ESL Education Program, Instructional Model, 15 November, 2005, Updated September 2007, Brownsville Independent School District, Texas, http://www.bisd.us/Bilingual_Education/INSTRUCTIONAL MODEL UPDATED SEPT 2007.pdf Judy Haynes, SIOP: Making Content Comprehensible for ELLs, everythingELS.net,

The Book a Christmas Carol Essay Example for Free

The Book a Christmas Carol Essay In the book A Christmas Carol, by Charles Dickens, the main character, Scrooge, has many experiences with new emotions throughout the book. These new emotions are fear, sadness and happiness. Scrooge gets scared when Marley, his old business partner, who has been dead for seven years, appears as a ghost at his door. Scrooge got so frightened the he slammed his door shut and double locked it. Scrooge was also visited by the ghost of Christmas past and Scrooge is sad to see his childhood. He saw how he was neglected as a child in the past and this contrasted to his new emotional experience. After being visited by three ghosts, Scrooge becomes a very happy man. He instantly becomes a man of joy and changes the ways that he acts about Christmas. Throughout the book, Scrooge feels many emotions, some new and some old emotions. Scrooge gets scared during multiple occasions throughout the book when he see’s Marley’s ghost and his future. Marley’s ghost appears at Scrooge’s door, Scrooge gets very frightened and double locks the door shut. Marley says to Scrooge, â€Å"‘You will be haunted,’ resumed the Ghost, ‘by Three Spirits’â€Å"(Page 18). Scrooge cannot believe what he is seeing and hearing. Marley goes on to say that tomorrow the first spirit will come to visit him. Scrooge meets the ghost of Christmas yet to come and he fears the ghost very much. The ghost shows Scrooge his grave and is very frightened and he also sees how the people react to his death, and nobody cares. Next the ghost shows him how he dies in his future and he is immensely scared of his future. Scrooge is feared by his future that the ghost showed him and he changes his attitude and become a man full of joy. Scrooge is visited by the ghost of Christmas past and he is sad to look back on his childhood. Scrooge awakes in a dark and dismissal room and he believes that he has slept through the day. He counts down to minutes and  then he sees a super natural figure with the body of a child but the face and hair of a man. Scrooge meets the ghost of Christmas past and the ghost says to Scrooge, â€Å"Rise! And walk with me!†(Page 24). The ghost of Christmas past wants him to rise up with him and the ghost will show him his past. The ghost shows Scrooge his childhood and he sees how he was neglected as a child by his friends. Scrooge is very sad to look back on his childhood and to see how he was treated. Scrooge remembers a young boy who came caroling to his door and he never made a donation. Scrooge mutters, â€Å"I wish†(Page 28), putting his hand in his pocket, and looking about him, after drying his eyes with his cuff, â€Å"but it is too late now†(Page 28). Scrooge is very sad that he did not make a donation to the young boy. â€Å"One more shadow!† exclaimed the ghost (Page 36). Scrooge cried, â€Å"No more!†(Page 36), but the ghost forced him to observe what happened next, scrooge was again saddened about what he had seen and told the spirit he could not take it no longer. The ghost of Christmas past showed Scrooge different parts of his past that made Scrooge feel very sad which was a new emotion to Scrooge. After being visited by the three ghost of Christmas, Scrooge becomes a very happy man. Scrooge awakes in his bed after he has seen the last spirit and the three spirits are gone. He awakes very happy on Christmas day full of Christmas spirit. Scrooge runs out to the street and asks a young boy to find him the biggest turkey possible. Then he asked the boy to send it to Bob Cratchits house. Later Scrooge sees a man from his accounting house that he refused to make a donation to. Scrooge then makes a donation to the man because of his new joyful attitude. Scrooge goes to visit his nephew Fred, and he knocks on his door and a very nice girl lets him in. Scrooge yelled, â€Å"Fred/ it’s I. Your Uncle Scrooge. I have come to dinner, will you let me in, Fred† (Page 83-84). After dinner Scrooge went to see Bob Cratchit to raise his salary. Scrooge questioned Bob about why he was there at that time of day. Bob thought he was going to get yelled at by Scrooge but Scrooge said to Bob, â€Å"/I am about to raise your salary!†(Page 84). Bob was shocked to hear Scrooge say that to him, and Bob was extremely happy. After being visited by the three ghost of Christmas, Scrooge turned out to be an amazing man full of joy and Christmas spirit. In the book A Christmas Carol, by Charles Dickens, the main character, Scrooge, has many experiences throughout the play with new emotions such as fear, sadness and happiness. Scrooge becomes very scared when he sees Marley’s ghost, who has been dead for seven years, when he meets the first ghost of Christmas and when the ghost of Christmas yet to come shows him his future. Scrooge was visited by the ghost of Christmas past and Scrooge was extremely sad to look back on his childhood and that he did not make a donation the young boy who was caroling. After being visited by three ghost of Christmas, Scrooge becomes a very happy man full of Christmas spirit. Scrooge feels many new emotions throughout the book and they all lead up to one very good emotion, happiness.

Effect of H1N1 Swine Virus on Humans

Effect of H1N1 Swine Virus on Humans How does the new H1N1 swine virus infect humans compared to the common influenza virus? SUMMARY Pandemic influenza viruses cause significant mortality in humans. In the 20th century, there are 3 influenza viruses which caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. All three aforementioned pandemics were caused by viruses containing human adapted PB2 genes. In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of strain surveillance, the virus spread worldwide to many countries by human-to-human transmission (and perhaps due to the airline travel). In 2 months time, 33 countries had officially reported 5.728 cases resulting in 61 deaths, and by June 2009 WHO reported 30 000 confirmed cases in 74 countries. On June 11 of 2009, this led the World Health Organization (WHO) to raise its pandemic alert to level 5 (Human-to-human spread of the virus into at least 2 countries in 1 WHO region) of 6 (Human-to-human spread of the virus into at least 1 other country in a different WHO region in addition to phase 5 criteria). According to the sayings of Smith et al. (2009), this virus had the potential to develop into the first influenza pandemic of the twenty-first century. In the early summer of 2009, the causes of the human infection and influenza spread among humans had still remained unknown although many publications of that period tried to elucidate this influenza outburst. For example, according to the sayings of Palese, the new H1N1 could also die out entirely. â€Å"Theres a 50-50 chance it will continue to circulate†, he predicts. Conclusively, in that early period, the fuzziness of the data about this new viruss behaviour led scientists only to speculate using past data. Today the 2009 H1N1 virus has ultimately created the first influenza pandemic, has disproportionately affected the younger populations (which perhaps reflects the protection in the elderly due to their exposure to H1N1 strains before 1957), bu t turned out to be not highly pathogenic because the majority of cases of 2009 influenza A H1N1 are mild. Genomic analysis of the 2009 influenza A (H1N1) virus in humans indicates that it is closely related to common reassortant swine influenza A viruses isolated in North America, Europe, and Asia. Therefore, it contains a combination of swine, avian, and human influenza virus genes. More studies need be conducted to identify the unrecognized molecular markers for the ability of S-OIV A (2009 H1N1) to replicate and be transmitted in humans. As a result these additional studies would help us to determine the mechanism by which an animal influenza A virus crossed the species barrier to infect humans. Additionally, these molecular determinants can be used to predict viral virulence and pathogenicity for diagnosis. 1. LITERATURE REVIEW 1.1. Introduction â€Å"Swine flu† †influenza A [Family Orthomyxoviridae (like influenza B and C viruses), Genus Influenzavirus A] is currently the greatest pandemic disease threat to humankind (Salomon and Webster, 2009). The incidence and spread in humans of the â€Å"swine flu† influenza A virus has raised global concerns regarding its virulence and initially regarding its pandemic potential. The main cause of the â€Å"swine flu† has been identified to be the human infection by influenza A viruses of a new H1N1 (hemagglutinin 1, neuraminidase 1) subtype, or â€Å"2009 H1N1 strain† (Soundararajan et al., 2009) that contains genes closely related to swine influenza (SI) [also called swine flu, hog flu and pig flu]. Thus, the strains of virus that cause the annual seasonal flu are different than the new swine flu viruses that emerged in the spring of 2009. Consequently, as it will be analyzed in the subsequent chapters, the new swine flu virus has a unique combinatio n of gene segments from many different sources (a combination that has not been previously reported among swine or human influenza viruses) and specifically is thought to be a mutation of four known strains of the influenza A virus, subtype H1N1: 1. one endemic in (normally infecting) humans, 2. one endemic in birds, 3. and two endemic in pigs (swine). According to Yoon and Janke (2002), the constant evolution of influenza A viruses through mutation and reassortment present a complex and dynamic picture which is to be unfolded in the remaining Literature Review section more specifically for the H1N1 2009 virus. 1.2. Influenza Influenza is historically an ancient disease of global dimension that causes annual epidemics and, at irregular intervals, pandemics. Influenza is an infection of the respiratory tract caused by the influenza virus (see  § 1.3). When compared with the majority of other viral respiratory infections (such as the common cold), the infection by influenza often causes a more severe illness (Smith, 2003). Influenza-like illness (ILI) is defined by the CDC (Centers for Disease Control and Prevention) as fever (with temperature above 37,8 °C) and either cough or some throat in the absence of any other known cause. According to Webster (1999), influenza is the paradigm of a viral disease in which the continued evolution of the virus is of paramount importance for annual epidemics and occasional pandemics of disease in humans which is attributed to the fact that the H1N1 virus does not fit to the strict definition of a new subtype for which most of the population has not any experience of previous infection (Sullivan et al, 2010) as it is justified later in this Literatute Review section ( § 1.8). Influenza is transmitted by inhalation of microdroplets (because the transmission via large-particle droplets requires close contact which is attributed to the fact that these large-particle droplets cannot remain suspended in the air for a long period of time) of respiratory secretions, often expelled by coughing or sneezing, that contain the virus or from other bodily fluids (such as fomites, diarrheal stool etc.). The incubation period is between 1 to 5 days. Symptoms typically include fever, headache, malaise, myalgia, cough, nasal discharge, and sore throat. In severe cases of influenza, a secondary bacterial pneumonia can lead to the death of a patient (Suguitan and Subbarao, 2007). Vaccination and antiviral treatment constitute the two major options for controlling influenza and are the most effective means of preventing influenza virus infection and further transmission in humans. 1.2.1. Pandemic Influenza An influenza pandemic is a large-scale global outbreak of the disease, whereas an epidemic is considered more sporadic and localized. The aforementioned (in the Summary section) situation of pandemic influenza occurs when a previously circulated human influenza A virus [although all the three types (A, B, and C) of influenza viruses can infect humans)] acquires novel antigenic determinants from an animal-origin influenza virus and now can infect and propagate in humans in the absence of any pre-existing immunity (see  § 1.7 for details). Several influenza subtypes have infected humans. Historical accounts led us to consider that an average of three influenza pandemics have occurred each century, at intervals ranging from 10 to 50 years (Garcia-Sastre, 2005). The three influenza pandemics which occurred in the previous (20th) century are: 1. The â€Å"Spanish† influenza pandemic of 1918 (H1N1 subtype), 2. The 1957 â€Å"Asian flu† (H2N2), and 3. The 1968 ‘‘Hong Kong flu (H3N2). These pandemics resulted in high morbidity, death, and also considerable social and economic disruption. They provide health authorities information on which to base preparations for a future pandemic.The first influenza pandemic of the 21st century, due to a new strain of A(H1N1) virus, was declared on 11 June 2009 by the Director-General of the World Health Organization (WHO) [Collin et al., 2009] by raising the H1N1 flu virus pandemic alert level to phase 6 as it was mentioned in the Summary section. Although influenza B viruses do not cause pandemics, during some epidemic years they have caused more significant mortality and morbidity than influenza A viruses (FLUAV) [Garcia-Sastre, 2005]. 1.3. Influenza Virus It was already mentioned that influenza viruses are divided into three types designated A, B, and C (according to the antigenic differences of their internal structural components as it is discussed below in the current chapter). Influenza types A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates for hospitalization and death. As it was mentioned in the previous chapter, influenza A virus has also the capability of developing into pandemic virus. Type C infection usually causes either a sporadic mild or asymptomatic respiratory illness or no symptoms at all (Smith, 2003). In comparison to B and C influenza types which are specific to humans, type A viruses can have different hosts, both birds and different mammals (e.g. horses and pigs) including humans (Ã…sjà ¶a and Kruse, 2007). Specifically, influenza B virus strains appear to infect naturally only humans and have caused epidemics every few years (Schmitt and Lamb, 2005). On the other hand, influenza A viruses are significant animal pathogens of poultry, horses and pigs, and multiple antigenically diverse strains exist in a aquatic wild bird reservoir (Garcia-Sastre, 2005). Migrating aquatic birds carry viruses between the continents and thereby play a key role in the continuing process of virus evolution (Murphy et al., 1999). Influenza C virus causes more limited outbreaks in humans and according to Schmitt and Lamb (2005) also infects pigs. Although influenza viruses belong to the best studied viruses, according to Haller et al. (2008), the molecular determinants, which govern the increased virulence of emerging virus strains in humans and which may be associated with their transmission and transmissibility, are presently not well understood. Influenza viruses are negative-strand RNA[1] viruses with a segmented genome (which replicates in the nucleus of the infected cell) belonging to the Orthomyxoviridae family. The morphology of the influenza virion is described in the next chapter. On the basis of antigenic differences influenza viruses are divided into influenza virus types A, B and C. Influenza A viruses are classified on the basis of the antigenic properties of their haemagglutinin (H or HA) and their neuraminidase (N or NA) structural spike-shaped surface glycoproteins (antigens): to date, 16HA (H1-H16) and 9NA (N1-N9) subtypes have been identified (Osterhaus et al., 2008) which gives a theoretical possibility of 144 serological subtypes. Subtypes of influenza A viruses are constantly undergoing small antigenic modifications (antigenic drift) [which is a serotypic change] due to the accumulation of point mutations in their genetic material. In addition, due to the segmented genome, genetic reassortment occurs perio dically when HA and NA genetic material is exchanged between viruses, thereby causing major antigenic changes (antigenic shift) [Yoon and Janke, 2002], the emergence of a new subtype (Smith, 2003) and perhaps the potential for a pandemic outbreak. Both antigenic shift and drift are discussed in  § 1.7. The family Orthomyxoviridae, except the aforementioned influenza viruses A, B and C, also contains the Thogoto viruses. Thogoto viruses are transmitted by ticks and replicate in both ticks and in mammalian species and are not discussed as part of this assignment (Schmitt and Lamb, 2005). 1.4. Influenza Virus Virion This paragraph describes the (belonging to the Orthomyxoviridae family) virus virion[2] morphology. These virions are spherical or pleomorphic, 80-120 nm in diameter (see 1). Some of them have filamentous forms of several micrometers in length. The virion envelope[3] is derived from cell membrane lipids, incorporating variable numbers of virus glycoproteins (1-3) and nonglycosylated proteins (1-2) [Fauquet et al., 2005]. 1. (Left) Diagram of an Influenza A virus (FLUAV) virion in section. The indicated glycoproteins embedded in the lipid membrane are the trimeric hemagglutinin (HA), which predominates, and the tetrameric neuraminidase (NA). The envelope also contains a small number of M2 membrane ion channel proteins. The internal components are the M1 membrane (matrix) protein and the viral ribonucleoprotein (RNP) consisting of RNA segments, associated nucleocapsid protein (NP), and the PA, PB1 and PB2 polymerase proteins. NS2 (NEP), also a virion protein, is not shown (Fauquet et al., 2005). (Right) Negative contrast electron micrograph of particles of FLUAV. The bar represents 100 nm (Fauquet et al., 2005). The lipid envelope is derived from the plasma membrane of the cell in which the virus replicates and is acquired by a budding process (see  § 1.5) from the cell plasma membrane as one of the last steps of virus assembly and growth (Schmitt and Lamb, 2005) which is initiated by an interaction of the viral proteins. Virion surface glycoprotein projections are 10-14 nm in length and 4-6 nm in diameter. The viral nucleocapsid (NP) is segmented, has helical symmetry, and consists of different size classes, 50-150 nm in length (Fauquet et al., 2005). The nucleocapsid segments (the number of which depends on the virus type) surround the virion envelope which has large glycoprotein peplomers (HA, NA, HE). There are two kinds of glycoprotein peplomers[4]: (1) homotrimers of the hemagglutinin protein (NA) and (2) homotetramers of the neuraminidase protein (NA) [see 1 and 2]. Influenza C viruses have only one type of glycoprotein peplomer, consisting of multifunctional hemagglutinin-esterase molecules (HE) [see  § 1.4.1 for further details]. Genomic segments have a loop at one end and consist of a molecule of viral RNA enclosed within a capsid composed of helically arranged nucleoprotein (NP) as it is shown in 2 (Murphy et al., 1999). 2. Schematic representation of an influenza A virion showing the envelope in which three different types of transmembrane proteins are anchored: the hemagglutinin (HA) and the neuraminidase (NA) form the characteristic peplomers and the M2 protein, which is short and not visible by electron microscopy. Inside the envelope there is a layer of M1 protein that surrounds eight ribonucleoprotein (RNP) structures, each of which consists of one RNA segment covered with nucleoprotein (NP) and associated with the three polymerase (P) proteins (Murphy et al., 1999). The aforementioned in the previous paragraph NP protein (arginine-rich protein of approximately 500 amino acids) is the major structural protein of the eight RNPs and it has been found to be associated with the viral RNA segments. Each NP molecule covers approximately 20 nucleotides of the viral RNAs. The NP mediates the transport of the incoming viral RNPs from the cytoplasm into the nucleus by interacting with the cellular karyopherin/importin transport machinery. In addition, the NP plays an important role during viral RNA synthesis, and free NP molecules are required for full-length viral RNA synthesis, but not for viral mRNA transcription (Palese and Garcia-Sastre, 1998). 1.4.1. Influenza Viral Proteins Influenza A and B viruses possess eight single-stranded negative-sense RNA segments (see 2) that encode structural and nonstructural proteins [NS][5]: 1. Hemagglutinin (HA), a structural surface glycoprotein that mediates viral entry (see  § 1.5 for further details) by binding (the HA1 fragment) to sialic acid residues (present on the cell surface) on host fresh target cells, is the main target of the protective humoral immunity responses in the human host (Suguitan and Subbarao, 2007). HA is primarily responsible for the host range of influenza virus and immunity response of hosts to the infection (Consortium for Influenza Study at Shanghai, 2009). After the binding, the virus is taken up into the cell by endocytosis. At this point, the virus is still separated by the endosomal membrane from the replication and translation machinery of the cell cytoplasm (Fass, 2003). HA is initially synthesized and core-glycosylated in the endoplasmic reticulum (ER)[6] as a 75-79 kDa precursor (HA0) which assembles into noncovalently linked homo-trimers. The trimers are rapidly transported to the Golgi complex and reach the plasma membrane, whe re HA insertion initiates the process of assembly and maturation of the newly formed viral particles (33-35). Just prior to or coincident with insertion into the plasma membrane, each trimer subunit is proteolytically and posttranslationally cleaved into two glycoproteins (polypeptides), HA1 and HA2 ( 3), which remain linked by a disulfide bond (Rossignol et al., 2009) and associated with one another to constitute the mature HA spike (a trimer of heterodimers). In that way, the membrane fusion during infection is promoted. Cleavage activates the hemagglutinin (HA), making it ready to attach to receptors on target cells (Murphy et al., 1999). Conclusively and in addition, the HA undergoes various post-translational modifications during its transport to the plasma membrane, including trimerization, glycosylation, disulfide bond formation, palmitoylation, proteolytic cleavage and conformational changes (Palese and Garcia-Sastre, 1998). HA1 is the subunit distal from the virus envelope, whereas HA2 contains a hydrophobic region near the carboxy terminus that anchors the HA1-HA2 complex in the membrane ( 3) [Fass, 2003]. The HA complex is brought to the cell surface via the secretory pathway and incorporated into virions, along with a section of cell membrane, as the virus buds from the cell. HA1 is the subunit distal from the virus envelope, whereas HA2 contains a hydrophobic region near the carboxy terminus that anchors the HA1-HA2 complex in the membrane (see 3) [Fass, 2003]. 3. Primary structure of influenza HA and spatial organization of subunits with respect to the membrane. Cleavage of the influenza HA precursor protein HA0 yields the two subunits HA1 and HA2. HA1 is white, the fusion peptide and transmembrane segments of HA2 are black, and the remainder of HA2 is cross-hatched. For clarity, a monomer of the HA1-HA2 assembly is shown. The amino and carboxy termini of HA2 are labelled ‘‘N and ‘‘C, respectively (Fass, 2003). 2. Neuraminidase (NA) is the other major surface glycoprotein, whose enzymatic function allows the release of newly formed virions, permits the spread of infectious virus from cell to cell, and keeps newly budding virions from aggregating at the host cell surface. This catalytic function of the NA protein is the target of the anti-influenza virus drugs oseltamivir (Tamiflu[7]) and zanamivir (Relenza7). Although these compounds do not directly prevent the infection of healthy cells, they limit the release of infectious progeny viruses thus inhibiting their spread and shortening the duration of the illness. These NA inhibitors are effective against all NA subtypes among the influenza A viruses and may be the primary antiviral drugs in the event of a future pandemic as it proved true in the current â€Å"swine flu† influenza A outbreak. Antibodies to the NA protein do not neutralize infectivity but are protective (Suguitan and Subbarao, 2007). Influenza C viruses lack an NA protein, and all attachment, entry and receptor destroying activities are performed by the aforementioned single spike glycoprotein: hemagglutinin-esterase-fusion (HEF) protein (Garcia-Sastre, 2005). The HEF protein distinguishes the antigenic variants of the genus C of the Orthomyxoviridae family, and the antibody to HEF protein neutralizes infectivity (Schmitt and Lamb, 2005). Of the three virus types, A and B viruses are much more similar to each other in genome organization and protein homology than to C viruses, which suggests that influenza C virus diverged well before the split between A and B viruses (Webster, 1999). Three proteins comprise the viral polymerase of the influenza viruses: two basic proteins (PB1 and PB2) and an acidic protein (PA). They are present at 30 to 60 copies per virion. The RDRP (RNA-dependent RNA polymerase) complex consists of these 3 polymerase proteins (Lamb and Krug, 2001). Together with the aforementioned scaffold protein NP (helically arranged nucleoprotein), these three polymerase proteins associate with the RNA segments to form ribonucleoprotein (RNP) complexes (Murphy et al., 1999). Thus, the RNPs contain four proteins and RNA. Each subunit of NP associates with approximately 20 bases of RNA (Lamb and Krug, 2001). The RNP strands usually exhibit loops at one end and a periodicity of alternating major and minor grooves, suggesting that the structure is formed by a strand that is folded back on itself and then coiled on itself to form a type of twin-stranded helix (Schmitt and Lamb, 2005). RDRP transcribes the genome RNA segments into messenger RNAs (mRNA). The RDR P complex carries out a complex series of reactions including cap binding, endonucleolytic cleavage, RNA synthesis, and polyadenylation[8]. The PA protein may be involved in viral RNA replication and, in addition, the expression of the PA protein in infected cells has been associated with proteolytic activity. The functional significance of the latter activity is not yet understood (Palese and Garcia-Sastre, 1998). Two viral RNA segments (7 and 8) encode at least two proteins each by alternative splicing. Gene segment 7 (see 4) codes for two proteins: matrix protein M1, which is involved in maintaining the structural integrity of the virion, and M2, an integral membrane (surface) protein that acts as an ion channel and facilitates virus uncoating. It is widely believed that the M1 protein interacts with the cytoplasmic tails of the HA, NA, and M2 (or BM2) proteins and also interacts with the ribonucleoprotein (RNP) structures, thereby organizing the process of virus assembly (Schmitt and Lamb, 2005). The drugs amantadine and rimantadine bind to the influenza A M2 protein and interfere with its ability to transport hydrogen ions into the virion, preventing virus uncoating. Amantadine is only effective against influenza A viruses (Suguitsan and Subbarao, 2007). Therefore, for the antiviral therapy, there are two classes of drugs which are currently available for the chemoprophylaxis and the treatment of influenza (Rossignol et al., 2009). These include the aforementioned NA inhibitors oseltamivir and zanamivir, which impair the efficient release of viruses from the infected host cell, and amantadine and rimantadine, which target the viral M2 protein required for virus uncoating. Passively transferred antibodies to M2 can protect animals against influenza viruses, but such M2-specific antibodies are not consistently detected in human convalescent sera (Black et al., 1993), suggesting that this type of immunity may play a minor role in the clearance of influenza virus in humans. Gene segment 8 (see 4) is responsible for the synthesis of the nonstructural protein NS1 and nuclear export protein (NEP, formerly called NS2) [Murphy et al., 1999] which is a minor structural component of the viral core and that mediates nucleo-cytoplasmic trafficking of the viral genome (Garcia-Sastre, 2005). NEP (NS2) plays a role in the export of RNP from the nucleus to the cytoplasm. NS1 protein suppresses the antiviral mechanism in host cells upon viral infection (Chang et al., 2009) and is involved in modulating the hosts interferon response (Garcia-Sastre, 2005). Recently, an unusual 87-amino acid peptide arising from an alternative reading frame of the PB1 RNA segment has been described (Chen et al., 2001). This protein, PB1-F2, is believed to function in the induction of apoptosis[9] as a means of down-regulating the host immune response to influenza infection. Specifically, it appears to kill host immune cells following influenza virus infection. It has been called the influenza death protein (Chen et al., 2001). PB1 segment encodes this second protein from the +1 reading frame. This protein consists of 87-90 amino acids (depending on the virus strain). This protein is absent in some animal, particularly swine, virus isolates. PB1-F2 protein is not present in all human influenza viruses. Human H1N1 viruses encode a truncated version. However, it is consistently present in viruses known to be of increased virulence in humans, including the viruses that caused the 1918, 1957, and 1968 pandemics. PB1-F2 localizes to mitochondria and treatment of cells with a synthetic PB1-F2 peptide induces apoptosis9 (Neumann et al., 2008). 4. Orthomyxovirus genome organization. The genomic organization and ORFs are shown for genes that encode multiple proteins. Segments encoding the polymerase, hemagglutinin, and nucleoprotein genes are not depicted as each encodes a single protein. (A) Influenza A virus segment 8 showing NS1 and NS2 (NEP) mRNAs and their coding regions. NS1 and NS2 (NEP) share 10 amino-terminal residues, including the initiating methionine. The open reading frame (ORF)[10] of NS2 (NEP) mRNA (nt 529-861) differs from that of NS1. (B) Influenza A virus segment 7 showing M1 and M2 mRNAs and their coding regions. M1 and M2 share 9 amino-terminal residues, including the initiating methionine; however, the ORF of M2 mRNA (nt 740-1004) differs from that of M1. A peptide that could be translated from mRNA has not been found in vivo. (C) Influenza A virus PB1 segment ORFs10. Initiation of PB1 translation is thought to be relatively inefficient based on Kozaks rule[11], likely allowing initiation of PB1-F2 translation by ribosomal scanning (Fauquet et al., 2005). In the same way, the M2 protein is anchored in the viral envelope of the influenza A virus, the ion channel proteins BM2 (it is encoded by a second open reading frame10 of RNA segment 7 of influenza B virus, and its function has not been determined) and CM2 are contained in influenza B and C viruses respectively ( 5). The CM2 protein is most likely generated by cleavage of the precursor protein. The influenza B viruses encode one more transmembrane protein, or NB, of unknown function (Garcia-Sastre, 2005). The cellular receptor for the influenza C virus is known to be the 9-0-acetyl-N-acetylneuraminic acid, and its receptor-destroying enzyme is not an NA, as it was already mentioned, but a neuraminate-O-acetylesterase. Like the HA protein of A and B viruses, the HEF of influenza C viruses must be cleaved in order to exhibit membrane fusion activity (Palese and Garcia-Sastre, 1998). 1.5. Viral Entry Influenza virus infection is spread from cell to cell and from host to host in the form of infectious particles that are assembled and released from infected cells. A series of events must occur for the production of an infectious influenza virus particle, including the organization and concentration of viral proteins at selected sites on the cell plasma membrane, recruitment of a full complement of eight RNP segments to the assembly sites, and the budding and release of particles by membrane fission (Schmitt and Lamb, 2005). Viral entry is a multistep process that follows at ­tachment of the virion to the cellular receptor and re ­sults in deposition of the viral genome (nucleocapsid) in the cytosol[12] (receptor-mediated endocytosis). The entry of enveloped viruses is exemplified by the influenza virus ( 6). The sequential steps in entry include (Nathanson, 2002):  § Attachment of the HA spike [the virus attachment protein (VAP)] to sialic acid receptors (bound to glycoproteins or glycolipids) on the cellu ­lar surface (see  § 1.4.1 for further details). This step contributes to pathogenesis, transmission, and host range restriction.  § Internalization of the virion into an endocytic vacuole.  § Fusion of the endocytic vacuole with a lysosome[13], with marked lowering of the pH (see 6). In endosomes, the low pH-dependent fusion occurs between viral and cell membranes. For influenza viruses, fusion (and infectivity) depends on the cleaved virion HA (FLUAV and FLUBV: HA1, HA2; FLUCV: HEF1, HEF2) [Murphy et al, 1999]. The infectivity and fusion activity are acquired by the post-translational cleavage of the HA of the influenza viruses which is accomplished by cellular proteases. Cleavability depends, among other factors, on the number of basic amino acids at the cleavage site. It produces a hydrophobic amino terminal HA2 molecule (Fauquet et al., 2005). 6. Diagram of the stepwise entry of influenza virus at a cellular level. Key events are attachment of the virion; internalization of the virion by endocytosis; lowering the pH of the endocytic vacuole leading to drastic reconfiguration of the viral attachment protein (hemagglutinin, HA1 and HA2); insertion of a hydrophobic domain of HA2 into the vacuolar membrane; fusion of the viral and vacuolar membranes; release of the viral nu ­cleocapsid into the cytosol (Nathanson, 2002).  § A drastic alteration in the structure of the HA1 trimer, with reorientation of the HA2 peptide to insert its proximal hydrophobic domain into the vacuolar membrane (Nathanson, 2002).  § Fusion of viral and vacuolar membranes (Nathanson, 2002).  § Integral membrane proteins migrate through the Golgi apparatus to localized regions of the plasma membrane (Fauquet et al., 2005).  § New virions form by budding, thereby incorporating matrix protein and the viral nucleocapsids which align below regions of the plasma membrane containing viral envelope proteins. Budding is from the apical surface in polarized cells (Fauquet et al., 2005).  § Release of the viral nucleocapsid into the cy ­tosol: After the formation of fusion pores, viral ribonucleoprotein complexes (RNPs) are delivered into the cytosol. RNPs are then transported into the nucleus, where transcription and replication occurs (see 7) [Garten and Klenk, 2008]. How the replication and the transcription of the genome of influenza virus take place in the nuclei of infected cells is summarized in detail by Palese and Garcia-Sastre (1998) [ 7]. (1) Adsorption: the virus interacts with sialic acid-containing cell receptors via its HA protein, and is intenalized by endosomes. (2) Fusion and uncoating: the HA undergoes a conformational change mediated by the acid environment of the endosome, which leads to the fusion of viral and cellular membranes. The inside of the virus also gets acidified due to proton trafficking through the M2 Ion channel. This acidification is responsible for the separation of the M1 protein from the ribonucleoproteins (RNPs), which are then transported into the nucleus of the host cell thanks to a nuclear localization Signal in the NP. (3) Transcription and replication: the viral RNA (vRNA) is transcribed and replicated in the nucleus by the viral polymerase. Two different species of RNA are synthesized from the vRNA template: (a) full-length copies (cRNA), which are used by the polymerase to produce more vRNA molecules; and (b) mRNA. (4) Translation: following export into the cytoplasm the mRNAs are translated to form viral proteins. The membrane proteins (HA, NA and M2) are transported via the rough endoplasmic reticulum (ER) and Golgi apparatus to the plasma membrane. The viral proteins possessing nuclear signals (PB1, PB2, PA, NP, M1, NS1 and NEP) are transported into the nucleus. (5) Packaging and budding: the newly synthesized NEP protein appears to facilitate the transport of the RNPs from the nucleus into the cytoplasm by bridging the RNPs with the nuclear export machinery. M1-RNP complexes are formed which interact with viral proteins in the plasma membrane. Newly made viruses bud from the host cell membrane (Palese and Garcia-Sastre, 1998). 1.5.1. Sialic Acid Receptors of Influenza Viruses Sialic acids (Sias) are a family of negatively charged 9-carbon sugars typically occ Effect of H1N1 Swine Virus on Humans Effect of H1N1 Swine Virus on Humans How does the new H1N1 swine virus infect humans compared to the common influenza virus? SUMMARY Pandemic influenza viruses cause significant mortality in humans. In the 20th century, there are 3 influenza viruses which caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. All three aforementioned pandemics were caused by viruses containing human adapted PB2 genes. In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of strain surveillance, the virus spread worldwide to many countries by human-to-human transmission (and perhaps due to the airline travel). In 2 months time, 33 countries had officially reported 5.728 cases resulting in 61 deaths, and by June 2009 WHO reported 30 000 confirmed cases in 74 countries. On June 11 of 2009, this led the World Health Organization (WHO) to raise its pandemic alert to level 5 (Human-to-human spread of the virus into at least 2 countries in 1 WHO region) of 6 (Human-to-human spread of the virus into at least 1 other country in a different WHO region in addition to phase 5 criteria). According to the sayings of Smith et al. (2009), this virus had the potential to develop into the first influenza pandemic of the twenty-first century. In the early summer of 2009, the causes of the human infection and influenza spread among humans had still remained unknown although many publications of that period tried to elucidate this influenza outburst. For example, according to the sayings of Palese, the new H1N1 could also die out entirely. â€Å"Theres a 50-50 chance it will continue to circulate†, he predicts. Conclusively, in that early period, the fuzziness of the data about this new viruss behaviour led scientists only to speculate using past data. Today the 2009 H1N1 virus has ultimately created the first influenza pandemic, has disproportionately affected the younger populations (which perhaps reflects the protection in the elderly due to their exposure to H1N1 strains before 1957), bu t turned out to be not highly pathogenic because the majority of cases of 2009 influenza A H1N1 are mild. Genomic analysis of the 2009 influenza A (H1N1) virus in humans indicates that it is closely related to common reassortant swine influenza A viruses isolated in North America, Europe, and Asia. Therefore, it contains a combination of swine, avian, and human influenza virus genes. More studies need be conducted to identify the unrecognized molecular markers for the ability of S-OIV A (2009 H1N1) to replicate and be transmitted in humans. As a result these additional studies would help us to determine the mechanism by which an animal influenza A virus crossed the species barrier to infect humans. Additionally, these molecular determinants can be used to predict viral virulence and pathogenicity for diagnosis. 1. LITERATURE REVIEW 1.1. Introduction â€Å"Swine flu† †influenza A [Family Orthomyxoviridae (like influenza B and C viruses), Genus Influenzavirus A] is currently the greatest pandemic disease threat to humankind (Salomon and Webster, 2009). The incidence and spread in humans of the â€Å"swine flu† influenza A virus has raised global concerns regarding its virulence and initially regarding its pandemic potential. The main cause of the â€Å"swine flu† has been identified to be the human infection by influenza A viruses of a new H1N1 (hemagglutinin 1, neuraminidase 1) subtype, or â€Å"2009 H1N1 strain† (Soundararajan et al., 2009) that contains genes closely related to swine influenza (SI) [also called swine flu, hog flu and pig flu]. Thus, the strains of virus that cause the annual seasonal flu are different than the new swine flu viruses that emerged in the spring of 2009. Consequently, as it will be analyzed in the subsequent chapters, the new swine flu virus has a unique combinatio n of gene segments from many different sources (a combination that has not been previously reported among swine or human influenza viruses) and specifically is thought to be a mutation of four known strains of the influenza A virus, subtype H1N1: 1. one endemic in (normally infecting) humans, 2. one endemic in birds, 3. and two endemic in pigs (swine). According to Yoon and Janke (2002), the constant evolution of influenza A viruses through mutation and reassortment present a complex and dynamic picture which is to be unfolded in the remaining Literature Review section more specifically for the H1N1 2009 virus. 1.2. Influenza Influenza is historically an ancient disease of global dimension that causes annual epidemics and, at irregular intervals, pandemics. Influenza is an infection of the respiratory tract caused by the influenza virus (see  § 1.3). When compared with the majority of other viral respiratory infections (such as the common cold), the infection by influenza often causes a more severe illness (Smith, 2003). Influenza-like illness (ILI) is defined by the CDC (Centers for Disease Control and Prevention) as fever (with temperature above 37,8 °C) and either cough or some throat in the absence of any other known cause. According to Webster (1999), influenza is the paradigm of a viral disease in which the continued evolution of the virus is of paramount importance for annual epidemics and occasional pandemics of disease in humans which is attributed to the fact that the H1N1 virus does not fit to the strict definition of a new subtype for which most of the population has not any experience of previous infection (Sullivan et al, 2010) as it is justified later in this Literatute Review section ( § 1.8). Influenza is transmitted by inhalation of microdroplets (because the transmission via large-particle droplets requires close contact which is attributed to the fact that these large-particle droplets cannot remain suspended in the air for a long period of time) of respiratory secretions, often expelled by coughing or sneezing, that contain the virus or from other bodily fluids (such as fomites, diarrheal stool etc.). The incubation period is between 1 to 5 days. Symptoms typically include fever, headache, malaise, myalgia, cough, nasal discharge, and sore throat. In severe cases of influenza, a secondary bacterial pneumonia can lead to the death of a patient (Suguitan and Subbarao, 2007). Vaccination and antiviral treatment constitute the two major options for controlling influenza and are the most effective means of preventing influenza virus infection and further transmission in humans. 1.2.1. Pandemic Influenza An influenza pandemic is a large-scale global outbreak of the disease, whereas an epidemic is considered more sporadic and localized. The aforementioned (in the Summary section) situation of pandemic influenza occurs when a previously circulated human influenza A virus [although all the three types (A, B, and C) of influenza viruses can infect humans)] acquires novel antigenic determinants from an animal-origin influenza virus and now can infect and propagate in humans in the absence of any pre-existing immunity (see  § 1.7 for details). Several influenza subtypes have infected humans. Historical accounts led us to consider that an average of three influenza pandemics have occurred each century, at intervals ranging from 10 to 50 years (Garcia-Sastre, 2005). The three influenza pandemics which occurred in the previous (20th) century are: 1. The â€Å"Spanish† influenza pandemic of 1918 (H1N1 subtype), 2. The 1957 â€Å"Asian flu† (H2N2), and 3. The 1968 ‘‘Hong Kong flu (H3N2). These pandemics resulted in high morbidity, death, and also considerable social and economic disruption. They provide health authorities information on which to base preparations for a future pandemic.The first influenza pandemic of the 21st century, due to a new strain of A(H1N1) virus, was declared on 11 June 2009 by the Director-General of the World Health Organization (WHO) [Collin et al., 2009] by raising the H1N1 flu virus pandemic alert level to phase 6 as it was mentioned in the Summary section. Although influenza B viruses do not cause pandemics, during some epidemic years they have caused more significant mortality and morbidity than influenza A viruses (FLUAV) [Garcia-Sastre, 2005]. 1.3. Influenza Virus It was already mentioned that influenza viruses are divided into three types designated A, B, and C (according to the antigenic differences of their internal structural components as it is discussed below in the current chapter). Influenza types A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates for hospitalization and death. As it was mentioned in the previous chapter, influenza A virus has also the capability of developing into pandemic virus. Type C infection usually causes either a sporadic mild or asymptomatic respiratory illness or no symptoms at all (Smith, 2003). In comparison to B and C influenza types which are specific to humans, type A viruses can have different hosts, both birds and different mammals (e.g. horses and pigs) including humans (Ã…sjà ¶a and Kruse, 2007). Specifically, influenza B virus strains appear to infect naturally only humans and have caused epidemics every few years (Schmitt and Lamb, 2005). On the other hand, influenza A viruses are significant animal pathogens of poultry, horses and pigs, and multiple antigenically diverse strains exist in a aquatic wild bird reservoir (Garcia-Sastre, 2005). Migrating aquatic birds carry viruses between the continents and thereby play a key role in the continuing process of virus evolution (Murphy et al., 1999). Influenza C virus causes more limited outbreaks in humans and according to Schmitt and Lamb (2005) also infects pigs. Although influenza viruses belong to the best studied viruses, according to Haller et al. (2008), the molecular determinants, which govern the increased virulence of emerging virus strains in humans and which may be associated with their transmission and transmissibility, are presently not well understood. Influenza viruses are negative-strand RNA[1] viruses with a segmented genome (which replicates in the nucleus of the infected cell) belonging to the Orthomyxoviridae family. The morphology of the influenza virion is described in the next chapter. On the basis of antigenic differences influenza viruses are divided into influenza virus types A, B and C. Influenza A viruses are classified on the basis of the antigenic properties of their haemagglutinin (H or HA) and their neuraminidase (N or NA) structural spike-shaped surface glycoproteins (antigens): to date, 16HA (H1-H16) and 9NA (N1-N9) subtypes have been identified (Osterhaus et al., 2008) which gives a theoretical possibility of 144 serological subtypes. Subtypes of influenza A viruses are constantly undergoing small antigenic modifications (antigenic drift) [which is a serotypic change] due to the accumulation of point mutations in their genetic material. In addition, due to the segmented genome, genetic reassortment occurs perio dically when HA and NA genetic material is exchanged between viruses, thereby causing major antigenic changes (antigenic shift) [Yoon and Janke, 2002], the emergence of a new subtype (Smith, 2003) and perhaps the potential for a pandemic outbreak. Both antigenic shift and drift are discussed in  § 1.7. The family Orthomyxoviridae, except the aforementioned influenza viruses A, B and C, also contains the Thogoto viruses. Thogoto viruses are transmitted by ticks and replicate in both ticks and in mammalian species and are not discussed as part of this assignment (Schmitt and Lamb, 2005). 1.4. Influenza Virus Virion This paragraph describes the (belonging to the Orthomyxoviridae family) virus virion[2] morphology. These virions are spherical or pleomorphic, 80-120 nm in diameter (see 1). Some of them have filamentous forms of several micrometers in length. The virion envelope[3] is derived from cell membrane lipids, incorporating variable numbers of virus glycoproteins (1-3) and nonglycosylated proteins (1-2) [Fauquet et al., 2005]. 1. (Left) Diagram of an Influenza A virus (FLUAV) virion in section. The indicated glycoproteins embedded in the lipid membrane are the trimeric hemagglutinin (HA), which predominates, and the tetrameric neuraminidase (NA). The envelope also contains a small number of M2 membrane ion channel proteins. The internal components are the M1 membrane (matrix) protein and the viral ribonucleoprotein (RNP) consisting of RNA segments, associated nucleocapsid protein (NP), and the PA, PB1 and PB2 polymerase proteins. NS2 (NEP), also a virion protein, is not shown (Fauquet et al., 2005). (Right) Negative contrast electron micrograph of particles of FLUAV. The bar represents 100 nm (Fauquet et al., 2005). The lipid envelope is derived from the plasma membrane of the cell in which the virus replicates and is acquired by a budding process (see  § 1.5) from the cell plasma membrane as one of the last steps of virus assembly and growth (Schmitt and Lamb, 2005) which is initiated by an interaction of the viral proteins. Virion surface glycoprotein projections are 10-14 nm in length and 4-6 nm in diameter. The viral nucleocapsid (NP) is segmented, has helical symmetry, and consists of different size classes, 50-150 nm in length (Fauquet et al., 2005). The nucleocapsid segments (the number of which depends on the virus type) surround the virion envelope which has large glycoprotein peplomers (HA, NA, HE). There are two kinds of glycoprotein peplomers[4]: (1) homotrimers of the hemagglutinin protein (NA) and (2) homotetramers of the neuraminidase protein (NA) [see 1 and 2]. Influenza C viruses have only one type of glycoprotein peplomer, consisting of multifunctional hemagglutinin-esterase molecules (HE) [see  § 1.4.1 for further details]. Genomic segments have a loop at one end and consist of a molecule of viral RNA enclosed within a capsid composed of helically arranged nucleoprotein (NP) as it is shown in 2 (Murphy et al., 1999). 2. Schematic representation of an influenza A virion showing the envelope in which three different types of transmembrane proteins are anchored: the hemagglutinin (HA) and the neuraminidase (NA) form the characteristic peplomers and the M2 protein, which is short and not visible by electron microscopy. Inside the envelope there is a layer of M1 protein that surrounds eight ribonucleoprotein (RNP) structures, each of which consists of one RNA segment covered with nucleoprotein (NP) and associated with the three polymerase (P) proteins (Murphy et al., 1999). The aforementioned in the previous paragraph NP protein (arginine-rich protein of approximately 500 amino acids) is the major structural protein of the eight RNPs and it has been found to be associated with the viral RNA segments. Each NP molecule covers approximately 20 nucleotides of the viral RNAs. The NP mediates the transport of the incoming viral RNPs from the cytoplasm into the nucleus by interacting with the cellular karyopherin/importin transport machinery. In addition, the NP plays an important role during viral RNA synthesis, and free NP molecules are required for full-length viral RNA synthesis, but not for viral mRNA transcription (Palese and Garcia-Sastre, 1998). 1.4.1. Influenza Viral Proteins Influenza A and B viruses possess eight single-stranded negative-sense RNA segments (see 2) that encode structural and nonstructural proteins [NS][5]: 1. Hemagglutinin (HA), a structural surface glycoprotein that mediates viral entry (see  § 1.5 for further details) by binding (the HA1 fragment) to sialic acid residues (present on the cell surface) on host fresh target cells, is the main target of the protective humoral immunity responses in the human host (Suguitan and Subbarao, 2007). HA is primarily responsible for the host range of influenza virus and immunity response of hosts to the infection (Consortium for Influenza Study at Shanghai, 2009). After the binding, the virus is taken up into the cell by endocytosis. At this point, the virus is still separated by the endosomal membrane from the replication and translation machinery of the cell cytoplasm (Fass, 2003). HA is initially synthesized and core-glycosylated in the endoplasmic reticulum (ER)[6] as a 75-79 kDa precursor (HA0) which assembles into noncovalently linked homo-trimers. The trimers are rapidly transported to the Golgi complex and reach the plasma membrane, whe re HA insertion initiates the process of assembly and maturation of the newly formed viral particles (33-35). Just prior to or coincident with insertion into the plasma membrane, each trimer subunit is proteolytically and posttranslationally cleaved into two glycoproteins (polypeptides), HA1 and HA2 ( 3), which remain linked by a disulfide bond (Rossignol et al., 2009) and associated with one another to constitute the mature HA spike (a trimer of heterodimers). In that way, the membrane fusion during infection is promoted. Cleavage activates the hemagglutinin (HA), making it ready to attach to receptors on target cells (Murphy et al., 1999). Conclusively and in addition, the HA undergoes various post-translational modifications during its transport to the plasma membrane, including trimerization, glycosylation, disulfide bond formation, palmitoylation, proteolytic cleavage and conformational changes (Palese and Garcia-Sastre, 1998). HA1 is the subunit distal from the virus envelope, whereas HA2 contains a hydrophobic region near the carboxy terminus that anchors the HA1-HA2 complex in the membrane ( 3) [Fass, 2003]. The HA complex is brought to the cell surface via the secretory pathway and incorporated into virions, along with a section of cell membrane, as the virus buds from the cell. HA1 is the subunit distal from the virus envelope, whereas HA2 contains a hydrophobic region near the carboxy terminus that anchors the HA1-HA2 complex in the membrane (see 3) [Fass, 2003]. 3. Primary structure of influenza HA and spatial organization of subunits with respect to the membrane. Cleavage of the influenza HA precursor protein HA0 yields the two subunits HA1 and HA2. HA1 is white, the fusion peptide and transmembrane segments of HA2 are black, and the remainder of HA2 is cross-hatched. For clarity, a monomer of the HA1-HA2 assembly is shown. The amino and carboxy termini of HA2 are labelled ‘‘N and ‘‘C, respectively (Fass, 2003). 2. Neuraminidase (NA) is the other major surface glycoprotein, whose enzymatic function allows the release of newly formed virions, permits the spread of infectious virus from cell to cell, and keeps newly budding virions from aggregating at the host cell surface. This catalytic function of the NA protein is the target of the anti-influenza virus drugs oseltamivir (Tamiflu[7]) and zanamivir (Relenza7). Although these compounds do not directly prevent the infection of healthy cells, they limit the release of infectious progeny viruses thus inhibiting their spread and shortening the duration of the illness. These NA inhibitors are effective against all NA subtypes among the influenza A viruses and may be the primary antiviral drugs in the event of a future pandemic as it proved true in the current â€Å"swine flu† influenza A outbreak. Antibodies to the NA protein do not neutralize infectivity but are protective (Suguitan and Subbarao, 2007). Influenza C viruses lack an NA protein, and all attachment, entry and receptor destroying activities are performed by the aforementioned single spike glycoprotein: hemagglutinin-esterase-fusion (HEF) protein (Garcia-Sastre, 2005). The HEF protein distinguishes the antigenic variants of the genus C of the Orthomyxoviridae family, and the antibody to HEF protein neutralizes infectivity (Schmitt and Lamb, 2005). Of the three virus types, A and B viruses are much more similar to each other in genome organization and protein homology than to C viruses, which suggests that influenza C virus diverged well before the split between A and B viruses (Webster, 1999). Three proteins comprise the viral polymerase of the influenza viruses: two basic proteins (PB1 and PB2) and an acidic protein (PA). They are present at 30 to 60 copies per virion. The RDRP (RNA-dependent RNA polymerase) complex consists of these 3 polymerase proteins (Lamb and Krug, 2001). Together with the aforementioned scaffold protein NP (helically arranged nucleoprotein), these three polymerase proteins associate with the RNA segments to form ribonucleoprotein (RNP) complexes (Murphy et al., 1999). Thus, the RNPs contain four proteins and RNA. Each subunit of NP associates with approximately 20 bases of RNA (Lamb and Krug, 2001). The RNP strands usually exhibit loops at one end and a periodicity of alternating major and minor grooves, suggesting that the structure is formed by a strand that is folded back on itself and then coiled on itself to form a type of twin-stranded helix (Schmitt and Lamb, 2005). RDRP transcribes the genome RNA segments into messenger RNAs (mRNA). The RDR P complex carries out a complex series of reactions including cap binding, endonucleolytic cleavage, RNA synthesis, and polyadenylation[8]. The PA protein may be involved in viral RNA replication and, in addition, the expression of the PA protein in infected cells has been associated with proteolytic activity. The functional significance of the latter activity is not yet understood (Palese and Garcia-Sastre, 1998). Two viral RNA segments (7 and 8) encode at least two proteins each by alternative splicing. Gene segment 7 (see 4) codes for two proteins: matrix protein M1, which is involved in maintaining the structural integrity of the virion, and M2, an integral membrane (surface) protein that acts as an ion channel and facilitates virus uncoating. It is widely believed that the M1 protein interacts with the cytoplasmic tails of the HA, NA, and M2 (or BM2) proteins and also interacts with the ribonucleoprotein (RNP) structures, thereby organizing the process of virus assembly (Schmitt and Lamb, 2005). The drugs amantadine and rimantadine bind to the influenza A M2 protein and interfere with its ability to transport hydrogen ions into the virion, preventing virus uncoating. Amantadine is only effective against influenza A viruses (Suguitsan and Subbarao, 2007). Therefore, for the antiviral therapy, there are two classes of drugs which are currently available for the chemoprophylaxis and the treatment of influenza (Rossignol et al., 2009). These include the aforementioned NA inhibitors oseltamivir and zanamivir, which impair the efficient release of viruses from the infected host cell, and amantadine and rimantadine, which target the viral M2 protein required for virus uncoating. Passively transferred antibodies to M2 can protect animals against influenza viruses, but such M2-specific antibodies are not consistently detected in human convalescent sera (Black et al., 1993), suggesting that this type of immunity may play a minor role in the clearance of influenza virus in humans. Gene segment 8 (see 4) is responsible for the synthesis of the nonstructural protein NS1 and nuclear export protein (NEP, formerly called NS2) [Murphy et al., 1999] which is a minor structural component of the viral core and that mediates nucleo-cytoplasmic trafficking of the viral genome (Garcia-Sastre, 2005). NEP (NS2) plays a role in the export of RNP from the nucleus to the cytoplasm. NS1 protein suppresses the antiviral mechanism in host cells upon viral infection (Chang et al., 2009) and is involved in modulating the hosts interferon response (Garcia-Sastre, 2005). Recently, an unusual 87-amino acid peptide arising from an alternative reading frame of the PB1 RNA segment has been described (Chen et al., 2001). This protein, PB1-F2, is believed to function in the induction of apoptosis[9] as a means of down-regulating the host immune response to influenza infection. Specifically, it appears to kill host immune cells following influenza virus infection. It has been called the influenza death protein (Chen et al., 2001). PB1 segment encodes this second protein from the +1 reading frame. This protein consists of 87-90 amino acids (depending on the virus strain). This protein is absent in some animal, particularly swine, virus isolates. PB1-F2 protein is not present in all human influenza viruses. Human H1N1 viruses encode a truncated version. However, it is consistently present in viruses known to be of increased virulence in humans, including the viruses that caused the 1918, 1957, and 1968 pandemics. PB1-F2 localizes to mitochondria and treatment of cells with a synthetic PB1-F2 peptide induces apoptosis9 (Neumann et al., 2008). 4. Orthomyxovirus genome organization. The genomic organization and ORFs are shown for genes that encode multiple proteins. Segments encoding the polymerase, hemagglutinin, and nucleoprotein genes are not depicted as each encodes a single protein. (A) Influenza A virus segment 8 showing NS1 and NS2 (NEP) mRNAs and their coding regions. NS1 and NS2 (NEP) share 10 amino-terminal residues, including the initiating methionine. The open reading frame (ORF)[10] of NS2 (NEP) mRNA (nt 529-861) differs from that of NS1. (B) Influenza A virus segment 7 showing M1 and M2 mRNAs and their coding regions. M1 and M2 share 9 amino-terminal residues, including the initiating methionine; however, the ORF of M2 mRNA (nt 740-1004) differs from that of M1. A peptide that could be translated from mRNA has not been found in vivo. (C) Influenza A virus PB1 segment ORFs10. Initiation of PB1 translation is thought to be relatively inefficient based on Kozaks rule[11], likely allowing initiation of PB1-F2 translation by ribosomal scanning (Fauquet et al., 2005). In the same way, the M2 protein is anchored in the viral envelope of the influenza A virus, the ion channel proteins BM2 (it is encoded by a second open reading frame10 of RNA segment 7 of influenza B virus, and its function has not been determined) and CM2 are contained in influenza B and C viruses respectively ( 5). The CM2 protein is most likely generated by cleavage of the precursor protein. The influenza B viruses encode one more transmembrane protein, or NB, of unknown function (Garcia-Sastre, 2005). The cellular receptor for the influenza C virus is known to be the 9-0-acetyl-N-acetylneuraminic acid, and its receptor-destroying enzyme is not an NA, as it was already mentioned, but a neuraminate-O-acetylesterase. Like the HA protein of A and B viruses, the HEF of influenza C viruses must be cleaved in order to exhibit membrane fusion activity (Palese and Garcia-Sastre, 1998). 1.5. Viral Entry Influenza virus infection is spread from cell to cell and from host to host in the form of infectious particles that are assembled and released from infected cells. A series of events must occur for the production of an infectious influenza virus particle, including the organization and concentration of viral proteins at selected sites on the cell plasma membrane, recruitment of a full complement of eight RNP segments to the assembly sites, and the budding and release of particles by membrane fission (Schmitt and Lamb, 2005). Viral entry is a multistep process that follows at ­tachment of the virion to the cellular receptor and re ­sults in deposition of the viral genome (nucleocapsid) in the cytosol[12] (receptor-mediated endocytosis). The entry of enveloped viruses is exemplified by the influenza virus ( 6). The sequential steps in entry include (Nathanson, 2002):  § Attachment of the HA spike [the virus attachment protein (VAP)] to sialic acid receptors (bound to glycoproteins or glycolipids) on the cellu ­lar surface (see  § 1.4.1 for further details). This step contributes to pathogenesis, transmission, and host range restriction.  § Internalization of the virion into an endocytic vacuole.  § Fusion of the endocytic vacuole with a lysosome[13], with marked lowering of the pH (see 6). In endosomes, the low pH-dependent fusion occurs between viral and cell membranes. For influenza viruses, fusion (and infectivity) depends on the cleaved virion HA (FLUAV and FLUBV: HA1, HA2; FLUCV: HEF1, HEF2) [Murphy et al, 1999]. The infectivity and fusion activity are acquired by the post-translational cleavage of the HA of the influenza viruses which is accomplished by cellular proteases. Cleavability depends, among other factors, on the number of basic amino acids at the cleavage site. It produces a hydrophobic amino terminal HA2 molecule (Fauquet et al., 2005). 6. Diagram of the stepwise entry of influenza virus at a cellular level. Key events are attachment of the virion; internalization of the virion by endocytosis; lowering the pH of the endocytic vacuole leading to drastic reconfiguration of the viral attachment protein (hemagglutinin, HA1 and HA2); insertion of a hydrophobic domain of HA2 into the vacuolar membrane; fusion of the viral and vacuolar membranes; release of the viral nu ­cleocapsid into the cytosol (Nathanson, 2002).  § A drastic alteration in the structure of the HA1 trimer, with reorientation of the HA2 peptide to insert its proximal hydrophobic domain into the vacuolar membrane (Nathanson, 2002).  § Fusion of viral and vacuolar membranes (Nathanson, 2002).  § Integral membrane proteins migrate through the Golgi apparatus to localized regions of the plasma membrane (Fauquet et al., 2005).  § New virions form by budding, thereby incorporating matrix protein and the viral nucleocapsids which align below regions of the plasma membrane containing viral envelope proteins. Budding is from the apical surface in polarized cells (Fauquet et al., 2005).  § Release of the viral nucleocapsid into the cy ­tosol: After the formation of fusion pores, viral ribonucleoprotein complexes (RNPs) are delivered into the cytosol. RNPs are then transported into the nucleus, where transcription and replication occurs (see 7) [Garten and Klenk, 2008]. How the replication and the transcription of the genome of influenza virus take place in the nuclei of infected cells is summarized in detail by Palese and Garcia-Sastre (1998) [ 7]. (1) Adsorption: the virus interacts with sialic acid-containing cell receptors via its HA protein, and is intenalized by endosomes. (2) Fusion and uncoating: the HA undergoes a conformational change mediated by the acid environment of the endosome, which leads to the fusion of viral and cellular membranes. The inside of the virus also gets acidified due to proton trafficking through the M2 Ion channel. This acidification is responsible for the separation of the M1 protein from the ribonucleoproteins (RNPs), which are then transported into the nucleus of the host cell thanks to a nuclear localization Signal in the NP. (3) Transcription and replication: the viral RNA (vRNA) is transcribed and replicated in the nucleus by the viral polymerase. Two different species of RNA are synthesized from the vRNA template: (a) full-length copies (cRNA), which are used by the polymerase to produce more vRNA molecules; and (b) mRNA. (4) Translation: following export into the cytoplasm the mRNAs are translated to form viral proteins. The membrane proteins (HA, NA and M2) are transported via the rough endoplasmic reticulum (ER) and Golgi apparatus to the plasma membrane. The viral proteins possessing nuclear signals (PB1, PB2, PA, NP, M1, NS1 and NEP) are transported into the nucleus. (5) Packaging and budding: the newly synthesized NEP protein appears to facilitate the transport of the RNPs from the nucleus into the cytoplasm by bridging the RNPs with the nuclear export machinery. M1-RNP complexes are formed which interact with viral proteins in the plasma membrane. Newly made viruses bud from the host cell membrane (Palese and Garcia-Sastre, 1998). 1.5.1. Sialic Acid Receptors of Influenza Viruses Sialic acids (Sias) are a family of negatively charged 9-carbon sugars typically occ