Cultural Aging

This paper is designed to illustrate a cultural or ethnic group of my choosing and how they feel about the aging process. Also, to give detail of their background, their perspective and how it coordinates with the group, how they feel it effects aging on the older population, the elderly role in this cultural or ethnic group and and historical information in the group perspective if they immigrated in the United States. Within my findings I found out that African American woman (in particular) are concerned with aging but are not as concerned as Caucasian women. Being that African Americans have more melanin in their skin, wrinkles are not as common at the age of 65 as it would be of women who are the same age but of the Caucasian race. For my paper on the perspectives, I chose to research African Americans and take a look in to how they perceive aging, how they feel it effects aging on the older population, their roles and if there are any historical changes in their perspective. Most African Americans are the descendants of captive Africans held in the United States from 1619 to 1865. Blacks from the Caribbean whose ancestors immigrated, or who immigrated to the United States, also traditionally have been considered African American, as they share a common history of predominantly central Africans roots or west African, the middle passage and slavery. In the past, it was these people who were referred to and self-identified collectively as the American Negro, who now generally consider themselves African Americans. The history of African Americans are highlighted and celebrated annually in the United States during February, which is respectfully known as Black History month, and their history is the sole focus that time. Others who some times are Americans who descended from slaves, are referred to as African Americans, and who may self identify as such in United States government censuses, include relatively recent black immigrants from Africa, South America and elsewhere who self-identify as of African descent. A big percentage of African Americans descended from slaves, most of which were sold by African states or kidnapped by African, Arab, European or American slave traders. The existing market for slaves in Africa was exploited and expanded by European powers in search of free free labor for New World plantations. Are African Americans less concerned with the consequences of aging? Let's take the cosmetic world for example to emphasize my points to come. The cosmetic world is filled with all sorts of products designed to keep women (and occasionally men) look (and feeling) young. The products are primarily geared towards skin care and more specified for wrinkles. Let's take a look at cosmetic commercials and ads, you mist find something very interesting: there are few black women. Of course, there are women of different ethnic groups, which by way of sending a message that all women, no matter ethnicity are concerned with aging. For the most part, it seems that Caucasian women (more so than black women) are concerned about the aging process. To aid in my point, I'll use the statistics from the Society of Plastic Surgeons that proves that African Americans are still one of the smaller groups requesting plastic surgery. Whites account for 69% while blacks have only 8%. There is a very popular phrase within the African American community affirming that â€Å"black don't crack†. This phrase is an exact implication that African Americans typically look younger in age versus other ethnic groups, mainly the white ethnic group. A person's physical health, one's lifestyle and health definitely play a role in this. It is usually quite common for people to mistake a black women who may be 65 and be mistaken for 55 and for women in their 40's to be mistaken as being in their 30's (Yeo, 2001). The most common and scientifically proven reason for this is because African Americans typically have more melanin that a person has in their skin, the more complex it is for the skin's harmful rays to penetrate, creating wrinkles, spots, lines and other anomalies. For some reason, it has not been until recently that cosmetic companies begun targeting African-American women for anti-aging products. In a 2006 article in Essence magazine, it purports that the cosmetic industry in general has seen a marked increase in toiletries and cosmetic advertising in general, marketers choosing non-black publications to reach an additional demographic. â€Å"The myth is that women of color don't care about aging,† the president of Essence, Michelle Ebanks has stated. â€Å"We don't wrinkly as early, but we care about it†. That confirms it! That statement is a pure indication that black women are just as concerned about their aging physical appearance as other ethnic groups. However, Ebanks also shed great insight on another important note; women of color are more likely to share information about beauty products by word of mouth, rather than through heavy media commentary. This in and of itself may give the impression that black women are less concerned with aging. The general theory that black women give birth at a younger age than other ethnic groups also might have a little something to do with the perception that they care less about aging (Yeo, 2001). While this may sound stilted and just outrageous, do consider the fact that if a woman gives birth to her first child by the age of 20, by the time that child is able to enter college, the mother is still at her youthful age, barely reaching 40. If this birth cycle (or similar variations of it) continues, then the mother will be able to call herself â€Å"Grandma† before she even reaches the age of 50. Although, black women who become grandmothers rather early very often feel less inclined to be concerned with aging; because they have already completed a life cycle that others take many years to establish. It could be said that as stigma of young motherhood becomes more irrelevant, so do the women's concerns about growing old. The elderly are treated with high regard and respect in the African American community. Those women who enter this â€Å"elder† phase of life early (25 to 38 years old) feel the pressure of role conflict and tension in the social support they receive(Dorthy, 2004). They perceive grand parenthood as a â€Å"tenuous† role. Those who enter grand parenthood â€Å"on time† (42 to 57 years old) have less conflict but can also feel the pressure of integrating family and occupational roles(Ada, 1998). Women in this age usually occupy a traditional family role, that â€Å"lofty† and respected position of a grandmother. She is also the nurturer and disciplinarian of children, the family historian, the hub of the family network in which decisions are made, and the convener of family events.

Buddhism: Religion or Philosophy?

Whether or not Buddhism is a religion revolves around the contestation of whether or not it is a philosophy instead. This presents myriad problems of logic, as even the definitions of religion and philosophy are themselves a point of contestation. There is the school of thought that defines religion as a belief system, a firm ascription to a set of rules and utmost truths that therefore make religion of whatever kind dogmatic. To use this definition is to make Buddhism anything but a religion, as Buddhism essentially discourages any sense of rigidity in any belief system.It even does not advocate the supremacy of its own doctrines – the 4 noble truths, the 5 Skandhas, the eight-fold path. There are no parameters. The other thought line on religion defines it as a search for transcendence; a quest for an existence, purpose and authority higher than oneself, as advocated by the likes of Karen Armstrong. In this sense, Buddhism is a religion because it seeks to bring those who pr actice it to a new, profound realization of themselves and the world around them; to ‘see the world as it is’, which is the Buddhist idea of ‘realization’.This probably explains why there are quite a number of brands of Buddhism. Still, others wonder why anyone should be distinguishing between religion and philosophy. According to some, this distinction is a fairly new phenomenon, as recent as the 18th century. Throughout history, it is argued, philosophy and religion have been intertwined; take Plato’s Euthyphro for example. In it, the virtue of piety is inextricably argued from a standpoint of what ‘the gods’ believe is right or wrong, even though the whole discourse follows logic.Similar observations can be made in the Epistles of Apostle Paul in the New Testament. Distinguishing the two, it is said, betrays our own biases rather than clarifies things. Dogmatism v. Reason In following up on the more popular definition of religion bein g a set of beliefs, and therefore inherently dogmatic, religion has been criticized as being irrational – that one is required to have faith in absolute truths that not only make little sense to him, but provide no means through which they can be proven factual or otherwise.I this sense, religion is superstitious and irrational, throwing a spanner into attempts at objective human reasoning. Religions after all, have been the source of the greatest conflicts in world history, more fierce than quests for imperialism or economic dominance. In contrast to religion by popular definition, Buddhism encourages objective discourse through reason in a quest for truth, i. e. it is philosophy, just like Plato and Aristotle practiced it.This is however complicated by the fact that while some brands of Buddhism, such as Zen, do not ascribe to a deity, others actually do have absolute truths. But then again this might only fuel the argument that it is not a religion, seeing as there is no u nifying commonality as is common in other religions – Christ in Christianity, Mohammad in Islam, etc. Mysticism Allowing someone to find their own truth wherever they will is to tell them that whatever direction will take you to your destination, and most Buddhist practices have inevitably ended up in mysticism.Hence, when one asks what Buddhism is, in many cases they are told that they have to experience it, as words cannot sufficiently explain it. This trait is inherently religious rather than philosophical. In the latter, one must be unambiguous, while in the former, things like faith, revelation and prophecy are cornerstones. Being mystical, therefore gives Buddhism the appearance of religion rather than philosophy. All in all, I guess Buddhism is what one makes it.

Basketball Essay Research Paper BasketballBasketball is a

Basketball Essay, Research Paper Basketball Basketball is a great game that is one of the most popular in America. In this athletics you have to hold good purpose to hit, good jumping accomplishments to bounce, you have to be speedy, and besides have good ball managing accomplishments. In a existent game there are merely five participants on the tribunal, referees, foul outs, and regulations like no running with the ball, no fouling, out of bounds and no running over the other squads participants on discourtesy. I truly bask playing this game and I pattern a batch outside on my tribunal and drama for P.A.L in the winter. I think I am a pretty good participant and dream of playing for the NBA one twenty-four hours. Following twelvemonth I # 8217 ; m traveling to drama varsity for our school alternatively of wrestle and seek my best to assist the squad win. If I try truly difficult and pattern everyday I could be an highly good participant. I normally play with my friends after school for merriment or merely to drama about and hold a good clip, pattern on my ain to pattern things I need work on, or pattern with my pa and allow him give me some arrows. I love watching hoops games on Television and normally watch the Knicks drama. Out of all of the 28 squads in the NBA my favourite squads from best to least favourites are the New York Knicks with Patrick Ewing, Larry Johnson, John Starks, Charlie Ward, Chris Childs, Charles Oakly, and Allen Houston. Then I like the Charlotte Hornets with Anthony Mason, Tyrone Bouges, Glenn Rice, Gladie Divac, and Curry. My 3rd favourite squad is the Seattle Super Sonics with Shawn Kemp, Gary Payton, Schremph, and Perdue. My 4th and concluding favourite squad is the Orlando Magic with my favourite participant Anfernee Hardaway, Horris Grant, and Nick Anderson. My three favourite participants in the NBA are: 1 ) Anfernee Hardaway/ moniker: # 8220 ; Penny # 8221 ; 2 ) Larry Johnson/nickname: # 8220 ; Grandma # 8221 ; 3 ) Shawn Kemp/nickname: # 8220 ; Rainman # 8221 ; These participants have a batch of endowment and I enjoy watching them drama. For case Anfernee is a leader for the squad and has good base on ballss, good dribble, and good shot accomplishments. While Larry Johnson has good rebounding, reasonably good shot, and good dunking accomplishments. Last but non least Shawn Kemp who has great rebounding and dramatic dunking accomplishments including fancy stuff shots and great allyoops. I think hoops is a great athletics and that it will go on to be popular athletics for a really really long clip and that many states will play. As long as you try and pattern you can be a great participant and rule the tribunal. It besides helps if you # 8217 ; re large so you can acquire recoils and stuff shot but if you are smaller you can still be an first-class dribbler and shot and be a guard alternatively of the large centre in the center. To sum it all up hoops is a great athletics that uses a batch of different accomplishments so that everyone can seek to play.

Personal Statement,The purpose of the study Statement

,The purpose of the study - Personal Statement Example My doctoral degree in educational technology would equip with huge knowledge and skills and help me contribute to expanding educational programs through new medium of digital technology. Communication technology promotes highly innovative approach to education and my interest in online educational programs would get a great boost through my doctoral program. In recent times, online education has increasingly become popular across the globe. It offers new hope to people who were hitherto not able to pursue education or higher education due to personal constraints. Online education or distance education provides people with vast options to acquire new skills and knowledge to meet the challenges of time and compete successfully. I would like to contribute to the online education through highly creative methodology of web design and introduce design educational animations. I strongly believe that multimedia in education hugely facilitates learning abilities of students and helps meet their individual needs for optimal achievement. My PhD would help gain expertise in the chosen field so that it could be used to achieve my long term and short term goals in life. I am also highly driven individual with ambitious goals in the area of online educational programs. I would like to attain the highest level of professional excellence, in terms of gaining knowledge and experience so as to reach the position of Professor in a renowned university. The evolving instructional technology is hugely challenging and offers huge scope for personal and professional development. Most importantly, in the area of distance education, online courses utilize technology judiciously to deliver the wider goals of education and make it accessible to people from different demographic segment across the globe. Moreover, the online courses also help evolve new curricula and approach that not only

The Evolution and transformation of the American kitchen Research Paper - 1

The Evolution and transformation of the American kitchen - Research Paper Example The preliminary commencement of American architecture dates back to the regal tradition of the United States and the practices that transpired as a result of the evacuation of European background. The American melting vessel grew and both the edifice and planning practices advanced. This in turn led to the dawn of the colonial style which became the cornerstone of the architectural progress of the United States. The outstanding consideration of these designs focus on the balance between classical and gothic ideals. Some of the common European monuments like Gloucestershire serve as benchmark for this piece of work. It therefore goes without objection that the kitchen is inextricably correlated to this discovery. The hearth remains in various historical sites helps to establish the dating of this. Instead of the fridges of the 19th century, root cellars were used to maintain the cold temperature of foods during summers and offered a conducive environment for preservation of food stuff s during winter (Smith 76). Another preservative method during the ancient kitchen era was the smoke house. It was very vital for preservation of both fish and meat. The early hearths invented were either of clay or stone origin. The hearths could either be deep or shallow, depending on the size of the homesteads. The fire places had fixed revolving spits and clips that could be used to hang meat. This had to be substituted with the wake of change though gradual. Pertaining to this urge of putting up a desired kitchen, there emerged a bottleneck.

Two One page orders for a discussion post - not a paper just to be Essay - 3

Two One page orders for a discussion post - not a paper just to be done as a discussion board post - Essay Example cientists and leaders like John Adams and Owen have understood the wider implications of education and believed that along with propagation of knowledge, it should also become a tool for preserving the constitution of the nation. Gutek, the modern educationalist has been quite vociferous in promoting radical reforms in the education system to meet the challenges of the contemporary environment of pluralistic society and fast advancing technology. He reaffirms the relevance of the philosophies of Mann, Adams etc. and categorically says that educational institutes must widen their vision and mission to include children and people from diverse background. The goals of NCLB have thus, brought the Public schools to the common man who can now access education, especially in the public schools that are considered a seat of academic excellence but which were well-known for their preferences to the elite class. In the early eighteenth and nineteenth century, education was not universal and catered to the select few who could afford it. Though, the philosophers through the ages have advocated education as the mainstay of development of the nations, historians have shown that the Americans had realized early its importance and reformers like Jefferson, Adams, Mann etc had advocated an education system that would help gain knowledge that could be used for the wider welfare of the society. In the subsequent years, the emergence of public schools, private schools and government schools had promoted politics of segregation, based on social status, racism and class difference. To make education universal and accessible to all, No Child Left Behind is the most commendable program, taken by the Bush government to reduce the increasing disparity in the education system in the United States. The four pillars of the program greatly support the accessibility to good education through ‘accountability, choice, and flexibility in Federal education programs’ (USDOE). NCLB has

Canadian Real Estate Vertical Go to Market Plans and Strategy Term Paper - 1

Canadian Real Estate Vertical Go to Market Plans and Strategy - Term Paper Example The paper utilizes suitable illustrations to support the relevant details. The paper terminates in suitable conclusion that emanates from prior discussions of the paper and illustration provided. CREV endeavours to succeed in the Canadian real estate market. However, realization of the above requires the firm to enact an ambitious advertisement plan that will expand the firm’s clientele base. Such an undertaking will require an appositely coined strategy. The strategy should adequately appraise the nature of the market. This write-up will seek to institute an opposite promotional approach that will culminate in the success of the above real estate entity. Evidently, the above strategy will be critical since the real estate sector has encountered key upheaval due to the economic crisis. The market base is dwindling. Consequently, CREV requires to repositioning itself ensuring it maintains and boosts its clientele base. This strategy will enlist certain data and relevant illustration to support it assertions. The assertion will relate to strategy that the entity should adopt. This strategy has identified communication as an integral element in this industry. Therefore, advertising has sizeable implications on the fortune of real estate firms (Vertical news). Rogers is promotional firm enlisted to undertake the above task. The marketing strategy aims at enacting appropriate measures that will ensure that it has sizeable share of the market. This plan will enlist of information from credible informer that have undertaken through research. Evidently, the Canadian real estate sector is overly competitive (Canadian real estate association). Consequently, marketing will serve as an integral tool of boosting the clientele base. However, the realization of the benefits of marketing will demand utilization of shrewd advertising campaign. Therefore, CREV will require enlisting

Marketing Strategy Based on the Apex City of London Hotel Essay

Marketing Strategy Based on the Apex City of London Hotel - Essay Example Apex should also choose between business and tourist traffic in order to build a competitive edge. The prime location will not yield adequate returns with only a 4-star rating, and the management should plan for an upgrade. London is a major financial, tourist, and historical center. The 2012 Olympic Games and its aftermath will open additional market segments. The city also has a very large number of established and competitive lodging and boarding facilities. Hence, the long term prospects of a new hotel such as Apex cannot succeed without creative and systematic segmentation and accurate targeting as well (Payne, 2002). Apex targets both affluent tourist traffic, as well as middle-level business executives. This is apparent from how the rooms have been appointed, the location chosen, and the conference facilities (Welcome, 2007). This kind of blend is a copy of tactics followed in the past by competing 4-star facilities, but it is not an optimal strategy for Apex to follow. The hotel should either focus on tourist traffic, or specialize as a convention center. It will weaken its branding by trying to do both things (Nijssen and Frambach, 2000). It is true that London has potential revenues from both segments, but since Apex is a late entrant in a mature market, it would do better to specialize in any one of the two segments which it has served during its first year. Generic Strategy Apex could have focused on becoming a luxury hotel for top executives and for celebrity visitors to the city. The prime location chosen makes it suitable for such use. This find of focus generic strategy would have offered the management superior returns on investment (Porter, 1991). However, the hotel has chosen to compete on price. The discounts promotions, deals, and special offers, which Apex offers makes it a place of choice in the prime locality where it is situated. This generic strategy may be difficult to sustain in the long run, and it is probably not required given the enormous traffic through London. The hotel has probably lost significant cash flows through its deep discounts. The forthcoming London Olympics will impact this low-price strategy, as the hotel has established a reputation for discounts in travel circles, which it may not be able to withdraw during peak tourist arrivals (Barger & Kirby, 1995). Overall, the company has not tried to maximize returns on its ne w investment, and has probably

IDiscusson board reply Coursework Example | Topics and Well Written Essays - 250 words

IDiscusson board reply - Coursework Example Many organizations driven by quality would implement a pay-for-performance system that will improve employees’ performance. They will set mechanisms to gather, analyze and interpret unbiased data of all employees through annual or semi-annual performance appraisals linked directly to an individual. This will remove biases and challenge employees to work harder since the industrious ones get appreciated through rewards such as promotion (NIV, Mathew 25.21). Linking employees’ performance to rewards will give the administration the best program to design salaries and wages. It will also help in performance, monitoring and evaluation, which will translate into quality production, profitability, low turnover and organizational discipline (Rehman, & Ali, 2013). However, such scenarios may not occur in organizations where management is bossy. Such management always has conflicts with employees resulting in a general decrease in production capacity despite high salaries. Healthier lifestyles will save organizations costs related to medical expenditure and production. The organizations are also developing employee wellness programs such as regular medical examinations focused on preventing health issues before they develop and increasing employee insurance premiums. Huang, S., & Lai, W. (2014). A study of the effect of incentive system on job performance- locus of control as a moderator. Journal of International Management Studies, 9(1), 89-98. Retrieved from http://search.proquest.com/docview/1517530191?accountid=45049 Rehman, R., & Ali, M. A. (2013). Is pay for performance the best incentive for employees? Journal of Emerging Trends in Economics and Management Sciences, 4(6), 512-514. Retrieved from

Manufacturing Operations Management (Logistics And Supply Chain Dissertation

Manufacturing Operations Management (Logistics And Supply Chain Management) - Dissertation Example Promanager analysis As pointed out in the article, Promanager faces a lot of problems. First, the company delivery system’s performance is poor and traditional. It fails to achieve customers’ delivery dates which frustrate the customers. As argued out by the Quinn (1986: PP 1-5), failure to deliver on time loses a substantial confidence and trust in product offered in the market. In this company, the product exhibits high levels of commonality and are similar in both aesthetic and performance attributes. It is argued that this firm’s the product look similar from outside and are confusing instead of exhibiting realistic and meaningful simple operating procedures. The products lack creativity and innovativeness has enabled their products to be inefficient and ineffective. This has led to dwindling of sales volume and subsequent squeeze of the market share. As the suggested in the article, the market has been flooded by the products of the Asian competitor implying that customers have shifted their loyalty from the firm’s products to the competitors’ making the company lose their customers, reputation and may lose jobs in the long run if the rate continues. There is a possibility from the report that the products are of poor technology. This has fuelled and oiled the competitors’ impetus in gaining the market share in the oil and gas industry. Second, there is a problem in the actual production process. Companies which have been in the market leader employ the customer-driven focus in their production processes. This corporation uses the batch production system based on the mass production with emphasis being given to marketing and other advertising strategies. There is a possibility of heavy operating costs that are incurred by the firm as a result of heavy and massive marketing and advertising campaigns. This is also expensive and unprofitable. As a result, it has led to fear of making bold investment by its executives in ventures such as product and market development. The company lacks a strategic approach in their course of management as evidenced. There is no evidence that the company undertakes strategic planning, no evidence of industry analysis having being carried out, there is distinct strategy that differentiates this firm from others in the same business. It can also be noted the company is on the bream line of perishing for lack of simple and operable policies, procedures and vision. The entrepreneurial culture in this company is null and void because there is no creativity and innovativeness in its operations, product outputs and service rendered to their customers. The firm also lacks a systematic and structured manufacturing and planning schedules. This is evidenced in the lack of accuracy and forecasts. This has led to mismatch between demand and supply of their product thereby resulting in failure to reach optimal results. This firm lacks strategic manufacturing plans, sound polic ies and actions plans that set in motion the policies to effect and assist the company leapfrog in sales, growth and profitability. In terms of human resource, there lacks motivation on part of employees especially the sales force. This is detrimental as it has led

Odyssey- Odysseuss Behavior Essay Example for Free

Odyssey- Odysseuss Behavior Essay Odysseus’s behavior was ironic when he deliberately concealed part of Circe’s prophecy from his men because when Odysseus and his men went through Scylla, all of the men were scared and some of the men were killed. In the Odyssey it said that: â€Å"My men all blanched against the gloom our eyes were fixed upon that yawning mouth in fear of being devoured† (Homer886) This quote showed that Odysseus’s behavior was ironic because since he did not tell his men that they were going through Scylla so they were terrified. The men just saw this huge whirlpool in the middle of the sea and were not really pleased to hear that they were going through that and not knowing the outcome. They were very scared because the outcome could result in them dying. When the Odyssey was talking about when Odysseus’ men were getting killed The Odyssey said: â€Å"Then Scylla made her strike, whisking six of my best men from the shop. It happened to glace aft at ship and oarsmen and caught sight of their arms and legs, dangling high overhead† (Homer886). This quote is showing that Scylla ate six of Odysseus’ best men while they were traveling by her. This was the aftershock of Odysseus not telling his men that they were going to see Scylla in this journey and most likely get eaten. Yet again all of the me were ate only because Odysseus did not tell his men about the ending that they could of all been dead in the end. In conclusion, Odysseus’ behavior was ironic when he deliberately concealed part of Circe’s prophecy from his men because Odysseus did not tell his men that they would travel though her and get scared and eaten.

Kelley School of Business Essay Example for Free

Kelley School of Business Essay I. I strongly believe that my education at the Kelley School of Business will help me achieve my goals. To begin with, it has been my short-term goal to obtain as much information about Finance to be an efficient Fund Manager of an investment company. This position requires me to maximize the profits of the company as well as the clients. An MBA degree will contribute a lot to pursuing this goal. As the program says, the MBA education at Kelley teaches leadership first and foremost, and when leadership has been laid all the other principles of Finance is given. This is what I wanted to acquire, for I know this is going to be useful for me in my career path and plans. I also learned many values in my four years with Jaesung Jinheung in South Korea as a Quality Controller. Most of my leadership and social skills were shaped by my stay there, and it also allowed me to learn how to treat others working for my department under me. My experiences in CB Richard Ellis Korea during my internship also exposed me to different financial situations that helped me apply what I learned from my Bachelor’s Degree in Business. Translating English documents into Korean, the internship gave me a heads up on the financial world and trained me with all aspects of business while refreshing all that I have learned. These work experiences give me the edge in my chosen profession. With experience and values, I am confident that I can achieve my career potential to the fullest. But this short-term goal is not my only motivation to pursue an MBA degree. It is also my goal to be a Chartered Financial Analyst or a CFA. To qualify for this title, I need a minimum of four years experience in the financial investment industry. I hope to have this requirement through the Fund Manager position that I want to serve. Apart from this, I also need to learn more to be able to pass the three examinations required of aspiring Chartered Financial Analysts. Backed with an MBA degree from Kelley and the work experiences that I had, I know that becoming a CFA is not very hard. I have designed my goals to complement each other. I felt that it will be easy to achieve something if it has been planned out in accordance to how the processes of planning have been. This is why I wanted to tackle Fund Management; I know I leads to my ultimate goal of becoming a CFA. Considering these goals, I am motivated with the MBA degree knowing that it will do so much for my advancement. My work experiences in Korea are likewise a big help. Work allowed me to apply theoretical knowledge into practical settings. It took my knowledge from my books into my hands, so to speak. From work I learned leadership, sociability, patience, problem-solving skills, and perseverance. Given these work and educational foundations, I am confident that my short and long term goals will not be too hard to achieve. II. If I have to choose three persons to ride with me in a cross-country trip, I will have to choose those who have been efficient in their roles in their respective fields. I will also consider the feasibility of the trip, and the comfort of traveling with those three people. This way, I can be sure that I will be learning a lot and will be able to get something from them that I can use with my own educational and career path. Of course, when business is the topic, many names come to mind. Still, one can single out people who will be beneficial to learning about life and work among others. I would like to have J.P. Morgan in the backseat. We will most probably talk about how he saved the Wall Street and figure out how important this financier’s role is to history. I hope to learn from him how to manage incoming and outgoing finances, and how to delegate allocations properly in a way that the value of finances is maximized. I will be asking a lot of questions, including business problems he has encountered and how he was able to see himself through them, for I know that the bigger a businessman the bigger his problems too. Most of the questions will focus on money and investment management. I will have clients in mind when speaking with Morgan, putting a future client’s possible case and asking Morgan about his opinion on it. Beside J.P. Morgan will be Richard Branson. I like the idea that he can call for air help when something happens to us or to the car. Yet more seriously, I would also like to know how he managed to grow the Virgin Group to what it is now. I also hope to learn from him how he manages to grow the business while facing detractors and competition. I feel that Branson is the best person to ask about growing a business through rolling investment. Given my interest in investment management, this will be a lot of help for me and my career. Lastly, John D. Rockefeller is another person I want to drive with, and he will be staying in the front passenger’s seat. I hope to learn from him how he managed to make binding ties and affiliations with large companies that eventually cut costs for his trade and offered cheaper end-products for consumers. If there is anything that I would like to have from Rockefeller, it is his ability to communicate in a way that prospective business partners agree to him, and competitors sell out to him. Speaking with Morgan, Branson, and Rockefeller will earn me a lot of business insights. They will also give me a lot of information about businessman mindset, something I need to know more about to enable me to learn more about my future clients and how I can better help them with their finances. I am sure that the trip will be fruitful, and that it will enlighten me with my career path. Indeed, speaking with experienced individuals in a refreshing new environment will organize my thoughts and allow me to better serve my goals.

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