Case Write-Up

In the sense of the promotions, Population Services International distributed to both Raja and Maya $400,000 advertising dollars per year, which was the second largest of all advertisers In Bangladesh. Their approach was to skip the Intermediate level of Influences and go directly to consumers. In this case, It works to sell Raja condoms directly to the market since It's more like a one-time use consumer products. However, it'll be difficult for Maya to build up the brand image since customers perceived Maya as a drug, which will bring more concerns when people try to buy oral contraceptives.Hence, it still needs recommendations from doctors to convey the effectiveness and proper information about the drug. Third, the pricing of Raja and Maya can also be an influence to their performance when compared to their competitors' price. For example, Raja is priced more than competitor Tahiti, which is government sponsored condom manufacturer. The higher price of Raja made a premium image fo r customers to buy the condoms even If the price is higher. On the other hand, however, Maya is priced lower than its competitors, creating a hurting image that for oral medicines, cheaper may mean bad laity.And this situation got worse when it didn't get the recommendations from intermediate level influences. Finally, the distributions for both products were to focus directly to customers. So SSI planned to sell their products via pharmacies, general stores, and pan stores. Nevertheless, the difference in nature of these two products caused deferent performance. For Raja, it's easily to sell their products since men accounted for 80% of the purchasing behaviors of the birth control products.But it became difficult for Maya to have the same efficiency since people till prefer to see a doctors before decide which medicine is safe and reliable, which Is the critical cause for the sluggish sales of Maya. 2) How do you characterize the competitive environment in Bangladesh? That Is, whe n you look at SSI vs.. The other organizations In the space, how do they view each other? How does this differ from the other for-profit contexts we've studied? What might It mean for the strategy? ) Create a marketing plan for Improving sales of Maya Given the analysis that I described before, It Is the difference In nature that causes the difficulty to sell Maya successfully. In order to create a marketing plan for improvement, we need to modify the flaws in the previous one. To begin with I'll suggest to create a new brand. To explain, it's already been perceived by Bangladesh that Maya is a brand that is cheap and mistakenly regarded as an inferior product. Reputation, competing with their main competitors, which are the government sectors and Vast.So my recommendation for the price would be to price their oral contraceptives the same price around their competitors, getting rid of the inferior image of the product. Also, Its important to target their customers not only for males but males as well. The reason for this is because for the buying behaviors of the birth control products, 80% of the purchases were made by men. As a result. They can put more effort to their advertising to educate male customers the effectiveness of their products.Finally, to achieve SKI'S goal, which is to broaden their market share to help control Bangladesh population explosion, they'll need to increase their profit margin to retailers and RPM (Rural Medical Practitioners) in order for them to promote more diligently to the end customers to increase the overall market share. To explain, the profit for retailers now are low due to the low pricing of the Maya. So increasing the price of the product will enable SSI to provide higher profit margin to retailers, incentives them to put more selling effort to sell out new product.For Ramps, they can be critical since they are the one that can reach out to distant area and provide their recommendations to consumers. So including the in termediate level of influences will bring a better communication and education to customers, enabling a better brand perception and awareness of the new products. By providing more profit incentives to RPM, we'll be able to achieve this goal. 4) How will you evaluate your plan? How can you calculate the ROI? The â€Å"l† is relatively straightforward but how would you go about evaluating the â€Å"R? What challenges do you face in this regard as compared with most of the other cases we've discussed? How would you address it? In order for the plan to be feasible, we'll need to take into account multiple data and information from the current selling circumstance of Maya to make a thorough evaluation. To begin with, I'll conduct surveys to see how people perceive the Brand of Maya to make sure that the issue of he produce is the cheap quality and also to see the why customers are unwilling to try out Maya.Moreover, the COPY (Couple Years Protection) for industry and SMS (The So cial Marketing Project) products from Exhibit 8 is an indicator for us to observe the change of market share and growth rate from 1978 to 1983. And based on the change throughout the years, we can further conclude whether the approach for Maya had problem that need to be addressed. Finally, I'll try to get the distribution data from retailer, wholesaler, and smallholder to see how they sell their products in terms f the sales ranking of the products in the same category.Therefore, by using the data mentioned, we can reconstruct a new marketing plan for the new product and focus more on the culture of Bangladesh in terms of selling birth control products. Given our plan can be successfully implemented, we need to figure the challenge in the long run. And since the project is lunched by a not-for-profit agency, they mainly relied on funding to support their operation. According to the case, the barely earn profit by this product since the profit margin for the product is very low. Cha llenge, use project, longer no fund

Response to Beauty and the Beast

In every culture and throughout every generation the presence of fairytales and folklore has been evident, because just as each culture has its own morals and manners, so does every culture need its own fairytales to represent what is important to those people at that time in that place.While there are many fairytales told to children around the world every year, there are none so famous as Beauty and the Beast by Jeanne-Marie LePrince de Beaumont, a story in which a young maiden who is kind-hearted and loving to her father learns to love and appreciate a Beast, looking beyond his appearance to his soul.This fairytale represents a great deal of the important morals and values that are important to every generation, especially during the time it was written. The basic belief in goodness, faithfulness to one’s family, and the ability to love someone for who there are and not what they are becomes the themes of this fairytale, and the interpretation of its meaning becomes apparen t through analyzation of the characters and their actions. Fairytales can tell us a great deal about the time and place in which it was developed.Beauty and the Beast was written in 1756 by a French writer living in England and was based upon a folktale that was well-known at the time. The author wrote it to be included in a book for use by governesses when teaching their young female scholars â€Å"of quality†, and therefore by analyzing it the audience can learn about the types of lessons that would have been taught to young girls. All of the major characteristics expected of young women are embodied by the character of Beauty: selflessness, studiousness, a love of reading, hard-working, and devoted to her father and family.Young girls would have been able to look up to a character like Beauty, and society would have encouraged girls to be like her. The main character, after all, is faithful to God, obedient to her father, and compassionate to her family despite the fact he r sister’s are selfish and jealous. She works hard even when her father loses their fortune and she is forced to run a household without luxury. The story also stresses the importance of keeping one’s promises.In the one instance where Beauty does not keep her promise to return to the Beast in one week she is overcome with guilt and runs back to him, to find that he is nearly dead because of loneliness for her. When she does the right thing and keeps her word, she is rewarded with the Beast becoming a prince who gives her his kingdom. During a time and in a place where a girl’s formal education was more geared towards rearing them to be good daughters, wives, and mothers than scholars, these traits would have resonated with the girls who were looking for heroes to mirror themselves after.Like any good fairytale, Beauty and the Beast involves romance. Each generation loves romance and loves the thought of falling in love and of a young woman meeting her prince. I n this particular fairy tale, that is slightly different because the love interest isn’t a handsome prince at first, but a Beast. At first the Beast appears to be kind: caring for he father when he ends up stranded at the castle, leaving him food, and providing a place for his horse to stay. Yet, when the father picks a rose for his daughter Beauty we see the angry, frightening side of the Beast.With Beauty, however, we only see the caring side during their long conversation every night at 9 o’clock, when he would join her for a meal. Beauty describes him as being â€Å"kind and good, and that is sufficient†. Every night he would ask her to marry him, having fallen completely in love with her for her beauty and her kindness of heart. When Beauty decides to marry him for his goodness and is able to overlook his appearance and his lack of sense, Beast turns into a handsome prince and Beauty is given a kingdom to rule next to him.This romantic aspect of the story h as drawn in many fans, but it also conveys an important message to those who read it and use it as a moral allegory. The story is meant to show that it is not what is on the outside that counts, but what is on the inside. This theme is one of the oldest and most cliched, but it is a lesson that was thought to be important to young people hundreds of years ago, as well as today. Literature from this period and of this type is known for its symbolism and this demands interpretation to understand how it all fits together.The first object that requires a deeper look is the rose, which becomes the thing that creates the entire storyline. When Beauty’s father leaves and he asks his daughter what she wants him to bring back, she asks simply for a rose. When her father takes the rose from the Beast’s garden he is confronted by the Beast, who says that he loves his roses more dearly than anything, and that in payment he demands either the father’s life or one of his daug hters.Of course, Beauty submits herself to whatever fate she will have at the Beast’s hands, but what is interesting about the rose is that she becomes, in a way, the Beast’s most prized possession, much like the rose itself. At the end of the fairytale the two greedy sisters are turned into statues by the fairy, who says they will remain that way until they repent of their wrongs and so they can always see Beauty’s joy.The morals of the time would have taught young women to not be selfish, and that being that way would turn them into bitter old women, just as the sisters are turned into statues. The fairytale of Beauty and the Beast is one that is widely known and loved. Movies, books, and cartoons have all been made based on it, and in terms of literature, it holds up as a story that is beautiful and that would have been used to teach morals and values to generations of young women.While times change and the definition of womanhood changes with it, the values taught within Beauty and the Beast are not all to be disregarded. The idea that we can fall in love with someone for who they are and not how they look is one that still resonates, and the ability to be the best we can be and do what is right is also a value that everyone should embody. This story was meant as a moral allegory to young women and children, and today it still stands up as a fairytale to be told through the ages.

Impact of Selfishness on Personal Life Essay

Every day, people make several decisions that more or less influence their live. However, it is necessary to consider other people and results before the decisions were made, since selfish decisions can cause lots of problems. The selfish choices that selected by the main characters in both â€Å"On the Rainy River† and â€Å"A Pair of Silk Stocking† cause regret and raise conflict between the main characters and themselves . Regret can be caused by selfish decisions. On the one hand, O’Brien, the narrator of the â€Å"On the Rainy River† felt guilty and worried about his families during the way to Canada because he fled away from the war: â€Å"I would go to the war–I would kill and maybe die –because I was embarrassed not to. That was the sad thing† (O’Brien 12). Clearly, O’Brien explained why he decided to go to Canada and continued his life without contradicting his own beliefs. Here he lost his chance at having personal happiness and would have to live with regret from then on. Even though, O’Brien went back and join the army in the end, he still could not get away from the guilt that rose by his decisions: â€Å"I survived, but it’s not a happy ending. I was a coward. I went to the war† (O’Brien 14). Unlike most people, O’Brien did not regarded surviving form the war as a fortunate thing for him, instead, O’Brien considered himself as a coward and did not forgive himself for making the inappropriate decision from now on. On the other hand, Mrs. Sommer, the major character of â€Å"A Pair of Silk Stockings† also felt guilty about her family, for the mother used up all the fifteen pounds to purchase accessories and entertained herself instead of buying â€Å"so and so many yards of percales for new shirt waists for the boys and Janie and Mag†(Chopin 1). The fifteen pounds were supposed to spend on the clothing of their children according to Mrs. Sommers’s plan at beginning, but she spent all for herself. By the end of day, she did not want to go home: â€Å"in truth he saw noting—unless he were wizard enough to detect a poignant wish, a powerful longing that the cable car would never stop anywhere, but go on forever† (Chopin 3). Mrs. Sommers’s thought reflected her regret since she wished the cable can run forever, so that she did not need to go back home and face her families. Obviously, personal happiness cannot be achieved by selfishness, doing this can create nothing but regret that will follow a person through their life. Furthermore, the selfishness gives raise to conflict between people and themselves. In â€Å"On the Rainy River†, on the one side, O’Brien felt he was â€Å"too good for the war. Too smart, too compassionate, too everything† (O’Brien 3) since the war is completely unreasonable for him. He did not want to be killed or kill anyone else. On the other side, he found himself is completely irresponsible for both his family and country, for the simple reason that he neither supported his country nor protected his family during the most dangerous time. Due to his strong sense of morality and the honourable values like bolstering his own country, O’Brien struggled with two conflicting forces in himself. Similarly, Mrs. Sommers struggled against herself to repress the urges and temptation of the luxury items. At first, she planned to spend the money on her children. However, as soon as she entered the department store, she had a powerful desire for a moment of luxury. She tried to hide the desire because of her economic situations. Eventually â€Å"she went on feeling the soft, sheeny luxurious things—with both hands now, holding them up to see them glisten, and feel them glide serpent-like through her fingers. Two hectic blotches came suddenly into her pale cheeks† (Chopin 2) and undoubtedly she succumbed to her desires. By the end of the short story, Mrs. Sommers was extraordinarily desperate for the luxurious life to never end â€Å"a poignant wish, a powerful longing that the cable car would never stop anywhere, but go on and on with her forever† (Chopin 3). The cable in some way symbolized her dream life since at that time only wealthy people were able to afford cable. Her wish represented she still wanted to enjoy the feeling of that unrealistic luxurious life and was unwilling to return back to reality. Ultimately , being selfish leads to the conflicts between people and themselves and annoyance in their life. Overall, the two short stories namely â€Å"On the Rainy River† and â€Å"A Pair of Silk Stockings† emphasized the negative impact of selfishness on human life. Both O’Brien and Mrs. Sommer suffered the regret and conflicting forces that rose by their selfishness. Therefore it is necessary to consider the result before making a decision since selfish decisions, in long term, cannot bring any happiness and self-satisfactory.

The approach to disclosure in the Companies Act 2006 is preoccupied Essay

The approach to disclosure in the Companies Act 2006 is preoccupied with one audience, shareholders - Essay Example The obvious way for companies to prove legitimacy to the wider class of stakeholders is through reporting requirements. Unfortunately, the Companies Act 2006, while recognizing the social contract between the company and stakeholders, does not make social and environmental reporting mandatory. A close reading of the relevant sections of the 2006 Act reveals that environmental and social reporting are entirely voluntary. It is therefore reasonable to conclude that the Companies Act 2006 has shifted momentum in favour of stakeholder theory to the principle of shareholder primacy. Clark and Knight argue that the disclosure requirements contained in the Companies Act 2006 appear to meet the needs of shareholder and while they may appear to meet the needs of stakeholders, the disclosure requirements are motivated by the market value of the corporation rather than expanding the concept of corporate social responsibility. In this regard, the disclosure requirements of the Companies Act 2006 speaks to informing the shareholders of the company rather than to all stakeholders. Essentially, companies, may if they wish, inform stakeholders of their social and environmental activities and policies, while they must inform shareholders of their financial activities and policies. This is symptomatic of the ambiguous approach taken by the Companies Act 2006 to stakeholder and shareholder primacy.

Stradegies (or Barriers) Term Paper Example | Topics and Well Written Essays - 1750 words

Stradegies (or Barriers) - Term Paper Example Evidence of institutions structured racially were slavery, segregations, residential schools and Indian wars. In 20th century though, discriminations of all kinds were banned following activities of civil rights groups from all quarters who opposed these discriminations using various strategies, its fundamental to note that some like employment, housing, education and lending prejudices still happen in the present society. In this paper however, focus is on the Asian and African Americans as two of the groups that faced barriers (discrimination) in United States’ history and what strategies they used to overcome these challenges. In the first part of this paper we shall look at the African Americans and then proceed to second part of Asian Americans in order to create contrast in the strategies they deployed in fighting for their freedom. Perhaps the most prominent barrier of this group is the institution of slavery in which the African Americans were enslaved and viewed as property and treated as second class citizens, stigmatized and denied industrial jobs. It the perception of slavery that resulted in all the barriers faced by the Africans in America, it started in 1630s in prehistoric era and has been practiced for a long period of time due to sugar, tobacco and other plantations that seek more workforces. There are several issues that kept them invisible in all aspects of their lives: Their lives were incredibly difficult as slaves mostly for those who worked in the plantations, they could work from sunrise to sunset without exception of the old or the young all could work for this long period of time. It was considered to be lucky if the master gives the slave a day off from work or holidays like Christmas which was infrequent. In his free lucky time, the slave engage in his own activities of fishing or cultivating small piece of land in order to supplement what is given by the master that was poor in quality. As stated earlier it was

Dance Paper Assignment Example | Topics and Well Written Essays - 500 words

Dance Paper - Assignment Example Therefore, according to the narrator in the video, respect for other people’s ideas is paramount to encourage tolerance. He adds that silence is the worst form of decision because it stifles opinion on important matters. LaLaLa Human Steps: LaLaLa Human Sex duo no. is video by Edourd Lock and it runs for 1.6 minutes. It involves a gestural dance characterized by fast and difficult partnering during movements while using the horizontal plane. However, there are contrasting views concerning the male dancer’s energy including the body language to that of the female dancer. First, both dancers are vigorous in their undertaking to depict the gestures of sex when done without the necessary precaution (Minton 167). Second, the dominance on stage by the dances is demonstration of the unifying belief of the dangers posed by irresponsible sex. However, issues of gender stereotypes are being pushed in the choreography worth noting. For example, women are cast in the video as passive and, thus, direct recipients of the sexual innuendos. Likewise, the choreography assumes that only men are the stronger sexual beings as opposed to their counterparts. Smoke is a video by Mats Ek and it lasts for 20 minutes demonstrating the relationship between a man and woman namely Niklas Ek and Slyvie Guillem. The use of the wall, hence, is a vital platform to convey the tension between the dancers because it reveals the barrier in sexuality. It also displays the essence of continuation from a neutral background. On the other hand, the camera tricks such as retrograde and close-ups enable the telling of the story to assume authenticity because it makes both dancers in real in the choreography. In that perspective, the dancers mostly use their arms and bellies as surfaces for partnering to send a clear message of sexuality and its undertones. Ms Guillem’s character, however, during her sole takes the form of

20th Century Humanities Essay Example | Topics and Well Written Essays - 750 words

20th Century Humanities - Essay Example Artists like Pablo Picasso and Georges Braque challenged the conventional methods of painting in perspective that was practised since the Renaissance. They came up with a new way of seeing things in the modern age, known as Cubism and it was the first form of Abstract Art. As the phenomenon of Cubism moved on to other parts of the Europe, it took different forms and names e.g. Futurism in Italy and Expressionism in Germany. In this way, Art took on different forms and names as new concepts developed and artists from different regions of the world contributed to the development and evolution of Art. This is a continual process that has moved on from the Twentieth century to the Twenty-first century. Hence, the importance of 20th century Art cannot be refuted, as the foundations of contemporary and future art have their roots back there. The Twentieth Century is also phenomenal in the development of cross-cultural art, which is the basis of globalization today. The invincible barriers between different cultures were broken down and the cultural values were assimilated; thus the cultural scene took on a new shape. Harlem Renaissance was one such phenomenon during the 1920’s when the African-American culture found new definition and dimension. It heralded the liberation of the oppressed and suppressed Negroes and they discovered new ways of self expression. This is exactly what the world shall desire in the future- liberation of man and assimilation of cultures in order to give birth to a global culture. For the first time in history, an attempt was made in developing a universal culture to promote harmony and encourage mutual cooperation. For those who look forward to the developments in arts and literature in the future can understand the relationship between man, society and Arts by studying 20th Century Humanities.

Enhancing the Patient Experience Essay Example | Topics and Well Written Essays - 2250 words

Enhancing the Patient Experience - Essay Example Specifically, the patient journey and challenges incorporated the actual healthcare experiences with the textbook knowledge. The experience adds a new aspect to nursing care learning. The new knowledge delves into the importance of â€Å"person-centred care† (http:learn2.open.ac.uk 2012). Further, the journey experiences convince the nurse that learning includes gathering inputs from the healthcare environment (http:learn2.open.ac.uk 2012). The inputs include the patients’ inputs. The healthcare environment indicates that the patients have different culture-based inputs. The nurse compares the patients’ inputs with current medical databases. Tiago (2011, p. 268) reiterated â€Å"With the synergies and differences between the different theories and models that analyze and predict the acceptance of technology, its explanation identifies the advantages and disadvantages associated with them as well as a clear identification of variables that interpret end-user moti vation to accept IT/† Tiago (2011, p. 268) that a research of 43 Portugal medical doctors used the Electronic Medical Database system for their diagnosis and prescription activities. The doctors have different specializations. Consequently, the doctors tailor their database on their medical expertise. For example, the oncology expert keeps a cancer-related database Furthermore, the experience lessons persuade the nurse to search for references that will ensure positive outcomes from the patient-centred healthcare approach (http:learn2.open.ac.uk 2008). Positive output includes client’s receiving significant psychological benefits. Ella Stiles (2011, p. 35) theorised â€Å"To achieve best outcomes, patients must have a good understanding of the condition and should adopt a vigilant self-care approach. However, this may be difficult for patients with low health literacy because they may struggle with obtaining, understanding and applying health information.† The nu rses must encourage the patients to do their share in the healing process. The nurses cannot fully implement the healing process without the patients’ voluntary implementation of the medical doctor’s prescriptions. For example, the nurses should persuade the hypertensive patients to avoid fatty foods because fatty foods trigger the hypertension attacks. In addition, the positive outputs of the patient journey learning experiences include the nurses’ gaining psychological advantages from the patient-centred hospital experiences. Arturo (Bustamante, 2011, p 1921) states â€Å"physicians with 50 percent or more Latino patients were more likely than the reference group to report inadequate time with patients, patients' inability to pay, the lack of qualified specialists in their areas, not getting timely reports from other physicians, difficulties communicating with patients, and patient noncompliance with treatment.† ‘ The quote clearly shows that the language barrier reduces the implementation of a favorable communication between the Spanish-speaking Latinos and the English-speaking healthcare professionals. The research indicated that medical professionals serving more than 50 percent Latino patients’ medical needs had lesser confidence in their ability to communicate with the Latino patients, reducing the required healthcare quality service. Further, the patient journey experiences enrich the nurses’ knowledge that the healthcare practitioners, especially the nurses, must

Topic Essay Example | Topics and Well Written Essays - 1000 words

Topic - Essay Example The paradigm can be categorized into two functional parts: information retrieval and information dissemination or exposure. CCN directly routes and delivers pieces of content at the packet level of the network, allowing automatic and application-neutral caching in memory wherever situated in the network (Karl, and Andreas 331). This yields to efficient and effective delivery of content when required. Given that the architecture allows caching effects as an automatic consequence of packet delivery, memory can be utilized without building costly application-level caching services. Why do we need content-centric networking (CCN)? CCN’s security model centers on explicitly securing the content itself rather than endpoints, whereby packets travelling across the network content can be safeguarded against from alteration, damage, or snooping from unauthorized parties. Name data networking or content-centric networking represents an alternative approach to the architecture of computer networks. CCN draws from the principle that a communication network ought to allow a user to focus on the data that one needs instead of having to reference an explicit, physical location where the data is to be retrieved (Wang, Chen, Zhou, and Qin 93). The modern internet architecture centers on a host-based conversation model generated to enable geographically distributed users to utilize a number of significant, immobile computers. The content-centric networking pursues to adapt the network architecture to match the present network usage patterns. Content-centric networking presents a broad range of benefits such as content caching to minimize congestion and enhance delivery speed. CCN also allows simpler configuration of network devices, besides building security into the network at the data level; nevertheless, the change of communication paradigm may present challenges for network activities such as real-time multimedia applications (Karl, and Andreas 332). Recent research ha s demonstrated that such applications may be feasible. Moreover, building content routers that back content-centric networking at high speed remains an open problem to crack. How it works Application-layer designs forms the basis of content-centric interface. This presents benefits such as easier deployment, improved flexible delivery, and effortless backwards compatibility. The present internet establishment features a tree of physical equipment to link streams of packets from any leaf to another. The present system can be regarded as efficient for communication, but not for distribution. The overall proposal of content-specific networking appreciates that a significant amount of information produced once, and then repeated numerous times. Hence, it is sensible to distribute the copying of any correlated activities into the networks’ tree of equipment. In most of the instances, significant storage exist, and could be utilized more efficiently in the event that it could recog nize certain content and only remain with one copy of it. The structure of the network equipment (tree shape) scales content delivery to match the size of the audience and minimize up-stream equipment to the minimum required to generate the content. CCN utilizes a practical data storage cache at every level of the network, which in turn, dramatically minimizes the transmission traffic,

Law Enforcement Supervision Assignment Example | Topics and Well Written Essays - 1250 words

Law Enforcement Supervision - Assignment Example Leadership and Organizational Culture Negative images and observations of people within the law enforcement organizations create an unpleasant working environment. In turn, this adversely influences organizational effectiveness, which is needed to counter crime, turmoil and other services. Society is deprived of quality and expected police services due to the unhealthy functioning of the police agencies. A prosperous, fostering working environment enables police agencies to focus on providing premium police services in a time of meager resources. Every police organization has its own unique sub-culture (Crank & Caldero, 2000). In spite of this, police organizations share certain characteristics, which make them similar due to shared experiences. All police agencies deem themselves to be paramilitary agencies, different from the mainstream community, who are required to be hyper-vigilant all around the clock (Gilmartin, 2002). Likewise, they experience tedium, are compelled to work wh ile others go on vacations, and most importantly they live through life and death experiences together. Consequently, they became bound together in an emotional culture. This culture also serves to glue supervisors to the people and agencies they serve in. Additionally, it delineates the Cop confidential conduct in relation to promotions; and the act of getting detached from one police subculture and being bound to another. John G. Serier has noted in his report, that a mutual experience amongst first-line police supervisors was ‘leaving the stock’ (Serier J. , 2003). Initially in their career, supervisors occupy the same position as line officers, working sidelong them. However, promotion to supervisor separates them from others they had worked with for years. Hence, acceptance by peers of a police officer is an integral and prized stage for them (Manning, 1989). Becoming a supervisor denotes the leave of an officer from his peer group. Additionally, it also signifies seeking acceptance of novel peers and upper level management of police agencies. Supervisory models Supervisors act as influential figures for other officers owing to various mechanisms. For instance, the command supervisory model focuses on the formal authority in the hands of supervisors. It advocates that adherence to bureaucratic standards and setting high performance standards can positively influence subordinates’ behavior (Allen & Maxfield, 1983). However, the downside is that the command model mitigates the task environment. As opposed to this, the bargaining supervisory model advocates mutual dependence of supervisors and officers. Officers need to seek small favors from supervisors such as favorable working schedules, partners, cases, departmental discipline, and the like factors. On the other hand, supervisors are dependent on subordinates’ productivity and maintain a low profile to keep out of problems. This reciprocity instead of the authoritative chain of command positively affects the behavior of subordinates. The impact of supervisors will be then equal to the benefits that will be provided to the subordinates. However, these benefits are restricted in public agencies like police organizations that are governed by civil service laws. Hence, it can be concluded that subordinates’ attitudes are modestly affected by the priorities of supervisors. Transactional leadership

Abu Dhabi Police Essay Example for Free

Abu Dhabi Police Essay The focal point of this paper is to develop a plan that would be successfully implementing an organizational change management system within Abu Dhabi Police department in order to increase its efficiency, development and achieving future objectives. It should be stated that at the moment there are several problems related to the issue and it is needed to overcome those in order to gain more mileage in the long run. The main aspect of this problem lies in the traditional form of police and investigation procedures that are taken into account and executed with comparatively lesser efficiency. This could also be sated that the functionality of the Abu Dhabi police department is more ancient in approach and there is an essential need for the department to catch up with the rest of the world in terms of technology implementation and efficiency evaluation. Furthermore, it is also essential to look into the aspects of administrative reconstruction as the department is unable to work up to its true potential with the administrative structure located at a medieval scenario. (Lamb, 2004, 69) Thus it can well be stated that the problem with Abu Dhabi police is not only with it’s below the par utility and efficiency but also is related to the ill formulation of the administrative system. Quite logically, the department is in extreme necessity of finding solutions for negating these problems. It should be stated that at the moment there is a five step remedy to this malady. Firstly, it is essential to understand the present management of Abu Dhabi police department and identify the key areas of improvement. Similarly, it is important in the aspect of researching the past to get an understanding about Abu Dhabi Police department’s status and importantly eliminating the risk of following the old mistakes. Then, it should be noted that a wide study is incorporated with a variety of methods of change management practices and their applicability in Abu Dhabi Police department. Furthermore, it is important to investigate the potential of alternative methods of change management and the most advantageous will be launched. Lastly, a strategy would be created with prospective enhancement that can be introduced, understanding the structure and working culture currently present in Abu Dhabi police department. It should be mentioned that the theoretical framework will involve police and public interviews, police and public’s strategic interview, historical records, secondary research through the Internet and university database, it will also use strategic analysis tools for development of the evaluation of the best method between coercive and consensual policing. In this context it should also be mentioned that the purpose of the project is formulated in a mutually beneficial way such that from an academic perspective there would be a huge gain in the context of valuable experience, and simultaneously add value by providing insights as well as a fresh objective outlook on any matter relevant to the social context. Research design will follow the following method or schedule. Firstly the participants will be trained about data collection techniques and tools to be used to collect the relevant information. The participants will be including police officers, data collection officers, team leaders and other resourceful personnel. Secondly the areas to be interviewed will be identified and accessibility determined. These areas to be sampled for the research can range from 10-16 of these areas, say 5 will be where coercive policing will be imposed and other five consensual policing can be applied. The period of the research can take a period of minimum 3 months and a maximum of 6 months of which during this period data will be collected. Thirdly the data so collected will be prepared as a report of findings. Finally, the final reports will be analyzed and evaluation for determination of the difference between consensual and coercive forms of policy. The different is supposed to put more emphasis on the difference. In order to attain the objectives it is essential to recognize the existing practices in Abu Dhabi police department and also in the modern police departments of countries like USA, Germany, UK, Australia etc. This will be done by individual interviews of the officials in Abu Dhabi and the through questionnaires from other corners of the world. Primary research will be persistent on personal interviews with Abu Dhabi Police department officials that will give an inner view of the present positing and future goals. This will also be a key basis of understanding the indolence for change. This will help in bringing out the indication of the present managed system in Abu Dhabi police department organization. Ultimately the clients will help in providing the true print of Abu Dhabi Police department’s working and key areas of improvement. Data presented from this research will assist to evaluate the best practices model and the actual working. This will help in indicating the difference and the reason for Abu Dhabi police department organization to implement a successful change management. Abu Dhabi Police higher officials will be randomly selected with favorable time and place for the interviews to be carried out. Finally the research will be focused on the historical data by looking at the Abu Dhabi Police department’s strategy in the past. If any failure or any glitches are to be found in companies strategy they will be pointed in this research. This will help the writer to understand the Abu Dhabi Police department’s goals in the past and their implementation process. It is necessary to design a new experiment that test the statistical method. For the purpose it is necessary to collect a complete data of the site that would include different religion, ethnicity or gender. An open meeting with police as well as the general mass or public would be very relevant in this context in the initial stages. The mixed gender of male and female Police and public could well be excluded as that would complicate matters in the context of gender variable juxtaposed with other pre mentioned variables but considering other dependable factors sustaining it would yield to be fruitful in the long run. Data would be collected in relation to the gender, color, religion of the potential customers in respect to the composition of the management under the same parameters. All these variables are considered as very relevant and important features of the statistical method and it is to be seen if these aspects are fundamentally acceptable in practical world and it could well be mentioned that social service, especially security service industry, are a very relevant manifestation of the social dimensions. As a result if the test is carried out in a proper manner with proper calculations of the population involved then there is no reason that the results would be both logical and true at the end consideration. In accordance to the basic test selected it could be stated that it could be possible that the outcome would be relatively logical in the sense that it would ultimately follow the trends of social facilitation theory in marketing and thus it would be agreeable with the statistical method and thus a well formulated marketing strategy can be constructed for the benefit of the Police and public alike as a definite method can be chosen between coercive and consensual policing. However, it should be stated that there would be few independent variables in the context of the test that could not be explained by the statistical method statements. Here the ethical consideration of the potential Police and public or the ethnic background of the potential Police and public may not be a very relevant factor. Thus there could be some flaws to the collection of the population but if these aspects are kept in mind then the shortcomings would easily be negotiated during the ultimate computations. As a result the test would appear to be a full proofed measure that would be able to define and prove the fundamental aspects and statistical method applied. It should be noted that the access to the research participants is both easy and hard. In terms of the public interview it would be relatively easy to identify and access but the difficult part would be to frame the questioner in accordance to the color and creed of the participants in general. In case of the police interview there would be more homogenous pattern in terms of the questioner but the difficult part would be to gain access. For the purpose it would be arranged to acquire permission from the hope department. Data will be collected using two different methods. The first will be interviews, which involve citizens, police officers from the sampled areas. This is an advantage in that feedback can be obtained instantly. The second will be use of questionnaires, which will be administered to the sampled areas. The questionnaire to be used will be the opened type. The advantage of this method is that the information obtained can be quantified to reflect that the sampled group as part of the entire population. The advantage is that it is easier to analyze data collected through questionnaire method. It should be noted that reliability for the researcher was achieved in the assurance that only a specified group of men and women were utilized in regard to the research. That group was focused mostly on customers and retails along with administrative personnel. This gave the research a more focused view of the research goal. The validity was managed as a result of this focus and emphasized in the considerations involved in the data collection, variables, and sampling methods. Privacy and confidentiality methods included assigning numeric and alphabetic coding to each responding questionnaire. This ensured anonymity in regard to the researcher and the subjects of the research process and a thorough qualitative method would be used during data analysis. The basic advantages of qualitative measures are multifold. Firstly, it presents a completely realistic approach that the statistical analysis and numerical data used in research based on quantitative research cannot provide. Another advantage of qualitative measures is that it is more flexible in nature in terms of collected information interpretation, subsequent analysis and data collection. It also presents a holistic point of view of the investigation. Furthermore this approach of research allows the subjects to be comfortable thus be more accurate as research is carried on in accordance to the subject’s own terms. The best statistical method would be to interview long well formulated day to day working procedure at a specific and well selected location. Throughout the procedure, it should be noticed whether there are specific variables within the testable population or not. These variables would be extremely important while evaluating the basic data in the final stages where the adjustments would be made to the formulated data in accordance to the observations. As a conclusion to the outline of this paper it can always be stated that Qualitative research is a process that includes interpretative paradigm under the measures of theoretical assumptions and the entire approach is based on sustainability that is depended on people’s experience in terms of communication. It can also be mentioned that the total approach is based on the fact that reality is created on the social formulations. It can also be mentioned that the basic target of qualitative research is instrumented towards social context under normal circumstances where it would be possible to interpret, decode and describe the significances of a phenomenon. The entire process is operational under the parameter of interpretative paradigm that can minimize illusion and share subjectivity under contextualization, authenticity and complexity of the investigation. References: Lamb, Davis; (2004); Cult to Culture: The Development of Civilization on the Strategic Strata; National Book Trust; Wellington

Kingdoms of Life Essay Example for Free

Kingdoms of Life Essay On our planet earth we have what are called kingdoms, 5 to be exact, consisting of a very diverse group of living things. Using these five kingdoms we classify our species and organize information on what we are and what resides with us. When we place every living creature into one of the five kingdoms it better helps us understand the world around us and its habitants. The five kingdoms include: Moneran, Protist, Fungi, Plantae, and the one we call home, Animalia. 1. Monera The simplest of all organisms is the bacteria of the Moneran kingdom. They are broken down into two types: Eubacteria and Archaebacteria. Eubacteria is known as the â€Å"true bacteria† which makes up the roughly 10,000 species in the Moneran group. Archaebacteria or ancient bacteria if you will, is the minority of the group and are only found in extreme environments including but not limiting; swamps, salt lakes, deep-ocean hydrothermal vent, etc. There are many types of species belonging to the Moneran kingdom that have yet to be discovered. Monerans are also the only group within the five kingdoms that are all prokaryotes. Prokaryotes are one-celled or colony of cells. 2. Protista In this kingdom we have multi cellular organisms (Protista) which are not a part of nor do they fit, the Animal, Plant, or Fungus Kingdom. In the beginning, protozoa were placed in a sub-kingdom of Animalia but because of the problems this classification had, it later became its own kingdom. All members of this phylum have what are known as nucleated cells and live in aquatic habitats (both freshwater and marine). According to Lynn Margulis, K.V. Schwartz and M. Dolan (1994), the cells of all Protoctista originally formed by bacterial symbioses or symbiogenesis. Members of this kingdom are not considered animals because they do not come from an embryo, they are not plants nor are they considered fungi because they do not develop from spores. 3. Fungi There are some members of the Kingdom Fungi that are associated with algal cells of the Kingdom Protista and/or prokaryotic cyanobacteria of the Kingdom Monera. Fungi plays a very critical role in natures continuous rebirth: Fungi actually recycle all dead organic matter turning it into useful nutrients. Fungi consits of species like: mushrooms, molds, mildews, stinkhorns, rusts, puffballs and many others. There are on estimate 100,000 known species today with hundreds of new species being discovered each year. 4. Plantae  With over 1.6 million species of living organisms on earth and new species discovered every single day, in particular; insects and nematodes residing in rsecluded tropical regions. However, with the present rate of destruction, a majority of the virgin tropical rain forest are headed straight for extinction, leaving millions of species undiscovered by the human race. It is the theory that approximately 99 percent of species that ever resided on earth were extinct long before the human ever set foot on this planet. Even with humans having such an incredible significance to the development of earth, technically they are considered to be newcomers on this marvelous planet. If all theories are correct, earth is aged at about 4.5 billion years old, meaning the ancient life forms (such as the cyanobacteria) appeared roughly 2-3 billion years ago. 5. Animalia There are nine phyla of this kingdom including the following: Porifera (poriferans), Cnidaria (cnidarians), Platyhelminthes (flatworms), Nematoda (roundworms), Annelida (annelids), Mollusca (molluscs), Arthropoda (arthropods), Echinodermata (echinoderms) and Chordata (chordates). Animals are considered to be part of this group because they are all multi-cellular organisms whose cells are connected by a plasma membrane and not by a cell wall of cellulose like the others. The differences between plants and animals led to the division of all life into what is known as (referenced above) Plantae and Animalia. In animals, the cells are organized into tissues and specialized tissue systems that permit them to move freely in search of food. They build energy by acquiring and ingesting their food, unlike plants, which use the system photosynthesis to benefit from the nutrients they need to survive. A well developed nervous system with sensory and motor nerves is what enables animals to receive environmental stimuli as well as a response to the environment around them. It was found that some were plant like while others (protozoa) resembled animals in that they obtain locomotion by means of flagella and that they actually digest food. The Animal Kingdom holds the most species of all of the kingdoms, ringing in a little over one million. Interesting fact, is that more than half of the animal species are insects. The result of 300,000 beetles plus the 800,000 different insect species a make up the largest order of insects (one fifth of all speciesusing a total of 1.5 million). It has been said that if the species between plants and animals on earth were lined up at random, every 5th species would be a beetle. Viruses Viruses are out of the Kingdom assortment completely and sometimes they are said even to belong to their own kingdom, the kingdom Virus. The small and less complex infectious agent is made of tiny macromolecular units composed of DNA or RNA covered by an outer protein coat. Virus do not contain membrane-bound organelles, ribosomes, a cytoplasm, or any other source of energy formation of their own. They do not have the self-maintenance metabolic reactions of living systems, they lack cellular respiration and gash exchanges. They are completely capable of reproducing but only at the expense of a host cell. They can and will only survive as minute macromolecular particles outside of their body. Plant viruses are transferred between each other by insects that feed on sap, such as aphids, while animal viruses can be carried by blood-sucking insects (mosquitos for instance). http://www.biology-questions-and-answers.com/life-kingdoms.html

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