USAs Copyright Law - 1487 Words

Copyright Law 1.Copyright law offers copyright holders the exclusive right to reproduce, distribute, and publicly perform copyrighted work (Carnes). The copyright holder has the authority to govern how the copyrighted material is distributed by giving specific permissions in writing. Without a specific written permission, no one has the rights to distribute or sell the copyrighted work. By selling collections that contain the whole program of the copyrighted material, Software of the Month Club (SOMC) is selling the copyrighted material without permission from the copyright holder, Cybersell Impact, Inc. The claim of endorsing and distributing the shareware as performing a service for the creators infringes the copyright law because of the distributions of the whole program. The copyright laws allow a small portion of copyrighted material to be used for socially beneficial purposes, but not the whole program. And, there was a restriction on the distribution that allowed the sample portion to be distributed without charge to users. The actual charging of the software and the fact of the whole program being distributed violated the copyright laws and the restriction of the copyright holder. The behavior that is being encouraged by the copyright laws and the judges in this case is to treat each other fair and with respect. If the copyright holder gives permission, then it is ok to distribute and sell, depending on what is actually granted in the written permission. By notShow MoreRelatedPlay Analysis : The Realist International System1137 Words   |  5 Pagesround of trade agreements in 1994, the WTO established the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS agreement). This agreement effectively established an â€Å"international standard regarding intellectual property and copyright laws,† (WTO, 1995, 321). Yet states like China and India have allowed the continuous production of counterfeit goods in spite of the fact they are WTO member states. In this case, the IO cannot dictate policy to the sovereign states, thus reaffirmingRead MoreGp Essay Mainpoints24643 Words   |  99 Pagesbeautiful and transcendental experience †¢ Originality tends to be compromised as everyone uses similar software. Without education, not innovative, simply learn from manual Copyright issues †¢ Proliferation of file-sharing services such as Kazaa, Limewire and Toreentsearcher †¢ More avenues are open for copyright breach, and this removes incentive for artists to continue the creative effort †¢ If sales revenue from the sale of CDs plummet because the public opts for the cheaper alternativeRead MoreMarketing Project of Reckitt Benckiser19417 Words   |  78 PagesVanish hits the world No.1 spot! From its UK launch in 1999, Vanish becomes market leader in 75% of the 57 countries it now sells in. 2008 Reckitt Benckiser completes acquisition of Adams Respiratory Therapeutics, Inc., allowing it to enter the USAs over-the-counter market with Mucinex – the clear No.1 cough remedy in the US. 2009 Reckitt Benckiser launches its new corporate brand identity. Contemporary and bold, it reflects RBs spirit and what RB is all about as a business: The Power behindRead MoreMarketing Project of Reckitt Benckiser19403 Words   |  78 PagesVanish hits the world No.1 spot! From its UK launch in 1999, Vanish becomes market leader in 75% of the 57 countries it now sells in. 2008 Reckitt Benckiser completes acquisition of Adams Respiratory Therapeutics, Inc., allowing it to enter the USAs over-the-counter market with Mucinex – the clear No.1 cough remedy in the US. 2009 Reckitt Benckiser launches its new corporate brand identity. Contemporary and bold, it reflects RBs spirit and what RB is all about as a business: The Power behindRead MoreManaging Information Technology (7th Edition)239873 Words   |  960 Pagesfrom the Microsoft Corporation. This book is not sponsored or endorsed by or affiliated with the Microsoft Corporation. Copyright  ©2012, 2009, 2005, 2002, 1999 Pearson Education, Inc., publishing as Prentice Hall, One Lake Street, Upper Saddle River, New Jersey 07458. All rights reserved. Manufactured in the United States of America. This publication is protected by Copyright, and permission should be obtained from the publisher prior to any prohibited reproduction, storage in a retrieval systemRead MoreStephen P. Robbins Timothy A. Judge (2011) Organizational Behaviour 15th Edition New Jersey: Prentice Hall393164 Words   |  1573 PagesCredits and acknowledgments borrowed from other sources and reproduced, with permission, in this textbook appear on the appropriate page within text. Copyright  © 2013, 2011, 2009, 2007, 2005 by Pearson Education, Inc., publishing as Prentice Hall. All rights reserved. Manufactured in the United States of America. This publication is protected by Copyright, and permission should be obtained from the publisher prior to any prohibited reproduction, storage in a retrieval system, or transmission in any formRead MoreContemporary Issues in Management Accounting211377 Words   |  846 Pagespublished 2006 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulateRead MoreStrategic Marketing Management337596 Words   |  1351 Pages200 Wheeler Road, Burlington, MA 01803 First published 1992 Second edition 1997 Reprinted 1998, 1999, 2001, 2003 Third edition 2005 Copyright  © 1992, 1997, 2005, Richard M.S. Wilson and Colin Gilligan. All rights reserved The right of Richard M.S. Wilson and Colin Gilligan to be identified as the authors of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 No part of this publication may be reproduced in any material form (including photocopying or storing

Ethics Moral Values That Can Dictate An Individual...

Final Exam Ethics are moral values that can dictate an individual perspective on what is considered to be wrong or to be right in their existence. It can also determine the standard of the individual, who think what is right or wrong, such as the golden rule states that â€Å"respect others, how they respect you.† In this essay, I shall explain the argument of Mill’s â€Å"greatest happiness principle† what is right, then I shall criticize the agreement on what is rights or wrong. I disagree with Mill’s Greatest Happiness principle, since it incorrectly answered the question â€Å"What is right?† Rights are the actions in proportion to the amount of happiness they produce and wrongs are the actions in proportion to the amount of unhappiness they produce? Furthermore. Happiness can be described as the pleasure and the privation of pain. In addition, Mill’s greatest happiness principle had derived from the conception of utilitarianism, which is to â€Å"bring back the personal needs, wants, and interest into moral considerations† (Solomon 514). Utilitarianism objective â€Å"was to make most people as happy as possible, sometime sacrificing a short term pleasure for a longer enduring ones† (Solomon 514). There are two definition of right based on Mill’s principle, which I learned in Philosophy the first is from professor Van Patten and the second is from John Stuart Mill principle of greatest happiness. The correct one is from Professor Van Patten that defines right as an action that maximizesShow MoreRelatedAn Ethical Organization On Business Environment Essay1587 Words   |  7 Pagesethical standards that dictate the accepted principles of decision-making, stakeholder interaction, management style, among a myriad of other elements of organizational operations. For those organizations that take a stakeholder management approach, operating in an ethical fashion also includes acknowledging that diffe rent stakeholder groups deserve to have their rights recognized and to be treated with dignity and respect (Hill, et al., 2014, p. 381). An ethical organization values the relationshipsRead More Define Ethics And Social Responsibility Essay1556 Words   |  7 Pages Introduction: As recently as a decade ago, many peoples,companies or organizations viewed ethics,social responsibility,business ethics only in terms of administrative compliance with legal standards and adherence to internal rules and regulations. Today the situation is different. Attention to them is on the rise across the world and many companies or organizations realize that in order to succeed, they must earn the respect and confidence of their customers. Like never beforeRead MoreDefine Ethics and Social Responsibility and Explain Why They Share Common Characteristics in an Organisational Setting. Identify Recent Examples Where Ethical Practices or Social Responsibility Have Not Occurred and the Implications for Stakehold...1651 Words   |  7 PagesIntroduction: As recently as a decade ago, many peoples,companies or organizations viewed ethics,social responsibility,business ethics only in terms of administrative compliance with legal standards and adherence to internal rules and regulations. Today the situation is different. Attention to them is on the rise across the world and many companies or organizations realize that in order to succeed, they must earn the respect and confidence of their customers. Like never before, corporatonsRead MoreEthical Decision Making: What Are the Elements and the Impact?1366 Words   |  6 Pagesmeaning of morality. We continually make decisions without regard to ethics or moral values on a daily basis. We can define morality as a system of shared rules, or values that dictate specific behavior during the interaction of people. Morality or moral value is about doing the right thing and brings up questions on how we ought to act in any given situation. According to John Wilcox and Susan Ebbs, i n The Leadership Compass, Moral behavior is concerned primarily with how we treat one another individuallyRead MoreThe Appraisal Of Moral Worth : Kant Versus Nagel1253 Words   |  6 PagesThe Appraisal of Moral Worth: Kant Versus Nagel Since the moment we were born, our minds have been absorbing information and relaying that information into choices that subsequently dictate our life. Out of these choices, we face the dilemma of personal gain versus morality. It is in the best interests of all humanity that each individual shares similar values, such as trust, compassion, loyalty, and a desire for communal progress. When individuals share such values, it allows a society to buildRead MoreEssay about The Elements and Impact of Ethical Decision Making 1446 Words   |  6 Pagesmeaning of morality. We continually make decisions without regard to ethics or moral values on a daily basis. We can define morality as a system of shared rules, or values that dictate specific behavior during the interaction of people. Morality or moral value is about doing the right thing and brings up questions on how we ought to act in any given situation. According to John Wilcox and Susan Ebbs, in The Leadership Compass, Moral beh avior is concerned primarily with how we treat one another individuallyRead MoreCultural Relativism And Anti Foundationalism1556 Words   |  7 Pagesphilosophical doctrine that makes the claim that moral or ethical systems, which vary from culture to culture, are relative to culture and therefore equally valid. This is the chief argument to support the anti-foundationalist view of the pre-Socratic era that denies the possibility of an ethical or moral foundation, because of the multitude of cultural differences in ethical values. In essence, the argument is that as a product of society, individuals are subject to the standards imposed by their cultureRead MoreThe Values Of Philosophy : Questions1017 Words   |  5 PagesName Instructor Course Institution Date The Values of Philosophy Question #1 String theory seeks to explain the origins of universe and combines the four forces of nature. It is apparent that it was impossible to integrate the theories of quantum mechanics and general relativity before the string theory. For three decades, string theory has played a key role in theoretical physics because the theory explains the Big Bang that took place some 300 billion years ago, which led to violent riseRead MoreEthics And Principles Of Ethics991 Words   |  4 Pages Ethics is a system basic moral principals and concepts of civilized human conduct. it helps us develop ideas about what is moral, right from wrong and dictates of conscience. Ethics also helps to distinguish between honest and dishonest characteristics in people. In business, ethics is something that is essential to one’s moral compass. It is something that is taught through the child rearing process and into a child’s formative years. Ethics requires knowledge. Fundamentally this suggests thatRead MoreA Relativist Is More Tolerant?1314 Words   |  6 Pagescontrast morally contradictory cultural values. A Universalist proposes values that are based on his or her own set of values. This can promote intolerance because it provides a basis to make moral judgments between cultures. This is also an example of ethnocentrism, or judging another culture by the values of one’s own culture. Essentially, moral rightness and wrongness are expressions of conventions and nor ms that vary between cultures. There is no objective or moral truth because actions cannot be judged

Ed Rendell’s Philadelphia Free Essays

It is very rare for a public official to be regarded as a hero let alone a saint.   With the height of the recession and the scrupulous events that paved its way to politicians fighting over the hunger of power, fame and wealth; Ed Rendell of Philadelphia proved that he is a force to be reckoned with.   Sure, there have been several autobiographies written over the advantage of the famous. We will write a custom essay sample on Ed Rendell’s Philadelphia or any similar topic only for you Order Now But in this case, Buzz Bissinger, showcased not the glitz and the glamour of the politician but rather focusing on the urban world and how their leader, in the name of Mayor Rendell fought to save the sinking social and economic state of his jurisdiction (Bissinger, 1998). Philadelphia, as divided and as financially crippled in the face of the Western geographical affirm, reached a point where their means of living and the rising number of violence is headlined on the national paper.   Urban policies have long been issues in the government, to what extent shall the feds need to lend their hand on a certain area? Pulitzer Prize winner Bissinger researched and found interesting contexts on the trials and tribulations that the city underwent. Far more different than what those that hid in the buildings of the streets of New York or the tanning skins of those sitting pretty and well-financed in the beaches California.   Mayor Rendell was a leader in his own right and a philanthropist by heart.   He quotes David Cohen in the first chapter (Bissinger, 1998), â€Å"[h]ave I done the right thing here?†Ã¢â‚¬â€precisely the question most of those who served before Rendell served his tenure in office. First Term: The Meaningful Reforms Mayor Rendell’s first term in office (1992-1996) can be coined in one term: challenge.   Given the fact that he was to inherit an already failed economy, it was quite expected that he would either save the city or worsen the situation. As any other cynical human being would produce, they already anticipated for the latter. Philadelphia had an annual budget of $200,000 which in the light is expected to help its constituents that equals to 1.6 million. In a place clothed with bankruptcy and corruption, it was a near-death situation. It was like the urban poor society of the West and the chances of rising from the behemoth of doom were 10:90. So Ed Rendell looked for means to endow grant monies, reductions in federal layoffs and all other cost-cutting measures possible for his jurisdiction to survive. He lamented over the loss of jobs and the drastic increase of violence in every major event that transcribed.   He was to seek every help lent by those who are willing to shoulder their burden.   But he also had a humanistic side of him; he despised those who wrote provoking articles about his administration. He knew too well he only wanted what was best for his fellowmen—so he fought for his dignity alongside. The Characters’ Accounts A recovery plan was at hand.   Fifi Mazzcuza, famous for parenting the parentless, emphasized the dreadful reality of the place—drug dealings, theft, and all the other gang-related dilemmas that wrapped the city in its darkest. Linda Morrison for one has seen the painful reality of living in the suburbs—she witnessed in her naked eyes the bloodshed of those who are spiritually lost and in need of guidance. She has been assaulted by those whom she considered countrymen. And lastly, Jim Mangan, a typical Philly who suffered the torture of financial constraint. He wasn’t alone, there were many who had the same story as he does.   Finding a job in his time was like looking for a peck in a pile of sand, whilst the need to survive in the heavy rain that poured while they were painstakingly seeking. It was hard for them. And just when everything seemed to be hopeless, there was a spark of light. And their story continues. Reference Bissinger, B. (1998). A Prayer for the City. New York, NY: Vintage.    How to cite Ed Rendell’s Philadelphia, Papers

Hoping for a Second Chance Essay Example For Students

Hoping for a Second Chance Essay Have you ever wished you could turn back the clock and relive a particular moment or make sure it never happened? Well, unfortunately, we are unable to do that. I remember one day that I wish I could go back and erase. It was a warm summer morning the wind blowing through my hair and the sun shining down on my face. I remember the family rushing to get ready to go to the beach for the first time everyone smiling, laughing, and joking around while getting dressed. When we finally got to the beach around nine in the morning, there was a lot of families setting their umbrellas in the sand, laying towels down, and kids running towards the water. I still remember pulling my sister to hurry so we can get into the water with me like the other kids. When we got to the edge of the beach I stood there waiting for the water to come back up to the shore to cover my feet, once it did I couldn’t help but go in further into the beach as the waves kept pushing us back to the shore. I remember seeing something in the water so as I go down to reach for it I hear my mother yell to me and my sister to hurry and get out of the water, at that moment I knew it was time to go get on the boat to go in further into the beach. Now I’m on the boat in the middle of the ocean looking around in amazement I couldn’t believe how beautiful and clear the water, was it was like I was in a dream that I didn’t want to wake up from. As I’m getting closer to the side of the boat my mother warns me not to get to close unless I wanted to fall over, but of course I wanted to get a closer look at the ocean and I didn’t listen, the next thing I know a wave hits the boat really hard and I end up falling out, I remember thinking this is it I’m going to die I should have listened not long after I pass out. Finally, I wake up to a bright light in my eyes, a strange smell that I couldn’t recognize, and the sound of my mother crying while my father tried to calm her down. I’m finally able to make a noise to let them know I’m awake that I’m okay. My mother rushes over to me and tells my father to go get the doctor, I ask my mother where was I? What happened? She was finally able to tell me that I got to close to the edge and I fell over and that my dad jumped in to go get me, and by the time that I got back on the boat I was unconscious. That I had been in the hospital for about two hours. As she is telling me what happened I started to cry I couldn’t believe that I almost didn’t make it alive. Still to this day I am very grateful to still be alive, that things didn’t turn out with a different ending. Although this did happen a long time ago I can still remember it like it was yesterday and it still terrifies me to get on a boat. Well this is my second chance at life and I am willing to live it to the max with no regrets, life is too short to be taken for granted and not many people are able to see that.

Infrared and Ultraviolet Light Essay Example

Infrared and Ultraviolet Light Paper Name: Tutor: Course: Date: We will write a custom essay sample on Infrared and Ultraviolet Light specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Infrared and Ultraviolet Light specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Infrared and Ultraviolet Light specifically for you FOR ONLY $16.38 $13.9/page Hire Writer Infrared and Ultraviolet Light Infrared Light Infrared light is a form of electromagnetic radiation whose wavelengths are longer compared to visible light. The electromagnetic spectrum exhibits a vast range of wavelengths spanning from highly energetic gamma rays and short wavelengths to low-energy radio waves and long wavelengths. The visibility of this spectrum is extremely small. Infrared light is similar to normal light only that it has a longer wavelength thus making it impossible to see with the naked eye (White 42). The range of infrared wavelengths corresponds to an approximate frequency range of 430 THz to 300GHz. It also includes the thermal radiation given off by objects at room temperature. Infrared light is absorbed or emitted by molecules whenever they alter their vibrational-rotational movements. William Herschel discovered infrared radiation in the year 1800. He was performing a study on the heating effect of different light colors. The different colors of light were produced by a passing normal light through a prism. In his study, Herschel noted that the strength of the heat increased as he progressed from the blue end to the red end of the spectrum. He presented his results in London and called the red light ‘Calorific rays’. The term ‘infrared’ was adopted later in the 19th century (Read 32). Primarily, infrared is divided into three distinct spectrums. These include far infrared, mid infrared and near infrared. The division of infrared light on this basis depends on the wavelength. However, these divisions are not precise since they vary depending on the publisher. These divisions are used to observe temperature ranges in environments such as space. They are justified by the different responses humans have on radiation. In this case, near infrared exhibits radiation with the closest wavelength. This makes it visible to the human eye. Far and mid infrared categories, lie further away from the visual spectrum. Unfortunately, there are no international standards for such specifications. The boundary separating infrared light from visible light is not defined clearly. The sensitivity of the human eye is not designed to detect light with a wavelength above 700nm (White 64). Therefore, light with longer wavelengths does not make significant contributions to scenarios illuminat ed by common sources of light. Since its discovery, infrared light has proven useful in a number of fields. For example, infrared is used to facilitate night vision. Night vision devices function by converting ambient light photons into visible light. Additionally, infrared light can also be used in determining the temperature of objects through a process known as thermography. Thermography is mainly applied in industrial and military applications (Read 64). However, this technology is making its way into the public through infrared cameras, due to the reduced cost of productions. Since all objects emit infrared radiation based on their temperatures, thermography is used to have a clear picture of the environment regardless of whether there is visible illumination or not. Infrared homing or infrared tracking refers to a missile guiding system that tracks a target using its electromagnetic spectrum. Missiles that use this infrared technology are coined the term ‘heat seekers’. Many objects such as vehicle engines, aircrafts and people produce and retain heat. This heat can then be tracked using infrared technology. Additionally, infrared radiation can be used as a source of heat. One advantage of this is that the technology is used to create infrared saunas used to treat chronic health illnesses such as arthritis, congestive heart failure and high blood pressure. This technology is also used to thaw ice on aircraft wings. Infrared radiation is also becoming popular in safe heating therapy for physiotherapy and natural health. Additionally, heat from infrared radiation can be used in cooking. Primarily, infrared heaters include three parts, a heat exchanger, infrared bulbs, and a fan for blowing air into the exchanger for heat dispersion. Indeed, the discovery of infrared radiation has led to significant breakthroughs that have benefited humanity. However, this form of electromagnetic radiation has several disadvantages. For example, when this radiation is used in certain settings such as high heat industrial locations, it becomes a health hazard to the user’s eyes thus causing damage or blindness. Another disadvantage is that it has short-range transmission compared to other forms of transmission. Other than having short-range transmission, the transmission of infrared radiation is slow compared to wired transmission. Furthermore, all infrared signals can be interrupted by foreign materials when they are in the path of the transmission. Such materials may include people and walls. Ultraviolet Light Ultraviolet light or UV light is a form of electromagnetic radiation with a short wavelength compared to visible light. However, its wavelength is longer than that of X-rays. Similar to infrared light, ultraviolet light cannot be detected by the human eye due to its long wavelength. Blunt (18) argues that this form of radiation bears increased energy compared to visible light. It is capable of breaking bonds between molecules and atoms and altering the chemical composition of materials. UV light can also cause fluorescence in certain substances. This means that it causes certain materials to emit visible light. UV light, present in sunlight, is beneficial since it kills microorganisms and acts as a source of vitamin D. Even though UV light is not visible, we are aware of it through certain effects such as sunburn or suntan. With the sun acting as a major source of UV light, the ozone layer plays a vital role in blocking most of this light (97%) that would otherwise prove harmful to organisms if it gained access into the atmosphere (Blunt 37). The 3% that penetrates the atmosphere is not particularly harmful, although it can cause cancer and long-term damage to the skin. Primarily, the sun is a source of all categories of UV light such as UV-A and UV-B. The discovery of this radiation is associated with the phenomenon that silver salts become dark when exposed to light. Johann Ritter in 1801 observed that invisible light, after the violet end of visible light, darkened paper soaked in silver chloride. Initially, he named these rays â€Å"oxidizing rays† to differentiate them from heat rays (infrared) discovered in the previous year and to emphasize chemical reactivity. The terms â€Å"heat rays† and â€Å"chemical rays† were used to describe these rays throughout the nineteenth century, but they were later dropped for infrared radiation and ultraviolet radiation respectively (Read 32). UV light, UV-B in particular, benefits humans by allowing the manufacture of vitamin D. This is achieved by the conversion of skin chemicals into the sub-form of the vitamin, and then into the vitamin itself. This vitamin is beneficial to human health. Lack of this vitamin leads to immunity disorders, various cancers, high blood pressure, and cardiovascular diseases (Blunt 76). Severe lack of this vitamin causes bone diseases referred to as rickets. Inadequate supply of sunlight is the prime cause of the vitamin’s deficiency. UV light is also used in the technology of fluorescent lamps that apply the fluorescence phenomenon (Read 81). Most fluorescent lamps use UV light as their energy source to ionize mercury vapor. A special fluorescent coating absorbs this ionized vapor to produce visible light. Zoologists and biologists use ultraviolet light to take night surveys on organisms in the field. UV light is also used as insect traps. Since insects are naturally attracted to UV light, entomologists use it to attract them for studies. UV fluorescence is also used in parties and nightclubs by causing clothing to glow and make it appealing. Astronomers also use UV light in mapping galaxies such as the Milky Way. This allows them to make out the evolution of galaxies over time. Primarily, young stars emit more ultraviolet radiation compared to older stars. They also emit UV light at a higher proportion at the furthest end of the spectrum. Regions where new stars are born, therefore, produce a brighter UV glow. Astronomers use this knowledge to identify and map such regions. Despite the numerous benefits UV radiation provides humanity, it also has disadvantages. The ability of UV light to change the chemical composition is harmful. As UV light causes minor skin irritations such as sunburn, radiation that is more energetic, can lead to premature skin aging (Blunt 97). It can also lead to alterations of the DNA that can eventually cause skin cancer. Furthermore, overexposure to ultraviolet light causes the skin to produce a pigment known as melanin. Melanin is harmful to the skin and can lead to cancers such as melanoma. Works Cited Blunt, Katharine. Ultraviolet Light. Chicago, Ill: The University of Chicago press, 2011. Print. Read, F H. Electromagnetic Radiation. Chichester [Eng.: J. Wiley, 2010. Print. White, Laurie. Infrared Radiation. Amherst, N.Y: Amherst Media, 2009. Print.

Health Decisions and the Biopsychosocial Model Essay Example

Health Decisions and the Biopsychosocial Model Essay Example Health Decisions and the Biopsychosocial Model Essay Health Decisions and the Biopsychosocial Model Essay Cardiovascular disease and hypertension Is heredity In my family. Last year I had a chance to experience how biological factors Influenced my decision to have a complete checkup because of preventive care. This Included a complete blood work up and physical assessment. The outcome from the tests revealed that my cholesterol was elevated and my blood pressure as well. For some unknown reason, I put off seeing the doctor long as possible due to the possible risk of these diseases. The doctor provided me with education material on these diseases, and how to monitor the conditions. Also he recommended that I eat healthier. The positive decision to get a complete checkup has made me aware; that I can live a normal healthy life by maintaining a healthy diet and exercising as prescribed. Based on my decision to seek medical advice was a psychological factor that influenced the turning point in my life. I had emotional problems about accepting the Ruth, if the outcome was positive. I delayed the checkup because I did not want to face the possible risk of cardiovascular and hypertension. It seemed that I blocked it out of my mind due to my mom suffering and dying with the same diseases. I felt depressed and angry because I did not want to be diagnosed with the disease. But, on the other hand I wanted to be healthy, physical and mental. Learning to deal with the outcome has helped me to adjust my feelings, and has motivated my decision to cake care of my health. Social factors can definitely have an influence in one decision to stay healthy. For example, I have struggled with being overweight since I had my daughter. About six months ago I started to cut back on what I ate and stop eating out. I met a new friend and he constantly wanted to dine out before I knew it, I had started to gain the weight back. I am happy that I was able to re-evaluate and gain control of my life to eat healthier.

Hands by Sherwood Anderson Essay Example | Topics and Well Written Essays - 500 words

Hands by Sherwood Anderson - Essay Example The story is about Wing Biddlebaum, a fat little old man from Winesburg, Ohio. Wing Biddlebaum was driven out of Pennsylvania, his original hometown, after he was falsely accused of molesting a young boy in a school where he used to teach. This happened because of his habit of caressing the boys’ hairs and shoulders whenever he talked to them. Wing’s seemingly uncontrollable hands manifest his grotesqueness. The central symbol of this story is hands, which figure as agents of conflicting aims of different characters and demonstrate Wing’s helplessness and vulnerability. Discussion We are told that ‘Winesburg was proud of the hands of Wing Biddlebaum in the same spirit in which it was proud of Banker White's new stone house and Wesley Moyer's bay stallion’ (Anderson 16). His hands are a distinguished feature which amazes the citizens of Winesburg, but he seems not to notice and instead is afraid of them. Many citizens, including George Willard, have m any times wanted to ask him about his hands and why he seemed frightened by their power. This fear of his hands shows his grotesque nature. Wing hides his hands in fear that he might repeat the incident at the school. This is despite the fact that he had pure intentions in everything he did. ‘In a way, the voice and hands, the stroking of the shoulders and the touching of the hair was a part of the schoolmaster's efforts to carry a dream into the young minds.

History on the start of the U.S. Air Mail Term Paper

History on the start of the U.S. Air Mail - Term Paper Example Even the American Congress was not much interested in giving funding to the postal department for developing air mail system earlier. But the American military has come forward for the rescue of the postal department and they have extended great support to the postal department for developing air mail routes and to train the postal department pilots in using airplanes. Moreover, the American electrical companies has developed and provided navigation equipments for the usage of postal department planes and finally after watching the huge success of air mail system, American Congress also come forward to the rescue of the postal department. From there onwards American postal department never looked back and developed one of the most advanced air mail delivery system in the world. This paper analyses the American air mail history and early developments. Postal service was probably one of the ancient communication means in the world. Even though road, rail and sea paths were used earlier for mail deliveries, it caused lot of difficulties in sending and receiving mails through these mail methods. The need for fast delivery of mails has brought the idea of airmail delivery system. â€Å"THE FIRST aerial mail transportation may be traced back to 1870, when in that year letters were carried out of beleaguered Paris by free balloons, cast adrift in the winds.   The first of such flights was made on September 23, 1870, and carried 500 pounds of mail† (Keogh) The need for aerial route for fast mail delivery system has been realized even before the 20 th century. Most of the Airplanes which used earlier for war purposes were controlled by the military and hence air mail delivery using airplanes were not imaginable earlier. But the usefulness of airplanes in mail delivery has been realized by human kind at the beginning of the 20 th century itself and in countries like India, England and

MHE510, Occupational Health and Safety, Mod 4 Case Assignment Essay

MHE510, Occupational Health and Safety, Mod 4 Case Assignment - Essay Example In this case, the patient sued the company he is working for because he has mesothelioma and has been exposed to asbestos. He admits that he has had several positions and all of them exposed him to asbestos. The UK courts have determined that the exposure is work related and now must determine how much of the cost of the workmans compensation each of the companies are responsible for (OSullivan, 2010). Before this writer could take a position, there are some things that must be known? Does or has this employee actually worked in a company where he might have been exposed to asbestos? What kind of lung cancer does he presently have and is he a smoker? Have there been any tests to assure that this lung cancer is coming from exposure to asbestos? If the answer to number one is true and number three is positive, the answer has to be that this is a workmans comp case. Workmans compensation is meant to cover a disabled worker who has been injured on the job with a fixed income in an effort to avoid litigation because of the injury. These awards are awarded for disability or to the family in the case of death (cornell.edu, 2010). It was the first critical legislation that was provided in liability. It has changed quite a lot since that original ruling and there is more onus on the boards to determine whether an exposure was from work or personnel. In the case of asbestos, there are now very specific things, including small particle masks that an employer is supposed to use. If they do not and the employee is exposed, it is not difficult to determine where the exposure happened. There are other more difficult cases however (Anderson, 2000). An example of this is the firefighter that gets lung cancer and is also a smoker. It is known from studies (Guidotti, 2007) that firefighters are exposed to many carcinogens therefore the suggestion for those exposures is as follows. "There is presumption justified for the following cancers: bladder, kidney, testicular and brain

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