Informative Paper - Evolution of Internet Governance and Its Effect on Research

Informative - Evolution of Internet Governance and Its Effect on Global Internet Users - Research Paper Example 6). The term governance also had its share of controversy when it came to its interpretation. Many considered governance to have an extremely related meaning to the word government. The meaning, which is accepted by the Internet community, considers governance as governing the conducts and behavior of any institution, inclusive of the non-governmental institutions. A government project formed the origin of the Internet. In 1960, the United States of America sponsored a project considered as the mother of the Internet. This was a resilient communication project mandated with the development of the research named DARPA Net. With time, there took place the invention of Transmission Control Protocol/Internet Protocol (TCP/IP), which evolved the Internet (Gelbstein & Kurbalija 2005, p.11). The Internet is distributed in nature; one of them is the data packets nature to take a different path through any network, enabling the Internet to avoid traditional barriers, as well as control mechan isms. This theory is a total proof that, in the early days, in relation to the Internet, there is no central government, grand design and central planning. This made people consider the Internet as a unique tool, which could offer an alternative solution to the modern politics. In the 1980s, the term Internet governance was introduced, and it described the technical management of the Internet core resources globally. The core resources included IP address, domain names, Internet protocols as well as the root server system. The term Governance was used to show the outstanding differences between government and governance. After the emergence and discoveries of technology advancements such as the telegraph, the government in the early... According to the paper Internet governance is summarized as the act undertaken by Governments, civil society, and the private sector in the role of development and applications; it also involves their respective roles of shared norms, decision making procedures, rules, principles, and other elements that shape the process of Internet evolution. A computer specialist views Internet governance in the form development of various applications and standards. Lawyers focus mostly on the dispute and jurisdiction resolution. The essay makes a conclusion that the evolution of Internet Governance has been a long journey, which at the end has yielded fruits to all Internet users. The World summit on the Information Society has done an outstanding job to make sure that Internet governance is achieved. Other significant players associated with the success of developing and implementing Internet governance include private sectaors, international organizations, governments and young users. Currently, there are large numbers of young users using the Internet and the Internet governance has affected them in various manners. Internet governance has had both positive and negative social effects on the Internet users. However, studies show that the pros outdo the cons; therefore, Internet governance can be considered a success that has had a couple of challenges. Internet governance is a significant contributor towards forming a conductive social environment for the young Internet users. Therefore, the role of Inter net governance to the youth’s social life is of exceptional benefits.

America's Richest Men and Their Impact in the Country Research Paper

America's Richest Men and Their Impact in the Country - Research Paper Example Rockefeller soared to be the richest man in U.S due to the growing importance of kerosene and gasoline (Chernow, 1998, pp. 10) In 1853, his relatives shifted to Strongsville where he took a ten week course on book keeping and in 1856, he got his initial job as an assistant bookkeeper at the Hewitt & Tuttle firm. He worked long hours in that firm as he was delighted and was skillful in accounting and calculating the transport costs which later helped him in his career (Chernow, 1998, pp. 46-47). He earned $50 at the end of the month and donated 6% of these proceeds to charity. This donation later rose to 10% when he joined the Baptist church (Chernow, 1998, pp. 50) With his partner, Maurice B. Clark, in 1859, Rockefeller went into manufacturing commission trade where they raised a capital of $4000. From this, Rockefeller went into business gradually where he made money with each year (Segal, 2001, pp. 25). Together with his partner, they ventured into oil business where they first bui lt their company first in 1863 in â€Å"The flats† then moved it to the Cleveland’s growing Industrial area. The commercial oil trade by this time was in its young growing stage. Whale Oil was the only oil that was available and was very expensive and an alternative needed to be sought, a cheaper and all- purpose lighting fuel was needed (Chernow, 1998, pp. 73-74) Rockefeller later bought the Oil Company, which had started out as a partnership, in an auction. The company had started out as a partnership between him and the Clark brothers. He positioned his business and himself well to take advantage of the post –civil war successfulness and the large expansion of the territory westward which was nurtured by the constructions of the railway lines and a oil-fueled economy. He then sought for financing and reinvested the profits he gained and adjusted quickly to the changing markets (Segall, 2001, pp. 32, 35) In the 1890’s he flourished into iron ore and ore transportation. This then forced a conflict between him and his competitor steel magnate Andrew Carnegie. Then he later went on a huge buying fling where he acquired leases for crude oil production in Indiana, Ohio and West Virginia (Segall, 2001, pp. 84) From his first salary, Rockefeller tithed 10%of his proceeds to the church and he increased his giving with increase in wealth. He gave to the benefit of learning and communal health causes, fundamental science and the arts too (Ordway, 2009, p 107). Together with his consultants he discovered the conditional funding, which necessitated the beneficiaries to establish the organization in the interest of many people and that thereafter the recipient may be relied on to achieve the people’s interests and their cooperation (Fosdick, 1989, pp. 88). He funded heavily a College in Atlanta for African-American women and also gave appreciable contributions to Denison University and other Baptist Colleges. This then shows that Rockef eller supported education in US. He even founded a General Education Board in 1903 to endorse learning in the country. This played an important role in improving the living conditions of society around him (Jones-Wilson, 1996, pp.184) Rockefeller then established the Rockefeller institute for Medical Research in New York City which would still make him one of the immense beneficiaries of

Master of Business Administration Personal Statement

Master of Business Administration - Personal Statement Example For deals worth more than three million dollars, I work with a team in order to come up with proposals and pricing strategies. All of the opportunities that I handle are highly competitive. My company is in the commodity business. This means that prices are the deciding factor whether we achieve deals or lose them. The role I play in the company is vital. When I bid on an opportunity, finding the right price is crucial to winning business. It is important to find the line between a low enough price to win business and a price high enough to make a profit. Personal accountability in this field is the only way to achieve positive results. It is imperative to remember while going after new business, that one must also retain current customers. The competitive personal computer market needs employees that inspire customer loyalty. This makes retaining customers a top priority for me. It is my goal to generate good relations with new customers, while maintaining the same constructive relationship with current customers. This aspiration sometimes can be tedious, but I work hard to accomplish this objective. A long term intention is to use my sales and marketing experience to pursue a career in product management. While I am comfortable with numbers, working with product management would be more fulfilling.

Role of Visual Culture in the Contemporary Cultural Diversity Research Proposal

Role of Visual Culture in the Contemporary Cultural Diversity - Research Proposal Example In their articles, Mirzoeff, Ruby, Sturken, and Cartwright argue despite being instrumental in globalization, the impact of visual culture in the assimilation of cultural diversity is still debatable. Therefore, there is need to conduct a research that answers the following questions: 1. What is visual culture in the context of classical and contemporary cultural diversity? 2. How has visual culture enhanced globalization? 3. Has globalization changed the contemporary perspectives of cultural diversity? 4. Has visual culture enhanced assimilation of contemporary cultural diversity? Literature Review Different authors and scholars have had varied views on the role of visual culture within the multi-cultural society in the contemporary world. In both his works, Mirzoeff (â€Å"An Introduction† 3; â€Å"Visual Culture† 4) argue that visual culture depends of the circumstances under which various images are made and this may not have a significant impact in changing the per ceptions of the viewers in relation to accepting and assimilating cultural diversity. Ruby (1345) also adds that stakeholders in the visual culture are only concerned with the personal interpretation of the image presented. Consequently, the viewers are likely to have varied perceptions especially given the negative and positive feelings created by the image thereby acting differently as in the example of the fetish (Fusco 368). This explains why some countries or regions would censor images to avoid the negative feelings and interpretations (Sturken and Cartwright 390). The idea of having varied feelings brings about the idea that regions and people are different and so are people. This has only worsened the situation in the assimilation of cultural diversity perspectives especially in the contemporary world. Another argument by varied authors and scholars on the impact or role of visual culture towards enhancing assimilation of cultural diversity is the idea of individualism. Ther e are studies proposing that instead of inspiring communalism and acceptance of the diversity in culture, visual culture has actually inspired individualism based on the magnification of contrasts that exist between regions or people. Sturken and Cartwright (389) argue that there has been an increase flow of foreign ideas courtesy of globalization. Such ideas tend to bring new information, new perception, and create more contrasts, which only lead to the acceptance that regions and people can never be equal (Mitchell 298). However, Mirzoeff (â€Å"An Introduction† 3) argues that despite the liberty of receivers to interpret the images in relation to cultural diversity, the receivers have continuously interpreted the images negatively and this invokes the idea that no regions or people can ever be equal. Ruby (1345) discusses the barrier of visual culture to enhancing assimilation of culture diversity on the on the basis of impact of current culture in the lives of people. The current culture has had significant impacts on the lives of people with reference to the cultures of the other people. This creates the idea of differences between various cultures. In addition, there has been an increasing tendency to make comparison and contrast, which only lead to the widening of the gap between different cultures. Consequently, it becomes difficult for the viewers or receivers to interpret visual culture on a neutral ground. The lack of neutrality continues to widen the gap between various cultures, which make visual culture to be a barrier in the assimilation of cultural diversities. Nevertheless, Rose (25) and Dikovistskaya (71) argue that through visual culture viewers and receivers have been

Review and analysis of Educational Research Essay

Review and analysis of Educational Research - Essay Example The topic of the study revolves around the access factors faced by different employees concerning the learning in the workplace. From the two topics, it is evident that the two studies are somewhat related but completely different. First, the two studies deal with education for mature education, but Swain and Hammond (2011) focus on students in institutions of higher learning while Riddell, Ahlgren and Weedon (2009) focuses on individuals in the workplace. The other difference in the two articles is that Swain and Hammond (2011) try to focus on the individuals themselves and their motivations and benefits from the studies. Riddell, Ahlgren and Weedon (2009) focuses on the external factors that affect the individual, not what the individual feels. According to Brannen, the scope and scale of research refers to the exact areas covered by a researcher, the information presented in the study, and the factors that limit the research. This means that the scope and scale of research include s the lower and upper bounds of a study. In Swain and Hammond (2011), the researchers specifically deal with mature students in Higher education. The authors deal with these students with the aim of identifying their motivations and outcomes for studying part0-time. ... The study focuses on survey data to identify the extent and benefits of workplace learning in Scottish SMEs. The scope is further divided into information intensive organizations and traditional manufacturing and training organizations. Finally, this scope and scale is limited to workplace learning and the benefits derived by the employees for the companies being investigated. Contrary to the research by Swain and Hammond (2009), Riddell, Ahlgren and Weedon (2009) focus on the employer and not the individual. Research in social science is usually different according to the paradigms or extent of research conducted (Oakley, 2007). This means that different researchers aim to achieve different results by focusing on different research methods, mainly choosing from qualitative and quantitative research methods. The two methods mentioned usually differentiate the paradigm used in research, where the scientific theory or positivist theory is used for quantitative research while the constr uctivist paradigm focuses on qualitative research. Riddell, Ahlgren and Weedon’s (2009) background literature is read as statistical based, with emphasis on policies and the Scottish Government objectives of getting adults up to a level of education to create an equal Scottish society. The researchers’ literature reports the European study of lifelong learning as its driver, hence a study on government objectives. It does nevertheless highlight, â€Å"driving national economic growth, whilst at the same time increasing social mobility for socially disadvantaged workers through workplace learning programmes† (p.794) does not justify the government objective. This could indicate the perspective of the researcher could fall into

Realism In International Affairs Essay Example for Free

Realism In International Affairs Essay Realism in politics is a political philosophy, which tries to observe, shape and predict political relations. It is based upon assumption that power should be the primary goal of any political act, both in international or domestic sphere. As far as domestic affairs are concerned, this theory states that political figures are supposed to direct all efforts to maximizing their power. Accordingly, in the international sphere nation should aim at maximizing its power among other states. This theory can be regarded as a prescription to be followed by politicians and states or as a description of current affairs of the state or politician pursuing self-interest. Realism in politics is often defined as a principle of power supremacy, and it has a long history since the ancient times. It was reflected in Peloponnesian War by Thucydides. This theory was also touched by Machiavelli in his writing The Prince, as well as by other outstanding philosophers like Spinoza, Hobbes and Rousseau. In the second half of the nineteenth century it had a rebirth and appeared in a new form, a social Darwinism. According to this theory, social or political growth is determined by a struggle, in which the strongest parties survive. According to the theory of political realism, interests should be satisfied by means of power exercise, and the world is defined by competing powers. In this context, the adherents of Marxist theory refer to classes, while other political theorists to states. (Ahrensdorf) Political realism is explained in the following way: â€Å"Prior to the French Revolution in which nationalism as a political doctrine truly entered the worlds stage, political realism involved the political jurisdictions of ruling dynasties, whilst in the nineteenth century, nationalist sentiments focused realists attentions on the development of the nation-state, a policy that was later extended to include imperialist ambitions on the part of the major Western powers-Britain and France, and even Belgium, Germany and the United States were influenced by imperialism. † (Viotti, Kauppi). Important difference between social darwinism and other branches political realism is as follows: adherents of the former state that some nations are destined to rule over other nations, while other part of realists pays most attention to the need of ensuring that nation, culture or politician sets or secures own needs before needs or interests of others. Political realism in international affairs Political realism of an expressive kind stands for the suggestion that international commonwealth is distinguished by anarchy, since there is no absolute world government, that could rule with an all-purpose policy code. Since the anarchy does not need a chaotic nature, thus allowing member nations be involved into trading schemes or treaties, the theorists mostly agree that morality or law are not the dominating factors outside one particular state. In this particular characteristic this hypothesis agrees with the Hobb’s theory: Where there is no common Power, there is no Law: where no Law, no Injustice ? if there be no Power erected, or not great enough for our security; every man will and may lawfully rely on his own strength and art, for caution against all other men. (Hobbes, Leviathan , Part I, Ch. 13 Of Man, and Part II, Ch. 17, Of Commonwealth, cited in Griffiths, O’Callaghan). Respectively, without any supreme international force, nations treat each other with hostility or fear, and it damages the system. Another aspect of the theory is an assumption that a state can promote its interest against the needs and interests of other states, it proves that international surrounding is not stable. Any order is affected if states compete for the same need, and under such circumstances, as the realists state, the nation may rely on itself only. There are definite contradictions that can be found in the concept of political realism: descriptive realism may be regarded as a true theory or false concept. Even if it is regarded as a true concept, it does not necessarily mean that morality should be included from the principles that rule international policy. One of the strong forms if descriptive type of political realism states that states should be self-seeking, that they should build their policy basing upon desired gains of the nation and should not ignore their interests and demands. Simultaneously, â€Å"if descriptive realism is held, it is as a closed theory, which means that it can refute all counter-factual evidence on its own terms (for example, evidence of a nation offering support to a neighbor as an ostensible act of altruism, is refuted by pointing to some self-serving motive the giving nation presumably hasit would increase trade, it would gain an important ally, it would feel guilty if it didnt, and so on), then any attempt to introduce morality into international affairs would prove futile. † (Stern) The assessment of expressive kind of political realism power depends upon the chance of understanding political reasons, which requests understanding the causes of state diplomats and representatives. The pattern of officers’ relations, their motives and actions is complex. Waltz says that the closed nature of expressive realism includes a oppose scheme that nations does not serve any needs at all, or can serve the needs of others only. The logical value of the three theories resulting from this concept offers that preferring one condition to another is an optional decision, if an assumption is accepted, or not. (Waltz) The present international sphere of nations’ interaction is defined by the lack of supreme power. In the past, wars were a strong argument in support of political realism – there have been more than 200 wars since the middle of the 17th century. This condition seems to have a chaotic nature, and some thinkers are likely to compare it to domestic anarchy, when state government is not able to rule the state: ‘Without a world power, war, conflict, tension, and insecurity have been the regular state of affairs; just as a domestic government removes internal strife and punishes local crime, so too ought a world government control the activities of individual states-overseeing the legality of their affairs and punishing those nations that break the laws, and thereby calming the insecure atmosphere nations find themselves in†. (Kegley, Wittkopf) At the same time, such comparison leads to a conclusion that the relations between the state and the individuals are alike. Such argument includes the personification of the states and collectivization of individuals. Some theorists state that the relations between states and the citizens cannot be compared to the relations between the states and the relations of the individuals, and therefore should be differently judged. In addition to the propositions of descriptive realism, there are notions offered by prescriptive political realism, for instance, the statement that a certain nation should follow its own interests and needs independently of the relevant state of international relations. This theory can be divided into various aspects, depending upon proclaimed interest of the nation and the allowability of the tools that would be used to reach desired goals. As far as the national interest is concerned, there are distinct opinions of what it should be, but all of them agree that the state should be self-efficient in economical and political sphere, cutting dependency on other nations. (The Globalization of World Politics: an Introduction to International Relations) The statement supporting the supremacy of self-sufficiency of the state has appeared long time ago. Plato and Aristotle referred to this aspect as a ground necessary to provide security of the national power, they insisted that nation should import only insignificant commodities. This economic theory has been used for supporting political realism, especially in the 18th century the theorists of political sphere stated that the political power of the nation is reached and supported in the terms of reduced import and increased export only. Difference between neorealism and classical realism Conflict is regarded as a key element in politics, including international affairs, by all realists, however, there are two different sources of conflict, pointed out by different realist authors. For instance, classical realism theory starts with a pessimistic viewpoint on the human nature. As the adherents of this theory believe, selfish, competitive and striving for power behavior in inherent for the humans. Hans Morgenthau states that each individual is enforced to act uncaringly to protect himself, and this situation leads to the disagreement: â€Å"What the one wants for himself, the other already possesses or wants, too. Struggle and competition ensue. Man cannot [therefore] hope to be good, but must be content with not being too evil†. (Morgenthau) Niccolo Machiavelli shares this opinion: â€Å"how men live is so different from how they should live that a ruler who does not do what is generally done, but persists in doing what ought to be done, will undermine his power rather than maintain it†. (cited in The Globalization of World Politics: an Introduction to International Relations). These ideas performed specific approach to a strategy applied in international affairs: a careful statesman must avoid optimistic view on others’ aims and intentions and limits their initiatives to those that may help if the situation goes better. For instance, Henry Kissinger warned the leaders of the USA and Israeli against the intentions of Syria and Palestine, during the negotiations on Middle East conflict: â€Å"It is likely that agreements will be reached because the alternatives will, in the end, seem more dangerous. But when this happens, we must avoid euphoria. An agreement will represent a strategic interlude for the Syrians and most of the Palestinians, not a commitment to a new world order. † (Legro, Moravcsik) In other words, classical type of realism regards conflict and competition as essential element of international affairs, referring the origin of conflict to the human nature. Humans struggle with each other for resources they need and strive for power to rule over other people. This is a set pattern, which cannot be changed. Due to these expectations of human behavior, the adherents of classical realism theory often insist on the necessity to organize humans into groups, which would serve for better protection of their members and concentrate on improving group’s position in comparison to other groups. Another theory, neorealism or structural realism, refers the origin of conflict to interstate condition, the lack of legally restricting rules in particular, rather than to human nature. The adherents of neorealism state, that â€Å"the absence of a neutral authority that can enforce rules and agreements creates an insecure, self-help situation in which all policy makers are pressured to act competitively, regardless of their individual natures or personal preferences. † (Kegley, Wittkopf) This statement is not new, it appeared in the 17th century in the work of Thomas Hobbes. In his writing Leviathan he states that the in the world, which lacks supreme power that could provide security, people has a right to use any tools to protect themselves. Besides, he assumed that â€Å"all mankind [has] a per ¬petual and restless desire of power after power that ceases only in death. † (cited in The Globalization of World Politics: an Introduction to International Relations) Modern tradition in neorealist theory declines the assumption that individuals strive for power due to a natural inclination, and concentrates on the motives produced by a lack of a neutral power that can set rules for interstate relations. For instance, Kenneth Waltz says that â€Å"the main cause of war must lie in some regularity at the level of the interstate system, rather than within particular leaders or states, since war has been waged for all sorts of specific reasons and by good as well as bad leaders. † (Waltz) According to Waltz, this regularity is the pressure, produced by anarchy: â€Å"Without enforceable interstate rules, states must either resist possible domination by others through a policy of balancing against others power capabilities, or by bandwagoning-joining a coalition that supports an aggres ¬sive state, in hopes of turning its aggression elsewhere†. (Waltz) Waltz states that large states possess the capacity and desire to withstand the strength of other states. This results, as he sees it, in a tendency of competitiveness among states independently of the views of their leaders concerning domestic policy. Actually, the prediction of this statement is not much different from the assumption made by the adherents of classical realism. As soon as it is based on the assumptions concerning human nature, classic realists expect that the makers of policy also act competitively. The difference lies in the way this conclusion is reached. As Waltz sees it, this is the pressure of competitiveness, produced by anarchy, which significantly influences the human behavior. Those strategies that are oriented on power, appear because the leaders are forced to struggle for security, rather than because they desire just to obtain power. Realistic approach in modern international affairs Realism was a concept for analyzing world politics since remote times, because much of humankind history was characterized by wars. As soon as the states’ interests come across in conflict, it is expected that leaders pay much attention to their positions in power. â€Å"The classical realist worldview appealed to many statesmen during the period that states were evolving in Western Europe-an era rife with conflict, as medieval forms of rule broke down and rulers asserted new claims to authority against feudal lords or the Pope. It jumped to the United States when the experiences of World War II were followed by the onset of the Cold War. Neorealism later emerged when the bipolarity of the Cold War drew analysts attention to the effects of the structure of the interstate system†. (Lieven, Hulsman). At present, ethical realism is offered to the USA as a leading principle that should define the foreign policy of this state. As it is described by the supporters of this type of realism, it bases upon â€Å"prudence; a concentration on possible results rather than good intentions; a close study of the nature, views and interests of other states, and a willingness to accommodate them when these do not contradict Americas own truly vital interests; and a mixture of profound American patriotism with an equally profound awareness of the limits on both American power and on American goodness† (Lieven, Hulsman). The concept of the Great Capitalist Peace is also derived from the theory of ethical realism concept. It is based upon the ideas of Kennan and Morgenthau, including the concepts of diplomacy purposes and international order. It proclaims that a global order is needed to be agreed by the largest states, to provide the promotion of their interests and reduce the threat of terrorists. Accordingly, the USA power is treated as an element, vital for keeping the Great Capitalist Peace. At the same time, it is added that the limits should be put on the US power, in order to legitimate interests and needs of other states should be satisfied. Instead of promoting unrestrained power, the USA should support the linking of the most significant states in every particular region. For instance, in the Middle East region the USA should use its power and resources to support creation of a regional patter for the states, including Syria and Iran, and to make this pattern functional enough to regulate Iraq conflict after withdrawal of the US troops from this country. (Lieven, Hulsman) As far as the Far East is concerned, the USA should paid attention to the primary role, which should be played by China in this region, but not by the United States. China is treated as a state, ready to act in cooperation with other states and act responsibly, that’s why USA should allow China to occupy a leading position in finding resolutions to the actions of the regime in the North Korea, and other possible challenges in this region. (Lieven, Hulsman) Sources Waltz, K. N. Structural Realism after the Cold War. International Security. Summer. 2000 Morgenthau, H. J. Politics Among Nations: the Struggle for Power and Peace. McGraw Hill: NY, 1993. Stern, G. The Structure of International Society. London: Pinter Publishers, 2000. The Globalization of World Politics: an Introduction to International Relations. edited by Baylis, J. and S. Smith. Oxford University Press, 2004 Griffiths, M. , O’Callaghan, T. International Relations: The Key Concepts. London, Routledge, 2002 Kegley, C. Wittkopf, E. World Politics. Thomson/Wadsworth, 2005. Viotti, P. R. Kauppi, M. V. International Relations Theory: Realism, Pluralism, Globalism. Macmillan Pub Co, 1993. Legro, J. W. Moravcsik, A. Is Anybody Still a Realist? International Security. Fall 1999 Jervis, R. Realism, Neoliberalism, and Cooperation.. International Security. Summer 1999 Ahrensdorf, P. J. Thucydides realistic critique of realism. Polity Winter 1997 Lieven, A. Hulsman, J. Americas World Role Has to be Realistic and Moral. October 17, 2006, retrieved at http://www. realisticforeignpolicy. org/archives/2006/10/americas_world. php.

Role of mTOR in Pain

Role of mTOR in Pain Juliette Lanskey Introduction Pain perception protects the human body from damage, yet when the underlying mechanisms are disrupted pain can become a debilitating condition. There are almost 10 million Britains that suffer from pain on a daily basis affecting not only their personal wellbeing and quality of life but also the economy. Back pain is an example of chronic pain and back pain alone costs the NHS around  £5billion per annum and it was reported that 4.9 million days are lost per year to british businesses (http://www.britishpainsociety.org/media_faq.htm). Unfortunately, understanding the mechanisms that go awry leading to pain that is more harmful than beneficial is proving challenging. As a result, there is a deficit in treatments available to control chronic pain despite much research. There is therefore an urgent requirement to understand the mechanisms underlying pain perception in order for the development of therapeutics to reduce the sufferings of humans and the economy. This dissertation shall focus on a potential target, the mammalian target of rapamycin (mTOR), which recent research has highlighted as playing a significant role in chronic pain. Pain Pathways The processing of painful stimuli by the nervous system is termed nociception. Pain is nociception with additional psychological and emotional inputs. Noxious stimuli cause an action potential to run through a specialised set of neurons termed by Sherrington in 1906 as nociceptors; the pain neurons. Nociceptors have free nerve endings to detect noxious stimuli and can be classified into two main groups taking messages from the periphery to the central nervous system, called Aà ¯Ã‚ Ã‚ ¤ and C fibres. Aà ¯Ã‚ Ã‚ ¤ fibres are medium-diameter, mylinated neurons and this myelination and wider diameter allows rapid signal conduction. It is the Aà ¯Ã‚ Ã‚ ¤ fibres that transmit the first, sharp, localised pain of an injury whilst C fibres which are small-diameter, unmyelinated neurons transmit slow, diffuse, secondary pain 2009CELLULARANDMOLECULAR. Hence Aà ¯Ã‚ Ã‚ ¤ fibres are crucial in rapidly signalling an injury whilst the slow, burning pain from C fibres is important for protecti on during the healing period. These primary afferent nociceptors transfer messages from the periphery to the dorsal horn of the spinal chord. The dorsal horn is particularly important for processing and modulating noxious information. The dorsal horn is composed of six rexed laminae with transition zones approximately dividing different cell types. Indeed, nociceptors terminate in particular laminae. The majority of Aà ¯Ã‚ Ã‚ ¤ fibres terminate densely in lamina I, though some do also terminate in lamina V. C fibres mainly terminate in laminae I and II, although there are also a few C fibre terminations in lamina V. Thus the majority of neurons which terminate in the superficial dorsal horn specifically respond to noxious stimuli while neurons terminating deeper in the dorsal horn tend to respond to innocurous touch (large diameter, rapid conducting Aà ¯Ã‚ Ã‚ ¢ fibres transmit such innocuous information CELLULARANDMECHANMECHS2009). It is within the dorsal horn that nociceptors synapse onto central projection neurons which transmit the noxious information up to the brain. The main central pathways run up to the brain via the thalamus or brainstem and terminate in areas such as the periaqueductal grey and the parabrachial nucleus REF. There are also descending pain pathways originating in the periaqueductal grey, rostral ventral medulla and coeruleus which pass signals to the dorsal horn modulating nociception. There are also modulating circuits in the dorsal horn composing of exitatory and inhibitory interneurons contacting further neurons in the spinal cord (Fields2006thesis). Nociceptors have a pseudo-unipolar morphology allowing bidirectional signalling. This means that nociceptors are able to transmit action potentials antidromically from the the central nervous system to the nociceptor terminals (Dubin, 2010). A result of central processing is increased sensitivity of the area at and around a site of tissue damage or inflammation (PUBHUNT). A chemical soup of cytokines and growth factors is released at the site of injury and causes an increase in the sensitivity of a subset of surrounding nociceptors. This means that these nociceptors have a reduced threshold for noxious stimuli (thus will now respond to less intense stimuli than before) and also an increased response to noxious stimuli. This sensitisation of neurons at the site of injury is called primary hyperalgesia. mTOR inhibitors do not affect primary hyperalgesia and thus it is unlikely mTOR is involved, however there is another phenomenon called secondary hyperalgesia which mTOR does seem to be involved in. Secondary hyperalgesia is when a set of neurons not directly at the site of injury but in the surrounding, undamaged area undergo an increase in sensitivity due to central processing (pubhunt). Recent studies have demonstrated t hat the mTOR plays a role in creating this sensitivity. Acute pain is the pain that follows immediately after an injury to protect the body from further damage and aid the process of healing but when pain exists for more than 3 months it is defined as chronic pain (SITETHESISMerskey and Bogduk, 1994; Russo and Brose, 1998). This chronic pain does not protect the body but rather hinders the quality of life. The pathology of chronic pain often consists of decreased pain thresholds and increased response to stimsuli; the nociceptors are more sensitive. Moreover, whilst nociceptors are generally silent, firing action potentials only when stimulated (dubin2010), in chronic pain, there is an increased tendency for spontaneous activity (JULIUSANDBASBAUMTHESIS). Altogether, chronic pain leads to allodynia (pain from a normally non-noxious stimulus), hyperalgesia (heightened sensitivity to noxious stimuli) and spontaneous pain. mtor The mammalian target of rapamycin is a regulator a number of cellular processes including synaptic plasticity, protein synthesis and cellular metabolism (XONCUETALTHESIS). It is a molecule belonging to the kinase family and forms two complexes with raptor; mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). It is when part of these complexes that it administrates its cellular functions though much more is known about mTORC1 and so it is predominantly the role of mTORC1 in pain perception that this dissertation shall focus on. Signalling cascade There is a signalling cascade involving mTOR, the downstream targets of which lead to cellular activities resulting in the organisation of the cytoskeleton, the regulation of metabolism and cell survival (wullschlegerTHESIS). The signalling cascade is initiated by a signal such as a neurotransmitter acting on transmembrane receptors which activate phosphoinosital 3 kinase-AKT pathway. This results in the phosphorylation and thereby the activation of mTOR. Phosphorylated mTOR in turn phosphorylates the 4E-binding protein and in this phosphorylated state the 4E-binding protein is unable to bind and thus inhibit a protein called eIF4E. So when mTOR is activated it has the downstream affect of enabling eIF4E to associate with eIF4G, this is an essential step for initiating translation (TJ PRICE GERANTON). The fact that mTOR plays such a significant role in the regulation of translation is a hint of its importance in pain plasticity. Previously, it was thought by some that translation could only occur in the cell soma. However, others noted both the half-life of axonal proteins and the time it takes for a protein to travel down the length of the axon and concluded that the axoplasmic transport is too slow for protein synthesis only to occur in the cell soma HUNT. Indeed, following the discovery of ribosomes and ‘Golgi outposts’ in dendritic spines it is now believed that local protein synthesis at the sites of dendritic synapses plays a significant role in plasticity (2009REVIEW). Research demonstrates that chronic pain arises as a result of plastic changes that occur during persistent acute pain. During any pain there are noxious signals to the central nervous system enabling the pain to be perceived, if these signals persist it has been shown that this causes and maintains plastic changes that result in chronic pain. Indeed, it has been shown through advanced structural imaging methods that there are large scale alterations in the brain structure of sufferers of chronic pain CHRONICPAINPLASTICITY. There is relatively little research into the possibilities of targeting this pain plasticity to help patients cope with chronic pain in comparison with genetic studies. It is consequentially an exciting new avenue of exploration and the role of mTOR in pain plasticity is of particular interest. EARLIER As mTOR plays such a crucial role in cellular function it is unsurprising that mTOR dysfunction is believe to be involved in a number of maladies. The role of mTOR in cancer, diabetes and neurodegeneration is being explored and a number of mTOR inhibitors have already been tested for treating certain maladies. For example†¦..This has demonstrated that mTOR inhibitors are potential treatment regimes BUT THERE ARE SIDEEFFECTS MTOR THESIS MTOR SIGNALLING MTOR PLASTICITY see 2009reviewnociception and AMPKPG 6 is v good Dealing with pain MTOR AND RESEARCH thesis 2 Pain Pathways and Plasticity 3 The mammalian target of rapamycin 2007 Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR – mTOR’s role in nociceptive synaptic plasticity through translation regulation; ‘ the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociception’ †¦. mTOR is a major regulator of protein synthesis for it controls the initiation of translation (PUBLISHEDHUNT2009). It is thought that by controlling protein translation it maintains the sensitivity of nociceptors following local injury. Targetting mTOR could reduce the secondary hyperalgesia that occurs from pain and thus help patients cope with pain†¦ 4 The mTOR signalling cascade Unicellular organisms that are sensitive to nutrient availability in their environment control translation via a rapamycin-sensitive translation pathway. This process is controlled by a protein kinase, TOR, which is blocked by rapamycin. Interestingly, neurons appear to have co-opted this evolutionarily conserved mechanism to control activity-dependent local translation. Mammalian TOR, or mTOR, is activated by neurotransmitter receptor signaling cascades and phosphorylates downstream factors that control translation. Hence, mTOR is intricately involved in synaptic plasticity in the CNS, a mechanism that is linked to its role in controlling translation in dendrites (Jaworskiet al., 2006). The major mechanism of mTOR-regulated translation is control of the initiation of cap-dependent translation (depicted in Fig 1) (Gingras et al., 2004). This occurs because one of the major targets of mTOR phosphorylation is the elongation associated factor 4E-BP (Gingraset al., 1999). 4E-BP binds c c ap-binding factor eIF4E and, when it is hypo-phosphorylated, inhibits the formation of the eIF4E/eIF4G elongation complex preventing translation. When 4E-BP is hyper-phosphorylated, 4E-BP dissociates from eIF4E allowing eIF4G binding and the initiation of cap-dependent translation. Recently a small molecule inhibitor of eIF4G binding to eIF4E was discovered (4EGI-1) and this molecule inhibits cap-dependent translation (Moerke et al., 2007). Hence, mTOR is crucial for regulating activity-dependent translation in neurons via its regulation of elongation factors (Bankoet al., 2006; Tanget al., 2002; Tsokaset al., 2007) and the mTOR pathway is amenable to specific pharmacological manipulation. 6 Experiments suggesting inhibiting mTOR could help control pain 2007 Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR – mTOR’s role in nociceptive synaptic plasticity through translation regulation; ‘ the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociception’ NOT THAT RELEVANT – basically saying that because of mutation translation can’t happen properly†¦meaning mTOR has less control. However there is a subsection with rapamycin injections which does show decreased nociception with rapamycin 2011 – systemic inhibition of mTOR – mTOR regulation of nociceptive sensitivity; ‘ inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse models’ Good intro relating mTOR to chronic pain Local cutaneous intrathecal administration of rapamycin blocks activation of downstream targets of mTORC1 alleviating mechanical hypersensitivity – 21, 29 3 43 46 62 SHOULD PUT 1 OR 2 LOCAL EXPERIMENTS BEFORE THIS ONE If targeting mTORC1 signaling pathway has a potential thera- peutic application for controlling chronic pain, systemic rather than local administration (as has been used previously [21,29]) requires further investigation. Here we examined the effective- ness of temsirolimus (CCI-779), a clinically used rapamycin ester derivative, given systemically