Animal Farm’s Totalitarian Leader Essay

Animal Farm’s leader, Napoleon, has all the power. He is able to build up and hold onto that power as a totalitarian leader, which is a central government that controls over all aspect of life. Napoleon did many different things to get to that power and hold onto it. Napoleon first took charge after the rebellion against Mr. Jones. He and Snowball, who was the other smart pig on the farm, wrote the seven commandments. The other animals don’t know how to read, so Snowball needed to read it to them. â€Å"Never mind the milk, comrades!† cried Napoleon.(Orwell 44). â€Å"So the animals marched down to the hayfield to begin harvest, and when they came back in the evening it was noticed that the milk had disappeared.†(44) † So the animals trooped down to the hayfield to begin the harvest, and when they came back in the evening it was noticed that the milk had disappeared.†(44) â€Å"Comrades!† he cried. â€Å"You do not imagine, I hope, that we pigs are doing this in a spirit of selfishness and privilege? Many of us actually dislike milk and apples. I dislike them myself. Our sole object in taking these things is to preserve our health. Milk and apples (this has been proved by Science, comrades) contain substances absolutely necessary to the well-being of a pig. We pigs are brainworkers. The whole management and organization of this farm depend on us. Day and night we are watching over your welfare. It is for YOUR sake that we drink that milk and eat those apples. Do you know what would happen if we pigs failed in our duty? Jones would come back! Yes, Jones would come back!†(52). Napoleon and Snowball sent squealer to strike the animals with fear that Jones might return, and stole the apple and milk from them because they â€Å"require it†. Napoleon took care of everyone who was a threat to him.† At this there was a terrible baying sound outside, and nine enormous dogs wearing brass-studded collars came bounding into the barn. They dashed straight for Snowball, who only sprang from his place just in time to escape their snapping jaws.† (66) Napoleon got rid of Snowball because he was a threat to his power. Snowball was in favor of helping the farm, but Napoleon just wanted to get the power for himself.† To the amazement of everybody, three of them flung themselves upon Boxer. Boxer saw them coming and put out his great hoof, caught a dog in mid-air, and pinned him to the ground. The dog shrieked for mercy and the other two fled with their tails between their legs. Boxer looked at Napoleon to know whether he should crush the dog to death or let it go. Napoleon appeared to change countenance and sharply ordered Boxer to let the dog go, whereat Boxer lifted his hoof, and the dog slunk away, bruised and howling.†(92) Napoleon tried to get Boxer killed but Boxer did not realize that, that’s why Napoleon countenance. Napoleon tried to get Boxer killed because everyone looked up to him, and he was loyal to Napoleon. † ‘Alfred Simmonds, Horse Slaughterer and Glue Boiler, Willingdon. Dealer in Hides and Bone-Meal. Kennels Supplied.’ Do you not understand what that means? They are taking Boxer to the knacker’s!†(123).Everyone thought Napoleon was sending Boxer to the hospital, but really they were going to kill him. Napoleon tried keeping all of the animals dumb so it can be easier to take advantage of them. â€Å"It was the most affecting sight I have ever seen!† said Squealer, lifting his trotter and wiping away a tear. â€Å"I was at his bedside at the very last. And at the end, almost too weak to speak, he whispered in my ear that his sole sorrow was to have passed on before the windmill was finished. ‘Forward, comrades!’ he whispered. â€Å"Forward in the name of the Rebellion.† Long live Animal Farm! Long live Comrade Napoleon! Napoleon is always right. †Those were his very last words, comrades.† Here Squealer’s demeanor suddenly changed. He fell silent for a moment, and his little eyes darted suspicious glances from side to side before he proceeded.†(125) Squealer easily lied to them about them taking Napoleon to the hospital. Napoleon changed the Seven Commandments without the animals knowing, because they were working too much to have time to read. The original Commandments were:†1. Whatever goes upon two legs is an enemy. 2. Whatever goes upon four legs, or has wings, is a friend. 3. No animal shall wear clothes. 4. No animal shall sleep in a bed. 5. No animal shall drink alcohol. 6. No animal shall kill any other animal. 7. All animals are equal. â€Å"(43) In the end, Napoleon took them all out and left only one; Four legs good, Two legs better. Napoleon used many different techniques to build up and hold onto the power he has over Animal Farm. He kept the animals dumb, got rid of his threats and changed the commandments.

Arthur Reed Case Study Essay

This case study involves Arthur Reed who works for Blue Grocery Stores Incorporated as a warehouse supervisor (case study, 2010) and is having a difficult time fulfilling staffing requirements during the summer months he has tried some options that didn’t fulfill the needs of the business. This case study will help Arthur meet these goals. Staffing Issues The summer months were a staffing headache for the warehouse supervisor at Blue Grocery Stores Incorporated (case study, 2010). Everyone wanted to take their accrued vacation then. After all, summer time was the perfect time for family vacations and activities. What made this staffing issue a bigger headache was the fact that a significant number of employees were calling in for sick days during this time of year as well. Replacement workers hadn’t worked in the past so that’s another challenge to overcome. Options for Optimum Staffing The first suggestion would be for the company to pay for the costly steel-toed boots for the replacement workers and waive any union dues for the replacement workers (case study, 2010). If for some reason that didn’t work, the next suggestion in solving this staffing issue would be to hire a summer temporary force using college students. College students can always use extra money for school. I would suggest that the company to pay for the costly steel-toed boots, this would help attract more potential temporary employees for the summer months. The final option would be to adjust the warehouse hours for the summer time. Instead of working a day and afternoon shift, consolidate both teams of employees into one team with two different starting times, two hours apart. That will optimize the staffing, while eliminating the need to hire temporary employees for the summer. If corporations have to rely on temporary employees to fulfill the needs of the business, then they are risking the business objectives. Temporary employees are just that, temporary, and there is a strong possibility that the company performance would slip in relying on them. There could be compromises and arrangements made with the shipping and receiving of supplies so that the business goals are still obtained. This is the best option if successful, not only does it not rely on temporary employees to fulfill the business needs, this keeps the company budget down while maximizing the resources that are available.

Week 5 discussion and participation questions Essay

Week 5 discussion and participation questions - Essay Example An independent variable for this problem could be income. Hypothesis testing is a procedure that tests the validity of a statement in regards to a population parameter. A hypothesis is a statement about a population parameter. The five-step procedure for testing a hypothesis is: One of the reasons why hypothesis testing has been used in the business world for decades is due to its utility. The procedure can be used in a wide variety of scenarios or problem in order to test a potential hypothesis. One of the limitations of hypothesis testing is that there is a margin for error in the analysis. The ANOVA test compares the sample means through their variances. The test is applied by calculating two estimates of the variance population distributions: the variance between samples and the variance within samples. The application of regression analysis which uses both dependent and independent variables can be used in the business world to calculate a lot of different business problems and scenarios. For example a company can forecast the sales of the business for future periods utilizing the past historical sales data. A marketer could create an equation that uses dependent and independent variables to determine the preference in customer taste. In your example you mentioned the probabilities associated with card games. I am pretty sure that good Poker players are have an excellent understanding of probabilities and statistics. When I go to the casino I like playing blackjack. I know that when the dealer deals a lot of low cards and my turn is up the chances of the dealer giving me a high card increases. An equation that can be used to put the concept of dependent and independent variables into good use is the y = ax + b. In this equation x is the independent variable and y is the dependent variable. This equation can be used in the business world to solve a lot of different problems or scenarios. For example a research

Volcanoes and Tsunamis Assignment Example | Topics and Well Written Essays - 250 words - 1

Volcanoes and Tsunamis - Assignment Example Volcanic eruption creates various landforms such as plateaus, volcanic mountains and igneous rocks. The volcanic ash causes serious atmospheric challenges including acid rain and vision blockage affecting the flight industry. Plateaus, mountains, and volcanic ash are features that occur during eruption. Mountains and ash occur when lava is extruded at high pressure while plateaus occur when molten lava flows under low pressure and covers a wide area. The eruption of the Yellowstone Volcano creates a serious challenge for Tri-state especially because it will disrupt transport and may lead to loss of life because of the thrown up Lava. The state must be prepared for any eventuality because active volcanos may be triggered by slipping fault lines. Preparation for eventuality includes system monitoring for changes in the society. An earthquake in the sea causes massive water displacement which in turn accelerates towards the shores. The volume of water displaced causes serious challenge because as it travels it gains massive speeds which destroy everything along its path. The reduction of sea depth as the wave reaches the shore makes the water to gain more acceleration because it is forced to travel upwards. The restriction of sea depth and weight of the water increases the acceleration and thus increases t ability of the tsunami to destroy everything along its path. Coastal vegetation reduces the impact of tsunami by reducing velocity. Vegetation along the coastal shore will effectively reduce the destruction capacity of the tsunami. Sea depth is vital because it increases absorption of shocks. However, the declining depth increases the height of the water thus increasing destruction along the shores. The collapse of the protective walls of japan is as a result of the earth movements which affected the foundation of the walls by creating fault lines which in turn led to the collapse of the wall after impact. The result of the The aftershocks of the earthquake

Aircraft wing design Assignment Example | Topics and Well Written Essays - 1000 words

Aircraft wing design - Assignment Example Aircraft wing plays a vital role in its final operation and as such incorporates a number of fundamental design considerations. According to Kundu et al. (2003, p.241).   it literally impossible for one to design an aircraft part without comprehensively understanding the role of that part in the aircraft and the fundamental theories that accompany its design. In this paper, a detailed plan for design of an aircraft wing is described on that basis, an aircraft wing model proposed. Design considerations Various design considerations are put into consideration when designing an aircraft wing. these are below:The author states that the wing span is crucial in design. Basically, this is constrained by the size of the hangar, as well as the ground facilities. However, such must be based on the structural dynamic constraints. Measures must be the put in place to minimize the induced direct drag. Consideration is also taken not to raise the wing’s structural weight in a manner that extremely increases the savings on induced drag. the area of the wing, just like is the case in selecting the span considers various aspects include the drag constraint, speed of stalling and field length, as well as the volume of fuel. despite the fact that in some instances these factors allow for creation of small wings, the size of the wing in this case is increased in order to obtain a reasonably appropriate CL on basis of the pre-defined flight conditions (Moir & Seabridge, 2007; Raymer, 2008, p. 67).

Kurt Vonnegut, Slaughterhouse Five Essay Example | Topics and Well Written Essays - 250 words - 1

Kurt Vonnegut, Slaughterhouse Five - Essay Example The focus on Billy’s self-awareness creates a crucial moment in his character development. This discovery paves the way for Billy to spread the Tralfamadorian gospel on earth. His recognition of the effect of Febs on his psyche demonstrates a great deal of self-awareness. The interaction of Billy and the historian in chapter nine demonstrates the interchangeable nature of history and fiction. Despite his spurious stories of time travel and alien abduction, it is possible that Billy had been a soldier in World War II. My understanding of reality is confused by the things that Billy sees when he visits the bookstore in Times Square. There are books by Kilgore Trout in the store’s window. The books talk about aliens abducting a man. This is the most difficult thing to understand in this novel because I am left to wonder whether it a coincidence that Billy looks at the Trout book before he talks about his experience that is similar to what the book describes. In the last chapter, the novel suggests that a bird-talk makes as much sense as the talk of anyone about war. The problem of dignity returns. Vonnegut talks about the equalizing power of death that brings dignity at high price. He shows how the war has made the idea of climax

Audience Contact Analysis Assignment Example | Topics and Well Written Essays - 500 words

Audience Contact Analysis - Assignment Example The messages that are sent by the organization to its existing and potential customers are called contact points they are also defined as any tools used to distribute the marketing message (Hammond 195). The Toyota Company has been in operation since 1937 and has grown from a simple company into a multibillion Company worth 397.05 billion yen (as of May 2014). Marketing excellence has been the backbone of their success. Their major contact point is their website that gives all the company details as well as shows their wide range of products. The website is user-friendly and provides their customers with a wide range of information (Hammond 195). The website operates an online help desk to ensure that any new customers can have all their questions answered. The website helps retain the existing customers due to the high-quality amenity it offers to them. The company spends over 14 billion dollars every year on advertisements. Unlike other companies, their marketing department has the highest number of employees as compared to the other departments. They advertise themselves on television often and also use billboards in strategic points all over the world. They have a distinct company logo which they show in all their adverts, and it acts as a mark of class to their products. Their brand has gained popularity in the market due to their high-quality products and hence their name markets itself. The Toyota Company runs a Toyota exhibition twice a year whereby they showcase all their products. In such exhibitions, the company interacts with its existing customers, and this helps build a healthy relationship between them. The exhibition also brings potential customers since they are not discriminative on who attends the exhibition and do not charge any fee. Apart from exhibitions, another contact point is their warehouses that are often in open space. Customers are allowed to visit the warehouses and view the vehicles. The layout of the

Entrepreneurship Essay Example | Topics and Well Written Essays - 500 words - 6

Entrepreneurship - Essay Example Whatever the source, the opportunity should be able to generate profit. The business idea in this case came up due to an unmet need in the market. The entrepreneur after visiting several restaurants trying out different Indian cuisines was disappointed as he could not get really good fresh spices. After careful research, he discovered that there was lack of reliable source of good quality spices at an affordable cost and this presented an opportunity for a business venture. The idea could be exploited through development of a new product (high quality freshly ground spices). An entrepreneur has to consider the target market and aim at fulfilling unmet needs (Shane, 2003). As such this was a good idea as the market was untapped and many customers (restaurants) were in need of fresh good quality spices. Another aspect is that the idea should not be easy to imitate hence creating barriers for new entrants (Butler, 2004). This product was to be made using a new production process and storage system and this was made possible by use of a well qualified engin eer who could make such spices. The entrepreneur was well connected with people who knew buyers of spices and hence no problems with distributing the product (Greene, 2011). The idea was also feasible due to the fact that it does not require heavy investment as the production process is very simple. It involves use of freshly ground spices but which would not loose taste due to storage. Other producers were unable to store spices due to loss of taste hence could not fulfil the needs of the customers (Hougaard, 2005). Another advantage was that, since the idea was new there was no dominant design established. This could have hindered the entry of the new venture. Honest Tea was established in 1998 and the entrepreneurial opportunity arose when one of the founders discovered an unmet need in the beverage industry. After consuming beverages on a hot day, his thirst was not quenched thus

International Human Rights Assignment Example | Topics and Well Written Essays - 750 words

International Human Rights - Assignment Example In another dimension, human rights goals have been to endorse the issue of human dignity, which ensures that violations of human rights have been elucidated in order to foster peace thus socioeconomic development. Ways through which contemporary international human rights reflect values that transcend different cultural traditions International human rights have been cited to have contributed greatly on issues affecting citizens of different countries. This is evidenced by numerous issues affecting different countries in regard to various cultural traditions and values eminent in every country. In this regard, international human rights have been structured in such a manner that every country is well represented and their issues related to human rights articulated on. Therefore, international human rights recognize cultural differences, and put those differences into the context of standardizing human rights across the globe. For example, just like Piere and Weston noted, in the Unit ed States, Americans would be cited demanding better conditions for homeless and equality and sufficient health insurance. On the other hand, some countries like Cuba have issues related to its citizens demanding for freedom of speech and transparent elections (Piere and Weston 3). With such deliberations, it is apparent that the international human rights had to come up with a mechanism through which these cultural differences that are evidenced through violation of human rights could be addressed. In light with this, the first step involved probing into the possibility of elucidating human rights through universal declaration of human rights by the United Nations in 1948 (Fassbender 77). In order to standardize human rights everywhere, the commission on human rights mandated by the United Nations in drafting international bill of rights authorized all member states to formulate a draft of human rights that would have been used in the development of the international bill of rights . In light with this, it is apparent that such efforts reflect values that transcend cultural traditions across the globe. Rationale for sovereignty and its course on human rights Sovereignty and human rights have for a long time been seen as two opposed concepts with rights of the states being viewed as tending to control rights of individuals. This is more evident in liberal democratic countries. This is reflected by the way people’s rights are violated by the political elite. Although many people with sovereignty may be seen to guarantee human rights, it is apparent that some actions by those in power violate the same rights they promise to guarantee. In another dimension, there have been contentious issues in relation whether states are justified in any way to intervene in another country’s internal affairs in the bid to push for human rights protection. In as much as states can be justified in the intervening in another country’s internal affairs, the notio n of state sovereignty barring other states from interfering with internal affairs has always paved a way for some countries to violate human rights without the fear of any interference from other states. In fact, some people believe that non-intervention by foreign states is the best way to promote human rights as well as maintaining international peace (Piere and Weston 5). However, it is correct

Letter to Charlemagne Essay Example for Free

Letter to Charlemagne Essay His Majesty King Charlemagne:  With utmost diligence regarding the king’s instruction to go forth and inspect governments, administer justice, and reawaken all citizens to their civil and religious duties, herewith is the detail account concerning the outcome of this noble undertaking. Indeed, the kingdom under his majesty’s rule enjoys great peace and an enduring justice as the King’s officials such as the kingdom’s archbishops and abbot, the dukes and counts are doing their duties well, thanks to his majesty’s missi dominici which effectively performs their own duties of visiting every courts throughout the kingdom and to ensure that taxes were properly collected and that all the king’s decree were followed. His majesty’s victories against the Lombards and the Saxons as well as against the Avars have brought the kingdom stable peace (McDonald, p. 95) and genuine respect from the very citizens who were proud of his majesty’s victories. His majesty’s unexpected coronation by Pope Leo as â€Å"an Augustus† confirms his majesty’s â€Å"formidable power† (Brown 2004, p. 435), that certainly added much respect to the Kings court which prompted them to render their duties satisfactorily. However, despite of the general peace that the kingdom enjoyed as well as of the fine performance of civil duties, many people especially from the ranks of peasants and the nobility are poor and illiterate. In general, life was â€Å"brutal and harsh† (The History Guide) for the peasants as many of them were in abject poverty. Religion was less important as many of them were illiterate. This was also the case of the nobility who were mostly illiterate. Concerning religion, both the peasants and the nobility have little regard for religion for two reasons; the first one is that, since most of these groups were illiterate they cannot understand Christianity as their access to the Christian Bible were very limited. Second, most of the nobility spend their life in fighting. Given this problem, it is hereby presented to his majesty some solution to the problem in order that an enduring justice and peace will continue to flourish throughout the Kingdom. First is, the establishments of more schools so that everyone who can afford its cost whether they are peasants or nobility can have the opportunity to improve their condition. In matters of religion, the nobility were the most numbers of people who have no religious beliefs were in darkened by illiteracy because they spent much of their time in fighting. They mostly land less although compared to the peasants, they were quite better. With this situation, it is hereby noted that those soldiers who were given lands in recognition of their efforts in war were the most loyal of the king’s subjects and were ready to accept whatever is the king’s instruction, whether to encouraged them to embrace Christianity or to faithfully obey all the king’s decrees. In general, everything was under the king’s control although there also some isolated cases of dissatisfaction, everything were fine. The king should continue to promote religion as well as the establishment of more schools so that people can learn reading and writing in order for them to gain understanding which would open their minds to embrace Christianity and to their civil duties satisfactorily. References Brown, P.R.L. (2004) The Rise of Western Christendom: Triumph and Diversity, A.D†¦., Parts 200-1000 UK: Wiley Blackwell â€Å"Lectures on Ancient and Medieval European History† The History Guide http://www.historyguide.org/ancient/lecture20b.html Macdonald, M.H. (1996) Europe: A Tantalizing Romance: Past and Present Europe for Students and the Serious Traveler USA: University Press of America

Cellular Metabolism and the Immune Response Control

Cellular Metabolism and the Immune Response Control PRESTES, A. F. R. O.1; KONDO, F. V.2; HUETE, G. C.3; MURILLO, O.4 Keywords: mTOR, metabolism, Akt, immune system, regulation, mitochondria, inflammatory and anti-inflammatory I. Introduction Metabolism and immune system: The metabolic system was seen only as a system of power generation and metabolites for the functioning of cells. Today we know that changes in metabolic regulation may interfere directly in diseases that involve inflammatory processes. Thus, knowledge of the relationship between metabolism and cell signaling helps in understanding metabolic disorders, cancer, and also in the study of immune response (1,2). The relationship between metabolic and regulatory aspects of the immune system is not yet fully known. Even with major discoveries on the subject, the metabolism of many cells of the immune system is unknown (1,2). The metabolic changes during phagocytosis of three types of immune cells from pigs, leukocytes and peritoneal exudate monocytes and alveolar macrophages. In this study it was observed that macrophages depend on oxidative phosphorylation to produce energy during phagocytosis, whereas the other two cells only use glycolysis to produce energy (3). Another study confirms the close relationship between immune system and metabolism, which showed that incubation of dendritic cells (differentiated in vitro) with LPS provides an increase in glucose consumption, increased formation of lactate and reduction in oxygen consumption. Furthermore, these changes also reflected in increased CD86 co-stimulatory molecule indicating a functional modulation of these cells (4). The need for meta bolic resources to build active components of the immune system, the messenger function of certain classes of metabolites and metabolites, and the intimate relationship between parasite and mammalian defense mechanism, which is probably immune regulatory events are reflected in the metabolism (5). The metabolic profile of the cells of the immune system is also important to provide a tool that generates a systemic metabolic description induced by the parasite in the host, promoting a new direction of the immune response during infection by the parasite (5). In most biological systems, there is a stimulus that triggers an effector response, which usually makes the system back to the starting point. Although having different primary functions, the immune system and metabolic pathways are arranged in the same manner as in serum glucose levels in thermogenesis or bacterial infection, where the lipopolysaccharide stimulates TLR-4 receptor, which promotes the release of TNF-ÃŽ ±, improving bactericidal activity and vascular permeability reducing infection (2). Metabolism and associated pathways Akt/PI3K/mTOR: As well as the metabolic pathways generate energy, the means of regulation of protein synthesis involves several intracellular signaling pathways such as Akt as Akt (serine/threonine kinase), expressed in heart, lung, brain and skeletal muscle. Various stimuli, such as cytokines, growth factors and hormones, are responsible for the phosphorylation and activation of Akt, which is composed of three members, Akt1, Akt2 and Akt3 (6). The Akts proteins are recruited to the plasma membrane by PI3K, which acts as a lipid kinase. The Akt/PI3K pathway operates in promoting cell survival through evasion of apoptosis and cell proliferation through activation of mTOR in response to nutrient availability and to stimulation by growth factors. The mTOR protein stimulates translation that is required for cell cycle progression (7). mTORC1 activation is indirectly given when Akt phosphorylates TSC-2 one of the molecules of heterodimer TSC1 and TSC2, this activates the GTPase function of this heterodimer which reverses the inhibition of mTORC1, inhibiting RHEB to pass the ADP to ATP linked to this protein, by activation of cyclase function of the TSC heterodimer (8). Akt phosphorylation is important for neutralization and PRAS40, important for the activation and interactions mTOR1 and mTOR2 with their substrates (9). Thus, the mTOR pathway is also known as PI3K/Akt/mTOR. Despite the multiple substrates involved in this pathway. Additionally, Akt is not limited to this path and fulfills other functions at the cellular level. Metabolism and mTOR: Mammalian Target of Rapamycin is a serine/threonine protein kinase involved in regulation of many cellular events, such growth, survival, function, metabolism, and differentiation. It is constitutively expressed, and its regulation occurs predominantly post-translationally (7). This protein was discovery from searches about target of Rapamycin, that was originally found as a growth inhibitor which have immunosuppressive and anticancer properties (10). Additionally, due to the ability of mTOR activation to regulate metabolism, it promotes a crucial link connecting metabolic demands and cellular function (7). This link is mediated through the control of key transcriptional regulators. (11). mTOR fathers two functionally distinct signaling multi-protein complexes: mTORC1, which is composed of the scaffolding regulatory-associated protein of mTOR (RAPTOR), DEP domain containing mTOR-interacting protein (DEPTOR), Proline-Rich Akt Substrate 40 kDa (PRAS40), and mammalian Lethal with Sec13 protein 8 (mLST8); and mTORC2, which is composed of RAPTOR-independent companion of TOR (RICTOR), protein observed with RICTOR (PROTOR), mSIN1 proteins, mLST8 and DEPTOR. The connection of mTOR with these adapter proteins has functional distinct consequences (3,4). II. Metabolism and T cells differentiation Such described previously, the mTOR ability to play a role in cellular differentiation occurs through the regulation of transcription regulators. Follow, some these regulators and its role in metabolic programs regulation. HIF-1: The Hipoxia-inducible Factor is a hetrodimeric protein which regulates the expression of various genes crucial for cellular adaptation to a low-oxygen environment. This protein supports the differentiation of naà ¯ve CD4+ T cell to Th17 cell through the stabilization of the RORÃŽ ³t expression, as well as inhibits Treg differentiation through the inhibition of Foxp3, mediating its proteosomal degradation (3,5). Myc: The oncogenic transcription factor Myc regulates various metabolic pathways essentials for cellular growth and proliferation, such glycolysis, glutaminolysis, and fatty acid oxidation (14). PPARÃŽ ±: The peroxisome proliferator-activated receptor ÃŽ ± (PPARÃŽ ±) is a nuclear hormone receptor that regulates fatty acid metabolism and glucose homeostasis, playing a role as a intracellular sensor of endogenous fatty acids. This receptor induces Treg differentiation and inhibits effector differentiation (11). PPARÃŽ ³: Like its homolog PPARÃŽ ±, PPARÃŽ ³ is a nuclear hormone receptor that regulates adipogenesis, lipid metabolism and glucose homeostasis in cells. This receptor plays the same role in T cell differentiation (11). SREBP: The sterol regulatory element binding proteins (SREBP) plays a critical role in regulating cellular lipogenesis, facilitating the anabolic enzymes transcription, which is involved in cholesterol and fatty acid synthesis (11). This protein was found to associate with the IL17 promoter, where it interacts with and inhibits the activity of the aryl hydrocarbon receptor. This transcription factor is known to be important for expression of Th17-associated genes (5,7). Once the antigen is recognized, the integration of many factors from the microenvironment gives the effector fate of the naive CD4+ T cell. Until now, the T-cell subsets have been characterized only by their transcription factor expression and cytokine secretion profile. Nevertheless, it has currently proposed that each T-cell subset also hold a single metabolic profile and a corresponding set of signal requirements of mTOR complexes (11). According this metabolic classification, the T-cell would present these features: Th1 T cells phenotype exhibit a strong glycolytic phenotype and express high levels in surface of the Glut1 glucose transporter. Its development is dependent on the mTORC1 signaling complex (3,8). Th2 T cells phenotype also express high levels in surface of the Glut1 glucose transporter and exhibits a high rate of lactate production and glucose uptake following stimulation. These cells can develop in absence of mTORC1 but are dependent on the mTORC2 signaling complex (3,8). Th17 cells phenotype is the higher glycolytic T-cell subset. The IL-17-secreting CD4+ T cells development drastically decreases in T cells lacking mTOR, mTORC1 and treated with Rapamycin. Nevertheless, T cells lacking mTORC2 does not appear to have its development inhibited (3,8). Treg cells phenotype exhibits an oxidative metabolic profile which uses mitochondrial respiration and fatty acid oxidation to achieve energy. The treatment with process of glycolysis inhibitor compounds in naive CD4+ T cells importantly enhance its development, what also occurs with culture conditions that conduces to a low mTOR signaling (3,8). III. Regulation of cell B by mTORC The PI3K pathway to mTOR is required for B cell proliferation. Since the BCR is blocked by inhibition of mTOR. This was evidenced in mouse spleen cells, wherein inhibition of mTOR suppresses the proliferation and differentiation of B cells by CD40 (10,11). In humans, Rapamycin suppresses B cell proliferation when is activated in the presence of CD40L and B cell inducing cytokines. Rapamycin prevents antibody-mediated apoptosis, generating a reduction of B cells that produce IgG and IgM, also suppresses the production of cytokines that induce proliferation of B cells and IgM, as IL-2 in inflammation conditions (18). Some authors suggest that mTOR regulates IL-17, which is important in the proliferation of pro-B cells. Thus, if rapamycin in B-precursor acute lymphoblastic leukemia cell lines is evidence that IL-17 induces apoptosis in these cells is used. But when S1N1, an important element of mTORC2, is suppressed cell survival is increased possibly by the increased expression of IL-7R (20). In mature B cells, activation of TLRs and BCR induces activation of mTOR, even so, have been identified as Akt independently of mTOR regulates the BCR and this is accomplished by inactivating FoxO1 which is sequestered and degraded in cytoplasm after Akt is phosphorylated (21). When is deleted TSC1 or TSC2, is inhibited the maturation of cells B, contrary to what happened when Akt was active, in where B cells were significantly reduced in the marginal zone (MZ). But when rapamycin was fed this phenomenon was corrected, and once again the importance of mTOR is displayed in the control populations of B cells in MZ. Despite all the evidence to date is known that the PI3K pathway is a major regulatory functions and populations of B cells through regulating FoxO1. But do not have enough information to indicate the direct role of mTOR in the control and regulation of B cells, which is still under study and demonstration (22). IV. Metabolism and APCs Regulation Dendritic Cells (DC): crucial regulators of both cellular activation and tolerance in adaptive immune responses. The function which DC will perform depends on their activation and differentiation status (23). The DC activation occurs through PAMP stimulation of TLR, what leads a metabolic transition in the resting immature DC, which is characterized by a conversion from mitochondrial b-oxidation of lipid and OXPHOS to aerobic glycolysis (9,10). Once exposed to TLR agonists, in an early phase, the lacking of glucose in culture medium leads to critical faults in DC activation, such production of IL-12p40 and surface expression of CD40 and CD86. Afterwards, DCs activated by TLR signals are highly dependent on glucose for survival, becoming more sensitive to apoptosis by nutrient limitation. Thus, for full DC activation is essential initiating glycolysis at the time (9,10). Differently than OXPHOS, glycolytic pathway may be requested due to the necessity to produce substrates which will be used during DC activation. As an option, glycolytic pathway components can control protein translation and can be responsible to regulate the translation of crucial proteins for DC activation (24). Macrophagues: Macrophages can be classified into two major groups M1 (inflammatory) and M2 (anti-inflammatory). And each type of macrophage used different metabolic pathways, M1 uses energy mainly anaerobic glycolysis, mediated by HIF-1ÃŽ ±, while M2 employs FAO mediated PPARÉ ¤ and PGC-1ÃŽ ² (26). Evidencing with this, the relationship with of the metabolic function and and the population of macrophages. This regulation may be mediated by mTOR, which is an important nutrient sensor / power as processes such as protein synthesis, autophagy, glycolysis and regulation of immune response, de novo lipogenesis, among others. (27) Natural killer cells (NK cells): The NK cells rapamycin inhibits proliferation by blockade of the cell cycle in G1 phase in rat. Nevertheless, rapamycin does not affect interferon production by NK cells. When mTOR is inhibited in vitro, the death of T-cell YEC-1mediated by NK cells decreases slightly. In vivo, rapamycin reduces the number of NK cells in rat liver allografts (10). Neutrophils: Human neutrophil is inhibited the chemotaxis and chemokinesis induced by GM-CSF, when rapamycin is delivered. The same way, the response to IL-8. Rapamycin reduces polymerization of actin, important for leukocyte migration. mTORC1 is linked in activation of neutrophils and acute lung injury in association with TLR2 and TLR4 (18). V. Mitochondrial metabolism and regulation of immune response Effect Warburg: Is a termination used to describe a mechanism of some cancer cells to metabolize glucose via glycolysis, where the conversion of glucose to lactate with oxygen available to obtain energy with rapid generation but less efficient pathway for obtaining ATP (20,21). Carbon precursors necessary for the synthesis of nucleic acids, phospholipids, fatty acids, cholesterol and porphyrins can be provides by glycolysis (28). Glycolysis in normal tissues is the metabolism of 6-carbon glucose to 3-carbon pyruvate and the energy in the form of ATP occur via oxidative phosphorylation in mitochondria (30). Hexocinase-2 (HK-2) is an isoform over-expressed in many cancer cells and is located on the external mitochondrial membrane protein VDAC (voltage-dependent anion channel). HK-2 has preferential access to mitochondrial generated ATP via the mitochondrial adenine nucleotide translocator (ANT), and protection from inhibition by its product G-6-P. Cancer cells have overproduced HK-2 and making the reaction between ATP and the incoming glucose to produce G-6-P at a high rate (30). Studies suggest a link between cancer cells and Hif-1a, where high Hif-1a activity is demonstrated to mediate the Warburg effect. HIF-1a is able to produce enzymes hexokinase 2, triosephosphate isomerase, isomerase, glucose 6-phosphate, and pyruvate kinase M2 (PKM2) in glycolysis (31). HIF-1 is a transcription factor responsible for the change of gene expression during cellular response to low oxygen conditions. Amplifies HIF-1 transcription of genes encoding glucose transporters and glycolytic enzymes (32). Recent studies show Warburg effect have many mechanisms: tumor microenvironment and stabilization of HIF, oncogene activation and loss of tumor suppressor genes, mitochondrial dysfunction in cancer cells, nuclear DNA mutations, epigenetic changes, miRNA, glutamine metabolism, and post-translational modifications (28). Metabolic pathways and importance in the differentiation and function of immune cells: The response, proliferation, polarization or action of immune cells requires the supply of nutrients and high energy consumption, for this reason the contribution of ATP for these functions comes from differential form of the various metabolic pathways, from glycolysis, to pyruvate until lactate production or acyl-CoA, to enter the tricarboxylic cycle acid (TCA); or through of the fatty acids oxidation (FAO). Producing enough electrons (NADH and FADH2) to activate of the electron transport chain to fuel oxidative phosphorylation (OXPHOS) (1). It is also already considered that myeloid cells such as granulocytes, dendritic cells, macrophages, B cells and T cells mainly use glycolysis as a source of ATP via anaerobic when they present an effector or inflammatory profile (Figure XX)(1,2). This is evidenced by neutrophils that have few mitochondria and consume little oxygen (34). Under these conditions the Warburg effect is generated. Producing lactate and NADPH, an essential cofactor for the NADPH oxidase for the production of important microbicidal product H2O2 (35). Some authors suggest that eosinophils and basophils are metabolically similar to neutrophils (36) As with neutrophils, macrophages are important in the immune response and are distributed in all organs and tissues. Playing an important role in innate immunity and adopt different states of activation. Interferon-É ¤ (IFN-É ¤), in combination with TLR agonists, induces M1 (inflammatory), while IL-4 and IL-13 cytokines induces M2 (regulators) (37). M1 macrophages secrete IL-12, IFN-gamma promotes, thus inducing NK cells and T cells, addition of TNF-ÃŽ ±, that activate other immune cells, and NO. Contrary M2 macrophages, secret anti-inflammatory molecules and stimulate tissue repair. Activation of M1 and M2 is characterized by the use of different metabolic pathways (38). M1 using arginine as a substrate to produce iNOS occurs only in the M1, and not in M2. M2 using arginine as a substrate for Arginase1 expressed only in the M2, and not in M1(37). The M1 macrophages possess a glycolytic metabolism. Similar to the different types of activated cells such as dendritic cells and granulocytes. (Figure XX). The Macrophage M1 has higher basal mitochondrial oxygen consumption, the other macrophages. M2 macrophages inducing the mitochondrial OXPHOS through of IL-4 and FAO. in such a way, metabolism M2 is strongly biased towards the use of FAO and mitochondrial respiration to meet their energy needs (Figure XX) (39). DCs derived from cultured bone marrow stimulated with colony-stimulating factor granulocyte-macrophage, are a model of production of TNF-ÃŽ ± and inducible nitric oxide synthase (iNOS). At rest, the DCs oxidize glucose in the mitochondria, by OXPHOS, with little lactate production. But, once stimulated with TLR agonists, become dependent on Warburg metabolism to subsistence (40). PI3K and Akt are important in the activation of glycolytic metabolism (41); play an important role in the duration of glycolysis in DCs activated. As evidenced by DCs activated by more than 12 hours which increases glucose consumption and TCA and mitochondrial oxygen consumption cease (40), increasing lactate production, and the cells survive only by aerobic glycolysis (Fig. XX). The high production NO gas by iNOS from arginine, inactive mitochondrial respiration in these cells. So the activation of glycolytic metabolism in activated DCs induces the expression of iNOS and production of NO thus inhibits OXPHO S. This subsistence mechanism is vital for the rapid production of ATP in the absence of machinery for the production of mitochondrial ATP (42). As the cells of the innate immune system, the T and B cells activated Warburg metabolism used at the time of the proliferation. In contrast to most of innate cells, which use Warburg metabolism after activation but not proliferate (1). Contrary to activated effector T cells, memory T and B cells do not use aerobic glycolysis but if they use mitochondrial FAO for their development and persistence, maintain or adopt a catabolic metabolism (Figure XX) (43). Once an antigen recognized by naive T cells and with adequate costimulation, this growth rapid, proliferation, and acquisition of specialized effector functions is initiated. This requires of the T cell a metabolic reprogramming and energetic. This pass of a catabolic metabolism to an anabolic metabolism, changes the cell is not in a state of maintenance and homeostasis (1). Some molecules such P13K, Akt, Myc, and HIF are associated with immune and metabolic signals for the activation, function, development and upkeep of T cells. So the metabolic pathways induce a T helper subsets (1). As was evidenced in Treg cells mainly use mitochondrial OXPHOS and FAO for their development and subsistence (17) or in Th17 cells where glycolysis is primarily required (44). In activated T cells the IL-12 induce an increase in the glucose transporter and glycolytic metabolism. Besides glycolysis in maintaining the activity of active effector T cells, exist other pathways involved, as via the pentose phosphate and glutaminolysis as well as the use of key molecules such as citrate and malate (Figure XX) (1).It is important to consider the available nutrients, substrates, or other resources that can create an imbalance in the environment of immune cells, affecting the metabolism of cell function and fate of immune cells. Mitochondria in the production of iNOS and inflammation: All metabolic process to generate ATP by OXPHOS generates ROS, which are involved in oxidative stress of the mitochondria. Production of O2- in excess, induces activation of factors of redox-sensitive transcription, such as NF-kB, and thus an increase of cytokines, chemokines, inducible nitric oxide synthase (iNOS), eicosanoids, and adhesion molecules (45). Some of these superoxide anions combine with nitric oxide (NO) to produce peroxynitrite (ONOO-), a powerful oxidant. These ROS oxidize proteins, membrane lipid and mtDNA; damaging mitochondrial integrity (46). Being mitochondria, the inducer of the pro-inflammatory action by the action of innate immunity using redox sensitive or direct inflammasome activation molecules. Progression that result in the immediate activation of caspase-1, and subsequent activation of the inactive precursor of IL-1ÃŽ ² and IL-18 (47). DAMPs activate the same receptors that detect PAMPs, such as TLRs and cytoplasmic NOD and NLRs (46). Once activated, NLRP3 this is depolymerized and induces the recruitment of the adapter protein ASC and caspase-1 (and her cleavage), and other cytoskeletal proteins, glycolytic enzymes and caspase-7. This group of proteins called inflammasome. This complex induces pro-inflammatory, such as IL-1ÃŽ ² and IL-18.(47). Elevated levels of ROS generated by the mitochondria activate NLRP3 inflammasome. Interestingly, the humidity and the myth-AMPS can activate APCs, as well as other non-immune cells including mesenchymal stem cells and astrocytes. Additionally, IL-1ÃŽ ² pro-inflammatory IL-6, MCP-1 and TNF is induced by degradation of mtDNA in mouse primary astrocytes. (48). This activation of the inflammasome can activate NF-kB, increasing even more pro-inflammatory cytokines duration of the inflammatory response. This summation of events can be a clear explanation to the high deterioration of mitochondria (46). Biogenesis of mitochondria: The availability of nutrients and oxygen can determine the function of a time cell proliferate and differentiate. Under normal conditions the cell has high level out of ATP/ADP/AMP. Thus, an increase in AMP activates AMPK, activating ATP production by activating TSC 1 and 2 which blocks mTOR (7). After ATP levels are increased activated Akt/PKB promotes mitochondrial biogenesis by phosphorylation and nuclear translocation of NRF-1 and nuclear translocation with increased mitochondrial hexokinase (HK), using glycolysis coupled to OXPHOS with uptake mitochondrial ATP, especially in order to allow cell survival and maintenance of cell functions (49). An important protein in the biogenesis of mitochondria is BAD, which is involved in the initiation of a protein complex that catalyzes the first step of glycolysis by deHK-4 activation. But absent BAD gives a restriction of respiration in the presence of glucose and in the absence of glucose dephosphorylated BAD and induces apoptosis(50). This interaction between energy metabolism and the regulation of apoptosis, is important in mitochondrial biogenesis, and any imbalance can lead to mitochondrial failure and loss problems inducing pathological cell survival (51). Thus, the whole process of inflammation, oxidation and apoptosis, requires a high rate of mitochondrial replacement to allow the restoration of damaged mitochondria continuously and cell survival, which may serve as a signal that stimulates the production of mediators anti-inflammatories such as the IL-10. This is evidenced by the increased immune tolerance during periods of mitochondrial biogenesis may be a risk for recurrent or secondary infections evidencing with them a close relationship between immunosuppression and the regeneration of the mitochondria, this period of immunosuppression may be greater depending the damage level of the mitochondria involved in the initial inflammatory process.(49). VI. References 1. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. Elsevier Inc.; 2013 Apr 18;38(4):633–43. 2. Odegaard JI, Chawla A. The immune system as a sensor of the metabolic state. Immunity. Elsevier Inc.; 2013 Apr 18;38(4):644–54. 3. Oren R, Farnham AE, Saito K, Milofsky E, Karnovsky ML. Metabolic patterns in three types of phagocytizing cells. J Cell Biol. 1963 Jun;17:487–501. 4. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010 Jun 10;115(23):4742–9. 5. Saric J. Interactions between immunity and metabolism contributions from the metabolic profiling of parasite-rodent models. Parasitology. 2010 Aug;137(9):1451–66. 6. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999 Nov 15;13(22):2905–27. 7. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012 Jan;30:39–68. 8. Castro AF, Rebhun JF, Clark GJ, Quilliam LA. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem. 2003 Aug 29;278(35):32493–6. 9. Wang L, Harris TE, Roth RA, Lawrence JC. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007 Jul 6;282(27):20036–44. 10. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006 Sep;6(9):729–34. 11. Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012 Sep;249(1):43–58. 12. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009 Oct 15;122(Pt 20):3589–94. 13. Barbi J, Pardoll D, Pan F. Metabolic control of the Treg/Th17 axis. Immunol Rev. 2013 Mar;252(1):52–77. 14. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011 Dec 23;35(6):871–82. 15. Barbi J, Pardoll D, Pan F. Metabolic control of the Treg/Th17 axis. Immunol Rev. 2013 Mar;252(1):52–77. 16. Cui G, Qin X, Wu L, Zhang Y, Sheng X, Yu Q, et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest. 2011 Feb;121(2):658–70. 17. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011 Mar 15;186(6):3299–303. 18. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009 May;9(5):324–37. 19. Sakata A, Kuwahara K, Ohmura T, Inui S, Sakaguchi N. Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro. Immunol Lett. 1999 Jun 1;68(2-3):301–9. 20. Lazorchak AS, Liu D, Facchinetti V, Di Lorenzo A, Sessa WC, Schatz DG, et al. Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. Mol Cell. 2010 Aug 13;39(3):433–43. 21. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19;96(6):857–68. 22. Benhamron S, Tirosh B. Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells. Eur J Immunol. 2011 Aug;41(8):2390–6. 23. Dong H, Bullock TNJ. Metabolic Influences That Regulate Dendritic Cell Function in Tumors. Front Immunol. 2014 Jan;5:24. 24. Dong H, Bullock TNJ. Metabolic Influences That Regulate Dendritic Cell Function in Tumors. Front Immunol. 2014 Jan;5:24. 25. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010 Jun;115(23):4742–9. 26. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 2006 Jul;4(1):13–24. 27. Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun. Nature Publishing Group; 2013 Jan;4:2834. 28. Upadhyay M, Samal J, Kandpal M, Singh OV, Vivekanandan P. The Warburg effect: insights from the past decade. Pharmacol Ther. Elsevier Inc.; 2013 Mar;137(3):318–30. 29. Xie J, Wu H, Dai C, Pan Q, Ding Z, Hu D, et al. Beyond Warburg effect dual metabolic nature of cancer cells. Sci Rep. Nature Publishing Group; 2014 Jan;4:4927. 30. Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2 bound to mitochondria: cancer’s stygian link to the â€Å"Warburg Effect† and a pivotal target for effective therapy. Semin Cancer Biol. 2009 Feb;19(1):17–24. 31. Palsson-McDermott EM, O’Neill L a J. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays. 2013 Nov;35(11):965–73. 32. Cairns R a, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. Nature Publishing Group; 2011 Feb;11(2):85–95. 33. Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation. J Immunol. 2010 Apr 15;184(8):4062–8. 34. Van Raam BJ, Verhoeven AJ, Kuijpers TW. Mitochondria in neutrophil apoptosis. Int J Hematol. 2006 Oct;84(3):199–204. 35. Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood. 2008 Aug 15;112(4):935–45. 36. Sumbayev V V, Nicholas SA, Streatfield CL, Gibbs BF. Involvement of hypoxia-inducible factor-1 HiF(1alpha) in IgE-mediated primary human basophil responses. Eur J Immunol. 2009 Dec;39(12):3511–9. 37. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011 Nov;11(11):723–37. 38. Rodrà ­guez-Prados J-C, Travà ©s PG, Cuenca J, Rico D, Aragonà ©s J, Martà ­n-Sanz P, et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activat