Reconstruction And The Rights Of Former Slaves. In The

Reconstruction and the Rights of Former Slaves In the 1860s the United States was a nation that had been ripped apart by the Civil War and left in torn pieces. The war left many white southerners stripped of their slaves, land, and in destroyed towns with little to eat. The only people worse off than the white southerners at this point in history were the black southerners who had nothing to their names but the freedom they had recently been granted which left them penniless and searching for a place to go. In hopes of a resolution president Abraham Lincoln took charge in by announcing a reconstruction plan in hopes of bringing the country back together. President Lincoln believed the plans for reconstruction should be lenient on the†¦show more content†¦The act also gave the federal government the power to step in if any states attempted to intrude on the African Americans’ rights. By the 1870s the Civil rights Act in full force and the African American had gained th e right to vote, right to get married, equal protection under the law, the right to own land and a right to an education. The former slaves had come along way but things were not as great as they may seem. In many ways, the former slaves were still controlled by the white southerners. Many of the African Americans struggled to find work outside of working on plantations which left them with little money and without money life was difficult. The white southerners could go around the laws made by the Federal government and still for the most part control the African American southerners. A quote from our book, â€Å"We are sheep in the midst of wolves† stood out to me as a very accurate representation of what life would have been like for African Americans living in the South during this time. Overall though the African Americans had come a long way from slaves who worked the fields from dawn until dusk, but still needed to progress further. The Reconstruction and civil rights act would have been more of a successful if it was not for the North becoming less involved. The north became extremely involved with other factors and become less and less committed to the Civil Rights Act. Without the federal government aiding and protecting the FormerShow MoreRelatedThe Reconstruction Era ( 1865-1877 )1589 Words   |  7 PagesThe Reconstruction era (1865-1877) was a period of excitement for ex-slaves because they were declared free American citizens. However, all their expectations of freedom were not fulfilled as soon they expected because of the conflict their new freedom bore between them and their former masters. In this discussion, the focus of Eric Foner on the Reconstruction will be compared with that of P. Downs and Scott Nesbitt to get a clearer understanding of the occurrences of the period using their worksRead MoreThe Civil War: Reconstruction1156 Words   |  5 Pagesfarmers. The Reconstruction era was meant to be exactly how the name announces it to be. It was a time for the United States to fix the broken pieces the war had caused allowing the country to mend together and unite once again. The point of Reconstruction was to establish unity between the states and to also create and protect the civil rights of the former slaves. Although Reconstruction failed in many aspects such as the upraise in white supremacy and racism, the reconstruction era was a timeRead MoreThe During The Civil War966 Words   |  4 PagesWar, the period of reconstruction was filled with a similar sense of uncertainty; the Confederate states had to be assimilated back into the Union but there were many conflicting views on how this should be done. 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Not many African Americans knew how to read and write, because they were slaves and never had the opportunity to beRead MoreEssay on Success of Reconstruction777 Words   |  4 PagesSuccess of Reconstruction Reconstruction was the time period following the Civil War, which lasted from 1865 to 1877, in which the United States began to rebuild. The term can also refer to the process the federal government used to readmit the defeated Confederate states to the Union. While all aspects of Reconstruction were not successful, the main goal of the time period was carried out, making Reconstruction over all successful. During this time, the Confederate states were readmittedRead MoreReconstruction Dbq1448 Words   |  6 Pagesend of slavery in the United States. Although the former black slaves were now free, they had no land and very few rights, and most did not even have family. Though out reconstruction, blacks were able to gain rights, but were continuously repressed by the white Southerners. 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Reconstruction’s main goal was to reintroduce the South into theRead MoreAmerican Reconstruction after the Civil War Essay1228 Words   |  5 Pages Reconstruction was a period of time after the Civil War (1865-1877) that was supposed to be the rebuilding of America. It was also the process used to readmit all the Confederate states back into the Union. There was controversy, however, on how to go about rebuilding the nation. Abraham Lincoln proposed a lenient plan. After he was assassinated, Andrew Johnson proposed a very similar plan. The Radical Republicans, a group of legislators that were in favor of freedmen’s rights, were opposedRead MoreReconstruction : Johnson s Plans And His Battles With Congress1576 Words   |  7 Pages Reconstruction Johnson’s Plans and His Battles With Congress: Republican Abraham Lincoln chose Democratic Senator from Tennessee, in 1864, to be his vice presidential candidate. Abraham Lincoln was on the lookout for Southern support. He was hoping that choosing Johnson, would appeal the Southerners who never planned on leaving the union. Johnson also grew up in poverty. He hadn’t learned to write until he was around 20yrs old. He rose up to political power as a â€Å"backer† of a small farmer. InRead MoreEssay about Assignment 1 AMH2020639 Words   |  3 Pages During reconstruction, the meaning of freedom suited many different types of interpretation; the perception of freedom between former slaves and their slaves masters were very contradictory. To begin with, African-Americans had suffered severe abuse over those years of slavery, so to them, the meaning of freedom was basically a hope that in the future, they won’t experience all kind of punishment and exploration that they have been experienced so far. Besides that, formers slaves were demanding

Early Modern Period Free Essays

1450-1750 Early Modern Period Major Developments I. Questions of Periodization A. Major points 1. We will write a custom essay sample on Early Modern Period or any similar topic only for you Order Now Shift in power to the West a. Rise of the West with fall of China and India creates imbalance in power that favors Europeans for next 200 years 2. World becomes smaller – almost all civilizations touched by trade 3. New Empires – Spain, Portugal, England, France, Netherlands, Ottoman, Russian, Mughal, Ming 4. Age of Gunpowder B. Changes at end of Postclassical Era 1. Independent societies (Aztecs, Incas) falling apart 2. Arab power declining 3. New invasions – Mongols 4. Ottoman Empire gains power a. Europeans threatened by new force to East 5. Chinese flirt with trade, but Ming bureaucrats pull back 6. Europe enters age of exploration C. Western Europe 1. Unusual agricultural civilization 2. New view of family – nuclear a. Love toward spouse b. Affection toward children 3. Return to rational thought 4. Stable political structures a. Absolute monarchy b. Parliamentary monarchies 5. Religious reformers a. Reform the Church b. Protestant Reformation D. Effects of Global Economy 1. By 1750, almost everyone knows everyone 2. Food exchange – new staple crops to Africa (corn), Europe (potato) 3. Unequal relationships – master, slave, owners, workforce 4. Slaves and serfs 5. Diseases E. Themes 1. Declining emphasis of nomads 2. Direct relationships – ambassadors replace intermediaries (Nomads) 3. Gender relations remain patriarchal 4. Labor relations change – master/slave – abuse of indigenous peoples 5. A few commercial leaders get rich 6. Environmental changes a. ood, animal, disease exhange 7. Native vegetation a. Deforestation for staple crops b. Grazing land for newly introduced beasts of burden 8. Centralization of governments a. Modern government 1. bureaucracies 2. agencies 3. admiralties 4. treasuries 5. general staff 6. state banks 9. Nation-states began to emerge a. solid political units with fixed borders b. sense of national unity c. populations relatively homogenous – language/e thnicity F. Larger Trends 1. Americas overwhelmed by outsiders 2. Three trends a. Western expansion . Globalization of trade c. Gunpowder 3. Reactions a. Embrace by choice b. Embrace by force c. Choose to remain independent, involve in trade on own terms G. Why 1450 and 1750 1. 1450 a. End of the Middle Ages b. Beginning of the Northern Renaissance – away from Italian city-states c. English evicted from France d. Unified France began to exercise its power e. Globalization of trade begins f. Direct contact between Europe and sub-Saharan Africa/Americas g. End of the Byzantine Empire h. Ottoman Turks rise to power How to cite Early Modern Period, Papers

A Case Analysis and for United States Airline Industry

Question: Describe about the Strategy and Case Analysis for United States Airline Industry. Answer: Introduction According to the case study, the United States Airline Industry is one of the most renowned airlines that have gone through several ups and downs. The large carriers are facing significant competition from low cost carriers. The aim off this report is to study the competitive forces of the US airline industry. Firstly, an overview of the US airline industry is presented where the data is represented in the form of numerical figures. According to the case study, it is observed that the US airlines have gone through significant losses in the previous years. Therefore, the Michael Porters model of competitive forces is adopted for analysing the causes of low profitability in the airline industry. Further, according to the case study, the economic performance of the US airline industry is cyclical. The growth of the airline industry is cyclical as the business depends on the countrys economic growth. Therefore, a justification and thorough explanation regarding the same is provided. Furt her, after discussing the issues faced in US airlines, several strategies are identified that can be adopted to help make the airlines profitable. A justification for adopting the strategies is also provided. Last, but not the least, a critical discussion regarding the US airline industry scenario is made. The US Airline Industry: An Overview The US airline industry handles over 1,000,000 passengers annually (Statista.com 2016). It is ranked twelve among the thirty busiest airports in the world (Rita.dot.gov 2015). The US airline industry has faced significant ups and downs due to several consolidations and mergers. There are three major international carriers operating in US- American Airlines, Delta Airlines and United Airlines. Apart from these, there are nine large carriers with both domestic as well as international destinations such as Virgin America, JetBlue, Hawaiian Airlines, Frontier Airlines, Alaska Airlines, Southwest Airlines, Sun Country Airlines, Spirit Airlines and Allegiant Air. According to Statista.com (2016), Southwest Airlines hold the highest market share of 18.2% in 2015. Majority of the airlines have improved both in capacity as well as traffic. However, the pricing pressures and fall in oil prices and capacity growth has led to a decrease in passenger net revenues. Lorenzetti (2015) argues that the airlines are facing a lot of issues despite high profits. The US airlines have hit over $8 billion in the first six months of 2015, but the lower ticket prices have caused a decline in passenger unit revenue (Statista.com 2016). However, as soon as the labour cost and oil prices will increase, the airlines shall require the customers to spend more money that could be challenging job. The US airline industry has faced bankruptcies, technological advancements, presidential intervention and tumultuous attacks of 9/11 (Statista.com 2016). The airlines have downsized 160,000 jobs for cutting huge losses (Statista.com 2016). Services have been cut to multiple destinations. One of the significant mergers that changed the US airline industry scenario was the Southwest Airlines and AirTran thereby making Southwest the fourth largest airli ne in US. Majority of the airlines had to cut down prices due to low cost carriers. The overall travel experience of the customers also declined. The onboard conditions and cuts in food were also experienced. It is observed that the rising jet fuel and oil prices are making a heavy dent in the US airline industry (Statista.com 2016). Figure 1: Market Share Source: (Statista.com 2016) A Competitive Forces Analysis of the Industry A competitive analysis can be made using Porters five forces as it is a crucial methodology to analyse the external environment. The level of competition in the US airline industry is high. The US airline industry has been buffeted by strong headwinds from multiple external factors such as increasing operating expenses, greater landing and maintenance costs, declining passenger traffic, intense price competition from low cost carriers and various others. The US airline industry has also faced bankruptcy because of a global death spiral in the airline industry. The US airlines have also formed mergers to survive in the global landscape. The low profitability in the airline industry can be studied in greater detail due to the effects of following forces: Supplier power- There is a huge list of suppliers for the airline industry in US. The three main supplied are fuel, labour and aircraft which are directly influenced by the external environment. For example, the oil prices fluctuate according to the global price fluctuations. The geopolitical factors cause change in fuel prices. Further, labour is also affected by the power of unions who get costly concessions and unreasonable bargains from the US airlines. Lastly, the airlines depend on two aircrafts, Boeing and Airbus for the aircraft needs. Therefore, these three inputs- fuel, labour and aircraft make the bargaining power high and profitability low (Assaf and Josiassen 2012). Buyer power- The buyers have high bargaining power over the US airlines as it is not difficult for the customers to switch from one airline to another. The low switching cost, online ticketing and distribution systems makes the bargaining power of the customers high. Several low cost carriers have entered the US airline industry thereby causing price wars. The advancement of technology and internet has led to the creation of sites such as Orbitz, Expedia and Travelocity. Therefore, these websites allow comparison of prices thereby helping the airlines to keep the fares low. Further, the tight regulations are in favour of the customers. There are multiple airlines available from which the customers can choose from in the case of price discovery that again makes the buyer bargaining power high and low profitability in the US airline industry (Barros, Liang and Peypoch 2013). Entry and exit barriers- The entry and exit barriers in the US airline industry is high. This is because the airline requires huge capital investment for entering and exiting the sector. Not everyone can enter the airline industry as significant investment, knowledge, resources ad expertise is required. Moreover, the US airline regulators so not let the airlines exit the industry unless there is a strong and genuine business reason. Therefore, the airline industry leverages the synergies and efficiencies from the economies of scale. Such high government cost and operating cost are exceedingly complex. Therefore, the threat of new entrants is low while the exit barriers are high (Bilotkach and Lakew 2014). Intensity of Competitive Rivalry- The intensity of competitive rivalry in the US airline industry is high due to the entry of low cost carriers, tight regulations, high operating expenses and others. A few examples of large carriers are American Airlines, Delta Airlines and United Airlines. These are directly hurt by low cost carriers such as Southwest Airlines, AirTran Airways, Jet Blue and Virgin America. These airlines keep very low airfares that intensify the US airline industry competition (Dai, Liu and Serfes 2014). Threat of Complementarities and Substitutes- There is low threat from complementarities and substitutes in the US airline industry. A few examples of substitutes are the customers travelling in cars, trains, or buses which are only possible in short distance journeys. For long distances, people would travel in airlines. Therefore, there is low threat of substitutes. A few examples of complementarities are ala carte meals, provision of Wi-Fi services, and multiple other amenities. However, it is argued that the passengers find lower fares more attractive than the provision of such amenities (Mallikarjun 2015). Economic Performance The economic performance of the airline industry seems to be very cyclical. The growth of the airline industry is cyclical as the business depends on the countrys economic growth. In the times of economic prosperity in US, the disposable income is high. Therefore, the people are willing to spend a greater amount on the booming economy especially on air travel. Therefore, the airline revenue is higher in times of economic growth and vice versa (Marketrealist.com 2016). Figure 2: Economic Growth and US Airlines Revenue Source: (Marketrealist.com 2016) According to the reports by The International Airline Transport Association (or IATA) the demand for airline services increased 5.9% by July, 2016 (Marketrealist.com 2016). Due to low airfares and expansion in routes, the low cost carriers experienced highest growth and aggressive expansion. The airline demand seems to be slowing down and the global economic growth has subdued in the year 2016 (Marketrealist.com 2016). The terror attacks have also affected the travel demand adversely. However, the low prices are attracting the customers. The consumer spending accounts for around 70% of the US economy (Marketrealist.com 2016). The consumers increasingly contribute to the economy up to 4.2% on an overall basis (Marketrealist.com 2016). The job growth declined to 150,000 jobs in August 2016 (Marketrealist.com 2016). The main question is about the consumer spending and its effect on traffic growth of airlines. The consumer spending is not at pre-recession levels after 2008-2009 (Marketre alist.com 2016). The spending has declined as the race is tightening and election was drawing closer. The other factors affecting airlines demand is capacity, travel demand, utilization and yield. There has been a decline in the airline yields in US after the second quarter 2014 coinciding with the capacity restraint (Marketrealist.com 2016). The passenger yield has declined 5.1% during second quarter 2015 in comparison with the previous year (Marketrealist.com 2016). The airlines in US are facing revenue challenges while sustaining profit margins. The airline capacity is growing faster than the economy. Identifying Strategies for Airline Profitability Based on the above analysis, certain strategies are identified for enhancing profitability in the US airlines. As the US airlines have high labour cost, there are situations of bankruptcy. To avoid any strikes, the US airlines must address the labour demands. US airlines perform heavy maintenance and must emphasize control over product. Significant cost savings can be achieved by outsourcing mechanical labour. Various options can be explored if the maintenance can be performed at a lower price. Fuel efficient practices can be implemented as the prices are escalating. Not only the fuel efficiency can be improved, but the environmental impact of operations. The sensitivity to price fluctuations can also be reduced by continuous fuel efficiency initiatives. As US airlines are merging with other companies, it can also partner with low cost carriers as they are in high demand. Seamless service to customers can be provided. The international offerings can be enhanced so that the connections to Asian markets are better. New routes and hubs can be addressed so that the future delivery can be improved. Frequencies of routes can be enhanced so that greater number of passengers can be served (Oum and Yu 2012). Hub-and-spoke airlines can lower the operating costs through onerous labour agreements for United Airlines, American Airlines and US Airways. It shall also help in negotiating better deals with intermediaries and eliminate discretionary costs. The hub operations can be smoothened out. Adding low-cost subsidiaries shall be helpful in enhancing US economy. The legacy carriers can make a case for an incentives-based program that will preserve the viability of the network service they provide. A successful lobby for tax credits could position the legacy carriers to compete with low-cost carriers and return to sustainable profitability. The airport and onboard services can be separated so that the complex processes and systems can be eliminated. The US airlines must provide best quality services at low operating cost. The key service advantages can include destination breadth, onboard amenities and superior loyalty programs (Ratliff and Gallego 2013). Discussion The above report focuses on the issues faced by the airlines. Based on the above analysis, it is evident that competitiveness is one of the critical issues. The change in GDP is reflected in the fuel costs and airline usage. It is necessary for the airlines to make alliances be it with high-speed rail or other airlines (Zou and Hansen 2012). As an example, British Airlines gains immense benefits from the merger despite the non-integration of operations. Another matter of concern is the fuel price. The airlines impose fuel surcharges on the customers thereby leading to high costs. It is argued that with increasing fuel prices, the airlines shall have an effect on the bottom line. As seen in the case of Singapore Airlines, fuel is the greatest challenge. It is further argued that US airlines mainly compete on prices and not on quality service (Baker 2013). The US airline is facing tough competition due to a combination of low prices on the same routes with limited competition. This can be challenging for both regulators and consumers. There has been less competition at USs major airports and the passengers are willing to pay higher fares as they have higher disposable income. There has been an increase in the domestic airfares at a pace greater than inflation which is challenging due to decline in competition (Assaf and Josiassen 2012). It is argued that the passengers had limited choices and paid a higher price back in 1978 (Zou and Hansen 2012). Currently, the airlines choices are high in number. The US government had control over the prices and routes before the competition got intensified in 1980s (Zou and Hansen 2012). The market fares reduced as new entrants entered the market. The US airlines also faced financial shambles after the attacks of 9/11 and recession. There was bankruptcy in the US airlines and a number of deals were restructured starting 2008 (Zou and Hansen 2012). Therefore, it is argued that there is less competition in the US airline industry than before. Conclusion Conclusively, US airlines have gone through significant losses in the previous years. There are three major international carriers operating in US- American Airlines, Delta Airlines and United Airlines. The pricing pressures and fall in oil prices and capacity growth has led to a decrease in passenger net revenues. The US airline industry has faced bankruptcies, technological advancements, presidential intervention and tumultuous attacks of 9/11. The overall travel experience of the customers also declined. The US airline industry has been buffeted by strong headwinds from multiple external factors such as increasing operating expenses, greater landing and maintenance costs, declining passenger traffic, intense price competition from low cost carriers and various others. It is observed that the rising jet fuel and oil prices are making a heavy dent in the US airline industry. The low switching cost, online ticketing and distribution systems makes the bargaining power of the customers high. Further, the US airline regulators make the entry and exit barriers strong. The low cost carriers have grounded the larger carriers thereby making the competition in US airline industry intense. In the times of economic prosperity in US, the disposable income is high. main question is about the consumer spending and its effect on traffic growth of airlines. The consumer spending is not at pre-recession levels after 2008-2009. Significant cost savings can be achieved by outsourcing mechanical labour. The international offerings can be enhanced so that the connections to Asian markets are better. . The airport and onboard services can be separated so that the complex processes and systems can be eliminated. References Assaf, A. and Josiassen, A., 2012. European vs. U.S. airlines: Performance comparison in a dynamic market.Tourism Management, 33(2), pp.317-326. Baker, D., 2013. Service Quality and Customer Satisfaction in the Airline Industry: A Comparison between Legacy Airlines and Low-Cost Airlines.American Journal of Tourism Research, 2(1). Barros, C., Liang, Q. and Peypoch, N., 2013. The technical efficiency of US Airlines.Transportation Research Part A: Policy and Practice, 50, pp.139-148. Bilotkach, V. and Lakew, P., 2014. On sources of market power in the airline industry: Panel data evidence from the US airports.Transportation Research Part A: Policy and Practice, 59, pp.288-305. Dai, M., Liu, Q. and Serfes, K., 2014. Is the Effect of Competition on Price Dispersion Nonmonotonic? Evidence from the U.S. Airline Industry.Review of Economics and Statistics, 96(1), pp.161-170. Lorenzetti, L., 2015.Here's Why The Airline Industry Is In For A Rough Ride. [online] Fortune. Available at: https://fortune.com/2015/08/19/airline-industry-challenges-ahead/ [Accessed 15 Dec. 2016]. Mallikarjun, S., 2015. Efficiency of US airlines: A strategic operating model.Journal of Air Transport Management, 43, pp.46-56. Marketrealist.com, 2016.Flying in the Face of Investor Concerns, Airlines Add to Capacity - Market Realist. [online] Marketrealist.com. Available at: https://marketrealist.com/2016/09/flying-in-the-face-of-investor-concerns-airlines-add-to-capacity/ [Accessed 17 Dec. 2016]. Oum, T. and Yu, C., 2012.Winning airlines. 1st ed. Boston: Kluwer Academic Publishers. Ratliff, R. and Gallego, G., 2013. Estimating sales and profitability impacts of airline branded-fares product design and pricing decisions using customer choice models.Journal of Revenue and Pricing Management, 12(6), pp.509-523. Rita.dot.gov, 2015.2015 U.S.-Based Airline Traffic Data | Bureau of Transportation Statistics. [online] Rita.dot.gov. Available at: https://www.rita.dot.gov/bts/press_releases/bts018_16 [Accessed 15 Dec. 2016]. Statista.com, 2016.U.S. airline market share 2015 | Statista. [online] Statista. Available at: https://www.statista.com/statistics/250577/domestic-market-share-of-leading-us-airlines/ [Accessed 15 Dec. 2016]. Zou, B. and Hansen, M., 2012. Impact of operational performance on air carrier cost structure: Evidence from US airlines.Transportation Research Part E: Logistics and Transportation Review, 48(5), pp.1032-1048.

Nature or Nurture the Case of the Boy Who Became a Girl Essay Example

Nature or Nurture: the Case of the Boy Who Became a Girl Essay NORTHERN CARIBBEAN UNIVERSITY COLLEGE OF NATURAL AND APPLIED SCIENCE DEPARTMENT OF BIOLOGY, CHEMISTRY AND SCIENCE Presented in Partial Fulfillment of the Course: BIOL 395 GENETICS Section A TERM PAPER Nature or Nurture: The Case of the Boy Who Became a Girl Presented By: Nathalia allen Monique Malcolm Davena shaw Shaneek Campbell Part 1 1. Assuming that the nurture theory is valid, David as Brenda will have female behavior and believe he is a girl. From a physical point of view he will not develop secondary characteristics. Based on how hormones work by removing his testicles they denied him of his secondary characteristics. After puberty he would not have testicles to produce testosterone which would make him deficit of his secondary characteristics. 2. If Bruce was not subjected to gender reassignment surgery and raised as a boy, he would express the gender identity of a male. This is so because during the growing or maturing process he would recognize that he has more features of a male than of a female, physically. Although his genitals may look abnormal, he still has other features of a male. Part 2 1. According to the nature view of psychosexual differentiation, prenatal exposure to androgen could influence the development of gender identity. We will write a custom essay sample on Nature or Nurture: the Case of the Boy Who Became a Girl specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Nature or Nurture: the Case of the Boy Who Became a Girl specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Nature or Nurture: the Case of the Boy Who Became a Girl specifically for you FOR ONLY $16.38 $13.9/page Hire Writer David’s experience did not support the nurture theory. None of his characteristics supported the nurture theory. David being neat and tidy was not a feminine characteristic but rather one that was imposed upon by his mother. 2. According to the article David as Brenda resisted the treatment to be raised as gentle lady and eventually became unmanageable. Brenda frequently resisted girl’s toys, activities and clothing. He also mimicked her father’s behavior rather than her mother. She complained that she felt like a boy and viewed her physical characteristics as more masculine than feminine. Part3 1. They agree to a small extent as it relates to the nature theory. As seen with the rodents, once the neonates were exposed to testosterone (the male sex hormone) they would display male behavior; even the castrated male once exposed to this hormone would still show male traits due to its impact genetically. Similarly the controls; untreated males and females) exhibited male and female characteristics respectively as this was somewhat intrinsic based on their genome, that is, what is contained in their genetic makeup and not dependent on the environment they were raised in. his is synonymous with the studies done with 16 males in that the majority of genetically male children behaved as male despite being raised as females. This behavior was already encoded in their DNA. However, with the 43 girls, the effect of testosterone was nil on the behavior of the girls. They therefore did not act like boys even if they developed male genitalia. This does not support the nature theory as seen with the above examples. 2. The advice to parents would be not to reassign the child’s gender and by virtue of having the testicles the child’s brain would develop masculine characteristics and sexual male characteristics would develop at the onset of puberty. According to the article (gorski and Johnson) â€Å"brief exposure to the testosterone early in life promotes development of brain in ways that allow male behavior to be as an adult† 3. Based on the nature theory homosexual behavior in men and women can be related to hormonal imbalance. Sexual orientation is determined by the early levels (probably prenatal) of androgen on relevant neural structures. If highly exposed to these androgens, the fetus will become masculinized, or attracted to females. The reverse is true. 4. Based on the nurture theory homosexual behavior in men and women can be based upon environmental influences and that includes peer pressure, low self-esteem and parental influences. Experiment 5. Aim: To observe the effects of neonatal castration upon sexual and aggressive behavior in male and female chimpanzees. Hypothesis: It is speculated that aggression in male and female chimpanzees was an innate behavior rather than learnt behavior. It is also speculated that this behavior only occurs in male chimpanzees. Method: 100 female chimpanzees were identified in a population. An ultrasound was done to ensure that the females would produce 50 male offspring and 50 female offspring. Each newborn was then castrated one day after birth. 25 females were treated with testosterone and 25 males were treated with estrogen, the other 25 females were treated with estrogen and the remaining 25 males were treated with testosterone. The behavior of each newborn was observed over a two year period. Expected results: Based on the nature theory the 25 females that would be treated with the testosterone and the 25 males that would be treated with estrogen the concept of hormonal imbalance would have caused the production of two much or two little androgen. The hormone that was introduced would have interfered with the normal distribution of hormone in both male and female. The 50 offspring that were treated with their original hormones would display normal behavior. Aggressive behavior in females could have been due to two much production of testosterone and the behavior in males could have been due to the production of too much estrogen. It is common for adult male chimpanzees to act in an aggressive manner as such based on the nurture theory this behavior could have been imposed upon by parents or the environment that the offspring came from. This experiment has not been done due to ethical factors. It is not humane to perform castration on so many chimpanzees. The mere fact that some species are endangered would limit the amount of species that can be used in experiments and lessen the number of species to be preserved in the environment. Many experiments have been done and these have lowered the quality of life of these species. References Bull, J. J. , Pease, C. M. (2003) Biological Correlates of Being Gay: retrieved March 27, 2003 from http://www. utexas. edu/courses/bio301d/Topics/Gay/Text. html Joseph, J. (2004)The Gene Illusion: Genetic Research in Psychiatry and Psychology Under the Microscope. New York: Algora Kagan, J Segal, J. , Havemann, E. (2004) Psychology an Introduction 9th Edition: WadsworthThomas L earning. Belmont CA. Riemann, A. ; Jang, K. L. ; McCrae, R. R. ; Angleitner, R. ; Livesley, W. J. (1998). Heritability of facet-level traits in a cross-cultural twin sample: support for a hierarchical model of personality. Journal of Personality and Social Psychology 74 (6): 1556–1565.

Conservation of art works essays

Conservation of art works essays Principles of conservation (need to know) Preservation safeguards and protects art works, no direct intervention to the art work, climate control, appropriate packaging, appropriate display, controlling access. Conservation some direct intervention to art works to stabilise it chemical of physical repairs are sympathetic to original using like materials, prevents further deterioration, procedures are reversible. Restoration - incorporates preservation and conservation, the aim is to make the art work appear undamaged or like new, restoration is ethically problematic. Factors for safe storage and display Too much light causes objects to deteriorate Up to 50 lux for works on paper including photographs Up to 200 lux for paintings in oil, acrylic and enamel Up to 300 lux for objects of glass, ceramic and stone UV light is associated with sunlight Never display an artwork in direct sunlight Up to 30 microwatts per lumen is acceptable for works on paper Up to 75 microwatts per lumen for paintings Variations in humidity may damage artworks High humidity may cause mould to grow or metals to corrode Low humidity may cause cracking and embrittling of organic materials Recommended relative humidity level for museums is 55% (+/- 5%) or 50%-60% High and low temperature and variations in temperature may damage artworks Recommended temperature for museums in 21c (+/- 1c) This temperature must be maintained 24/7 Artworks must not be placed near heating appliances Insects are a common cause of damage to art works, especially in storage areas They lay eggs which are tiny and resistant to fumigation Good housekeeping is the best solution to this problem ...

College Science Fair Projects by Topic

College Science Fair Projects by Topic It can be a challenge to come up with a science fair project idea. There is fierce competition to come up with the coolest idea, plus you need a topic that is considered appropriate for your educational level.   A well-designed project at the college level can open the door to future educational and career opportunities, so it pays to put some thought and effort into your topic. A good project will answer a question and test a hypothesis. Planning and Research College students usually have a semester to complete their project, so they have some time to plan and conduct research. The goal at this level is to find an original topic. It doesnt have to be something complicated or time-consuming. Also, appearances count. Aim for professional-quality images and presentation. Handwritten work and drawings wont work as well as a printed report or poster with photographs. Possible ideas, divided by topic, include: Plants and Seeds Does the presence of detergent in water affect plant growth? In what ways? What is the implication regarding water pollution?Does magnetism affect the growth of plants? In what way?Is a seed affected by its size? Do different size seeds have different germination rates? Does seed size affect the growth rate or final size of a plant?How close does a plant have to be to a pesticide for the pesticide to work? What factors influence the effectiveness of a pesticide, such as rain, light or wind? How much can you dilute a pesticide while retaining its effectiveness? How effective are natural pest deterrents?What is the effect of a chemical on a plant? You can look at natural pollutants- such as motor oil or runoff from a busy street- or unusual substances, for example, orange juice or baking soda. Factors that you can measure include rate of plant growth, leaf size, life/death of the plant, the color of the plant, and ability to flower/bear fruit.How does cold storage affect the germinatio n of seeds? Factors you can control include the type of seeds, length of storage and the temperature of storage, light, and humidity. Food How does the shape of an ice cube affect how quickly it melts?Do the same types of mold grow on all types of bread? Are certain preservatives better at inhibiting dangerous molds than others?Is the nutritional content of different brands of a vegetable (such as canned peas) the same? How much variation is there in any given product? Miscellaneous What forms of recycling are available to students? If college students participated in these recycling programs, what would be the effect on cost, the environment?Do consumers prefer bleached paper products or natural-color paper products? What factors affect the preference? Age? Socioeconomic status? Gender?Solve a problem. For example, can you design a better type of street intersection?

Tidal Power Generation Term Paper Example | Topics and Well Written Essays - 750 words

Tidal Power Generation - Term Paper Example Tidal power generation essentially utilizes the vertical movement of a rising and falling water levels during high and low tide (Rajput). This difference in water levels is then used to operate a hydraulic turbine. The turbine subsequently generates power. A basic tidal power plant consists of three essential components; the dam or dyke, the sluice ways that run from the basin to sea and the power house. Each component has an essential purpose. The function of the dam or dyke is to serve as a barrier between the basin and the sea. While the sluice ways are controlled to fill or empty the basin during high or low tide. Lastly, the powerhouse contains the operational equipment for power generation. These include turbines, electric generators and other auxiliary equipment. The current technology employed to generate power through tidal power systems is divided into three major domains (Ehrlich). These domains make use of different energy characteristics of tidal waves such as their potential energy, kinetic energy, or a combination of both kinetic and potential energies. In accordance with these energy characteristics the three significant tidal power generation systems are the tidal barrage, the tidal stream generator and the dynamic tidal power generation system. The tidal barrage power generation system is a more conventional means of generating power through tidal waves (Breeze). The tidal barrage power generation system utilizes the potential energy of tidal waves. This potential energy arises from the vertical rise and fall of tidal waves. This particular system stores potential energy by allowing high tide water to be stored behind a dam or dyke in a basin. The basin serves as a reservoir. The sea and basin are connected by means of sluice ways with turbines. During high tide the water from the sea enters the basin where it is temporarily

The Evolution of International Tourism Essay Example | Topics and Well Written Essays - 3000 words

The Evolution of International Tourism - Essay Example hough it is prone to be unbalanced as the issue of price is less considered in long-duration tours but of importance in the shorter route destinations hence the aspect price elasticity (Rossellà ³, 2003). International tourism however has always performed better than other economic sectors as evidenced by past records that reveal that, ‘In the last fifty years, for every 1% rise in the per capita income of the world’s inhabitants, the number of travellers has risen by over 3%’ (Manera and Taberner, 2007, pg.4). In the period between 1950 and 2001, global per capita GDP grew by an average of 2.1 percent while the number of tourists within the same period grew by seven percent hence the UNWTO forecasted growth was a modest 1561 million or an average 1.6 billion ITAs by 2020 dependent on a steady upsurge in per-capita income and population growth patterns (Manera and Taberner, 2007). The UNWTO World Tourism Barometer 2009, all the major tourist designations recorded declines with only Africa depicting a growth of three percent. The world tourist arrivals suffered a sharp decline of negative eight percent in 2009, a downturn that started in the second half of 2008. This have inevitably attributed to the impact of the worldwide economic recession that has spelt doom for the international travellers as most tightened on their budgets. The international tourist arrivals (ITA) had by 2008 reached 922 million which was 1.9 percent appreciation from that of 2007, while the international tourism receipts (ITR) rose to US$944 or Euro 642 billion within the same period a 1.8 percent upsurge. The UNWTO (2009) indicated that approximately US$165 billion was generated from the international passenger transport for the combined total tourism expenditure to US$1.1 trillion that more than US$3 billion daily. The expansionist growth has mirrored the explosion of mass tourism stimulated by the era of packaged tours and the growth of the low-cost flights mainly in short haul

A world without Law would be a world without Sin Essay Example for Free

A world without Law would be a world without Sin Essay According to one of the Holy Books, the Bible, when God created the first man and woman, He knew as the author and finisher of man that he has mind, a conscience which is 2-sided. It could be destructive or constructive, it could embrace good or shun evil, it could love or hate based on the outline that he knows what is wrong and or right. That was the basic reason why God warned them or gave a strict Law against the act that lead to the very first sin, which is the eating of the fruit of knowledge. Hence, if there wasn’t any Law, the first and subsequent sins wouldn’t have existed. A car, an example of mechanical robot, will have no idea why it was created, which is a reason why a manual will be attached to it by the manufacturer for the use of the possible user[s]. We are all created for a purpose but the significant difference between Man and Machine is the choice and will power. These two tools can be shaped with Law[s] to guide man from being a weapon of personal and group calamity. And when there is no Law[s], then man can do whatever and anything he likes to suit his personal desire at the expense of others which would mean â€Å"No-Sin†. †¦At his best, man is the noblest of all animals; separated from law and justice he is the worst. - Aristotle It can be said man would be reckless, irresponsible, wild, thoughtless, uncontrolled or careless in a world without law. He would be pitiless when the taste for pleasure clouds his sense of reasoning. The mentality that anything he does is not wrong; just-do-it lingers in the mind of man in a world without Laws because there will not be any form of punishment. It would be a world of no hope for the poor. Government which is supposed to organize the society would not be in existence; there would not be anything like the Legislature to make laws, Executive to administer the laws and Judiciary to interpret the laws. Since the germane objective of Law is to maintain order in a society, the government agencies to carry out crime investigations and the professionals called Lawyers would have no space in a world without laws. Therefore, there will be a paradigm shift where jungle justice takes over the expected capacity of law. Discoveries and inventions will set the world in a state of entropy. Classified experiments such as cloning, stem cell growth and Nuclear weapons would know no limit. The world would be overpopulated for their will not be birth control regulations; strange diseases would be epidemic and pandemic. I can conveniently conclude that the world will fall apart without the law [which is tantamount to a world without sin].

First Draft :: Creative Writing Essays

First Draft =========== This poem is based in the 19th century. There are three main characters in the story. Cousin Kate, Cottage maiden and the Lord. The title of this poem is self-explanatory. As you can tell the poem is based on a character called cousin Kate. As she is the main character in the poem, the whole poem revolves around her. The poem is based on Triangular Conflict, which means that there is a conflict between three people. The poem basically tells us about 19th century life and peoples attitudes towards unlawful relationships. The poem tells us about a cottage maiden who had an affair with a Lord. She looses her virginity to him, and then regrets the whole ordeal. In the 19th century if you were not known as pure, then fellow friends and family would reject you. It was seen to be unclean and impure if you were to have sex before marriage. Men would then look down on you in disgust, as would friends and family. The poem demonstrates how a man can love a woman, then throw her away and move onto another as he pleases, and because he was a lord the cottage maiden could not say a thing. This brings into light the difference between higher and lower class people. If the cottage maiden had said anything, people would not believe her and would turn a blind eye to her, and to her accusations. Stanza 1 portrays the introduction to the poem. The issues raised in these two stanzas show that she was 'lured' by the lord. This tells us that he dragged her in like an animal luring its prey, waiting to attack its victim. At the beginning of stanza 1 it tells us that she is happy with her life. According to the introduction she works on a cottage and is happy with her life. According to this she is 'contented' her mates. She is happy with her friends and is all together happy with her life. She then goes on to say "why did a great lord find me out". This tells us that out of all the workers, or all the girls the lord knows, the cottage maiden was chosen. The start of the poem is written in first person narrative and carries on like that throughout the poem. The structure of this stanza is written in first person narrative, this means it was written from her point of view, and shows her feelings and no one else. The language used is very early 19th-20th century; it gives the impression of happiness leading to sadness.

Foundation and Empire 25. Death Of A Psychologist

After that there were only two weeks left to the life of Ebling Mis. And in those two weeks, Bayta was with him three times. The first time was on the night after the evening upon which they saw Colonel Pritcher. The second was one week later. And the third was again a week later – on the last day – the day Mis died. First, there was the night of Colonel Pritcher's evening, the first hour of which was spent by a stricken pair in a brooding, unmerry merry-go-round. Bayta said, â€Å"Torie, let's tell Ebling.† Toran said dully, â€Å"Think he can help?† â€Å"We're only two. We've got to take some of the weight off. Maybe he can help.† Toran said, â€Å"He's changed. He's lost weight. He's a little feathery; a little woolly.† His fingers groped in air, metaphorically. â€Å"Sometimes, I don't think he'll help us muchever. Sometimes, I don't think anything will help.† â€Å"Don't!† Bayta's voice caught and escaped a break, â€Å"Torie, don't! When you say that, I think the Mule's getting us. Let's tell Ebling, Torie – now!† Ebling Mis raised his head from the long desk, and bleared at them as they approached. His thinning hair was scuffed up, his lips made sleepy, smacking sounds. â€Å"Eh?† he said. â€Å"Someone want me?† Bayta bent to her knees, â€Å"Did we wake you? Shall we leave?† â€Å"Leave? Who is it? Bayta? No, no, stay! Aren't there chairs? I saw them-† His finger pointed vaguely. Toran pushed two ahead of him. Bayta sat down and took one of the psychologist's flaccid hands in hers. â€Å"May we talk to you, Doctor?† She rarely used the title. â€Å"Is something wrong?† A little sparkle returned to his abstracted eyes. His sagging cheeks regained a touch of color. â€Å"Is something wrong?† Bayta said, â€Å"Captain Pritcher has been here. Let me talk, Torie. You remember Captain Pritcher, Doctor?† â€Å"Yes- Yes-† His fingers pinched his lips and released them. â€Å"Tall man. Democrat.† â€Å"Yes, he. He's discovered the Mule's mutation. He was here, Doctor, and told us.† â€Å"But that is nothing new. The Mule's mutation is straightened out.† In honest astonishment, â€Å"Haven't I told you? Have I forgotten to tell you?† â€Å"Forgotten to tell us what?† put in Toran, quickly. â€Å"About the Mule's mutation, of course. He tampers with emotions. Emotional control! I haven't told you? Now what made me forget?† Slowly, he sucked in his under lip and considered. Then, slowly, life crept into his voice and his eyelids lifted wide, as though his sluggish brain had slid onto a well-greased single track. He spoke in a dream, looking between the two listeners rather than at them. â€Å"It is really so simple. It requires no specialized knowledge. In the mathematics of psychohistory, of course, it works out promptly, in a third-level equation involving no more – Never mind that. It can be put into ordinary words – roughly – and have it make sense, which isn't usual with psychohistorical phenomena. â€Å"Ask yourselves – What can upset Hari Seldon's careful scheme of history, eh?† He peered from one to the other with a mild, questioning anxiety. â€Å"What were Seldon's original assumptions? First, that there would be no fundamental change in human society over the next thousand years. â€Å"For instance, suppose there were a major change in the Galaxy's technology, such as finding a new principle for the utilization of energy, or perfecting the study of electronic neurobiology. Social changes would render Seldon's original equations obsolete. But that hasn't happened, has it now?† â€Å"Or suppose that a new weapon were to be invented by forces outside the Foundation, capable of withstanding all the Foundation's armaments. That might cause a ruinous deviation, though less certainly. But even that hasn't happened. The Mule's Nuclear Field-Depressor was a clumsy weapon and could be countered. And that was the only novelty he presented, poor as it was. â€Å"But there was a second assumption, a more subtle one! Seldon assumed that human reaction to stimuli would remain constant. Granted that the first assumption held true, then the second must have broken down! Some factor must be twisting and distorting the emotional responses of human beings or Seldon couldn't have failed and the Foundation couldn't have fallen. And what factor but the Mule? â€Å"Am I right? Is there a flaw in the reasoning?† Bayta's plump hand patted his gently. â€Å"No flaw, Ebling.† Mis was joyful, like a child. â€Å"This and more comes so easily. I tell you I wonder sometimes what is going on inside me. I seem to recall the time when so much was a mystery to me and now things are so clear. Problems are absent. I come across what might be one, and somehow, inside me, I see and understand. And my guesses, my theories seem always to be borne out. There's a drive in me†¦ always onward†¦ so that I can't stop†¦ and I don't want to eat or sleep†¦ but always go on†¦ and on†¦ and on-â€Å" His voice was a whisper; his wasted, blue-veined hand rested tremblingly upon his forehead. There was a frenzy in his eyes that faded and went out. He said more quietly, â€Å"Then I never told you about the Mule's mutant powers, did I? But then†¦ did you say you knew about it?† â€Å"It was Captain Pritcher, Ebling,† said Bayta. â€Å"Remember?† â€Å"He told you?† There was a tinge of outrage in his tone. â€Å"But how did he find out?† â€Å"He's been conditioned by the Mule. He's a colonel now, a Mule's man. He came to advise us to surrender to the Mule, and he told us – what you told us.† â€Å"Then the Mule knows we're here? I must hurry – Where's Magnifico? Isn't he with you?† â€Å"Magnifico's sleeping,† said Toran, impatiently. â€Å"It's past midnight, you know.† â€Å"It is? Then – Was I sleeping when you came in?† â€Å"You were,† said Bayta decisively, â€Å"and you're not going back to work, either. You're getting into bed. Come on, Torie, help me. And you stop pushing at me, Ebling, because it's just your luck I don't shove you under a shower first. Pull off his shoes, Torie, and tomorrow you come down here and drag him out into the open air before he fades completely away. Look at you, Ebling, you'll be growing cobwebs. Are you hungry?† Ebling Mis shook his head and looked up from his cot in a peevish confusion. â€Å"I want you to send Magnifico down tomorrow,† he muttered. Bayta tucked the sheet around his neck. â€Å"You'll have me down tomorrow, with washed clothes. You're going to take a good bath, and then get out and visit the farm and feel a little sun on you.† â€Å"I won't do it,† said Mis weakly. â€Å"You hear me? I'm too busy.† His sparse hair spread out on the pillow like a silver fringe about his head. His voice was a confidential whisper. â€Å"You want that Second Foundation, don't you?† Toran turned quickly and squatted down on the cot beside him. â€Å"What about the Second Foundation, Ebling?† The psychologist freed an arm from beneath the sheet and his tired fingers clutched at Toran's sleeve. â€Å"The Foundations were established at a great Psychological Convention presided over by Hari Seldon. Toran, I have located the published minutes of that Convention. Twenty-five fat films. I have already looked through various summaries.† â€Å"Well?† â€Å"Well, do you know that it is very easy to find from them the exact location of the First Foundation, if you know anything at all about psychohistory. It is frequently referred to, when you understand the equations. But Toran, nobody mentions the Second Foundation, There has been no reference to it anywhere.† Toran's eyebrows pulled into a frown. â€Å"It doesn't exist?† â€Å"Of course it exists,† cried Mis, angrily, â€Å"who said it didn't? But there's less talk of it. Its significance – and all about it – are better hidden, better obscured. Don't you see? It's the more important of the two. It's the critical one; the one that counts! And I've got the minutes of the Seldon Convention. The Mule hasn't won yet-â€Å" Quietly, Bayta turned the lights down. â€Å"Go to sleep!† Without speaking, Toran and Bayta made their way up to their own quarters. The next day, Ebling Mis bathed and dressed himself, saw the sun of Trantor and felt the wind of Trantor for the last time. At the end of the day he was once again submerged in the gigantic recesses of the library, and never emerged thereafter. In the week that followed, life settled again into its groove. The sun of Neotrantor was a calm, bright star in Trantor's night sky. The farm was busy with its spring planting. The University grounds were silent in their desertion. The Galaxy seemed empty. The Mule might never have existed. Bayta was thinking that as she watched Toran light his cigar carefully and look up at the sections of blue sky visible between the swarming metal spires that encircled the horizon. â€Å"It's a nice day,† he said. â€Å"Yes, it is. Have you everything mentioned on the list, Torie?† â€Å"Sure. Half pound butter, dozen eggs, string beans – Got it all down here, Bay. I'll have it right.† â€Å"Good. And make sure the vegetables are of the last harvest and not museum relics. Did you see Magnifico anywhere, by the way?† â€Å"Not since breakfast. Guess he's down with Ebling, watching a book-film.† â€Å"All right. Don't waste any time, because I'll need the eggs for dinner.† Toran left with a backward smile and a wave of the hand. Bayta turned away as Toran slid out of sight among the maze of metal. She hesitated before the kitchen door, about-faced slowly, and entered the colonnade leading to the elevator that burrowed down into the recesses. Ebling Mis was there, head bent down over the eyepieces of the projector, motionless, a frozen, questing body. Near him sat Magnifico, screwed up into a chair, eyes sharp and watching – a bundle of slatty limbs with a nose emphasizing his scrawny face. Bayta said softly, â€Å"Magnifico-â€Å" Magnifico scrambled to his feet. His voice was an eager whisper. â€Å"My lady!† â€Å"Magnifico,† said Bayta, â€Å"Toran has left for the farm and won't be back for a while. Would you be a good boy and go out after him with a message that I'll write for you?† â€Å"Gladly, my lady. My small services are but too eagerly yours, for the tiny uses you can put them to.† She was alone with Ebling Mis, who had not moved. Firmly, she placed her hand upon his shoulder. â€Å"Ebling-â€Å" The psychologist started, with a peevish cry, â€Å"What is it?† He wrinkled his eyes. â€Å"Is it you, Bayta? Where's Magnifico?† â€Å"I sent him away. I want to be alone with you for a while.† She enunciated her words with exaggerated distinctness. â€Å"I want to talk to you, Ebling.† The psychologist made a move to return to his projector, but her hand on his shoulder was firm. She felt the bone under the sleeve clearly. The flesh seemed to have fairly melted away since their arrival on Trantor. His face was thin, yellowish, and bore a half-week stubble. His shoulders were visibly stooped, even in a sitting position. Bayta said, â€Å"Magnifico isn't bothering you, is he, Ebling? He seems to be down here night and day.† â€Å"No, no, no! Not at all. Why, I don't mind him. He is silent and never disturbs me. Sometimes he carries the films back and forth for me; seems to know what I want without my speaking. Just let him be.† â€Å"Very well – but, Ebling, doesn't he make you wonder? Do you hear me, Ebling? Doesn't he make you wonder?† She jerked a chair close to his and stared at him as though to pull the answer out of his eyes. Ebling Mis shook his head. â€Å"No. What do you mean?† â€Å"I mean that Colonel Pritcher and you both say the Mule can condition the emotions of human beings. But are you sure of it? Isn't Magnifico himself a flaw in the theory?† There was silence. Bayta repressed a strong desire to shake the psychologist. â€Å"What's wrong with you, Ebling? Magnifico was the Mule's clown. Why wasn't he conditioned to love and faith? Why should he, of all those in contact with the Mule, hate him so. â€Å"But†¦ but he was conditioned. Certainly, Bay!† He seemed to gather certainty as he spoke. â€Å"Do you suppose that the Mule treats his clown the way he treats his generals? He needs faith and loyalty in the latter, but in his clown he needs only fear. Didn't you ever notice that Magnifico's continual state of panic is pathological in nature? Do you suppose it is natural for a human being to be as frightened as that all the time? Fear to such an extent becomes comic. It was probably comic to the Mule – and helpful, too, since it obscured what help we might have gotten earlier from Magnifico.† Bayta said, â€Å"You mean Magnifico's information about the Mule was false?† â€Å"it was misleading. It was colored by pathological fear. The Mule is not the physical giant Magnifico thinks. He is more probably an ordinary man outside his mental powers. But if it amused him to appear a superman to poor Magnifico-† The psychologist shrugged. â€Å"In any case, Magnifico's information is no longer of importance.† â€Å"What is, then?† But Mis shook himself loose and returned to his projector. â€Å"What is, then?† she repeated. â€Å"The Second Foundation?† The psychologist's eyes jerked towards her. â€Å"Have I told you anything about that? I don't remember telling you anything. I'm not ready yet. What have I told you?† â€Å"Nothing,† said Bayta, intensely. â€Å"Oh, Galaxy, you've told me nothing, but I wish you would because I'm deathly tired. When will it be over?† Ebling Mis peered at her, vaguely rueful, â€Å"Well, now, my†¦ my dear, I did not mean to hurt you. I forget sometimes†¦ who my friends are. Sometimes it seems to me that I must not talk of all this. There's a need for secrecy – but from the Mule, not from you, my dear.† He patted her shoulder with a weak amiability. She said, â€Å"What about the Second Foundation?† His voice was automatically a whisper, thin and sibilant. â€Å"Do you know the thoroughness with which Seldon covered his traces? The proceedings of the Seldon Convention would have been of no use to me at a as little as a month ago, before this strange insight came. Even now, it seems – tenuous. The papers put out by the Convention are often apparently unrelated; always obscure. More than once I wondered if the members of the Convention, themselves, knew all that was in Seldon's mind. Sometimes I think he used the Convention only as a gigantic front, and single-handed erected the structure-â€Å" â€Å"Of the Foundations?† urged Bayta. â€Å"Of the Second Foundation! Our Foundation was simple. But the Second Foundation was only a name. It was mentioned, but if there was any elaboration, it was hidden deep in the mathematics. There is still much I don't even begin to understand, but for seven days, the bits have been clumping together into a vague picture. â€Å"Foundation Number One was a world of physical scientists. It represented a concentration of the dying science of the Galaxy under the conditions necessary to make it live again. No psychologists were included. It was a peculiar distortion, and must have had a purpose. The usual explanation was that Seldon's psychohistory worked best where the individual working units – human beings – had no knowledge of what was coming, and could therefore react naturally to all situations. Do you follow me, my dear-â€Å" â€Å"Yes, doctor.† â€Å"Then listen carefully. Foundation Number Two was a world of mental scientists. It was the mirror image of our world. Psychology, not physics, was king.† Triumphantly. â€Å"You see?† â€Å"I don't.† â€Å"But think, Bayta, use your head. Hari Seldon knew that his psychohistory could predict only probabilities, and not certainties. There was always a margin of error, and as time passed that margin increases in geometric progression. Seldon would naturally guard as well as he could against it. Our Foundation was scientifically vigorous. It could conquer armies and weapons. It could pit force against force. But what of the mental attack of a mutant such as the Mule?† â€Å"That would be for the psychologists of the Second Foundation!† Bayta felt excitement rising within her. â€Å"Yes, yes, yes! Certainly!† â€Å"But they have done nothing so far.† â€Å"How do you know they haven't?† Bayta considered that, â€Å"I don't. Do you have evidence that they have?† â€Å"No. There are many factors I know nothing of. The Second Foundation could not have been established full-grown, any more than we were. We developed slowly and grew in strength; they must have also. The stars know at what stage their strength is now. Are they strong enough to fight the Mule? Are they aware of the danger in the first place? Have they capable leaders?† â€Å"But if they follow Seldon's plan, then the Mule must be beaten by the Second Foundation.† â€Å"Ah,† and Ebling Mis's thin face wrinkled thoughtfully, â€Å"is it that again? But the Second Foundation was a more difficult job than the First. Its complexity is hugely greater; and consequently so is its possibility of error. And if the Second Foundation should not beat the Mule, it is bad – ultimately bad. It is the end, may be, of the human race as we know it.† â€Å"No. â€Å"Yes. If the Mule's descendants inherit his mental powers – You see? Homo sapiens could not compete. There would be a new dominant race – a new aristocracy – with homo sapiens demoted to slave labor as an inferior race. Isn't that so?† â€Å"Yes, that is so.† â€Å"And even if by some chance the Mule did not establish a dynasty, he would still establish a distorted new Empire upheld by his personal power only. It would die with his death; the Galaxy would be left where it was before he came, except that there would no longer be Foundations around which a real and healthy Second Empire could coalesce. It would mean thousands of years of barbarism. It would mean no end in sight.† â€Å"What can we do? Can we warn the Second Foundation?† â€Å"We must, or they may go under through ignorance, which we can not risk. But there is no way of warning them.† â€Å"No way?† â€Å"I don't know where they are located. They are ‘at the other end of the Galaxy' but that is all, and there are millions of worlds to choose from.† â€Å"But, Ebling, don't they say?† She pointed vaguely at the films that covered the table. â€Å"No, they don't. Not where I can find it – yet. The secrecy must mean something. There must be a reason-† A puzzled expression returned to his eyes. â€Å"But I wish you'd leave. I have wasted enough time, and it's growing short – it's growing short.† He tore away, petulant and frowning. Magnifico's soft step approached. â€Å"Your husband is home, my lady.† Ebling Mis did not greet the clown. He was back at his projector. That evening Toran, having listened, spoke, â€Å"And you think he's really right, Bay? You think he isn't-† He hesitated. â€Å"He is right, Torie. He's sick, I know that. The change that's come over him, the loss in weight, the way he speaks – he's sick. But as soon as the subject of the Mule or the Second Foundation, or anything he is working on, comes up, listen to him. He is lucid and clear as the sky of outer space. He knows what he's talking about. I believe him.† â€Å"Then there's hope.† It was half a question. â€Å"I†¦ I haven't worked it out. Maybe! Maybe not! I'm carrying a blaster from now on.† The shiny-barreled weapon was in her hand as she spoke. â€Å"Just in case, Torie, just in case.† â€Å"In case what?† Bayta laughed with a touch of hysteria, â€Å"Never mind. Maybe I'm a little crazy, too – like Ebling Mis.† Ebling Mis at that time had seven days to live, and the seven days slipped by, one after the other, quietly. To Toran, there was a quality of stupor about them. The warming days and the dull silence covered him with lethargy. All life seemed to have lost its quality of action, and changed into an infinite sea of hibernation. Mis was a hidden entity whose burrowing work produced nothing and did not make itself known. He had barricaded himself. Neither Toran nor Bayta could see him. Only Magnifico's go-between characteristics were evidence of his existence. Magnifico, grown silent and thoughtful, with his tiptoed trays of food and his still, watchful witness in the gloom. Bayta was more and more a creature of herself. The vivacity died, the self-assured competence wavered. She, too, sought her own worried, absorbed company, and once Toran bad come upon her, fingering her blaster. She had put it away quickly, forced a smile. â€Å"What are you doing with it, Bay?† â€Å"Holding it. Is that a crime?† â€Å"You'll blow your fool head off.† â€Å"Then I'll blow it off. Small loss!† Married life had taught Toran the futility of arguing with a female in a dark-brown mood. He shrugged, and left her. On the last day, Magnifico scampered breathless into their presence. He clutched at them, frightened. â€Å"The learned doctor calls for you. He is not well.† And he wasn't well. He was in bed, his eyes unnaturally large, unnaturally bright. He was dirty, unrecognizable. â€Å"Ebling!† cried Bayta. â€Å"Let me speak,† croaked the psychologist, lifting his weight to a thin elbow with an effort. â€Å"Let me speak. I am finished; the work I pass on to you. I have kept no notes; the scrap-figures I have destroyed. No other must know. All must remain in your minds.† â€Å"Magnifico,† said Bayta, with rough directness. â€Å"Go upstairs!† Reluctantly, the clown rose and took a backward step. His sad eyes were on Mis. Mis gestured weakly, â€Å"He won't matter; let him stay. Stay, Magnifico.† The clown sat down quickly. Bayta gazed at the floor. Slowly, slowly, her lower lip caught in her teeth. Mis said, in a hoarse whisper, â€Å"I am convinced the Second Foundation can win, if it is not caught prematurely by the Mule. It has kept itself secret; the secrecy must be upheld; it has a purpose. You must go there; your information is vital†¦ may make all the difference. Do you hear me?† Toran cried in near-agony, â€Å"Yes, yes! Tell us how to get there, Ebling? Where is it?† â€Å"I can tell you,† said the faint voice. He never did. Bayta, face frozen white, lifted her blaster and shot, with an echoing clap of noise. From the waist upward, Mis was not, and a ragged hole was in the wall behind. From numb fingers, Bayta's blaster dropped to the floor.

Dementia

Dementia Dementia  has become an all-important  disease  because the population is aging rapidly and the cost of health care associated with  dementia  is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of  dementia  (BPSD) worsen patient's quality of life and increase caregiver's burden.Alzheimer's  disease  is the most common type of  dementia  and both behavioral disturbance and cognitive impairment of  Alzheimer's  disease  are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in  Alzheimer's  disease. We  reviewthe literature regarding  dementia  (especially  Alzheimer's  disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine.Literatures suggest that behavioral disturbance and cognitive impairment of  Alzheimer's  disease  may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in  Alzheimer's  disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms.We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of  Alzheimer's  disease. Prospective study using NMDA enhancers in patients with  Alzheimer'sdisease  and associated behavioral disturbance is needed to verify this hypothesis. Mental disorders constitute a huge social and economic burden for health care systems worldwide [1], raising the quest ion of effective and lasting treatments. Physical activity (PA) and exercise (EX) continue to gain the attention of practitioners and researchers with regard to prevention and treatment of different psychopathological abnormalities.In the general population, several epidemiological studies have found significant cross-sectional correlations between mental health and PA levels. In an adult US population, regular PA is associated with a significantly decreased prevalence of current major depression, panic disorder, agoraphobia, social phobia, and specific phobia [2]. A study from Norway confirmed this negative cross-sectional association between depression and leisure-time PA of any intensity (not work-related PA), and pointed out that social factors such as social support, rather than biological markers, play an important role [3].Recently, a Dutch study replicated this finding, reporting lower rates of any affective, anxiety, or substance use disorder in subjects who exercised at le ast 1 h/wk, without finding a linear dose-response relationship [4]. Prospectively, the overall incidence of mental disorders and co-morbid mental disorders, as well as the incidence of anxiety, somatoform, and dysthymic disorder, decreases by PA [5]. Furthermore, a four-year prospective study revealed that PA decreases the incidence rates of depressive and anxiety disorders in older adults [6].Finally, ten Have et al. reported in their epidemiological study that patients engaging in regular PA were more likely to recover from their mental illness at a three-year follow-up In psychiatric patients, different mechanisms of action for PA and EX have been discussed: On a neurochemical and physiological level, a number of acute changes occur during and following bouts of EX, and several long-term adaptations are related to regular EX training.For instance, EX has been found to normalize reduced levels of brain-derived neurotrophic factor (BDNF) and therefore has neuroprotective or even n eurotrophic effects [7-9]. Animal studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and positive effects of EX on stress reactivity (e. g. , the hypothalamus-pituitary-adrenal axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14].Potential psychological mechanisms of action include learning and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus of control, improved coping strategies, or simple distraction Several prospective studies have found that a high level of PA seems to delay the onset of dementia (see [74] for a review). Since improvements in strength and endurance after training were found in cognitively impaired patients as well as healthy controls [75], PA interventions are generally feasible in this population.For Alzheimer's disease (AD) , preliminary evidence suggests that EX interventions may improve communication performance [78], Mini Mental State Examination scores and verbal fluency [79], and disruptive behavior [80]. Four studies [81-84] found that PA slowed down and partially reversed the decline in performance of activities of daily living and progression of the cognitive symptoms related to dementia, in contrast to an older study, which did not find improvements in functional ability [85]. Zschucke , E. and Gaudlitz, K.Exercise and Physical Activity in Mental Disorders: Clinical and Experimental Evidence Zschucke , E. and Gaudlitz, K. (2013) Exercise and Physical Activity in Mental Disorders: Clinical and Experimental Evidence. Journal of Preventative Medicine and Public Health  , 46 (1), p. 12-21. Available at: http://www. ncbi. nlm. nih. gov/pmc/articles/PMC3567313/ [Accessed: 6th Mar 13]. Leptin, an adipocytokine produced in the peripheral system as well as in the brain, is implicated in obesity, food intake, glucose homeostasis, and energy expenditure.Leptin expression levels and signaling pathways may also be linked to the pathophysiology of neurodegenerative diseases including Alzheimer’s disease. Epidemiological studies have demonstrated that higher circulating leptin levels are associated with lower risk of dementia including Alzheimer’s disease, and lower circulating levels of leptin have been reported in patients with Alzheimer’s disease. Leptin receptors are highly expressed in the hippocampus, a brain area involved in learning and memory and severely affected during the course of Alzheimer’s disease.In laboratory studies, several in vivo and in vitro studies have shown that leptin supplementation decreases amyloid-? (A? ) production and tau phosphorylation, two major biochemical events that play a key role in the pathogenesis of Alzheimer’s disease. In this review, we will review the structure of leptin, the type of receptors of leptin in the brain, the various biological functions attributed to this adipocytokine, the signaling pathways that govern leptin actions, and the potential role of leptin in the pathophysiology of Alzheimer’s disease.Leptin exerts its functions by binding to the leptin receptor (ObR). This binding can involve several signaling pathways including JAK/STAT pathway, ERK pathway and the PI3K/Akt/mTOR Pathway. Modulation of these pathways leads to the regulation of a multitude of functions that define the intricate involvement of leptin in various physiological tasks. In this review, we will specifically relate the potential involvement of leptin signaling in Alzheimer’s disease based on work published by several laboratories including ours.All this work points to leptin as a possible target for developing supplementation therapies for reducing the progression of Alzheimer’s disease. Leptin is a 146 amino acid protein with a molecular weight of 16 kDa encoded by the  ob   gene and primarily, but not exclusively, expressed by the white adipose tissue (WAT) and is implicated in obesity, food intake, and energy homeostasis. Leptin protein was discovered by the molecular geneticist Jeffrey Friedman in 1994 at Rockefeller University and the work was published in a landmark  Nature  paper in December 1994 [1].The human  ob  gene has been mapped to chromosome 7q31. 3 [2] and encodes a 4. 5 kb mRNA transcript that is translated into a 167 amino acid peptide and subsequently processed in the ER into the 146 amino acid mature leptin protein [1]. Antecedent to the discovery of the leptin protein and positional cloning of the  ob  gene in 1994, the  ob/ob  mouse characterized by hyperphagia and a marked obese phenotype was serendipitously discovered by animal caretakers in 1950 at Jackson Laboratories [3].It was the general consensus that the  ob/ob  mouse possessed a mutation in the  obgene, but this was not elucidated and unequivocall y established until the discovery of the leptin protein and mapping of the  ob  gene by Friedman and colleagues in 1994 who showed that the mutation resulted in the loss of leptin production. In 1966, the  db/db  mouse was discovered, again at Jackson Laboratories, which not only exhibited a similar hyperphagic, obese phenotype, but also hyperglycemia [4].Tartaglia and colleagues in 1995 showed that the  db/db  mouse phenotype can be attributed to the mutation in the  db  gene that codes for the long-form of the leptin receptor obRb [5]. However, it was the seminal work of Doug Coleman and colleagues who demonstrated by a series of parabiosis experiments using  ob/ob  mice and  db/db  mice pairs and established that the  ob/ob  mice lacked a circulating factor whereas the  db/db  mice produced the circulating factor but were not able to respond to it [6,7].The validity of these breakthroughs was affirmed by subsequent discovery of the leptin protein a nd cloning of the  ob  gene [1] as well as the cloning of the  db  gene which coded for the long-form leptin receptor obRb [5]. Further corroboration emanated from the finding that the  db  mice produced the truncated form of obRb that was incapable of transducing leptin-mediated intracellular signal transduction [8-12] and administration of exogenous leptin obviated the obese, hyperphagic, hypothermic, and hypometabolic phenotype in  ob/ob  mice [13-15]. Go to: ————————————————-Leptin – structure, expression, and secretion The crystal structure of leptin has revealed the secondary and tertiary structure of the leptin molecule. The three dimensional crystal structure of leptin depicts the presence of four antiparallel ? -helices (A, B, C, and D) [16]. Two long crossover loops connect the A-B and C-D ? -helices, while a short loop connects the B-C ? - helices [16]. The entire leptin molecule is oblong shaped with the dimensions of 20x25x45 A0[16]. The entire molecule comprising of the bundle of four ? -helical loops adopts a bilayered stratified structure with ? helices A-D in one layer contiguous with ? -helices B-C in the other layer [16]. The conformation adopted by the leptin molecule results in the surface emergence of a few key hydrophobic residues like Phe41, Phe92, Trp100, Trp138, and Leu142  which not only play an indispensable role in the regulation of solubility and aggregation kinetics of the leptin protein, but are also critically requisite for as well as modulate the binding of leptin to the leptin receptor and determine the binding kinetics of the leptin-leptin receptor interaction [16].The three dimensional four-helical bundle crystal structure of leptin exhibits an overt, conspicuous congruence with other cytokines such as growth hormone (GH) [17], leukemia inhibitory factor (LIF) [18], and G-CSF (G-colony stim ulating factor) [19], despite lack of primary sequence homology with these proteins or other proteins [1]. Leptin is expressed primarily by the white adipose tissue [1,20] and circulating leptin levels are proportional to the white adipose tissue mass [21,22]. In humans, leptin expression in the subcutaneous adipose tissue is significantly more in magnitude than omental adipose tissue [23-26].Other studies have demonstrated no difference in leptin expression between the subcutaneous and omental adipose tissue [27]. Leptin expression in humans also exhibits sexual dimorphism with circulating leptin levels about 3-fold greater in females than males [25,28,29]. It is now certain that other tissues also produce leptin, including stomach [30,31], mammary gland [32], human placenta [33], ovaries [34], heart [35], skeletal muscle [36], pituitary gland [37], and the brain [37-39]. In the brain leptin mRNA expression and immunoreactivity has been seen in the hypothalamus, cortex, dentate gyr us and the hippocampus of the rat [38,39].Leptin immunoreactivity has also been reported in the mouse and hamster brain [40]. Leptin expression and circulating leptin levels are primarily contingent on the white adipose tissue mass [21,22] and are significantly elevated in obesity [21,22,41,42]. Consistent with this observation, weight loss is associated with a decrease in leptin levels in the plasma [22]. Leptin levels in the plasma also fluctuate in an ultradian manner and exhibit diurnal rhythm [43,44]. Leptin secretion occurs in a pulsatile rhythm with ~30 pulses of leptin secretion in a 24-hour cycle [43,45].Acute caloric restriction reduces leptin levels by ~30% within 24 hours [46-48] whereas caloric excess elevates leptin levels in the plasma by ~35% within 5-8 hours [47]. Therefore, nutritional intake regulates leptin expression in an acute as well as chronic fashion. The physiological and hormonal parameters that increase leptin expression include obesity [21,22,41], overf eeding or excess caloric intake [49,50], insulin [51-55], glucocorticoids [51,52,56,57], glucose [58], tumor necrosis factor ? (TNF? ) [54,59], estradiol [60-62], and IL1 [63,64] among others.The physiological and hormonal factors that decrease leptin expression include androgens [61,65], acute caloric restriction [49,50], growth hormone [66-69], somatostatin [68,70], exposure to cold temperatures [50,71,72], ? 3  adrenergic agonists [70,73-76], long-term exercise [77,78], cAMP (51, 57), PPAR? agonists such as thizolidinediones Pioglitazone, Troglitazone, and Rosiglitazone [79], and free fatty acids [80] among others. Go to: ————————————————- Leptin receptors Leptin receptors (obR) are encoded by the  db  gene [5].The obR are transmembrane spanning proteins that transduce and mediate leptin signaling. The obR exhibit structural and functional homology to the class I cytokine receptors [81,82]. The obR along with other class I cytokine receptors are typified by the characteristic presence of four cysteine residues and a â€Å"WSXWS† motif [81,83] which are a part of multiple fibronectin Type III subdomains in their extracellular domains [84]. The obR transcript undergoes alternate splicing to generate six different receptor isoforms (obRa – ob-Rf) [11].The six isoforms of obR are distinguished by and exhibit very little homology in their intracellular domain [85]. However, all the six isoforms have the same extracellular domain of over 800 amino acids and a transmembrane domain that spans 34 amino acid residues [85]. The six isoforms of obR are pigeonholed into three different groups, namely – short form, long form, and secreted obR [85]. The short-form of obR subsuming obRa (894 amino acids), obRc (892 amino acids), obRd (901 amino acids), and obRf (896 amino acids) possess a short 30-40 amino acid residue intracellular dom ain [85]. bRb (1162 amino acids) is the only functionally active leptin receptor isoform capable of transducing leptin signaling as it contains an intracellular domain that spans ~280 amino acid residues [5]. The obRe isoform (805 amino acids) lacks the intracellular domain and is therefore classified as a secreted soluble receptor and functions as a buffering system involved in the transport of leptin and bioavailibility of free circulating leptin [86,87].The short isoforms obRa, obRc, obRd, and obRf are abundantly expressed in the choroid plexus and endothelial cells of the brain microvasculature that form the BBB and may therefore regulate the flux of leptin across the BBB [88,89]. obRb is pervasively expressed in the human and rodent brain with the highest density in the ventromedial, arcuate, and dorsomedial hypothalamic nuclei [90-93]. obRb is termed the long-form leptin receptor and is solely responsible for propagating signal transduction mechanisms initiated by leptin [5,94 ].The short forms of the leptin receptor ob-Ra, ob-Rc, obRd, and obRf are devoid of intracellular signaling motifs that are obligatory for signal transduction [5]. However the short form receptors obRa and obRc are highly expressed in the choroid plexus and it is speculated that they mediate the uptake of leptin across the BBB (88, 89). obRb expression has been reported in several regions of the rodent and human brain including the hypothalamus [90,92,93], hippocampus, brain stem (nucleus of the solitary tract and the dorsal motor nucleus of the vagus), amygdala and the substantia nigra [92,93,95,96].In the hippocampus leptin receptor immunoreactivity is observed in the CA1/ CA3 region and the dentate gyrus [95,97]. Furthermore, axonal and somato-dendritic regions and hippocampal synapses exhibit leptin receptor immunolabeling in primary hippocampal cultures [97]. Go to: ——————————————à ¢â‚¬â€Ã¢â‚¬â€- Biological and physiological functions Leptin was discovered as the endogenous hormone that precludes obesity and regulates energy homeostasis [1].Antecedent to the discovery of leptin in 1994, about two decades ago, Doug Coleman had posited the role of a circulating hormone that thwarted obesity via its action in the brain to regulate food intake and energy homeostasis and in the peripheral tissues to regulate energy catabolism, thermogenesis as well as basal metabolism [7]. This was corroborated in the mid 1990s after the discovery of leptin by studies that demonstrated in rodents that administration of exogenous leptin decreased food intake and augmented energy expenditure [13-15,98,99].Leptin administration augments energy expenditure by actuating the ? -oxidation of fatty acids in the mitochondria and also inducing the expression of enzymes involved in ? -oxidation [100]. However, the notion that high levels of leptin augment weight loss and circumvent obesity must be tempered with the fact that high endogenous leptin levels have been effete in thwarting obesity in humans and other mammals [21,22,41]. This can be ascribed to a phenomenon termed â€Å"leptin resistance† [101-103]. Leptin plays a pivotal role in the induction of puberty and fertility.Leptin reinstates puberty, restores fertility in  ob/ob  mice, escalates puberty and fosters reproductive behavior in wildtype rodents [104-107]. Leptin directly regulates the hypothalamic-pituitary-gonadal (HPG) axis by inducing gonadotropin release and modulating estradiol production in the ovarian follicles [108,109]. Leptin also regulates the hypothalamic-pituitary-adrenal (HPA) axis by attenuating corticotrophin releasing hormone (CRH) production and release [110,111] as well as directly inhibiting ACTH (adrenocorticotropic hormone)-induced glucocorticoid release from the adrenal cortex [111-113].Leptin is also integrally involved in the physiological homeostasis of the circulat ory system. Emerging evidence implicates leptin in hematopoeisis as leptin is involved in proliferation and differentiation hematopoietic precursors [114-116]. Higher plasma levels of leptin (~100ng/mL), suchas those observed in obese individuals, foster and promote platelet aggregation [117]. Leptin is also one of the most potent inducers of vascular epithelial cell growth and angiogenesis and the short forms and the long-form of the leptin receptor is abundantly expressed in the vasculature [117-119].Go to: ————————————————- Leptin function in the brain Hypothalamus Leptin signaling in the hypothalamus regulates food intake and energy homeostasis in mammals. The arcuate nucleus (ARC), dorsomedial nucleus (DMH), and the ventromedial nucleus (VMH) of the hypothalamus express the obRb in the greatest density. In the ARC, the obRb is abundantly expressed in two disparate neu ronal cell types, ones that express neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the others that express pro-opiomelanocortin (POMC) [92,120-122].Leptin induced activation of the obRb in the POMC neurons results in depolarization and increased biosynthesis of ? -melanocyte-stimulating hormone (? -MSH) which signals downstream by actuating the melanocortin system comprising of melanocortin-3-receptors (MC3R) and melanocortin-4-receptors (MC4R) expressed by the second order neurons downstream to evoke an anorexiogenic (decreased appetite) response [122-127]. Activation of the melanocortin pathway not only suppresses appetite but also increases energy expenditure by increasing sympathetic tone resulting in ? oxidation of fatty acids in skeletal and adipose tissue. While leptin activates the POMC-expressing neurons, the actuation of obRb by leptin in the NPY/AgRP neurons results in the decreased genesis of NPY and AgRP peptides which are orexiogenic (increase appetite) in nature [122,128]. Therefore, in conspectus, leptin signaling in the hypothalamus results in the decreased expression of orexiogenic peptides (NPY, AgRP) and increased expression of anorexiogenic peptides (? -MSH) as well as increased energy expenditure in the adipose tissue and skeletal muscle tissue.Hippocampus Leptin receptors are abundantly expressed in the CA1 and CA3 regions of the hippocampus as well as the dentate gyrus [95,97]. Leptin regulates the excitability and firing of hippocampal neurons via the modulation of BK potassium channels [97]. Leptin also improves memory processing and retention when administered directly into the CA1 region in mice [129] and rodents that are deficient in the leptin receptor (db/db  mice and  fa/fa  rats) exhibit profound deficits in spatial learning and memory [129-131].Treatment of acute hippocampal slices with leptin results in the conversion of short-term potentiation (STP) to long term potentiation (LTP) by enhancing Ca2+  influ x through NMDA receptors [132]. Leptin increases synaptogenesis and aids in memory formation in the hippocampus and is purported to be a cognitive enhancer [133]. Leptin also increases neurogenesis in the dentate gyrus of adult mice [134]. Leptin also plays a critical role in hippocampal neuronal survival by activating the PI3K-Akt and JAK2/STAT3 signal transduction pathways [135].Leptin upregulates the expression of potent endogenous antioxidant enzyme Mn-SOD (manganese superoxide dismutase) and the anti-apoptotic protein Bcl-xL (B-cell lymphoma xL) in a STAT3-dependent manner in the hippocampus [135]. Leptin stabilizes mitochondrial membrane potential and attenuates the glutamate-induced mitigation in mitochondrial membrane potential and also extenuates the free iron-induced augmentation in mitochondrial ROS [135]. Go to: ————————————————- Leptin signalingLeptin binding to its long-form receptor obRb actuates four major signal transduction pathways that are coupled to obRb – JAK/STAT pathway, ERK pathway, PI3K/Akt/mTOR pathway, as well as the AMPK/SIRT1 signal transduction pathways. JAK/STAT pathway Leptin signaling via the obRb is integrally coupled to the JAK2/STAT3, JAK2/STAT5 and JAK2/STAT6 pathways [10]. The long-form of the leptin receptor obRb is constitutively coupled to Janus kinase 2 (JAK2) via the evolutionary conserved domains proximal to the membrane [136].The binding of leptin to obRb evokes a conformational change in the receptor that actuates JAK2 by phosphorylation at Tyr1007/1008  residues [136]. Activated phosphorylated JAK2 subsequently phosphorylates evolutionary conserved tyrosine residues of obRb [94] at Tyr985, Tyr1077  and Tyr1138  [137,138]. The obRb phosphorylated at Tyr1077  and Tyr1138  serves as a docking site and recruits Srchomology 2 (SH2)- and Src-homology 3 (SH3)-domain comprising roteins that sub sume proteins such as Signal Transducer and Activator of Transcription 3 (STAT3), Signal Transducer and Activator of Transcription 5 (STAT5), and Src homology region 2 domain-containing phosphatase 2 (SHP2) [139]. The phosphorylated Tyr1138  residue of obRb recruits STAT3 and STAT5 which are subsequently phosphorylated by JAK2 at Tyr705  and Tyr694  respectively. The phosphorylation STAT3 and STAT5 causes their disengagement from the leptin receptor, results in the dimerization of STAT proteins via their phosphotyrosine residues in the SH2 domains [140-142], and culminates in their nuclear translocation [142].In the nucleus, STAT dimers bind to distinct motifs or elements in the DNA called ? -IFN-activated site (GAS) in the enhancer regions of target genes and thereby modulate and regulate gene expression of target genes [142-146]. In the nucleus, the STAT signaling is abrogated by dephosphorylation and subsequent export of STAT proteins from the nucleus to the cytosol [142,14 4,147] or by targeted degradation of the STAT proteins via the Ubiquitin Proteasomal System (UPS) [148].The JAK/STAT pathway is negatively regulated by three classes of proteins, namely – suppressors of cytokine signaling (SOCS), protein inhibitors of activated STATs (PIAS), and protein tyrosine phosphatases (PTP) [149]. There are eight members of the SOCS family and their expression is induced by JAK/STAT signaling (STAT3 in particular) thereby suggesting the existence of a negative feedback loop that abrogates JAK/STAT signaling [150].The SOCS proteins negatively regulate the JAK/STAT pathway by competitively engaging and occupying the phosphotyrosine residues in obRb via their SH2 domains and obviating the recruitment of STAT proteins to obRb, thereby precluding STAT activation [150,151]. SOCS proteins via their SH2 domains also directly bind to JAK2 and extenuate the kinase activity of JAK2 [150,151]. The PIAS proteins negatively regulate the JAK/STAT signaling pathway by impeding the binding of STAT proteins to the response elements in the DNA by physically interacting and binding with STAT proteins via their zinc-binding RING-finger domains [151].SHP1 and SHP2 are most well characterized protein tyrosine phosphatases implicated in the negative regulation of the JAK/STAT pathway [149]. SHP1 and SHP2 possess two SH2 domains and therefore bind to phosphotyrosines of JAK2 and obRb and effectuate the dephosphorylation of JAK2 and obRb thereby terminating the JAK/STAT signaling [149]. ERK pathway The extracellular regulated kinase (ERK) pathway is an integral part of a larger signaling network called mitogen activated protein kinase (MAPK) pathway that is activated by leptin signaling via the leptin receptor (obRb).While phosphorylation of Tyr1138  and Tyr1077  are both requisite and mediate the activation of STAT3 and STAT5 respectively, the phosphorylation of Tyr985  of obRb mediates the activation of ERK pathway [138]. Leptin signaling via the obRb evokes the actuation of ERK pathway, both centrally and peripherally, as well as in  in vivo  and  in vitro  experimental paradigms [85]. Leptin evokes the activation of ERK pathway by both JAK2-mediated and JAK2-independent signaling effects [94,152].Contemporary evidence has implicated the protein tyrosine phosphatase SHP2 and the adaptor protein Grb2 (growth receptor bound 2) as the requisite mediators in the leptin-induced activation of ERK signaling pathway [153]. Leptin signaling also activates other members and signaling cascades subsumed under the MAPK signaling pathway, namely p38 [154-157] and JNK pathways [156]. PI3K/Akt/mTOR pathway Leptin signaling also induces the activation of the ubiquitous, pervasive, nutrient-sensitive anabolic, and the broad spectrum PI3K/Akt/mTOR pathway [152,158-161].Empirical evidence has demonstrated that the adaptor proteins IRS1 (insulin receptor substrate 1) and IRS2 (insulin receptor substrate 2) mediate the leptin-obRb induce d activation of PI3K-Akt pathway [94,158,162]. A multitude of studies have demonstrated that leptin induces the activation of Akt via phosphorylation of Akt at Ser473[163,164]. As a consequence, Akt activation is ensued upon leptin signaling which results in inhibition of GSK3? through phosphorylation at Ser9  residue [165-167].Evidently leptin also activates the serine/threonine kinase mammalian target of Rapamycin (mTOR) in the hypothalamus and macrophages [168,169] through the PI3K-Akt pathway [170]. mTOR is an evolutionary conserved kinase that modulates translation of several mRNA transcripts involved in cell growth and proliferation. mTOR regulates translation by phosphorylation and attenuation of the inhibitor of mRNA translation, eukaryotic initiation factor 4E-binding protein (4E-BP) [171-175], as well as through the phosphorylation and activation of S6 kinase (p70S6K1) [176,177]. TOR is autophosphorylated at Ser2481  and exhibits spontaneous intrinsic kinase activity u nder the activation of Akt [178,179]. mTOR phosphorylation and activation is negatively regulated by the TSC1/TSC2 protein complex [170]. Akt phosphorylates TSC2 causing disintegration of the TSC1/TSC2 complex which consequently results in mTOR activation [180]. Furthermore, Akt has been shown to directly phosphorylate mTOR at Ser2448residues and consequently activate mTOR [181,182].Therefore, Akt positively regulates mTOR activation by direct phosphorylation at Ser2448  as well as by indirect means which involves relieving the repressive effects of the upstream inhibitor TSC1/2 complex. Thus leptin, by virtue of its inherent ability to activate Akt, is expected to increase mTOR phosphorylation and activity. AMPK-SIRT1 pathway The 5’AMP activated protein kinase (AMPK) is the master regulatory kinase termed the â€Å"fuel gauge† that integrates signals from upstream mediators and effectors of hormones and cytokines to maintain metabolic homeostasis [183].AMPK activati on leads to increase ? -oxidation of fatty acids in the mitochondria and inhibition of lipogenesis [184,185]. Multiple lines of evidence have cogently demonstrated that leptin activates AMPK and consequently increases fatty acid oxidation [186-188]. One exception to this is the hypothalamic neurons, where leptin inhibits AMPK activation to evoke satiety and other hypothalamic effects of leptin [189-191]. In general, AMPK plays a catabolic role and engenders energy production via effects on glucose and lipid metabolism.AMPK activation also effectuates the induction of the NAD+  Ã¢â‚¬â€œ dependent deacetylase SIRT1 (silent mating type information regulation 2 homolog) [192,193], a metabolic master regulator unequivocally implicated in ageing and the regulation of lifespan [194-198] as well as regulating metabolism [199,200]. The anorexic effect of leptin mediated by the activation of POMC neurons in the hypothalamus is contingent on SIRT1 expression and activation in the neurons of the arcuate nucleus of the hypothalamus [201]. Go to: ————————————————- Role of leptin in Alzheimer diseaseAlzheimer Disease (AD) is a progressive, debilitating and the most prevalent neurodegenerative disorder typified by memory impairment and cognitive dysfunction eventually leading to fatality. The gross pathologic hallmarks of autopsied brains of patients with AD include atrophy with widened sulci and narrowed gyri in the temporal, parietal, and frontal lobes as well as the neocortex and cingulated gyrus areas of the cerebral cortex. The entorhinal cortex, amygdala, hippocampus and the para-hippocampal gyrus also exhibit pronounced atrophy due to neuronal loss [202,203].There is a decrease in gross weight of brain by 10-15% in AD patients [202]. The thickness of the six cortical layers (cortical ribbon) is usually reduced by 10-20% in AD [202] and ventricular dilation is apparent prominently in the temporal horn as a consequence of the atrophy of the amygdala and the hippocampus. Furthermore, there is a propensity for the loss of larger neurons than the loss of smaller neurons or glial cells in AD [202]. Microscopically, AD is characterized by two most common and distinct â€Å"hallmark† microscopic lesions namely senile plaques and neurofibrillary tangles (NFT).Senile plaques are extraneuronal deposits of accumulated and aggregated amyloid-? (A? ) protein in the brain parenchyma, while the NFT are intraneuronal aggregates of protein tau in the hyperphosphorylated state. Other pathological features of the AD brain include synaptic loss, neuronal and dendritic loss, neuropil threads, granulovacuolar degeneration, dystrophic neurites, Hirano bodies, and cerebrovascular amyloid deposition. There is substantial evidence that leptin modulates A? production and metabolism. Chronic peripheral leptin administration in Tg2576 mice has been reported to reduce the brain A? evels [204]. Moreover leptin also decreases the BACE1 activity in SH-SY5Y cell line [204]. Leptin decreases tau phosphorylation explicitly at residues Ser202, Ser396, and Ser404  in retinoic acidinduced differentiated SH-SY5Y cells, differentiated human NT2 cells (NT2N), and rat primary cortical neurons [205-207]. Leptin also increases synaptogenesis and aids in memory formation in the hippocampus and is purported to be a cognitive enhancer [133]. Leptin has been shown to convert STP into LTP in hippocampal cultures and hippocampal slices [132].Recent evidence suggests that leptin facilitates spatial learning and memory [130] and also increases neurogenesis in the dentate gyrus of adult mice [134]. Recent epidemiological studies have also unequivocally implicated decreased leptin levels in the pathogenesis of AD. In the Framingham prospective study, 785 subjects were followed between 1990 and 1994 from the original Framingham cohort [208]. The study conclud ed that leptin levels were inversely related to the risk of developing dementia of the Alzheimer type [208].A year preceding the findings of Lieb and colleagues, a morphometric study in Japan conducted by Narita and group found higher leptin levels were positively correlated with higher hippocampal volumes [209]. Leptin decreases Amyloid-? (A? ) levels by attenuating the genesis and augmenting the clearance of the peptide The A? peptide is derived from a two-step successive proteolytic cleavage of Amyloid-? precursor protein (A? PP) [210]. In the first step, A? PP is cleaved by the membrane-bound protease BACE1 (? -site APP cleaving enzyme 1) (also called ? secretase) to generate CTF? (carboxy terminal fragment ? ) (also known as C99 fragment) [211-215] which in the second step is subsequently cleaved by the ? -secretase complex to generate A? peptide [216-218]. According to the â€Å"amyloid cascade hypothesis†, A? is considered as the culpable factor in the instigation and progression of all the neurodegenerative events that characterize AD [219]. A plethora of studies have demonstrated that leptin decreases A? levels in several  in vivo  and  in vitro  paradigms [204,220-223]. Leptin has been shown to mitigate A? roduction by extenuating BACE1 activity in neural cultures [204]. Recent studies have implicated the AMPK/SIRT1 pathway in the leptin-induced modulation of A? levels [222]. Emerging data from our unpublished work has not only corroborated the finding that leptin regulates A? metabolism via SIRT1, but also implicated the ubiquitous transcription factor NF-? B as a SIRT1 target downstream in the modulation of A? genesis (unpublished). Leptin decreases A? levels by targeting all facets of A? metabolism, namely – production, clearance, and degradation.We have shown that leptin increases the expression levels of insulin degrading enzyme (IDE) putatively by activating the Akt pathway [223], thus augmenting the degradation of A?. Fur thermore, leptin also increases the expression levels of LRP1 [223], suggesting that leptin may foster the uptake of A? by astrocytes and microglia or reuptake of A? by neurons and therefore target A? for intracellular degradation or for clearance across the blood-brain-barrier (BBB). Leptin also effectuates the ApoE-mediated clearance of A? [204].Specifically, leptin dose-dependently increased the LRP1-mediated uptake of ApoE-bound A? , therefore committing A? toward the endosomal/lysosomal degradation pathway [204]. Leptin attenuates BACE1 expression and activity The first line of evidence linking leptin signaling dyshomeostasis in the pathogenesis of Alzheimer disease emanated from the work of Tezapsidis and colleagues [204], who demonstrated in neural cultures from transgenic mice that leptin mitigates BACE1 activity by evoking changes in lipid composition of lipid rafts of cell membranes.Furthermore, the study also demonstrated that the lipolytic ability of leptin as a conseque nce of increased ? -oxidation of fatty acids and decrease  de novo  synthesis of fatty acids and triglycerides underlies the mechanistic link between the effects of leptin on lipid composition of membranes and BACE1 activity. Recent data from our studies [223] and other laboratories [221] cogently demonstrate that leptin negatively regulates BACE1 expression, both  in vitroand  in vitro  paradigms.Moreover, Greco and colleagues have attributed this effect of reduced BACE1 expression on the ability of leptin to induce PPAR? expression and activation [221]. Indeed, leptin is a well characterized inducer of PPAR? expression and activity [220,224]. In light of this, it is important to reiterate that multiple lines of evidence exist in current literature demonstrating the role of PPAR? as a negative regulator of BACE1 expression [225]. Another mediator of leptin induced modulation of BACE1 expression may be the transcription factor STAT3.The BACE1 promoter contains a multitude of STAT3 binding sites [226]. Multiple lines of evidence have implicated STAT3 in the regulation of BACE1 expression [226-228]. Leptin may also modulate BACE1 activity via the activation of the PI3K/Akt and ERK signaling pathways [229]. BACE1 expression is also modulated by the master transcription factor NF-? B [230]. We have found that leptin represses NF-? B transcriptional activity via induction of SIRT1 expression and activity and thereby attenuates BACE1 expression (unpublished).Furthermore, inhibition of SIRT1 activity significantly compromised the mitigating effect of leptin on BACE1 expression (unpublished). Therefore, the entire range of discrete signal transduction pathways activated by leptin may be implicated in the modulation of BACE1 expression. Leptin mitigates tau phosphorylation It is now the consensus that tau hyperphosphorylation precedes and leads to PHF formation in NFT [231] and aberrant tau hyperphosphorylation is implicated in neurodegeneration in AD [232-23 6].Recent studies by Tezapsidis and colleagues as well as our work has cogently demonstrated that leptin decreases hyperphosphorylation of tau, primarily by the activation of known canonical signal transduction pathway coupled to leptin receptors. Firstly, Greco  et al. demonstrated  in vitro, in SH-SY5Y and NTera-2 human neuronal cell lines, that leptin reduces the phosphorylation of tau at Ser202, Ser396, and Ser404  residues [205]. In the same study, it was shown that leptin was ~300-fold more potent than insulin at mitigating tau phosphorylation and the activation of AMPK pathway was implicated in mediating this effect [205].The following year, the same group systematically investigated the involvement of other signal transduction pathways activated by leptin that may contribute to the attenuation of tau phosphorylation and concluded that leptin-induced activation of Akt, p38 MAPK, as well as AMPK were all intricately involved [206]. Notably, of great mechanistic importanc e, was the revelation that all the three aforementioned pathways activated by leptin, culminated in the phosphorylation of the tau kinase GSK3? at Ser9  residue leading to the inhibition of its kinase activity.Therefore, leptin-induced activation of Akt, p38 MAPK, and AMPK signal transduction pathways converged at the focal point – GSK3? , a bona fide tau kinase [206,207]. Data from our studies carried out in organotypic slices from the hippocampi of adult rabbits has also cogently demonstrated that leptin inhibits GSK3? -induced tau phosphorylation at AT8 (Ser202, Thr205) and PHF1 (Ser396, Ser404) epitopes via the activation of Akt [223,237]. Of greater importance and relevance, was the finding that 8-weeks of leptin treatment in CRND8 transgenic mice resulted in a ~2-fold decrease in tau phosphorylation at AT8 and PHF1 epitopes [221].Leptin fosters synaptogenesis and synaptic plasticity Several studies have shown that synaptic dysfunction and synaptic loss are the cardina l hallmarks of incipient AD [238-244]. Electron microscopy [238,241,245-248], immunohistochemical and biochemical studies [240,249-251] have demonstrated that synaptic loss in the neocortex and the hippocampus is an early episode in Alzheimer’s disease [252,253]. Synaptic loss is also the most important structural correlate of cognitive impairment in AD [250,254-260]. Synaptic dysfunction can be detected in patients diagnosed ith mild cognitive impairment (MCI), a condition which may or may not progress to AD and characterized by many as a prodromal state of AD [247,261]. Leptin plays an indispensable role in learning, memory, and maintenance of synaptic plasticity [262]. Leptin receptor mutant  db/db  mice and  fa/fa  rats have deficits in spatial memory and inadequate short term memory processing as assessed by the Morris water maze [130] and T-maze footshock avoidance test paradigms [129]. In the CA1 region of the hippocampus, leptin exclusively enhances the NMDA r eceptor-mediated synaptic transmission [132].Leptin facilitates the trafficking of NMDA receptors to the plasma membrane and this may contribute to the effect of leptin on enhancing the NMDA receptor-mediated current [133]. This was also corroborated in a  Xenopus  oocyte model system expressing recombinant NMDA receptors [132]. Leptin evokes the conversion of STP to LTP in acute hippocampal slices. Further delving into the molecular mechanism underlying this effect has implicated the PI3K/Akt and ERK signaling cascades at the nexus as the inhibitors of these signaling pathways mitigated this effect of leptin [132].Furthermore, in the CA1 region of the hippocampus, leptin also fosters the induction of a novel form of LTD and this effect was attributed to NMDA receptor activation [263]. The study by Durakoglugil also examined the signal transduction cascades involved in the induction of this novel LTD by leptin and concluded that this effect was contingent on the PI3K signaling c ascade, but independent of the ERK signaling pathway [263]. In addition to regulating synaptic strength by modulation of LTP and LTD, leptin also fosters synaptogenesis.The leptin deficient  ob/ob  mice have decreased synapse density and exogenous leptin corrects this deficit in these mice [264,265]. Leptin also induces the expression of a multitude of pre- and postsynaptic proteins such as synapsin2A and synaptophysin in the hippocampus [266]. Leptin also has a profound effect on dendritic morphology. Leptin augments filopodial stabilization, fosters mobility and boosts their density, thus promoting synapse formation [267]. Interestingly, this effect of leptin on filopodial stability and density is contingent on ERK signaling pathway and not on the PI3K signaling pathway [267].Leptin increases neuronal survival and mitigates cell death There is growing consensus that leptin is a growth and survival factor in the CNS. Leptin increases the viability of SH-SY5Y cells and suppresse s apoptosis by down-regulation of caspase-10 and TRAIL and this effect is contingent on the ability of leptin to activate the JAK-STAT, PI3K-Akt, as well as ERK signaling pathways [268]. Leptin has been shown to exert neuroprotective properties in cultured MN9D rat dopaminergic cells against 6-OHDA.Leptin also averted the 6-OHDA-induced dopaminergic cell loss in the substantia nigra of mice when administered intracranially [269]. This pro-survival effect of leptin on dopaminergic neurons was attributed to the JAK2-dependent activation of the ERK signaling pathway resulting in increased levels of survival factors p-CREB and BDNF [269]. Our recent work has unequivocally demonstrated that leptin upregulates the expression of Insulin-like Growth Factor – 1 (IGF-1), a known neurotrophic and survival factor in the brain [270].Leptin has also been shown to attenuate apoptotic cell death of cultured cortical neurons in an  in vitro  oxygen-glucose deprivation model of global isch emia [271]. Furthermore, the study by Zhang  et al. , also cogently showed that intraperitoneal administration of leptin in mice reduced the infarct volume and significantly improved behavioral parameters in a middle cerebral artery occlusion (MCAO) model of global ischemia [271]. This effect of leptin was attributed to the activation of ERK signaling pathway as the general inhibitor of ERK signaling abolished this effect of leptin, both  in vitro  and  in vivo  [271].Another study employing hippocampal cultures has demonstrated that leptin inhibits neuronal cell loss in response to growth factor withdrawal and oxidative insult by evoking JAK-STAT activation leading to enhanced expression Mn-SOD and Bcl-xL and stabilizing the mitochondrial membrane potential [135]. Leptin also mitigated neuronal loss in response to excitotoxic insult evoked by glutamate in hippocampal cultures by the aforementioned molecular mechanism [135]. Leptin also protected the hippocampal neurons fr om kainite-induced damage in response to excitotoxicity evoked seizures in a mice model of temporal lobe epilepsy [135].A recent study found that leptin also attenuates MPP+-induced cell death in neuronal cultures via the activation of STAT3 and inducing the expression of UCP-2 that culminates in the obviation of mitochondrial dysfunction by MPP+  [272]. Of particular interest is the finding that cultured cortical neurons secrete prodigious amounts of leptin in response to oxygen-glucose-serum deprivation that results in enhanced expression of IL-1? and increased intransigence to apoptotic cell death [273].Moreover, neutralization of this endogenous leptin with an antibody resulted in increased susceptibility of these cultured cortical neurons to oxygen-glucose-serum deprivation – induced cell death [273]. The salutary effects of leptin on neuronal viability and function have also been corroborated by electrophysiological studies. One such study has cogently demonstrated th at leptin combats the hypoxia-induced inhibition of spontaneously firing hippocampal neurons by activating the BK channels (large conductance Ca2+  activated K+  channels) [274].Leptin induces proliferation of neuronal progenitors – evokes neurogenesis As Alzheimer disease is typified with selective neuronal loss in the hippocampus and other regions of the brain, the debunking of the dogma that neurogenesis occurs exclusively prenatally and the revelation that neurogenesis persists in the adult mammalian brain has opened novel therapeutic avenues to combat the neuronal loss in AD. Chronic leptin treatment increases hippocampal neurogenesis in mice and induces proliferation of adult hippocampal progenitor cultures [134].This effect of leptin on adult hippocampal neurogenesis is attributed to increased cell proliferation in the dentate gyrus and not enhanced cell differentiation or cell survival [134]. The study by Garza and colleagues unequivocally implicated the JAK2-STAT 3 and PI3K-Akt signal transduction pathways in the leptin induced enhancement of hippocampal neurogenesis [134]. Furthermore, leptin rescues the attenuation in adult hippocampal neurogenesis in a mouse model of chronic unpredictable stress-evoked depression via the inhibition of GSK3? nd subsequent stabilization of ? -catenin [275]. Leptin has also been documented to evoke neurogenesis and angiogenesis in a mouse stroke model (Avraham  et al. , 2011). Go to: ————————————————- Conclusion Here we have reviewed the contemporary knowledge on the protective role of the adipokine leptin and its signaling in Alzheimer’s disease. In conspectus, leptin impinges on all facets of Alzheimer’s disease pathophysiology (Figure 1). These attributes of leptin such as the decrease in A? production and increase of A? learance, reduction in tau hyperphosphorylation as well as increased synaptogenesis, increased memory, increased spatial learning, and increased neurogenesis catapult leptin treatment as a unique therapeutic intervention and an indispensable tool in the elucidation of biochemical mechanisms involved in the etiology of the sporadic form of Alzheimer’s disease. Marwarha , G. and Ghribi, O. Leptin signaling and Alzheimer’s disease Marwarha , G. and Ghribi, O. (2012) Leptin signaling and Alzheimer’s disease. American Journal of Neurodegenerative Disease, 1 (3), p. 45-265. Lifestyle nonpharmacological interventions can have a deep effect on cognitive aging. We have reviewed the available literature on the effectiveness of physical activity, intellectual stimulation, and socialization on the incidence of dementia and on the course of dementia itself. Even though physical activity appears to be beneficial in both delaying dementia onset and in the course of the disease, more research is needed before intellectual stimulation a nd socialization can be considered as treatments and prevention of the disease.Through our paper, we found that all three nonpharmacological treatments provide benefits to cognition and overall well-being in patients with age-related cognitive impairments. These interventions may be beneficial in the management of dementia. Alzheimer's disease (AD) is a neurodegenerative disorder with devastating consequences [1]. Despite being the most common cause of dementia, affecting approximately 5. 4 million Americans [2] and almost 50% of people over the age 85 [3], no cure has yet been discovered.Efforts are also focusing on the development of more effective strategies to slow the progression of AD to increase the quality of life of those affected. Even a two-year delay in disease onset would reduce the prevalence of AD among Americans by two million people within fifty years [4]. If an intervention that delayed the onset of AD by five years had been applied back in 1997, we would have seen a 50% reduction in AD incidence [4]. Research on strategies to slow the development and progression of AD is arguably more important now than ever before, since the number of people with AD is expected to nearly triple over he next forty years [4], and dementia is the most important contributor to disability in the elderly [5]. Among others, three nonpharmacological interventions are particularly relevant as they might positively influence cognition, general functioning, and overall quality of life. These three strategies arephysical exercise,  intellectual stimulation,  and  social interaction. While there are studies that evaluate the role of individual and multimodal interventions on AD, there is a lack of literature on the combination of all three.The purpose of this paper is to review key areas of the literature that focus on the effects of physical exercise, intellectual stimulation, and socialization strategies on AD evolution, as they collectively play an important ro le in the management of Alzheimer's disease. Physical exercise encapsulates both aerobic exercises (e. g. , walking and cycling) and nonaerobic exercises (e. g. , strength and resistance training; flexibility and balance exercises). For intellectual stimulation, we examine studies that have evaluated the prognostic effects of either cognitive hobbies (e. g. reading, word puzzles, and card games) or cognitive training (e. g. , computer training games/paradigms that target specific cognitive domains such as memory and attention). Social interaction is defined as the participation of an AD patient in group-related activities, such as mealtime conversations, support groups, or other forms of social engagement. The health benefits attributed to physical activity are numerous and well known. Exercise has been associated with a lower incidence in many chronic diseases, such as coronary heart disease [6], type 2 diabetes [7], obesity [8], cancer [9], bone loss [10], and high blood pressure [11].We have reviewed the effects of physical exercise on cognition. Higher cardiorespiratory fitness has been related to higher scores on tests of cognitive function [12]. A meta-analysis of randomized controlled trials examining the relationship between exercise and cognition showed modest improvements in attention, processing speed, executive function, and memory among older adults in the treatment arms [13]. This is highly relevant for the elderly population, as it suggests that physical activity can serve as a preventative measure against age-related cognitive decline [14].Several large longitudinal studies followed older adults without cognitive impairments at baseline and measured rate of incident dementia to clarify the relationship between physical activity and incident cognitive loss. A large prospective study by Podewils et al. identified an inverse relationship between physical activity and dementia risk [15]. Compared to no exercise, physical activity has been linked wi th reduced risks of developing cognitive impairment and dementia [16] with the risk for dementia being further reduced with increasing levels of physical activity.Larson and colleagues found that persons who exercised three or more times per week had a reduced risk of developing dementia compared to those who exercised less, and the reduction was more marked among those with the poorest physical function at baseline [17]. These results were corroborated by Buchman et al. who found that participants in the lowest percentiles of physical activity had more than twice the risk of developing dementia than those in the highest percentiles of physical activity [18].Furthermore, Lautenschlager et al. demonstrated that these results might be transferable to adults with mild cognitive impairment (MCI), and, thus, at high risk for dementia; participants who underwent exercise training showed modest improvements in cognition after six months [19]. Physical exercise has, therefore, been recommen ded as a preventative measure of mild cognitive impairment and dementia [20,  21]. There is much less research focusing on the effect of physical activity in AD patients.This may be due to the challenges of implementing an exercise regime while managing the behavioral and emotional disturbances in AD patients, particularly in the later stages of the disease. However, the results in the available literature are promising. Early research involving AD patients in nonrandomized controlled trials showed significant cognitive improvements among participants who underwent cycling training and somatic and isotonic-relaxation exercises [22,  23]. Physical exercise may have beneficial effects in AD patients beyond cognition as well.A meta-analysis on 30 randomized controlled trials that employed exercise, behavioral and environmental manipulations in patients with cognitive impairment found exercise had positive effects on strength and cardiovascular fitness in addition to improvements in behavior and cognition [24–26]. Further evidence supporting multifaceted positive effects of exercise on AD can be traced to recent randomized controlled trials of physical exercise regimes on AD patients (Table 1). Compared to controls, patients in the intervention programs showed better physical functioning (functional reach, walking, and mobility).After treatment, these patients also showed improved performance of activities of daily living (ADLs), and less cognitive decline and cognitive improvement in some cases. Physical exercise, therefore, appears to be beneficial for AD patients. While the majority of the studies did not find any differences in depression, one study by Steinberg found increased depression and decreased quality of life in patients who underwent the exercise intervention [31]. Further research into the effect of physical exercise on mood and quality of life in AD patients is, therefore, required.When considering the role of exercise on AD, it is impor tant to note that any positive results may be due to a placebo effect, even in randomized controlled trials. However, due to the varied nature of the outcome measures used in these studies, it is unlikely that every intervention group demonstrated significant gains over the controls due to a placebo effect alone. Furthermore, control group members never appeared to show any improvement and often showed higher rates of functional and cognitive decline.Enhanced neuroplasticity might be underlying the improvements seen. Colcombe and colleagues demonstrated that older adults without dementia who performed aerobic exercises had greater grey and white matter volumes compared to adults who engaged in stretching and toning exercises [38]. Exercise has also been associated with functional connectivity between brain networks often affected by age, such as the default mode, frontal parietal, and frontal executive networks, in older adults without dementia [39].While randomized controlled trial s in AD patients examining the relationship between neuroplasticity and exercise are underway, correlational studies examining brain volumes and cardiorespiratory fitness have been done. In AD patients, cardiorespiratory fitness has been associated with brain volume. VO2peak, peak oxygen consumption, has been positively correlated with greater whole brain volume and white matter volume [40], notably in the inferior parietal lobule, hippocampal, and parahippocampal regions [41].Future results of randomized controlled trials will improve our knowledge in this field of research. Overall, physical activity offers promising outcomes for cognition and physical health in the elderly population and AD patients. Engagement in intellectually stimulating activities has been linked with reduced risk of developing AD and intellectual stimulation has been widely explored as a nonpharmacological treatment option for dementia [42]. Among cognitively ormal older persons, randomized control trials em ploying intellectual training concluded that cognitive interventions produce protective and potentially long lasting positive effects in various cognitive domains as well as activities of daily living [43]. There is also evidence that frequent engagement in hobbies, including reading, puzzles, and games, for at least six hours per week reduces the risk of incident dementia [44]. The concept of intellectual stimulation as a preventative measure for dementia in healthy older adults can be parallel to the notion of building a â€Å"compensatory mechanism† or â€Å"cognitive reserve† [45–48].Cognitive reserve refers to the hypothesis that individual differences shaped by inherent characteristics and external sources including intelligence, years of education, occupation, and intellectual activities, may provide neural protective support against dementia [45–47]. It has been argued that these collective life experiences may contribute to building cognitive res erve and, thus, provide skills to compensate for AD pathology [45–47].In other words, a greater cognitive reserve might delay the appearance of dementia despite the presence of neuropathology, after which a rapid progression of cognitive decline may ensue once pathology is significant enough to result in AD diagnosis. Thus, AD patients with higher education and occupation accomplishments suffer more rapid decline in cognitive abilities when compared to AD patients with less education and occupational attainment following diagnosis [49]. Another study by Helzner and colleagues [50] investigated the relationship between premorbid leisure activity and rate of cognitive decline in AD patients.Leisure activities were classified into four categories: intellectual, social, physical, and other. Higher-frequency participation in intellectual leisure activities prior to AD diagnosis was associated with delayed AD onset followed by faster cognitive decline. The study by Helzner and coll eagues [50] provides evidence for the benefits of intellectual stimulation on slowing down AD development. Besides reducing the risk of dementia, cognitive interventions later in life may affect functional decline in AD.Treiber and colleagues [51] explored the association between engaging in cognitively stimulating activities in late life and the rate of cognitive decline in incident AD. This study included a wide range of intellectual activities that required varying levels of cognitive demand, for example, completing puzzles, reading, watching television, listening to music, and cooking. The results suggested that higher-frequency participation in stimulating activities in early stages of dementia resulted in slower cognitive decline.However, as time progressed there was an overall decrease in participation in activities, which might reflect the nature of AD in terms of functional abilities. Intellectual stimulation can be divided into several categories including cognitive stimul ation, cognitive t