The International Operations Of Mcdonalds Business Essay

The International Operations Of Mcdonalds Business Essay The macroeconomics factors are one of the most main structure outlooks for a exacting business. It has is own analysis system to make sure that every business is done according to what is planned and organized. In that case, there are many in macro environment that will affect the planning and decision of managers of any businesses. Changes of tax, new laws, trade obstacle changes in demographic, changes in government document are some example of macro change. Some of these examples of factors do help in controlling the beyond which control the business. The examples of business which are in leading of pestle control are McDonalds. QUESTION 1 MAIN BODY POLITICAL FACTORS: The international operations of McDonalds are dramatically influenced by the solo countries policies obligatory by the government. For information, there are some groups in the foreign countries that clamors for state actions regarding in health implication in eating fast food. They have discovered that there are harmful substances in the fast food which can lead to obesity if it is taken regularly. On the other side, the company is under control of the individual policies and regulations of the operations. The market focuses more on different areas which concerns on health, environment, and the protection of workers. All of these elements are seen under the government control of licensing the restaurant in respective states of the country. For information, there are an impending legal dispute in McDonalds franchise, in India, where certain encroachment of rights and violation of sacred laws pertaining to the inside of the fast food. Extension of meat in the menu meal in India is officially unpleasant against the religion. There are also other studies those points to the violation of McDonaldss branches with reference to the existing employment laws in the particular target market. Since it is apparent that the company is increasing dramatically, it is fair to be deal with the proper establishment in a respective approach in the market that they intend to operate with. In this way the company can afford a better way in set up, a better relationship with the government. ECONOMICAL FACTORS Organizations in the fast food industry are not excused from any disagreement and troubles. In exact, they have their own individual concerns in linking economic control. Branches and franchise of McDonalds have the inclination to experience hardship in instance where the company of the respective countries, are hit by inflation and changes in the exchange of the rate. The customer therefore are facing, with a stalemate, of going over their individual account perhaps or not they should use up more on these fast food chain like McDonalds. Moreover these chains may have many to put up with the issues of the effects based on the economic environment. In this case, their problems are depending on the response of the consumers, on these essentials how it could influence the general sale In regarding the operations of the company, McDonalds tend to import many of their raw materials, into a specific countrys territories if there is dearth of supplies. The exchanges of rate oscillate that plays a major roles in the operations of the company. For information, McDonalds stores have to take great deal in deliberation with reference to their microenvironment. The international supply for the country, as well as the existing rate is a part overall for the components where assurance success is needed for the foreign operations of McDonalds. Moreover, it is essential that the company be cognizant of the tax accessible condition needed by the individual government on which they operates. These actually guarantee that planned operations of the McDonalds franchise. In the same way, the company also has to declare the economic standing of the company that they operate. The rate at which the economy of that particular country determine growth, by purchasing power of the consumers in that country. Besides that, in case a franchise operates in certain economically weak country, their value of the products should be higher than the other developing products in the market, then these franchise should know some steps in maintaining the economic scale. In idea, before penetrates the market, the market should carry out a very well conduct market research, especially in movements of the economic environment. SOSIO -CULTURAL FACTORS Articles regarding the international strategies of McDonalds seem to function on several fields to guarantee profitable returns for the organization. To illustrates, the organization has improve in establish a positive mind-set from their regular consumer. McDonaldss indulge types of consumers with definite variety of characteristics. It is also has noted company have given market markets such as United States and India. McDonalds has launched a very sensible valued set of meal, which produces a reliable level of amount to the respective markets where it operates. Additionally, those who are aged just below thirty five are said to be more common consumers of McDonalds franchise. The multi character of business is reflected nowadays towards the tough significance of the details regarding the subject of the accessible markets. This method is fundamentally identified as a market research in the business field. Details regarding the request and possible fields of markets would double as obstacle towards the success of the company, if this area of operations abandoned. In the case of McDonalds they establish a proper plan system in determining the needs of the markets. The company uses the consumer behavior concepts in as a product personality and purchase plan to its advantage which is clearly apparent in case of India, as the company has planned in removing Pork and Meat products from the menu. McDonalds should obtain the applicable details from the target of markets in an additional to individuals customers of the organization. It is imperative that before a franchise is granted to a particular business, a well sketch and complete market research should be conducted initially so as to establish the acts that would confirm to good mores, public policies, and ethics of the said countrys society. Similarly, the company should find out the shifts, in areas example like the consumer behavior and purchasing formula of the markets. Basically, this is the key condition for perform a suitable customer relationship management organization. Moreover the company should also make a review learn more about the local society to understand better and produce more blueprint for a better product. TECHNOLOGICAL FACTORS McDonalds produce order for their own products. There are similarly some claims that McDonalds are disposed to curiosity the younger populations more. Other revelation in marketing policy is perceptible in the commercials they use. Other advertising department has employed other person to subsidize for their company foodstuffs. The like has developed into endorsers for McDonalds wide-reaching I am loving it crusade Moreover the business McDonalds have appreciably infused with new machinery. Essentials like the account coordination and administration of the assessment sequence of company allows for easy payments for their purveyor and other retailer which the individual stores in particular markets to transaction with. The amalgamation of equipment in the procedure of McDonald does have a propensity to add charge to their goods. Basically, this is apparent in the enhancement on its value chain. The development of the supply system as well as its provide chain consent to the company to function in an worldwide perspective. McDonalds use internet to their pro. The rate-efficiency, interactivity and authentic time possessions of the statement are a high-quality way to find dealer. The corporation must also look into the utilize of IT to develop their supply function. As the process in its inbound and outbound look up company will expect important savings and decline of expenditure in the operations. ENVIRONMENTAL FACTORS The public tasks of McDonalds on the country are dominant to the process of the business. These grip indictment of environmental dent. Among the motive why they are stimulating which such assert is the employ non-biodegradable material for their drinks glasses and Styrofoam reserves for the food. Several municipal clusters in India have made procedures to make the McDonalds authorization in India of the relatively profuse use of Styrofoam containers and the consequential abuse of the environment. The company should find out the environmental command that rule the operations in every market. It should also observe the dissipate dumping of the corporation. McDonalds should reduce the usage of Styrofoam resources and synthetic cups. Unvarying update of the social corporate duty is very important. This should also require that the headquarters should take in hand, a approach of internal organize of those that would disobey upon this company goal. Sanctions such as annul of the franchise authorize or a particularly high fine should be establish to serve as prevention or a violation. LEGAL FACTORS There has been the persistent bellowing in disagreement to the fast food production. This has likewise made, McDonalds relate a more careful contemplation on their corporate common responsibilities. The status of McDonalds is actually a very enormous issue. Seen on the website of the company, it look as if that they have obtain tread to take in hand the key social criticize that they have been rebuke them in the long-ago decades. The company has offered their consumers the applicable data that they need with allusion to the dietary essence of their product. This is to focus to the advice of obesity charged aligned with the foodstuffs of the company. As a specialized fast food operator, there are many convention and dealings that McDonalds should go after. McDonalds should look after its reliability and consumer assurance by make sure all resources and procedure are as declare or must tag on. The company should appoint local guidance to deal with the permissible disagreement in individual markets on which the company may come across. This shall make sure the company that the lawyers that will grip their legal dealings are more versed with the legal management that would relieve out certain difficulty on their maneuver. QUESTION 1 CONCLUSION As we all know that the most major role of this cohort is the grouping of globalization and internationalization in the business subdivision. Developments in the global settings have an consequence on the more exacting factors in the process in individual association. Modification could take place and entail concentrated modification to the process such that it could have an unpleasant effect on the complete arrangement of the company. However, as categorize in the above PESTEL breakdown this could be obtain by setting a firm level of suppleness can basically be attain through the associate of both the interior and exterior environment of the corporation. QUESTION 2 INTRODUCTION Sole proprietorship and Partnerships are form of business. Both have their own roles and specialty in forming a business. The advantages and disadvantages are very important in concerning more on the business plannings. Before starting the business, every person who going to start the business should make a research regarding types of business they are going to make decision. So business planning is very important and has to be taken care by each businessman or businesswomen. QUESTION 2 MAIN BODY SOLE PROPRIETORSHIP Also known as Sole Trader. Is a type of business unit that is holds and run by one person and in which there is no official peculiarity between the holder and the trade The owner obtain all turnover (subject to taxes specific to the business) and has boundless liability for all fatalities and credit. Every property of the business is own by the administrator and same goes to all credit in the business. It is a sole proprietorship in similarity with partnerships. A sole proprietorship is a business owned and restricted by one man although he may have many other people functioning under him. A sole proprietorship may use a trade name or business name other than his or her official name. Examples of sole proprietorship business are plumbers, electricians, PC technicians, hairdressers and storekeeper. ADVANTAGES They have the capability to move up capital either widely or privately to bound the personal charge of the officers and manager, and to bound jeopardy to shareholder Sole proprietorships also have the least government official procedure moving it. Owners have complete organize over all the portion of his or her business and can take any administrative decisions that he or she wants to take. It is a simple set up function. DISADVANTAGES Elevate capital for a proprietorship is more tricky because an not linked backer has less peace of mind regarding the use and safety of his or her asset and the investment is more difficult to sanctify other sort of business unit have more citations. The venture may be crippled or refined if the owner becomes sick. Since the business is the same official entity as the proprietor, it causes to survive upon the proprietors decease. Because the enterprise rests entirely on the person, it often has trouble raising long-term possessions PARTNERSHIP Partnership is an unincorporated association which consists of 2-20 members. Partnership does not have a separate legal unit. All partners provide financial bear for the business and enjoy both profits and losses on agreed percentage, depends on the assistance of each individual in the partnership business. Partnerships have unlimited legal responsibility and each partner is jointly liable with the other members for any debt incurred by the business. The agreement between partnerships is usually drawn up by a lawyer (or a legal counsel) which details the contribution of each partner (in cash or in kind). ADVANTAGES No double duty of income or gain from sale of business assets. The assumption for ordinary and necessary expenses taken by partners personally to extent of other income, subject to basis limitation. Flexible portion of items of income and deductions. DISADVANTAGES Unconstrained charge of general partners, including acts done by other partners or employees in furtherance of partnerships business. There are deductions for health insurance same as sole proprietorship. Partnership union strongly suggest and essential if partners wish special allocations of income or assumption. CONCLUSION As a result, partnership is the better way to start up a business. A partnership is the relationships existing between more than two persons who involve on a trade or business. Partnership is something we can share profits and loss together from the production of the business. We can gain experience through starting business with partners, rather then alone. We will get to know more information about starting up a business and we can capable with what we can do with PARTNERSHIP management. In a concluding, starting a business with partner will be more helpful for every person. So, we must know the benefits and loss that we will get through PARTNERSHIP. REFERENCE

The Greatest Literary Emblem of the Middle Ages Essay -- Literary Anal

In order to study the troubadours, it is of high importance to understand the context in which they flourished and developed, which was the Medieval Era. The Middle Ages is the period of European history that goes from the collapse of the Roman civilization to the beginning of the Renaissance, and it extends from about 500 to 1500 ca. (â€Å"Middle Ages†). This period is called the â€Å"Dark Ages† since it is regarded by the Renaissance scholars as a long interval of superstition, ignorance, barbarism, and social oppression due to the fact that the Medieval era was a fight to establish a new society independent from the Roman standards and philosophy. However, it is now acknowledged that it was a dynamic period, in which Europe built a new distinct cultural unit. Moreover, it profoundly reorganized the European political, social, economic, and most importantly cultural structures (â€Å"History of Europe†), but its effects greatly differ from country to countr y, and one of the most influenced countries was France, mainly because of its cultural, artistic (painting, architecture, literature), and philosophical enhancement. The main characteristic of the Middle Ages in France was the development of love and romance, mainly in the literary aspect. Nevertheless, only certain high-class and educated people could have this privilege, and the main representatives of this love and romance literary expansion, despite coming from all kind of social classes, were the troubadours because of their poetry, origin, and values. To begin with, it is important to remember that during the Middle Ages, the great majority of population was not educated, and some people could not even read and write, so nobody was able to produce literary works. Consequently, Ga... ...Britannica. Encyclopà ¦dia Britannica Online Academic Edition. Encyclopà ¦dia Britannica Inc., 2012. Web. 14 Mar. 2012. . "Bernard de Ventadour." Encyclopà ¦dia Britannica. Encyclopà ¦dia Britannica Online Academic Edition. Encyclopà ¦dia Britannica Inc., 2012. Web. 14 Mar. 2012. . Maccarone, Christian E. "Les troubadours: au-delà   des chansons d'amour." sssstrinakria.org. Centro Studi Storico-Sociali Sicilani. Web. 14 Mar. 2012. . "Chivalry." Columbia Electronic Encyclopedia, 6Th Edition (2011): 1. MasterFILE Premier. Web. 16 Mar. 2012. .

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

Financial Analysis Using The Lawrence Sports Simulation Finance Essay - Free Essay Example

Sample details Pages: 6 Words: 1787 Downloads: 3 Date added: 2017/06/26 Category Finance Essay Type Argumentative essay Did you like this example? The art of Working Capital Management is like juggling with the cash flow and outflow, in good times and bad. In the Lawrence Sports simulation, the payment and collection periods have been compressed from the standard practice in the US to illustrate the principles of cash management (2007). Reviewing the Lawrence Sports Simulation the authors created capital policies that reduce future difficulties and made recommendation for which policy Lawrence Sports should implement. These recommendations include the following: an evaluation of the risk, contingences, performances measures that are used, and an implementation plan. Conservative Approach Don’t waste time! Our writers will create an original "Financial Analysis Using The Lawrence Sports Simulation Finance Essay" essay for you Create order In using the conservative approach, Lawrence Sports would alter much of its short-term financing to longer debt obligations. By substituting increasing rates with low fixed rates on long-term financing, this approach could keep interest low. This enables using long-term financing for some of its temporary current assets and for all long-term and permanent current assets. When asset needs are high, short-term financing would be used. When asset needs are low, they could take advantage of the opportunity to apply excess funds into more marketable securities. Since most sports are seasonal, financing a portion of its funds for particular needs on a long-term basis would build more of a safety margin (Emery, Finnerty, Stowe, 2007). Maturity Matching Approach With maturity matching, Lawrence Sports can dodge the risk of defaulting and interest rates, by matching the maturities of its assets and liabilities in the form of $1.2 million bank loans, (Emery, Finnerty, Stowe, 2007). Lawrence Sports will still have to arbitrate with the suppliers to pay back the burden of the loan and lessen the deficit of cash. No excess funds will be available by using the maturity matching. Although having excess funds would benefit the company more than having no funds, it is not recommended to use the maturity matching approach because the capital will be tied-up for the long-term, making the company less fluid. Aggressive Approach Management prefers an aggressive approach to finance working capital to raise profitability (Emery, Finnerty, Stowe, 2007). All seasonal or temporary needs are financed using short-term funds but the aggressive approach uses long-term funds to finance only the fixed part of current assets. In order to capitalize on the increased profitability provided by aggressive financing, Lawrence Sports will need concrete information and data on cash flow requirements to lessen the need for liquidity. Risk is provoked due to the potential of market fluctuations. The use of short-term loans allows for higher returns but not without added risk (Emery, Finnerty, Stowe, 2007). Recommendation It is recommended that the company implement the conservative approach based on the current policies of Lawrence Sports. This method decreases risk associated with reduced liquidity, increasing interest rates, and economic changes affecting the availability of business loans. Evaluation of Risk The optimal solution cannot be deemed successful unless the desired changes is acquired and end stated goals are met. Ongoing processes and metrics must be in place to monitor the success of the optimal solution and capital management policy. Lawrence Sports can evaluate the solutions implemented by applying basic ratios to financial statements. Checking values for debt-to-equity ratios and return on investment ratios can provide a clear picture of whether or not the company building cash reserves and investing cash in a positive manner. Other metrics include the cash conversion cycle, average collection period and accounts receivable aging. In the events the cash conversion cycle does not get reduced then Lawrence Sports will need to evaluate other areas for improvements such as the time lapse between getting the finished product delivered and the collection cycles. Longer cash conversion cycle creates greater dependencies on short-term financing to pay the bills until money is collected. A shorter cash conversion cycle would indicate the new policies are effective. Average collection period which measures the length of time from invoice issuance to the time Lawrence Sports receives payment. Monitoring the average collection period will reveal if the newly implemented credit and collection policy is effective. Accounts receivable aging summaries will define whether or not receivables are being collected in a timely manner or if further evaluations need to be done. Contingencies A contingency plan is a plan developed for a certain situation that bears unforeseen events. Businesses typically have a contingency plan that can save them when unfortunate events hit their field of operation. Plan B also helps in recovering from an unlucky position with minimum time and cost possible as well as providing a safety cushion of enough funds and appropriate amount of time to preserve cash inflows that aid in meeting payment deadlines. ÂÂ  The plan detailed herein contains three solutions that would help Lawrence Sports in this respect. Lawrence should develop a negotiation plan by sending a shrewd representative to set firm deadlines for Mayo that obligates the latter to make payments on time thus saving on interest payments for the loans obtained by Lawrence. Financing long term debts that require high interest rates should be avoided in favor of short term ones. The amount involved in such a process, more than 15% versus 10% in interest, can be devoted to other issues within the company such as paying necessary overhead or even lend the money to other business partners and make money out of this lending process. Reach-out to different partners other than the ones existing who had defaulted several times making advantage of the rapport. Mayo contributes to 95% of Lawrences sales, yet fails to make payments on time causing money shortage to their providers. Therefore, extending the arms of Lawrence to different retailers, without damaging the relationship with Mayo, is a step that should be kept within the account of the former as a wise alternative. Managing liquidity reflects any firms ability to meet its obligations as they come due (Emery, 2007). It is the art of Juggling day to day cash of a company in its endeavor to achieve its highest goals in satisfying business partners in addition to keeping its own financial concerns at the maximum level of balance. Maximization of shareholder wealth is the goal of working capital management, and it involves cash investments, marketable securities, inventories and receivables according to Emery. Lawrence Sports needs to focus on good planning as well as quicker responses (Lawrence simulation, 2007). Performance Measures for Evaluation When evaluating working capital policies at Lawrence Sports we must make many considerations. Borrowing money from banks our other companies should be avoided as much as possible. Banks will be hesitant to give money, even to big companies, in an unstable economy. The new policy must also allow the company to collect accounts receivable as much as possible. Stretching the payments due too many weeks or even into the next month could be devastating to our company. If our company has a bad month for making sales we may not have the money to support another companys debt. We must also be able to be flexible because not allowing a partner such as Mayo Retail Company could be detrimental to Lawrence Sports. If we disturb that relationship we could lose enough business to ruin our company (Lawrence simulation, 2007). Risk-Return Trade-Off When evaluating the new plan the risk return trade off principles must be considered. For example, allowing a company like Mayo Retail company extra time to pay us account has some risk but is probably worth doing to maintain a valuable relationship. What if they had outstanding payments due for months building up massive debt to Lawrence Sports? We would have to consider not risking future financial trouble with the company in hopes we would have a better working relationship with another company. The new plan must address the Risk-Return principle (Emery, Finnery, Stowe, 2007). Versatility In order for the new working capital plan to perform effectively it must be versatile. The new plan should have the ability to offer short term financing and long term financing when appropriate. A long-term partner who is trusted may be able to pay our company accounts receivable in a long-term payment plan (Emery, Finnery, Stowe, 2007). For example if Mayo Retailers is having a period of low sales they may not have the ability to pay the account immediately. The risk of doing something like this would have to be considered. A company must be trusted and have a good history of paying debts to be considered for long-term finance. Short-term collections on accounts should be used whenever possible. Also our company would be well suited to partner with companies that allow us to pay back debts long term if need be. Gartner will not allow us much leverage because we are not major customers of theirs. We may not be able to negotiate long-term payments with them. The new plan should poss ibly involve a vending partnership with Murray exclusively because involving Gartner may hurt our ability to be versatile (Lawrence simulation, 2007). Implementation When evaluating and measuring the performance of the new recommendation the previously mentioned criteria should be considered. The recommendation should focus on the risk-return principle in some aspect when implemented. Lawrence Sports must be versatile in order to borrow our make payments in a short-term our long-term fashion. Long-term payment plants can be implemented on a limited basis only. They should only be used on trusted partners who have a good history of paying money back to the company. Implementing two long-term plans simultaneously could be troublesome for our business. If Lawrence Sports has a down sales period and low accounts payable it could force the company into a money borrowing situation that puts us in debt. While one long-term payment plan is in action the other partners should be on short-term payment plans. When Lawrence Sports is paying its accounts the company should use a maximum of one long-term payment plan otherwise it is too hard to keep track of f inances. The new policy needs to be implemented swiftly but with finesse. Being too aggressive with collecting finances can strain important business relationships (Lawrence simulation, 2007). However, we have to consider the well being of our company. Constant outstanding debts owed by other companies are unacceptable. Lawrence Sports should be able to apply a flexible finance collecting policy but also be able to adapt into a more aggressive approach when necessary. Conclusion A manager handling the day-to-day cash of a company also has to balance many things like collections, bad debts, disbursements, future revenues, borrowing, and loan repayment simultaneously (Lawrence simulation, 2007). Hence, working the capital policies will help reduce future difficulties. The authors made recommendations for the following: an evaluation of the risk, contingencies, performance measures and have an implementation plan for the Lawrence Sports Simulation. It requires good planning and quick responses when managing or juggling with cash flows and outflows.