Why the Great Depression Occurred

Introduction As observed by Romer (2003), â€Å"the great depression took place in the late 1920s to the late 1930s and was the longest and most severe depression ever experienced in the industrialized Western world† (p 1). The world wide economic downturn that originated from the United States was characterized by massive decline in output, widespread unemployment, and acute deflation in most economies across the globe (Romer, 2003).Advertising We will write a custom research paper sample on Why the Great Depression Occurred – a Public Budgeting Stand Point specifically for you for only $16.05 $11/page Learn More However, the timing and magnitude significantly varied in various regions across the world with some parts of the world such as United States being adversely affected while other regions were mildly hit. In the United States, the great depression set off in 1929 and continued until early 1933 where it was set on a road to recovery but these efforts unfortunately failed and the American economy was highly characterized by drastic falls in prices and real output (Romer, 2003). In addition, the industrial production of the country’s economy fell by 47% while the real gross domestic product fell by 30% and the whole sale price declined by 33% resulting into deflation; further, the unemployment rate is believed to have exceeded 20% which negatively impacted on the purchasing power of the individuals consequently reducing aggregate demand (Romer, 2003). Poverty and despair were the main features of the great depression in American region with most people being unable to access the basic needs of food, decent clothing and shelter and relying on aid from charity organizations (Burgan, 2001). The depression was the worst to ever hit the nation and when president Franklin D. Roosevelt brought new policies and ideas to Washington, there was a link of optimism in the region but this was short lived since the depr ession worsened in 1938 and did not end until the country went into world war ll in 1941 (Burgan, 2001). Factors That Led To the Great Depression The prevailing government policies at the time highly facilitated the occurrence of depression and the failure and derailment in recovery of major economies. From 1929-1933, the American economy experienced substantial reduction in money supply from the federal reserves (Edwards, 2005). This, coupled with subsequent bank failures served to intensify monetary contraction in the economy and destabilize the economy which precipitated the occurrence of depression (Edwards, 2005). Scholars believe that substantial decline in money supply which was attributed to Federal Reserve decisions had severe contractionary effects on overall output in the economy as well aggregate demand (Romer, 2003).Advertising Looking for research paper on history? Let's see if we can help you! Get your first paper with 15% OFF Learn More This may have si gnificantly influenced people’s decisions to spend as there was widespread fear and uncertainties with consumers and business owners anticipating decreases in wages and prices in the future (Romer, 2003). To further worsen the situation, most states prohibited banks from diversifying their portfolios across jurisdictions which significantly promoted bank failures while in countries like Canada which allowed nationwide bank branching, incidences of bank failures during the period were not experienced (Edwards, 2005). Bank failures led to widespread bank panics across the American economy whereby depositors lost confidence in the solvency of banks consequently withdrawing their deposits from banks (Romer, 2003). Increased withdrawals by depositors forced banks to liquidate loans in order to raise the required money which served to increase bank failure in United States (Romer, 2003). The early 1920s was characterized by tax reductions which facilitated economic boom in the Amer ican economy during the period (Edwards, 2005). However, President Hoover signed a revenue act in 1932 which created a provision for significant tax increment in the region increasing the tax rate from 25% to 63% while President Roosevelt further increased individual and corporate taxes with the highest individual rate increasing to 79% (Edwards, 2005). The tax increment killed the laborers’ incentives for work as well as investment and entrepreneurship consequently reducing the amount of spending which intensified the effects of depression and frustrated the efforts of recovery (Edwards, 2005). In addition, the Smoot-Hawley trade act which had been established to boost farm incomes by reducing foreign competition in agricultural production in America may have played a significant role in reducing world trade during the period of depression (Edwards, 2005). The trade act had raised import tariffs to an average of 59% on more than twenty five thousand products which prompted o ther countries to retaliate by imposing increased restrictions on United States’ products consequently reducing trade such that by 1933 the overall international trade had reduced by two thirds of the level prevalent before the recession (Edwards, 2005). However, some scholars believe that this policy had minimal significance in the occurrence of the depression but may have contributed to extreme decline in world price of raw materials which resulted in severe balance of payment problems for primary products exporting countries (Romer 2003). Another damaging trend that may have facilitated the occurrence of the depression was the prevalent inequality in wealth distribution whereby in 1929, the richest 24000 families in the US owned 34% of all the monetary savings in the country while an approximate 21 million families lacked any savings (Burgan, 2001).Advertising We will write a custom research paper sample on Why the Great Depression Occurred – a Public Budgeting Stand Point specifically for you for only $16.05 $11/page Learn More Consequently, only few Americans could afford to locally produce goods despite the fact that factories kept on producing goods which led to under consumption which further led to the weakening of the economy (Burgan, 2001). Conclusion The great depression caused devastating effects to major economies of the world and adversely affected international trade. Numerous measures implemented by the government proved fruitless in containing the situation and the contemporary economies should learn from this occurrence in order to avoid incidences of depression in the current dynamic economy. Reference List Burgan, M. (2001). The Great Depression. Minneapolis: Compass Point Books. Edwards, C. (2005). The Government and the Great Depression. Retrieved from https://object.cato.org/sites/cato.org/files/pubs/pdf/tbb-0508-25.pdf Romer, D. C. (2003). Great Depression. Web. This research paper on Why the Great Depression Occurred – a Public Budgeting Stand Point was written and submitted by user Arielle R. to help you with your own studies. You are free to use it for research and reference purposes in order to write your own paper; however, you must cite it accordingly. You can donate your paper here.

To What Extent Was the Decline of the Staple Industries Essay Example

To What Extent Was the Decline of the Staple Industries Essay Example To What Extent Was the Decline of the Staple Industries Essay To What Extent Was the Decline of the Staple Industries Essay To what extent was the decline of the staple industries the most significant development affecting the people of Wales and England 1880 – 1929? The decline of the staple industries was a very significant development in people’s lives. Before the decline of the staple industries, Britain was known as the â€Å"workshop of the world† this was due to the fact that Britain producing 2/3 of the worlds coal, 50% of the worlds iron and 5/7 of all the worlds’ metal. This all changed when countries like Germany and the US used cheaper methods of extracting and producing these resources that Britain’s buyers looked else wear, the decline of these main industries caused a wave of job losses and other main industries to suffer. Britain lost its place as the most powerful empire; there were many reasons for this. Britain didn’t have the necessary raw materials needed for industrialisation; Britain’s farming industry couldn’t produce enough food to feed the growing population. The Liberal reforms were very significant in people’s lives. There were many reasons for why the liberals decided to reform Britain and these issues are highlighted in Booth and Rowntrees reports about people living below the poverty line. These reports tell us that if someone lost their job before the reforms they had to rely on their savings, family and friends, and the pawn brokers or depend on the poor laws which were the only sort of social protection they had. The government hardly ever stepped in to help people, the conservative government and member of the House of Lords all believed that if a person was poor that meant they were lazy; these reports discovered that that wasn’t the case and that in fact the majority of the poorest in society were born there. Some shocking statistics had shown that 11% of primary school children were malnourished and in 1900 the height for enlisting was reduced to 5 feet and even 50% who enlisted were in too ill health. There was a major need to reform, because working conditions needed to be improved in order to improve Britain’s employed for the future. Another significant factor that affected the people of Britain was the changing role of women in Britain. The main cause in the change to women was primarily down to world war one. The war opened up a wider range of occupations to female workers and hastened the collapse of traditional womens employment, particularly domestic service. From the 19th century to 1911, between 11 and 13 per cent of the female population in England and Wales were domestic servants. By 1931, the percentage had dropped to under eight per cent. For the middle classes, the decline of domestic servants was facilitated by the rise of domestic appliances, such as cookers, electric irons and vacuum cleaners. The popularity of labour-saving devices does not, however, explain the dramatic drop in the servant population. Middle-class women continued to clamour for servants, but working women who might previously have been enticed into service were being drawn away by alternative employment opening up to satisfy the demands of war. The number of women in the Civil Service increased from 33,000 in 1911 to 102,000 by 1921. The advantages of these alternative employments over domestic service were obvious: wages were higher, conditions better, and independence enhanced. Another reason was the general strike. The general strike was called by the TUC to support the miners in their quarrel with the mine owners, who wanted to reduce their wages by 13 per cent and increase their shifts from seven to eight hours. Workers in industries such as iron, steel and coal were encouraged to stay off work. The strike affected people across the country because these industries were at a standstill this caused the rest of the country to suffer. To conclude, I think that there were many significant factors that affected the British people and the declined of the staple industries was one of them. However, i think that the most significant factor was the war, as this affected all sexes and age groups across the country and no one was left unscathed by it.

M7 Deforestation and Kaibab Deer Discussion Assignment

M7 Deforestation and Kaibab Deer Discussion - Assignment Example ifferent ways including destruction of recreation area in the national and tropic forests which provide the locals more returns compared to logging, drying up rivers as alternative sources of income and increase in atmospheric carbon dioxide (Merrill, 2008). Deforestation generally interferes with other important or beneficial economic activities such as hunting, recreation and fishing in both the tropic and the national forests. Deforestation of tropic forests lead to increased emission of greenhouse gases as well as enhance susceptibility of surrounding areas to tropic storms and floods. Floods are associated with increase in certain diseases such as cholera and malaria through breeding mosquitoes on stagnated waters (Merrill, 2008). Cholera resulting from floods can be addressed the public health sector through controlling of the floods through encouraging mitigation measures such as tree planting or re-afforestation. The disease can also be controlled through distribution of clean drinking water during such floods. A significant decrease in the number of wild animals especially the potential extinction the mule deer the Kaibab due to increased hunting activities led to the decision to make Kaibab a Forest Reserve. This decision was made to facilitate restriction of hunting activities through prohibition hunting within the forest reserve and the Grand Canyon National Park (Kay, 2010). Nevertheless, the move resulted into increased number of wild animals which posed another threat other forms of wildlife with such areas. As a result, this incident has been quoted in many wildlife decisions especially in justifying the need to authorize hunting to achieve significant ecological balance (Kay, 2010). Hunting has been supported on economic basis in which the activity is believed to contribute significantly to the national economy. Charitable organizations benefit from donations made from hunting activities both in monitory and food forms (North Carolina Wildlife

Response Assignment Example | Topics and Well Written Essays - 250 words - 18

Response - Assignment Example The student should clarify this. Moreover, the student does not identify any nonverbal communication. In a noisy environment, it is quite obvious that the two would have probably used several facial expressions or gestures. These are important aspects of the transactional model of communication. Student 2 was having a discussion with his friends at the San Francisco Aquarium. The two friends were discussing their previous experiences. Student 2’s friend responded using nonverbal communication when asked if they liked the beach in San Diego. Student 2 was keen to observe the facial expression and gestures of his friend. He noted the wink and thumb up which indicated that his friend liked the place. The success of the communication was based on the ability of student 2 to understand non-verbal communication. I agree with the idea that, the reaction from his friend indicated that he liked the place, and he would like to visit the place again. Their conversation was interrupted by the loud noise of the train. They could no longer communicate and had to get back to the aquarium. Noise interrupts the smoothness of a conversation and can stop conversations. However, the student should clarify if they attempted nonverbal communication during the noise. This is necessary in e xplaining the transactional model of

Modification of the 4-Quinolone Scaffold

Modification of the 4-Quinolone Scaffold Discovery: Quinolones are antibacterial agents that are of major importance in the antibacterial field as the can act as the model antibiotic. This is due to their broad range of activity, the high potency and good bioavailability with both intravenous and oral administration possible. This is coupled with high serum levels and a distribution within tissues that specifies concentration levels and results in, theoretically, few occurrences of unwanted side effects.1 The timeline for the development of this class of antibacterial agents begins with the isolation of the bactericidal naphthyridine, nalidixic acid, in the 1960s by George Lesher as the first synthetic quinolone antibiotic. Nalidixic acid is illustrated in Figure 1 below and is a by-product that was isolated from a chloroquine synthesis.2 Figure 1: Nalidixic Acid The clinical use for naldixic acid was to treat urinary tract infections (UTIs) caused by gram negative organisms. The successive generations of quinolones had activity against both gram negative and gram positive bacteria as well as anaerobic bacteria. This development lead to fluoroquinolones which are latest in quinolone antimicrobials. The clinical uses for the quinolones today include respiratory tract infections, bacterial meningitis and gastrointestinal infections as well as the historical use of treating UTIs. The development of fluoroquinolones resulted in a more extended spectrum of activity and improved pharmacokinetics then the first generation of quinolones.3,4 Structure: The general quinolone class of molecules is comprised of 4-quinolone and 1,8-napthyridine ring structures. The naphthyridine ring structures differ slightly from the 4-quinolone core due to the presence of two nitrogen atoms in the rings of the molecule (Figure 2). The substituents R5, R6, R7 and R1 were added to improve the activity of the quinolone core before the development of highly potent fluoroquinolones.1 Figure 2: General Structure of 4-Quinolones The first fluoroquinolone to be developed was Flumequine; illustrated in Figure 3. It had a fluoro-group at the 6 position and was the first compound to show that modifications of the quinolone core could results in improved activity against the gram-positive bacteria that nalidixic acid had no effect on.1 Figure 3: The first fluoroquinolone- Flumequine Mechanism of Action: Inhibition of bacterial DNA gyrase (topoisomerase II) and topoisomerase IV is achieved by quinolones. These enzymes play a vital role in the uncoiling of DNA. DNA gyrase acts as the target in gram negative microbes and topoisomerase IV as the target in gram positive microbes for quinolone activity. The widely-accepted mechanism of action is that quinolones bind to complexes, formed between DNA and one of the enzymes, to generate a Quinolone-DNA-Enzyme complex that inhibits DNA replication. The binding of quinolones and topoisomerase is enabled by a water-metal ion bridge. The inhibition is bacteriostatic as replication is reversible.   Eventually apoptosis occurs due to the fragmentation of the DNA ends of the complex. This results in bactericidal inhibition. The most common form of resistance to the quinolones is due to specific mutations in the topoisomerase II and IV that interfere with the water-metal ion bridge interaction.2,3 Development: Quinolones are grouped into generations depending the activity of the molecules. The first generation showed activity against gram negative bacteria that caused UTIs. The second generation showed enhanced activity against gram negative bacteria and improved activity against gram positive. This enabled the list of conditions that quinolones could treat to expand. This generation displayed improved pharmacokinetics; due to the use of a C7-piperdinyl substituent. The third generation provided improvement in efficacy in inhibiting gram positive and anaerobic pathogens. 3,5 The fourth generation of drugs observed dramatically increased activity against DNA gyrase and gram positive microbes, improved pharmacokinetics and pharmacodynamics. The major changes were the addition the fluoro-group at the C-6 position and a ring substituent at C-7. Norfloxacin (1), second generation, was the first broad spectrum quinolone with ciprofloxacin (2) the first quinolone to have activity observed beyond the treatment of UTIs.2 Currently, Garenoxacin (3), fourth generation, is of interest due to its distinct carbon-carbon bond at position C7 and its broad spectrum of activity.3 Figure 4:Generations of quinolone drugs. Three modified quinolone cores have acted as templates for drugs that are on the commercial market. The cores were 4-oxo-1,4-dihydroquinolone (4), 7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-d,e]-1,4-benzoxazine (5) and 4-oxo-1,4-dihydro-[1,8]-naphthyridine (6). These selected cores are illustrated in Figure 5.3 Figure 5: Cores used as templates for commercial drugs Retrosynthesis: Scheme 1: Retrosynthesis of 4-Quinolone core6 A carbon-carbon disconnection between the ketone and the aromatic ring, the reverse would be a Friedel-Crafts reaction.   The double bond is opened and the hydroxyl group that is added is converted to a carbonyl group. The final disconnection, N-C, results in the starting materials; a keto ester and the substituted aniline. Synthesis: Several synthetic approaches have been taken to generate the 4-quinolone core. The Gerster-Hayakwa and Chu-Mitscher reactions are used specifically for the synthesis of the drug Levofloxacin. The Chu-Li route was established primarily for 9-cyclopropylpyrimidinones. The Gould-Jacobs reaction, Grohe-Heitzer cycloacylation and Conrad-Limpach-Knorr are appropriate methods of synthesising the generic 4-quinolone core.3 The Conrad-Limpach-Knorr synthesis will generate quinolones but this reaction will give different products depending of the whether it is kinetically or thermodynamically controlled. Aniline and 3-keto ester are mixed and at room temp the keto group joins the nitrogen of the aniline giving an enamino ester (kinetic product) and cyclisation at 250 °C results in a 4-quinolone. Thermodynamically controlling this reaction, by carrying it out at 140 °C, results in an amido-ketone dominating regardless of the less reactive ester on the keto ester being the centre of the first nucleophile attack. Ring closure results in a 2-quinolone.7 Scheme 2: Conrad-Limpach-Knorr Synthesis (kinetically controlled) As the substrate for the cyclisation needs to be the high-energy tautomer and cyclisation causes loss of aromaticity in the ring, solvents with high boiling points are generally used in this synthesis.8 The reactions are encouraged by electron-donating substituents in the aromatic ring including methoxy or amino groups. These give increased yields in the condensation and ring closure steps. A CF3 group can act as an acceptor at C-4.9 The short reaction sequence limits possibility of loss of yield. Rational Drug Design: Illustrated in Scheme 3 is the process of rational drug design. Computational screening is used to identify the target and generate the lead compound. This is modified considering the biological aspects, the 3D structure, the QSAR and reactivity of the compound. This generates a new lead which is optimised and put forward for preclinical trial. Scheme 3: Rational Drug Design Process10 Nilsen et al. used endochin as a lead for optimisation in a rational drug design study. The target selected was the multiple stages of the life cycle of malaria. Endochin is potent against malaria but is not active in vivo due to rapid and extensive metabolisation. Optimisation was required to form endochin-like quinolones (ELQ) that retained the activity of endochin but were biologically active. The aims for optimisation was to improve metabolic stability and aqueous solubility as well as eradicate cross-resistance.11 Figure 6: Structural Representation of Endochin The EQLs were synthesised by converting the quinolones to quinolines, followed by nucleophilic displacement. The quinoline undergoes Suzuki-Miyaura coupling with a boronic ester and finally the protecting group is removed (Scheme 4 A). An OCF3 group was also added to the side chain for further optimisation (Scheme 4 B). Scheme 4: Synthesis of ELQ An orally active class of quinolones were synthesised; 4(1H)-quinolone-3-diarylethers. The initial lead, ELQ-233 (Figure 7: ELQ-233Figure 7), displayed low nano-molar IC50 values. The optimisation step was to introduce an aryl group at C-3. A lipophilic diphenylether side chain was used as it had been previously reported as integral in other antimalarial drugs. This was to work with the methyl group at C-2 to cause out of plane movement of the sterically large aromatic ring, altering the à Ã¢â€š ¬Ãƒ ¢Ã‹â€ Ã¢â‚¬â„¢Ãƒ Ã¢â€š ¬ stacking from the numerous H-bonds. This variation would not be perused as ELQ-233 was equipotent to endochin. Figure 7: ELQ-233 Due to the success of adding a fluoro group to the quinolone, to further build on the optimisation of endochin, a fluorine was added at C-6 on a second optimised molecule (7) along with a methoxy group at C-7 (as is in the endochin structure); illustrated in Figure 8.11 The methoxy group is a useful substituent due to its lipophilic and hydrophilic components in close proximity. Figure 8: Illustration of Compound 7 However, both ELQ-233 and 7 were metabolically unstable and therefore did not fulfil the optimisation requirements. Table 1: Values obtained for the optimised molecules Compound cLogP EC50 (nm) Endochin 3.35 3.8 ELQ-233 3.70 8.4 7 3.73 40 8 5.66 2.2 Further derivatives were generated and the pattern that emerged indicated that the substitution pattern on the aromatic ring influenced the reactivity with malaria. This result led to the rational design of further ELQ derivatives. Straight-forward reactions were continued to be used. The boronic ester with a varying diarylether side chain undergoes palladium mediated coupling with the quinolone then a demethylation occurs using hydrobromic acid to give the desired product. Repositioning the OCF3 group to the side chain increased the efficacy and the metabolic stability. The compounds that was found to be metabolically stable and potent had a chloro-group at C-6 and OCH3 ­at C-7. Figure 9: Structural representation of compound 8 Although compound 8 was the most potent compound, the high logP value is a disadvantage as it does not follow Lipinskis Rule of Five which is the basis for most developed drugs. To improve solubility and allow for lower dosages of 8, bioisoteres of the side chain were employed. The OCF3 was replaced by CF, Cl and F by Nielson et al. and displayed subnanomolar activity. Other options would be to double the terminal OCF3 group, double the substituents on the diaryl side chain, convert the diphenyl ether side chain to a dipyridine ether side chain or replace a phenyl ring in the side chain with a cyclopropane group. Phenyl rings can be replaced by a heteroaromatic ring or a saturated ring to improve efficacy, lipophilicity and specificity of binding. The introduction of a pyridine ring should reduce the metabolism of the phenyl ring and toxicity of metabolites.12 In heterocycles, metabolism can be more complicated with hetero-atoms being oxidized and/or ring opening reactions possible- slowing metabolism. Cyclopropane was explored as derivative of the phenyl ring resulting in compounds with reduced molecular weights and lower lipophilicities. It also limits the conformations available and increase yields of ELQs.11 Scheme 5 below are the same coupling reactions that are stated by Nielson et al. but with the suggested changes to further improve the lea d. Caution must be taken when adding substituents to the side chain so that Lipinskis rule of five is obeyed; there must be no more than 5 hydrogen bond donors or 10 hydrogen bond acceptors and the molecule should be below 500 Da. Scheme 5: Suggested further optimised lead molecules Rational drug design is an advantageous modification method as it is a streamline process when compared with SAR or QSAR as there is no trial and error, all leads and derivatives are prepared having been predicted by computational means previously. The computational aspect allows for all compounds and potential targets to be envisaged in 3D before they are synthesized. This computed information is then stored on large databases which can assist future drug development work. Rational drug design can be an expensive technique as a specialized team is required with knowledge in biology, chemistry and computer science. Costs rise due to payment of wages for the team and the specialized equipment and computer software that is vital. Although the computational aspect of this method is beneficial it can also be a disadvantage as not all predicted compounds can be synthesized and if the compounds are synthesized they may not act as predicted when in vivo.   Specifically, in this ratio nal drug design study, the reactions utilised readily available reagents that were also inexpensive. They were straight-forward reactions that gave high yields and could be scaled up. These are vital as the cost of antimalarial drugs must be kept down so that all people can afford to access it.11 Structure-Activity Relationship (SAR): SAR studies examine how the structure of the molecule effects the activity. SAR considers structural characteristics and relates them the activity therefore it is necessary to have a well characterized database to compared the results against. The basic principle of SAR, that structure determines properties and reactivities in a biological system, is of importance when determining toxicological properties. This is of huge significance for quinolone development as they must be nontoxic in vivo while remaining bacteriosidal.13 Figure 10: Areas SAR Studies consider13 These studies examine which modifications are possible to the core ( Figure 11) and which substituents cannot be modified without negatively interfering with the activity and potency of the drug.   There can be qualitative and quantitative aspects to these studies. The quantitative considerations are part of a quantitative structure activity relationship (QSAR) which will be discussed later. Figure 11: Quinolone core positions for the SAR study Table 2: Important Positons on the Quinolone core-SAR Study results14 Position Influence On: Preferred substituent: Effect of substituent: 1 The pharmacokinetics and has control on overall potency. Cyclopropyl increase activity against gram negative microbes 5 Activity against gram-positive bacteria. NH2 and CH3 moiety improve activity against gram-positive bacteria 7 Spectrum of activity and pharmacokinetics. 5/6 membered N heterocycle (aminopyrrolidines and piperazines) Alkyl group Aminopyrrolidines: increase activity against gram-positive bacteria Piperazines: increase activity against gram-negative bacteria. Alkyl: enhance gram- positive potency and lengthen the serum half-life 8 Pharmacokinetics and specific activity on anaerobes. CF, CCl and COMe improve activity against anaerobic bacteria. alter specific interaction of the agent in vivo. SAR studies reveal that a hydrogen at R2 is preferred. Any larger moiety would likely cause steric hindrance with the adjacent carboxyl group at C-3 and the oxygen at C-4. These substituents are vital for activity as these positions are where binding to DNA bases occur before the sites are made available for other hydrogen bonding to proceed by DNA gyrase. A small molecule is best for potency at R6. This is usually a fluorine group in later generations of quinolones as it produces molecules of between 5 to 100 times greater potency that when a hydrogen is positioned at R6.14 Ciprofloxacin (Figure 12) is one of the original patented quinolone anti-bacterial agents. It is first generation as it has moderate activity towards gram negative bacteria, poor pharmacokinetics and poor bioavailability. Figure 12: Structural representation of Ciprofloxacin However, using the results of the SAR, Ciprofloxacin can be further optimized. Scheme 6 utilizes straight-forward reactions to attach an -NH2 moiety to the core at positon 5 where the SAR study indicates it has the greatest influence. Firstly, nitration of the aromatic ring occurs, followed by a reduction of the nitro group to an aniline with palladium on carbon. Scheme 6: Further optimisation based on SAR Study Results The new lead is still in agreement with the SAR results as the carboxyl and oxygen are present at C-3 and C-4 respectively. The preferred substituent as stated in Table 2 are also used throughout the reaction scheme; the piperazine is at position 7, the fluoro group at positon 6 and the cyclopropyl group at positon 1. These substituents can positively influence the spectrum of activity the potency and the overall pharmacokinetics of the molecule. The addition of extra hydrogen bond acceptors/donors must be limited so as not to disobey Lipinskis rule of five by having more than 5 hydrogen bond donors or 10 hydrogen bond acceptors. These reactions, like the rational drug design reactions, utilize readily available, generally inexpensive reagents which is important to keep the cost of the anti-malarial drug down. Palladium is an exception as it is a rare metal but cheaper alternatives could be used for this step such as Raney Nickel although this generates intermediates before the aniline is formed unlike the direct formation when the palladium catalyst is used.15 SAR studies can represent molecules as 2D, atoms and bonds, or 3D, steric effects and electrostatics. 3D is best for when the receipt-mediated mechanism is known. Successful SAR studies also need appropriate methods of analysis which depend on whether quantitative or qualitative analysis is being perused and if the mechanism is known. The ideal SAR model should have adequate molecules for fair statistical analysis, a wide range of activities and an even distribution of molecules in each compound class. This model is rarely found when toxicology is considered.13 Quantitative Structure-Activity Relationships (QSAR): The basic principle of QSAR is that similar molecules have adequate similar mechanistic elements so that a common rate-determining step is shared among them and that they have comparable energy requirements for activity. This principle is taken further and the assumption is that differences in reaction rates results in differences in activity or potency.13 Lipophilic, electronic and steric effects are considered in QSAR studies. QSAR provides an equation that quantifies the SAR and allows for predictions about which property has an important role in the distribution/ mechanism of the drug. Predictions cut down on the volume of analogues to be synthesised. Equations are only applicable to compounds of the same structural class. Outliers indicate when a feature is important and can produce new leads. The QSAR may not give accurate predictions as the parameters have covariance on each other; the predicted model may vary in vivo.6 Lipophilicity/Hydrophobicity: This can be considered as the lipophilicity of the molecule or the lipophilicity of the substituents attached. Partition Coefficient, P, is the parameter associated with the lipophilicity of the molecule and is measured by Equation 1. Equation 1: Representation of the lipophilicity parameter. Solvents chosen to represent the Central nervous system The activity of a molecule can be related to the P value as a molecule must be able to cross membranes and be transported through the body to its target site which is dependent on its lipophilicity. Varying substituents on the core can alter the P value in whichever direction is more beneficial for the activity of the molecule. From SAR studies increased quinolone activity occurs when a lipophilic substituent, such as a halogen, is attached at C-6. Simple reactions, including nitration and chlorination (Scheme 7), will add these substituents to the core, again using cheap and readily available reagents. In general, increasing lead hydrophobicity increases activity (Figure 13). This does not go to infinity as there is a point at which the lead is to hydrophobic to be transported in vivo.6 LogP should not be more than 5 per Lipinskis rule of 5; high enough to bind, low enough to be released. Scheme 7: Addition of lipophilic substituents to the quinolone core to alter the P value Figure 13: Linear relationship between biological activity 1/C and lipophilicity6 Electronics: This parameter can influence ionisation and polarity which alters how a drug passes through a membrane or how strongly it binds to a receptor. Hammett substitution constant (à Ã†â€™) is the measure of the electron withdrawing or donating ability for substituents on an aromatic ring. à Ã†â€™ affects the equilibrium and the value is dependent on induction/resonance effects and whether the substituent is para or meta directing. Ortho is not considered due to sterics.6 Table 3:Substituents that can alter the à Ã†â€™ parameter Electron Donating Group (para): Electron Withdrawing Group (meta): -NH2 -NO2 -OH -CONH2 Halogen -CN Generally, electron-withdrawing substituent, positive à Ã†â€™ values, increase activity (Table 3). Simple reactions like those illustrated in Scheme 7 are used to attach the à Ã†â€™-influencing substituents to the quinolone. Sterics: Drug molecules must approach and successfully bind to a receptor and the sterics of the molecule can alter this approach. Bulk can result in nonbinding as the drug is sterically hindered from approaching the target site. It can also limit the available conformations so that only the most efficient arrangement binds to the receptor. Table 4: Parameters for measurements of steric effects6 Measure of Steric Effect: Key Feature: Other Factors: Tafts Steric Factor (Es) Quantifies steric feature of substituents Limited to use on certain substituents Molar Refractivity (MR) Measures volume occupied by atom(s) Corrects for ease of polarisation. Verloop Steric Parameter Computer programme calculates steric values For use with any substituent Using the quinolone core, modifications can be made so that the sterics prevent rapid metabolisation of a drug molecule in vivo which will extend its half-life and lead to better activity. Binding the quinolone to a large side chain restricts it from binding to smaller sites which Nilsen et al. conclude lead to better selectivity.11 Scheme 8 illustrates the addition of bulky side chains that can give better selectivity as they will only approach the sites they fit into. Furthermore, the double bond linkage and aromatic rings restrict the conformation that the molecule can adopt, increasing selectivity. Bulky side chains can prevent rapid metabolism occurring. When adding bulk, caution must be taken to ensure the molecule stays below the recommended 500 Da. Scheme 8: Reactions to alter the sterics of a quinolone core16 3D-QSAR: 3D-QSAR considers the relative spatial arrangement of model compounds and aims to correlate the features across molecules that affect activity and are required for ligand binding. 3D-QSAR studies the geometry, pharmacophore and molecular field. Key assumptions of 3D-QSAR13: The model compound and not its metabolite cause the biological response. The studied conformation is bioactive. Solvent effects are not considered The system is in equilibrium All compounds bind in the same manner to the one target. 3D-QSAR puts compounds with common configurations in a 3D grid, calculates the interaction and tabulates the results. An equation is then created based on the relationship between the calculations and the reported values. This verifies QSAR results. Conformers are superimposed to display the common ligand-binding orientation to the receptor. Probe atoms calculate steric and electrostatic fields.13 3D-QSAR studies on 1,3,5-triazine, quinolone derivatives, determined less bulky groups on the heteroatom ring, more bulk on the aro

Coffee and Starbucks Essay

Walk several blocks in almost any city in America and you’ll pass at least one Starbucks, if not more. And the same is true for most cities outside of the United States. The Starbucks empire has grown to 6,000 U.S. outlets and about 2,500 international locations. For some consumers, Starbucks is an obsession, and they just can’t begin their day without their cup of Starbucks coffee! In addition, while years ago people used to hang out at the corner candy store, today many people spend considerable time at their local Starbucks. They drink coffee, tea, and/or other specialty beverages, they bring their laptop and wirelessly connect to the Internet, they meet friends to chat, or they meet business associates to make deals. Is there anyone in America, at least old enough to be in kindergarten, who doesn’t know what Starbucks is? Questions Since everybody knows Starbucks, answer the following questions in the Indian context. For example, against question 1 below view the person as an India; and in response to question 4, identify an Indian celebrity. Some search on the internet about Starbucks and what its brand imagery stands for would help you with your answers. 1. If Starbucks was a person, describe the person in terms of demographics, personality, and lifestyle characteristics 2. If Starbucks was an animal, which animal would it be, and why? 3. If Starbucks was a color, which color would it be, and why? 4. If Starbucks was a celebrity (e.g., a sports figure, a movie or TV star), which celebrity would it be, and why? And why was your choice male or female?

Strengths and Weaknesses of the Qualitative Methodology

Cotte’s paper primarily deals with the Economic, Symbolic and Hedonic motives of gambling (2-3). Her method is centered on Ethnographic Participant Observation (1). The study was conducted on a Northeastern casino (10) for 90 hours that was accumulated through 30 visits between October 1995 and March 1996 (9). This critique will concentrate on the analysis of Cotte’s Literature Review, Research Design and Methods and Subjects chosen for the study. Literature Review Cotte’s literature review tackles the economic, symbolic and hedonistic motives of recreational gambling.With an emphasis centered on â€Å"Experiential Consumption† (6) which explains the role of motives in human behaviors and decisions, the paper was able to prove its point that the human drive to gamble stems out from the desire to learn and evaluate the game (12), to have a feeling of a â€Å"rush† (14), to demonstrate self definition such as being a â€Å"variety-seeker, rebel, and casino pro† (15), to fulfill the desire to be a risk-taker (18) and to view â€Å"cognitive self classification† that is primarily achieved through â€Å"interpersonal relationships† (19).Similarly, the study reveals that urge for â€Å"emotional self classifications† are also evident (19); similarly, human competition (20) and communion (21) are also part of the characteristics that were studied. The paper’s main criticism for the author’s literature review is: Cotte, by opting to focus on the hedonistic aspect of gambling has established the claim that recreational gambling primarily is a result of emotion in its most â€Å"barbaric sense† and provides no rational explanation whatsoever on the concept of recreational gambling.Cotte presented eight cells (12-21) which tells the reason in a form of conversation between her (i. e. the researcher) or other people through overheard conversations or observations explaining why people gambl e. It could be significantly noted that Cotte have made various explanations linking the results of the observation and or interview to her related literature; and it appears that those explanations are only liked to the situations wherein there is an emphasis on the hedonistic drive (12-18).The author explained that the feeling of excitement, rush, the unknown etc are the primary reasons why people keep on coming back to the casino and even bringing their families with them to gamble as well (18). However, the paper would like to assert that although the first few cells are significantly linked on the theories that the author used, the last three cells were explained by the author in such an abrupt manner that she suddenly inserts a theory that in no way was she was able to elaborate on her literature review (19, 21).The Utilitarian Theory which definition is not established or discussed at all was inserted and was used to explain â€Å"emotional self classification† (19) an d communing (21) . In virtue of its philosophical roots, the Utilitarian theory was introduced by JS Mill and is commonly known of having this maxim: the greatest amount of happiness for the greatest number of people. However, the paper would want to establish that the author coined a different concept to the theory by equating utilitarianism to â€Å"rationality† which is definitely not the case.The paper acknowledges however that linguistics of course allows convention to give a different meaning to a particular word. However, if this is the case, the author should have at least provided an operational definition on her review of related literature. Research Design and Methods The author’s method is qualitative research focusing on Ethnographic Participant Observation (1). Her data gathering method was done primarily through unstructured interviews (Bailey, 1994) and observation (Holloway, 2002). The paper has two main criticisms: (1) Unstructured interviews are rela tively prone to bias (Bailey, 1994, 195).The unstructured interview wherein the interviewer has the advantages of probing her subjects more has a high degree of possibility to be interpreted in a different manner than what the subjects really intend it to be (195). Also, in comparing the unstructured interview to the structured interview, Bailey argued that â€Å"the mere fact that a highly structured interview has a neatly typed questionnaire is easy to code, and seems to be reliable does not ensure that the information gathered will be superior to that gathered with an unstructured interview† (195).(2) The second criticism of the paper is that observations that are primarily documented through field notes and should be in four types: condensed account, the expanded account, the fieldwork journal, and analysis and interpretation notes (Holloway, 2002, 135). However, it could be noted that the author has made clear on her paper that she only has â€Å"field notes† (whi ch is a generalized note) and â€Å"introspections† (10) for her data gathering. Holloway (2002) by quoting Spradley (1979) on her book explained that it is necessary that all of these field notes should be done by any researcher who will use the Ethnographic method.However, the paper also recognizes the advantages of the unstructured research. It is also noted by Bailey (1994) that most cases reveal that unstructured interviews have the capability of eliciting more favorable responses from its subjects. The fact that the interview is more informal in its setting and is generally friendly, most researchers are able to get the innermost feelings of their subjects that the subjects on the other hand might not consciously realize that they possess.Similarly, the descriptive ethnography method (Holloway, 2002) is capable of presenting an account of a particular behavior on a specific area or industry. Similar on the case of the recreational gamblers in the northeast, the author w as able to present what type of recreational gamblers those people are going in that casino. Cotte’s output as she stated on the latter part of her paper could be grounds for better and improved researches. Subjects of the Study The subjects of the study are randomly chosen.As evident on the research conducted, the author claims that most of the data gathered are from abrupt conversations, overheard conversations and observations. Hence, the paper claims that there is no way that the author could further verify if the same emotions or motives still apply after that particular day or the days after that particular study. Similarly, the context of the study (Holloway, 2002) that is in Northeast America does not allow the study’s conclusion to be extended to other locations or cultural contexts. Conclusion:The paper would say that the author’s attempts to verify that recreational gambler’s motivations in gambling are primarily driven by their hedonistic moti ves are successful. However, there should be enough detail that should be given in terms of the literature’s completeness, further efforts to make the methodology more valid and a more diverse choosing of the respondents. Literature Cited Holloway, I. (2002). Qualitative Research Methods in Public Relations and Marketing Communications. London: Routledge. Bailey K. (1994). Methods of Social Research. New York: The Free Press.