GraduateWriters.net Mission to Help Students Achieve Academic Excellence Essay Example for Free

GraduateWriters.net Mission to Help Students Achieve Academic Excellence Essay PHOENIX, AZ, JUNE 24, 2014 /PRESSRELEASEPING/ ACADEMIC WRITING IS AN IMPORTANT ACTIVITY done by every student, at all level of education in order to satisfy course work requirement. Students are required to undertake a variety of academic writing task that could range from short essays, assignments, SAT, IELTS or lengthy term papers, dissertations and thesis. This type of writing could be done either under time demanding pressure or syllabus requirement. As a result students are expected to output a number of papers at the end of each day, week, semester or term. But such time demanding output doesn’t always guarantee quality of resultant paper, says Peter Wartson consultant at GraduateWriters. net. In fact a research by National Academic Council for Academic Excellence found that many students resort to borrowing or stealing the work of others in order to beat deadlines and as result the rate of plagiarism has become so common place, that if every student who plagiarized was to be flunked, the rate of dropout will be worse than that massive open online learning courses (MOOC). â€Å"With this in mind many students sort the services of freelance  academic writers, who are seen as the first level examiners. They guide students on how to structure their research papers, perform proof reading and help students to avoiding mistakes related to grammar, spelling, phrasing and plagiarism. states Peter, â€Å"Freelance academic writers, should not be confused with people who helps students achieve shortcut by doing their assignments, no they are honest writers who guide students the way a teacher will do†. While this may help students reduce stress related to academic demand, some concerns has  been raised concerning the qualification of writers who handle students’ academic work. Mary White an academic consultant at GraduateWriters. net, stated that â€Å"Students should look at the pool of writers a freelance company has, example GraduateWriter. net, is comprised of only graduate writers who have various qualification in their field of interest that range from MSc, MBA, MRes, EM, LLM, MEng, MA, Phd, and DS. At that company, writers undergo series of test approved by our senior writers to ascertain academic prowess and professional skills in writing and research. The advantage of this pool of workforce is that clients are always guaranteed the best quality writing and editing service, which cannot be found elsewhere on the Internet. Writers are specialist, with background in Education, Medicine, Nursing, Finance, Communication, Media, Arts, Humanities, Social Sciences, Engineering, IT, Law etc. Other qualities that prospective student should look at before selecting an academic writing company include privacy and security, originality, timeliness, quality, revision policy, orders tracking, support and response to queries. A lot of emphasis should be placed on privacy as it is not only a right but a demand that every users online should be guaranteed of. If an online company published a student paper online, without their formal approval, it could lead to plagiarism and dismissal from school. Therefore students should look for companies that adhere with privacy policies and not let third party have access to their client papers. articulates Peter. ABOUT GRADUATEWRITERS. NET Graduate Writers is an academic editing and writing company that help student in carrying out  research work, gives advice on writing, referencing and proof reading. The company is composed of Graduate writers with specialties in field which can be advantageous to students. PO Box 89670 Phoenix, AZ Peter Wartson Graduate Writers LLC +1-480-409-1822 [emailprotected] net http://graduatewriters. net Source URL: http://pressreleaseping. com/graduatewritersnet-mission-help-students-achieve-academic- excellence.

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

A New Journey - Original Writing :: Papers

A New Journey - Original Writing A journey begins with a step, a voice, a vision or a loved one. My journey first began with a cry, unknowing what the future beholds, but in the end, I found myself at a destination which I did not visualise. A destination that was not meant to be. An end that became a new beginning. "Please don't do this to me, Ma." I said with a shaky voice. Already annoyed, my mother said, "I just can't afford it, okay?" "But what about my future? If I don't go to college, I won't even have one." "You know something? You are selfish. All you care about is yourself. Have you ever thought about my position? I don't have a job. I don't have a stable income. And you know what your father is doing about this? Nothing. Don't talk to me about this now." She said as she walked away. I followed her to the kitchen, unwilling to give in. "I'm selfish? You're the one who is selfish! Now all you think about is Gary. I'm your daughter! I came first! I'm supposed to be number one!" I shouted. My vision began to blur as a film of tear coated my eyeballs. "Why are you doing this to me, Ma? Every time you come home, all you do is talk to Gary. You know I'm alone. You know I don't have friends. And now I've lost you. I might as well be dead." I grumbled. "You are just so bloody stubborn! Go on. Go hang yourself." She ended the conversation with such hurtful words. With uncontrollable tears streaming out of my eyes, I ran into my room and slammed the door hard. I took out my journal and put in writing everything that had just happened. As I was doing so, I thought about my father; I hate him. It is his fault all this had happened. It was his cruel gesture that caused this mess. How is it that he had the heart to do

Womens Control in Ken Keseys One Flew Over the Cuckoos Nest :: One Flew Over Cuckoos Nest

Women's Control in Ken Kesey's One Flew Over the Cuckoo's Nest "One Flew Over the Cuckoo's Nest" by Ken Kesey is about a man named Chief Bromden. He is half Indian and is locked up in a mental institute. He has led everyone in the ward to believe that he is deaf and dumb; instead he is just quiet and observant. Big Nurse is the head of the ward and mentally controls every patient she has, not allowing them to become better. McMurphy is a transfer to the ward and loosens up the atmosphere. He is a very relaxed, outgoing, funny guy that loves to joke around and be loud. When he too notices the Big Nurse's mental control on everyone, he sets out to help the patients become sane and not be influenced by the Big Nurse. One of the possible themes for this story is that women, although not physically stronger than men, can mentally be stronger than men and can control them with that alone. In the following paragraphs I will show how Kesey portrays women's control. The Big Nurse was the first women introduced in the novel, and she definitely has the most overpowering characteristics. She is the main woman with power throughout the novel. She is introduced and described by Kesey through the eyes of Chief Bromden. Ken shows her overpowering nature by writing, "She dips a nod at me as she goes past. I let the mop push me back to the wall an smile and try to foul her equipment up as much as possible by not letting her see my eyes-they can't tell so much about you if you got your eyes closed"(10). From this passage you can tell that the Big Nurse terrifies Chief and has a mental advantage over him. She keeps him scared and willing to do what she wants. A man named Harding is also in the institute. While at a meeting, Mrs. Ratched, The Big Nurse, starts talking about Mr. Harding's wife. She is a beautiful woman that receives many stares from other men. Because of this Harding is afraid that his wife is cheating on him. Ratched shows her mental superiority by asking the other patients to comment on the subject, which further embarrasses Harding making him even more intimidated by the nurse. Kesey shows his embarrassment when he writes, "Harding shuts his eyes, and nobody says anything" (44). Women's Control in Ken Kesey's One Flew Over the Cuckoo's Nest :: One Flew Over Cuckoos Nest Women's Control in Ken Kesey's One Flew Over the Cuckoo's Nest "One Flew Over the Cuckoo's Nest" by Ken Kesey is about a man named Chief Bromden. He is half Indian and is locked up in a mental institute. He has led everyone in the ward to believe that he is deaf and dumb; instead he is just quiet and observant. Big Nurse is the head of the ward and mentally controls every patient she has, not allowing them to become better. McMurphy is a transfer to the ward and loosens up the atmosphere. He is a very relaxed, outgoing, funny guy that loves to joke around and be loud. When he too notices the Big Nurse's mental control on everyone, he sets out to help the patients become sane and not be influenced by the Big Nurse. One of the possible themes for this story is that women, although not physically stronger than men, can mentally be stronger than men and can control them with that alone. In the following paragraphs I will show how Kesey portrays women's control. The Big Nurse was the first women introduced in the novel, and she definitely has the most overpowering characteristics. She is the main woman with power throughout the novel. She is introduced and described by Kesey through the eyes of Chief Bromden. Ken shows her overpowering nature by writing, "She dips a nod at me as she goes past. I let the mop push me back to the wall an smile and try to foul her equipment up as much as possible by not letting her see my eyes-they can't tell so much about you if you got your eyes closed"(10). From this passage you can tell that the Big Nurse terrifies Chief and has a mental advantage over him. She keeps him scared and willing to do what she wants. A man named Harding is also in the institute. While at a meeting, Mrs. Ratched, The Big Nurse, starts talking about Mr. Harding's wife. She is a beautiful woman that receives many stares from other men. Because of this Harding is afraid that his wife is cheating on him. Ratched shows her mental superiority by asking the other patients to comment on the subject, which further embarrasses Harding making him even more intimidated by the nurse. Kesey shows his embarrassment when he writes, "Harding shuts his eyes, and nobody says anything" (44).

Realism vs. Romanticism in Hawthornes Young Goodman Brown Essays

     Ã‚   Nathaniel Hawthorne’s classic tale â€Å"Young Goodman Brown† is a good example of a short story embodying both characteristics of realism and characteristics of romanticism. M. H. Abrams defines romantic themes in prominent writers of this school in the late eighteenth and early nineteenth centuries as being five in number: (1) innovations in the materials, forms and style; (2) that the work involve a â€Å"spontaneous overflow of powerful feelings†; (3) that external nature be a persistent subject with a â€Å"sensuous nuance† and accuracy in its description; (4) that the reader be invited to identify the protagonist with the author himself; and (5) that this be an age of â€Å"new beginnings and high possibilities† for the person (177-79).    Let us examine â€Å"Young Goodman Brown† in light of the above. First of all, Hawthorne was a real innovator in his use of the psychological approach to characters within a story. A. N. Kaul considers Hawthorne â€Å"preeminently a ‘psychological’† writer – â€Å"burrowing, to his utmost ability, into the depths of our common nature, for the purposes of psychological romance. . . .† (2). Q. D. Leavis says: â€Å"Hawthorne has imaginatively recreated for the reader that Calvinist sense of sin. . . . But in Hawthorne, by a wonderful feat of transmutation, it has no religious significance, it is as a psychological state that it is explored† (37). The reader experiences most of the story through the eyes and feelings of the protagonist, Goodman. In the following passage the reader is allowed, as is typical, to read his thoughts:    "Poor little Faith!" thought he, for his heart smote him. "What a wretch am I, to leave her on such an errand! She talks of dreams, too. Methought, as she spoke, there was troubl... ... Swisher. San Diego, CA: Greenhaven Press, 1996.    Hawthorne, Nathaniel. â€Å"Young Goodman Brown.† 1835. http://www.cwrl.utexas.edu/~daniel/amlit/goodman/goodmantext.html    James, Henry. Hawthorne. http://eldred.ne.mediaone.net/nh/nhhj1.html    Kaul, A.N. â€Å"Introduction.† In Hawthorne – A Collection of Critical Essays, edited by A.N. Kaul. Englewood Cliffs, NJ: Prentice-Hall, Inc., 1966.    Leavis, Q.D. â€Å"Hawthorne as Poet.† In Hawthorne – A Collection of Critical Essays, edited by A.N. Kaul. Englewood Cliffs, NJ: Prentice-Hall, Inc., 1966.      Ã¢â‚¬Å"Nathaniel Hawthorne.† The Norton Anthology: American Literature, edited by Baym et al.   New York: W.W. Norton and Co., 1995.    Swisher, Clarice. â€Å"Nathaniel Hawthorne: a Biography.† In Readings on Nathaniel Hawthorne, edited by Clarice Swisher. San Diego, CA: Greenhaven Press, 1996.   

Experience from Part Time Job

EXPERIENCE FROM PART-TIME JOB Every young person eventually needs to consider a career path, and working part-time jobs are a common way to gain experience in determining which career field is right for the individual. Part-time jobs are good way to gain experience not only in a particular position, but are also instrumental in teaching a newcomer to the working world a number of important skills that are necessary to succeed in the long-term. From the real situation – one day to be a serving staff at a coffee shop, I myself find that part-time work activities give me many useful lessons.Working environment is the way to have many interactions between us and customers, partners, also the managers. The important thing I want to mention is â€Å"to be welcoming, friendly and polite†. Sometimes, the complaint of customers, the criticism of the manager make u so confused. However, learning how to suffer from such things like that is also a lesson when you are engaged in a p art-time job. So, â€Å"work quickly and stay calm under pressure†. Besides, being in working environment compels me to improve communication skills. At the first time, I felt so shy because of my influent communicability.But, thank to character of the job, I try to overcome myself and make it better as much as possible. I think it works some way. Finally, what I learned from a part-time job is ability to multi-task. Having organization skills is very important even in the most unorganized, chaotic atmosphere. Although the part-time job I chose is not relevant to my major, I still think it`s useful, at least in the current time. Part-time jobs are a good way to learn experience not only about working, but offer a number of soft skills that I am sure it will be very necessary for my job in the future.

Indianapolis: Activity-Based Costing Essay

1- Yes, government should perform a cost analysis before privatization, especially if the government will remain as a participant in the bidding process. The cost analysis will provide the government with cost information for accurately pricing the bid. In case the government is not going to be a participant in the bidding process, the cost estimate will provide the government with an estimate on how much to pay for a service. For example, if the government wants to engage in a firm fixed price contract, a cost analysis will provide an accurate estimate of the cost and government can adjust the estimate for labor contractor rates and profit to price the contract. 2- For pothole filling activity direct labor and materials are relatively easy to trace directly, but it is more difficult to allocate indirect costs to the service. In order to apply ABC in Department of Transportation, reconciling with controller’s records, the team correctly identified in phases 1 and 2 all the basic activities. There were 35 activities, one of them being â€Å"pothole patching†. The labor hours and direct materials assigned for this activity were easy to be traced so the direct labor and materials were precisely determined in the â€Å"Pothole Filling Cost† table. A few comments about the overhead costs: The model allocated costs for fixed assets and unused equipment, which is one of the strengths. The model also adjusted the current year capital purchases and added back the depreciation (the consumed portion of the purchase price). We think that was an appropriate decision in order to have a true cost for this activity. The city already had an accounting system to trace the depreciation, and that was an advantage. It is debatable the decision not to include the headquarters expenses. In fact those costs may vary up or down depending on who does the pothole filling – municipal workers or private contractors. Decision was that these expense to â€Å"remain in the city† but they don’t necessarily have to. A true  cost for the service would be to allocate them in the overhead costs. It is a bit unclear if the overhead costs captured in the â€Å"Pothole Filling Cost† table are strictly associated with pothole filling activity. We know that the team identified the indirect and support costs associated with the 35 primary activities. It is difficult however to allocate those costs to pothole filling activity only. For example how much would be Facility Expense slice for this service? We should assume that a reliable allocation method was utilized, since the other 34 activities should also have overhead costs traced for other potential bids. Regarding overhead costs allocation by region, a brief calculation reveals that some sort of allocation was utilized for costs, however it is not clear on what basis. Four fixed costs out of seven do follow the same allocation pattern, however that allocation does not follow the â€Å"tons filled† ratio. We should also notice that the model analyzed the cost occurred during winter months, in order to prepare a bid for spring. If pothole filling is a season specific activity, the actual costs could be slightly different and the bid should be adjusted accordingly. Maybe a better idea was to apply the ABC model considering actual costs incurred during the previous spring. 3- Yes, letting the municipal employees see the ABC estimates and giving them the opportunity to reduce their costs was a good practice as it provided several benefits. Due to several past factors, the city’s departments had been operating on a less than optimal level and had high overhead costs. For example the supervisor to worker ratio was too high, and the department of transportation carried excessive capital assets (vehicles). Sharing the ABC estimates and giving the opportunity to reduce costs allowed them to improve efficiency. The municipality was able to pinpoint the problem issues and fix them, such as half the supervisors were dismissed. This would allow the city to be competitive with the private sector in the bidding process. ABC estimate sharing provided an additional benefit as a buy-in from the  employees and the union. As the employees and the ABC estimators worked together to generate the estimates, they realized the data was showing the problems that they did not anticipate such has the high supervisor ratio. They recognized that ABC will be very essential for them to lower their costs and become competitive. The employees needed to be competitive with the private sector to keep their jobs. 4- We will assume that the â€Å"Indirect Cost Pool† includes supervisor’s expenses (which should be reduced by 50%) and overhead costs. In this case the bids for Northwest and Northeast quadrants are calculated in Exhibit B. Comparing with the actual pothole filing costs per ton in January-March, we could clearly see a dramatic decrease of indirect costs and rolling stock costs. Overall the bid for both quadrants is by far more competitive than it would have been without the ABC analysis and cost reduction. 5- If the administration continues to outsource city services through competitive bidding and assuming the private sector is able to aggressively under bid the city, the administration will have to dismiss the idle workforce, selloff unused fixed assets and update the ABC estimates accordingly. As the number of outsourced contracts grows in count and size, the administration will also need to enhance its contracting and performance management capabilities.