The Monstrosity: a Common Trait in Shakespeare’s Macbeth and Shelley’s Frankenstein

Through time, the theme of the monstrosity has been a prominent subject in many novels and plays. In the play â€Å"Macbeth,† Macbeth illustrates monstrous traits though his ambition as he strives to become the king of Scotland. Victor in Shelley’s Frankenstein also displays monstrous behaviors by using science along with his ambition to create his prodigious mammoth. Moreover, Both Lady Macbeth and the three witches imply their satanic traits by influencing Macbeth to become the monstrous king that he is while Victor become influence by both his place in time which is the Romantic Era and by the monster himself. In addition, both Macbeth and Lady Macbeth died as a result of their diabolical actions. This is comparable to the sufferings of Victor and Elizabeth because of the monster’s revenge plans and Victor himself. Thus, in Shakespeare’s Macbeth and Shelley’s Frankenstein, monstrosity is apparent throughout the ambitions, influences and outcomes of the main character’s actions. In the play, the main character Macbeth has the ambition to become and remain king. In order to become king, Macbeth needs to kill Duncan who has done absolutely nothing wrong. Duncan is a very noble king. However, Macbeth’s ambition leads him to be more abnormal and it hurts his reputation in the process. â€Å"I’ll go no more. I am afraid to think what I have done; Look on’t again, I dare not† (Shakespeare 2. 2. 53-55). Here, Macbeth intensifies his ambition and drive by trying to become the king of Scotland. Macbeth contemplates the idea that being king, he could do whatever he wants to. The truth is that to attain that position, Macbeth had to murder many innocent people like Duncan. He wants to be king so badly that he never looks back at what he did. By looking back at the situation, Macbeth thinks that it will bring guilt to him. Similarity, Lady Macbeth cold-bloodily expands her ambition to become queen of Scotland. Some of her ambition rubs off on Macbeth. It is she who has the idea to kill Duncan. She goes as far as to call out the spirits. â€Å"That croaks the fatal entrance of Duncan under my battlements, come you spirits that tend on moral thoughts, unsex me here and fill me from the crown to the toe-top full† (Shakespeare 1. 5. 38-41). Here, Lady Macbeth wants to unsex herself. She wants to be more of a powerful, uncaring human by getting rid of her feminine side. It allows her to achieve her ambition. Furthermore, she talks about the crown going from head to toe. Just like her husband, she needs Macbeth to be king so she can be queen. Lady Macbeth is willing to pay any price. Ambition plays a big role in both Macbeth and Lady Macbeth’s lives as they try to rule Scotland. In Shelley’s Frankenstein, Victor and the monster show their ambition during their quest for knowledge. On the night when Victor formulates his creature, he realizes that his ambition has been a failure just by looking at his creation. Moreover, his plans became ruined. He had expectations that kind of came to an unexpected stop. â€Å"How can I describe my emotions at this catastrophe, or how delineate the wrench whom with such infinite pains and care I had endeavored to form? His limbs were in proportion, and I had selected his features as beautiful. Beautiful! Great God† (Shelley 43)! Victor’s ambition has now been a catastrophe. He compares the monster to a wrench because he sees the being as a letdown and a bad accomplishment. His words displays that his feelings are monstrous. By comparing his creature to a wrench, he is being very discriminatory, making him monstrous. He attempts to be recognized by society and from his perspective; it is impossible to achieve that. Like Lady Macbeth, Victor has also unsex himself because while Lady Macbeth gets rid of her feminine side, Victor gets rid of his world view and put aside all of the caring values at home. However, he did not intend to be evil, he did it for the purpose of science. Similar to Victor, the monster has his own ambition. The monster had the ambition to meet new people despite his ugliness. When he introduces himself to the De Laceys, they strike back. â€Å"Agatha fainted, and Safie, unable to attend to her friend, rushed out of the cottage. Felix darted forward, and with supernatural force tore me from his father, to whose knees I clung; in a transport of fury, he dashed me to the ground and struck me violently with a stick† (Shelley 123-124). Here, the monster tries to fulfill his ambition by meeting the De Laceys. He attempts to explain his ambition. However, things turn out wrong for him. Because of the way, Felix discriminates against him and considers him a monster based on his looks. His social drive leads him to being a satanic-appearing creature in the eyes of the De Laceys. That is why Felix hits him with a stick and Safie runs away. They do not believe in him. Likewise, Macduff sees evil in Macbeth, as he does not attend his coloration. He just like Felix thinks that he is a monster. Nonetheless, Macbeth is really evil and has evil ambitions. The monster on the other hand does not. Thus, monstrosity is portrayed in the ambitions of both Victor and the monster throughout their intentions to be accepted in society. Macbeth not only shows monstrosity through his own ambition, he also shows it as a result of other influences. One huge influence on Macbeth is none other than his wife. Although Macbeth had the ambition to become king, he does not have the drive to carry through. This is where Lady Macbeth comes in. She is the one who drives Macbeth into killing Duncan, becoming a temptress in the process. â€Å"We fail? But screw your courage to the sticking-place, And we’ll not fail. When Duncan is asleep, Whereto the rather shall his day’s hard journey soundly invite him, his two chamberlains will I with wine and wassail so convince that memory, the warder of the brain, Shall be a fume, and the receipt of reason a limbeck only† (Shakespeare 1. 7. 59-67). Here it shows that Lady Macbeth takes an enormous role in Macbeth’s ambition. Through her words, Lady Macbeth displays her gruesome traits. She is willing to take the initiative and kill Duncan for Macbeth. Sadly, Macbeth falls for it. The thought of murdering someone is indeed monstrous. The three witches additionally have influence Macbeth in a way that drives Macbeth to become king. When Macbeth first listens to the predictions of the three witches, he is in shock. He later realizes that it can be a reality. The witches are temptresses in Macbeth’s eyes. â€Å"All hail Macbeth, hail to thee, Thane of Glamis. All hail Macbeth, hail to thee, Thane of Cawdor. All hail Macbeth, that shalt be king hereafter† (Shakespeare 1. 3. 46-48). Here, the three witches are predicting the future of Macbeth as they tell him that he will become king one day. This evil influence propels Macbeth to do whatever it takes to become king. They make Macbeth believe that he can be king. This influence kick starts Macbeth’s plans to kill Duncan. Thus, monstrosity is demonstrated as both Lady Macbeth and the witches act like temptresses to Macbeth while he strives to become king. Victor also had some influences that cause him to display some monstrosity. The Romantic Era could be a huge influence on Victor as he thrives to create his creation. His society is described as a revolutionary and rebellious one. As scientists in the Romantic Era make new and new discoveries, it thrusts Victor into creating his own. When the professor reveals that Victor wrong about his theory on why the tree lit up, it causes Victor to revolutionize the world of science. â€Å"As I stood at the door, on a sudden I beheld a stream of fire issue from a old and beautiful oak which stood about twenty yards from our house; and so soon as the dazzling light vanished, the oak had disappeared, and nothing remained but a blasted stamp. When we visited it the next morning, we found the tree shattered in a single manner† (Shelley 26). Here, Victor sees a tree being shattered by lightning. A modern philosopher introduces Victor about his ideas on electricity and galvanism and why the tree completely shattered. He proves that all the scientist Victor follows like Cornelius Agrippa, Paracelsus, and Albertus Magnus were wrong. As the science professor proves Victor wrong, it causes Victor to create and do something bigger so that he can top him one day. He has the thirst for knowledge, knowing that in the Romantic Era, anything is possible. This era also poses some supernatural and mystical effects that might cause Victor to create his monster. It foreshadows that Victor would isolate himself from his family in order to modernize the science world. The isolation of Victor proves that his is monstrous. Victor gets hints from the Romantic Era similarly to Macbeth getting hints from Lady Macbeth and the witches. The monster has also influence Victor to becoming more atrocious throughout the back and forth affair with the two. The conflict between Victor and the monster starts to take its course. Victor promises the monster to make him a female companion so that the monster would not feel lonely. Conversely, Victor destroys the monster, thinking that it would take over and corrupt the world. This causes the monster to be angry. Additionally, he tells Victor that he will be there on his wedding night. Victor becomes paranoid to the point where he starts bringing out weapons. â€Å"In the meantime I took every precaution to defend my person in case the fiend should openly attack me. I carried pistols and a dagger constantly about me and was ever on the watch to prevent artifice, and by these means ained a greater degree of tranquility† (Shelley 182). Victor’s one mistake of abandoning the monster at birth has cause the monster to seek revenge by killing William and Justine. Victor sees this and accepts the monster’s request of creating a female companion, but later destroys it. This triggers the creature to strike back at Victor on his wedding night. At his wedding night, he carries around weapons in case the monster shows up. Victor becomes paranoid ever since the monster utters that he will be there on Victor’s wedding night. However at the same time, Victor is scaring Elizabeth with all his weapons. In Elizabeth’s eyes, Victor seems more evil. Victor is being more horrific to Elizabeth even though he is protecting her. Plus, she does not even know that the monster coming; Victor hides this information it from her. This shows that Victor is worried more about the monster (self-protection) than Elizabeth, which makes him monstrous. Thus, Victor displays monstrosity, as he becomes influence by the Romantic Era and the monster. Macbeth and Lady Macbeth both illustrate their monstrous personality, which leads to some key outcomes during their ruling as king and queen. According to the witches, Macbeth gets paranoid that either Banquo or his son Fleance might become the next king. So he calls out three murderers to kill them. He does not have this drive before, but once he is king, he wants to remain king and is willing to do anything. Moreover, he calls murderers to kill the family of Macduff since he poses as a threat to him. â€Å"I have no words, my voice is in my sword, thou bloodier villain than terms can give out to thee† (Shakespeare 5. 8. 6-8). This shows that Macbeth’s immoral actions done on the family of Macduff have made him angry. Macbeth causes his angriness due to what transpired. Macduff calls Macbeth a villain because he is the one who kills Lady Macduff as well as his son. From the looks of it, Macduff really want to get his hands on Macbeth and kill him. Macduff has the quest for revenge and is eager to go the distance. In the end, the outcome is that Macbeth’s actions has cause him to die in the hands of Macduff because of his monstrous traits. Lady Macbeth also dies as a result from her own monstrous actions. Before she commits suicide, she realizes that it is her fault that Banquo died. She is the one who built Macbeth into more of a devilish being, thus making herself monstrous. Wash your hands, put on your night-gown, look not so pale. I tell you yet again, Banquo’s buried; he cannot come out on’s grave† (Shakespeare 5. 1. 54-56). This shows that Lady Macbeth has guilt for what she has done throughout the play. Lady Macbeth just like Victor creates her own monster in Macbeth and now, she suffers the consequences. She cannot even wash away her sins. She feels that it is her fault that Banquo dies. Furthermore, she commits suicide as a result because she can no longer handle he guilt. Lady Macbeth immoral actions have become a weight of guilt on her to the point where she commits suicide. Hence, the deaths of Macbeth and Lady Macbeth were as an outcome of their monstrous actions done toward Scotland. Likewise, the conflict between Victor and the monster causes them to be horrific and as a result of their actions, both died which is similar to Macbeth and Lady Macbeth. Ever since Victor abandons the monster at his house, the monster always wants to seek revenge against Victor. He even kills all of Victor’s family members. He soon realizes that killing all those innocent people was not the right thing to do. â€Å"That is also my Victim! He exclaimed. In his murder my crimes are consummated; the miserable series of my being is wound to its close! Oh Frankenstein! Generous and self-devoted being† (Shelley 209). The monster now has guilt in him. He believes that his monstrous traits would be the main force towards the death of Victor. The monster put Victor through so much as he tries to reach the North Pole. He calls Victor his own victim even though he never really kills him. The monster realizes his corruptive mistakes, but it is too late. This also foreshadows the death of the monster. Like Lady Macbeth, the monster has a weight of guilt on his shoulders. He dies so that he could avoid that guilt. Also, because of Victor killing the female companion of the monster, it sparks the monster so much to the point where he uses monstrous traits to kill Victor’s female companion, the harmless Elizabeth. â€Å"Great God! Why did I not then expire! Why am I here to relate the destruction of the best hope and the purest creature on earth? She was there, lifeless and inanimate, thrown across the bed, her head hanging down and her pale and distorted features half covering by her hair† (Shelly 186). Here, this displays that the monster uses his scandalous individualities to kill Elizabeth. This is comparable to Macbeth as he kills the members of the Macduff family. This is probably because Victor himself demonstrates some monstrosity by killing the monster’s female companion. In a way, it was Victor’s own satanic actions that cause the monster to kill Elizabeth. Also, Victor shows his monstrous traits as he objectifies Elizabeth. Elizabeth is been treated as an object according to Victor. Elizabeth had been objectified her whole existence by Victor. Thus, the monster and Victor proves they have monstrosity and as a result, Victor, Elizabeth, the monster and others die. Therefore, ambition, influential actions, and outcomes are three aspects of the main characters that display monstrosity in Shakespeare’s Macbeth and Shelley’s Frankenstein. Macbeth and Lady Macbeth have the ambition to become king and queen, but they use monstrous actions like killing Duncan in order to get these positions. In comparison, both Victor and the monster uses monstrosity to achieve their goals on gaining knowledge. Furthermore, temptresses like Lady Macbeth and the three witches have influence Macbeth to be king by using scandalous characteristics of their own. Both the monster and the Romantic Era itself has cause Victor to further pursue his goal of gaining knowledge but in the process, he portrays monstrosity. Macbeth’s and Lady Macbeth’s shameful characteristics has also resulted in the deaths of countless others including themselves. The lurid conflict between Victor and the monster has also cause their deaths, as well as the deaths of the other members in the Frankenstein family. Thus, the monstrosity is recognized in both Shakespeare’s Macbeth and Shelley’s Frankenstein throughout the main protagonists and antagonists.

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Affirmative Action Essay Example for Free

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President Barack Obama, in a speech at Osawatomie Kansas in 2011, told his audience that, â€Å"this kind of inequality—a level that we haven’t seen since the Great Depression—hurts us all†, the inequality that strikes him most is in the distribution of income, the provision of basic resources that will spur the economy back on track. Though it is true, as observed by Kamalu and Kamalu (2004), that the ultimate goal of the Civil Rights movement and the struggle for equal opportunity is to see an African American emerge as President, the implementation of affirmative action goes beyond the interest of the President. Pauwels (2011) observes that since an African American has been elected President, the future of affirmative action is uncertain and the discussion has been removed from the public domain. Pauwels observation may be true to an extent, though the election of Barack Obama has bridged the racial gap, class distinction remains an issue for discourse. President Obama’s struggle for the restoration of the middle class is proactive, and suggests that he is conscious of the inequality in the society from the class structure than in the racial perspective, this concurs with Bill Clinton’s remarks as stated in his speech to Congress. However, in the light of the observations in Pauwel and Kathlenberg, also in the views of the proponents of affirmative action, the election of Barack Obama as President has removed the discussion from the public domain, but he has followed the discussion in the perspective that is most expedient and conforms with his economic policies. The economic emancipation of minority groups should be the driving force of any legislation or government policy initiative aimed at providing equal opportunity in the society. When middle-class families can no longer afford to buy the goods and services that businesses are selling, when people are slipping out of the middle class, it drags down the entire economy from top to bottom. As Barack Obama emerged President of the United States, protagonists of civil rights and equal opportunity would have thought that he will be the champion of affirmative action, being of the minority stock himself. Nevertheless, he has redirected the discussion to suit the burning issue of the time – the economy and distribution of income. Surprisingly, Barack Obama has not elevated the discussion of affirmative to the height and enthusiasm it was taken to by Bill Clinton, who in his speech to congress was emphatic as to the way forward stating â€Å"today I am directing all our agencies to comply with the Supreme Court’s Adarand decision, and also to apply the four standards of fairness to all our affirmative action programs that I have already articulated: no quotas in theory or practice, no illegal discrimination of any kind, including reverse discrimination; no preference for people who are not qualified for any job or other opportunity ; and as soon as a program has succeeded, it must be retired. Any program that doesn’t meet these four principles must be eliminated or reformed to meet them† (Clinton 1995). Some scholars have posited that a major step in guaranteeing affirmative action is by winning the political war as well, by electing friends of affirmative action to the presidency, state courts, and top judicial positions and the election of judges who are â€Å"judicial activists† to the bench to continue to uphold the constitution to meet the needs of contemporary American society (Kamalu Kamalu 2004). This position may not always hold sway as we can see from the present circumstances that even those perceived to be friends of affirmative action may not be seen to further the cause so generously. Meanwhile, the emergence of an affluent black middle class also made affirmative action claims seem increasingly suspicious, climaxing with President Barack Obama’s election, dubbed by some the ‘death knell’ of affirmative action (Maglio cca 2008). African Americans are now gradually coming to terms that the wings of racial discrimination have been broken, and to a large extent turned to the annals of history with the election of Barack Obama as President. If the racial content of equal opportunity is undermined, as can be seen in the decisions of courts, then it is obvious that what is left in the legislation will not be for the benefit of minorities only, but for the underprivileged class in the society. Who else would have been more silent on the issue of affirmative action if not someone perceived to be a beneficiary? To many Americans, affirmative action has now become irrelevant, a concept only debated in narrow academic circles that cling to the outdated idea of institutionalized racism (Young 2009). Apparently, affirmative action programs have been reformulated to avoid polarization, they don’t focus overtly on race and ethnicity, they cast the net wide so as to seem all-inclusive and they are backed up by strong court cases and judicial decisions in favor of reverse discrimination, and strong opposition for racial preferences. Opponents of affirmative action have often advanced the views that the fundamental principles of capitalism and the market economy do not provide for absolute equality, it would be utopian for anyone to wish that there will be equality in the distribution of resources. Nevertheless, the struggle for equality that is rooted in the civil rights movement was informed by outright racism and economic deprivation designed through policies of government that were inherently exclusive at the time. It is this struggle for equality that is manifest in the consciousness of the people especially for African Americans to see the election of Barack Obama as a relief for this long struggle for racial equality and economic emancipation. The struggle for racial equality ultimately goes with so many expectations, which practically includes getting one from the minority stock into highest position of governmental decision making. The election of Barack Obama obviously came, civil rights activists had to heave a sigh of relief and it became a turning point. It has turned out good, everyone has rested his case and the expectation is now focused on the results of the performance of the President in this regard. Immediately after the general election, in November 2008, a New York Times/CBS poll found that the proportion of people who believe blacks ‘‘have an equal chance of getting ahead’’ had risen to 64 per cent, up from 46 per cent in 1997 (Pauwels 2011). Clegg (2008), in his study was very critical of race based affirmative action, he argued that pursuing the cause of affirmative action will undermine the fundamental principles of free enterprise and the spirit of hard work that accompanies economic independence. He went further to state that â€Å"the American Dream has always been that any American can work toward the life he or she wants, and will have the opportunity and the freedom to achieve and accomplish what he or she wants in life. There will be hurdles to overcome, but one barrier that should not be there is the color of an Americans skin or where an Americans ancestors came from† (Clegg 2008, 991), we all know that for many years—for centuries—that dream was not allowed to many Americans. Too often discrimination because of race or ethnicity denied Americans the equality of opportunity they should have had. President Bill Clinton in 1995 restated the fundamental principles of affirmative action that â€Å"the purpose is to give our nation a way to finally address the systemic exclusion of individuals of talent on the basis of their gender or race from opportunities to develop, perform, achieve and contribute†. Affirmative action is an effort to develop a systematic approach to open the doors of education, employment and business development opportunities to qualified individuals who happen to be members of groups that have experienced longstanding and persistent discrimination. Nevertheless, the Obama administration has recognized equality from the perspective of the distribution of resources not opportunities. Like he said in Kansas, â€Å"America was built on the idea of broad-based prosperity, of strong consumers all across the country. That’s why a CEO like Henry Ford made it his mission to pay his workers enough so that they could buy the cars he made. It’s also why a recent study showed that countries with less inequality tend to have stronger and steadier economic growth over the long run. Inequality also distorts our democracy. It gives an outsized voice to the few who can afford high-priced lobbyists and unlimited campaign contributions, and it runs the risk of selling out our democracy to the highest bidder. It leaves everyone else rightly suspicious that the system in Washington is rigged against them that our elected representatives aren’t looking out for the interests of most Americans†, this is vintage Barack Obama substantiating an argument for the sustenance of the middle class in America, knowing full well that empowering the middle class will drive the economy through increased consumption and productivity and ultimately economic growth. What is most intriguing about the arguments of affirmative action is that there is a shift of the premise due to several reasons: affirmative action was supposedly temporary and targeted at the black community only; in fact, these measures were extended over the years to an increasing number of new categories; w omen (who are today acknowledged as being their prime beneficiaries), then most other ethnic minority groups, including new immigrants (Pauwels 2011). Its primary rationale became blurred in 1978 when the Bakke decision shifted the goal of affirmative action from repairing past injustices against the black community to the much more ambitious and less clearly defined justification of achieving diversity (Frymer and Skrentny, 2004). Even President Bill Clinton realized this shift in his 1995 speech to congress when he said â€Å"that affirmative action has not always been perfect, and affirmative action should not go on forever. It should be changed now to take care of those things that are wrong, and it should be retired when its job is done. I am resolved that that day will come, but the evidence suggests indeed that that day has not come†. However, that day finally came with the election of an African American as the President of United States, whose drive is no longer affirmative action but equality in income distribution and the provision of basic opportunities for the benefit of all and sundry especially creating a formidable middle class that will cut across all races and ethnic origins. Cited Works Clegg, Roger 2008, â€Å"Unfinished Business: The Bush Administration and Racial Preferences† Harvard Journal of Law, Public Policy, 32, 971 – 997. Clinton, Bill 1995, â€Å"Remarks by the President on Affirmative Action†, Essential Speeches 2009. Academic Search Premier. Frymer, P. and Skrentny, J.D., 2004, â€Å"The rise of instrumental affirmative action: law and the new significance of race in America† Connecticut law review, 36 (3), 677_723. Kahlenberg, Richard 1995, â€Å"Class Not – Race: An Affirmative Action that works†, The New Republic April 3, 1995. P. 21 Kamalu, Johnson and Ngozi Kamalu 2004, â€Å"From Bakke to Grutter: The Supreme Court and the Struggle over Affirmative Action in the Era of Globalization† The Western Journal of Black Studies, 28:4, 489-502. Magliocca, G.N., 2008. The Obama realignment (and what comes next). Working Paper [online], December 2. Available from: http://ssrn.com/abstract_1310202 Obama, Barack 2011, â€Å"The New Nationalism: On the whole and in the long run we shall go up or down together† President of the United States: Speech delivered at Osawatome High School, Osawatome, Kansas December 6, Pauwels, Marie – Christine 2011, â€Å"Does Affirmative Action have a Future in Barack Obama’s America?† Journal of Intercultural Studies, 32:3, 309-319 Young, C., 2009. â€Å"Obama: Race and Affirmative Action†. Real clear politics [online], 27 January. http://www.realclearpolitics.com/printpage/?url_http://www.realclearpolitics. com/articles/2009/01/dnp_obama_race_and_affirmative.html

High Throughput Screening (HTS) Assays: Uses and Formats

High Throughput Screening (HTS) Assays: Uses and Formats The increasing demands placed upon the pharmaceutical industry to produce a rapid turnaround of new drugs is a driving factor in the automation of the processes at the initial screening stage of drug discovery. This has lead to the development of numerous high throughput screening (HTS) assays, with the increasing miniaturization of the whole process (1). An explosion in genomic and proteomic studies in recent decades has lead to the generation of large numbers of functional protein molecules. The physiological function of these proteins has yet to be elucidated, but many could be important future drug targets, such as receptors or enzymes involved in disease pathogenesis (2). These ‘orphan receptors’ can be studied by high throughput screens of small molecules, which may be potential ligands. These chemicals can be sourced from existing drugs, pharmaceutical company chemical compound libraries or from natural products, such as plants or animals (figure 1; 3). Chemical l ibraries are now vast, since the advent of combinatorial chemistry, which produces novel compounds by high throughput methods. These mixtures can then be assessed for biological activity against a specific target molecule (most commonly a protein), either as a mixed chemical pool, or in parallel. A positive/active interaction, or ‘hit’, can then be further explored. Numerous assay detection formats that are suitable for automation have been developed to detect such receptor – ligand and enzyme – substrate interactions, to allow the potential drug molecule to be further explored. Each assay has advantages and problems and the most commonly applied techniques are discussed in this review. As research progresses these processes become modified to overcome problems created by the progressive automation and miniaturization of the assays. Use of computation to analyse the interactions and extract more information from them is also increasing (4). Recent advances in the literature suggest that future development of HTS is likely to result in ultra-HTS assay formats, which may be within closed systems such as glass capillaries, or on silicon wafer chips. References Fonseca MH List B (2004) Curr Opin Chem Biol, 8, 319-326. Gilchrist A (2004) Expert Opin Ther Targets, 8, 495-8. Bleicher KH, Bohm HJ, Muller K, Alanine AI (2003) Nat Rev Drug Disc 2, 369-378. Kato R, Nakano H, Konishi H, Kato K, Koga Y et al. (2005) J Mol Biol, 351, 683-92. Techniques in molecular biology, chemistry and their associated branches are advancing at a rapid rate. This has enabled the mechanisms underlying many diseases to be explored at the molecular level. The ever-increasing sophistication of proteomic and genomic research procedures are producing an explosion in the number of possible drug targets. Until the development of high throughput screening (HTS) assays, the time taken to evaluate the potential bioactivity and usefulness of compounds to act on target molecules and become drugs to act to ameliorate symptoms or even cure or prevent a disease from occurring, was a rate-limiting factor. Since the automation of a number of suitable assays for HTS the trend has led to the number of compounds available for testing against targets becoming the limiting factor. This has spurned the growth of combinatorial chemistry, to such an extent that many consider it to be a branch of chemistry in itself. HTS can be defined as an automated method of conducting a large number of in vitro assays on a small scale (Patrick 2005). Most commonly, 96-well plates of 0.1ml are used for a number of bioassays to detect the biological activity of compounds which have the potential to be developed as drugs. These may interact with the target, as a ligand-receptor interaction, or may involve inhibition of an enzyme or interaction with a nucleic acid macromolecule. The reaction produces a detectable output change, which can be detected and/or measured. Thousands of chemicals can easily and quickly be screened this way, and only active compounds taken to the next stage of testing to find out if it has the potential to become marketed as a drug. There is increasing pressure on drug companies to produce new drugs to keep pace with developments in medical research, as well as an increasingly demanding public and share holders. HTS technology is a crucial to meeting these demands, and continues to be dev eloped to produce faster, cheaper and more efficient ways of screening compounds during the initial stages of the drug discovery process. ROLE OF HIGH THROUGHPUT SCREENING IN DRUG SCREENING Molecular biology techniques are allowing us to understand more about the mechanisms of disease, thus providing biomacromolecular targets for potential drugs to interact with. Such targets include receptors, enzymes and nucleic acids and may require inhibition (enzymes) or agonistic/antagonist receptor ligand binding to produce the desired pharmaceutical effect. In addition, studies using proteomic and genomic techniques are revealing more and more ‘orphan receptors’; these are proteins (predominately), lipids and nucleic acids (and to some extent carbohydrates) that are now known to be produced by the body, but their messenger and function is unknown. Using these as targets against which to screen compounds will help to elucidate their function, and more importantly, may turn out to be drug target interaction sites which will be beneficial in disease. As the function of these targets is unknown, there are no lead compounds that could be used as a starting point for exploration, so HTS is particularly beneficial for screening vast numbers of compounds in the hope that at least one will interact with the mystery target. The number of potential drugs to be screened is vast; pharmaceutical companies have libraries of 0.5-2 million synthetic compounds (King 2002) that have not made it through screening to become marketed drugs. There are also commercially available libraries of compounds, such as the Chemical Abstract Service (CAS) registry file, which contains 39 million compound (Abraham 2003). Intermediates in synthetic processes to make another drug should also be screened, as they may have the desired pharmaceutical properties. Isoniazid is an intermediate and has now been developed into an effective anti-tuberculosis drug. Existing drugs are also worth screening, as their biological activity may stretch beyond that for which they are intended. For example, cyclosporin A was isolated from soil and had been intended for use as an antibiotic, until its immune-suppressive properties were observed and for which it is now sold. The body’s own endogenous chemical messengers, such as morphine, whi ch has similar activity to released endorphins, could also be screened as they may provide a lead compound that can be modified to enhance activity. Combinatorial synthetic processes can also be used to generate vast numbers of novel compounds, which is crucial to prevent the availability of new compounds being a limiting factor in drug development, as HTS is able to screen them so quickly (Carell et al. 1995). It is common for combinatorial synthesis to produce mixtures of compounds, which can be tested as a chemical pool or batch by HTS for biological activity against a specific target macromolecule. This means that thousands of compounds can be screened in a very short time and only pools containing biologically active constituents screened further. This usually involves deconvolution processes (such as micromanipulation, recursive deconvolution or sequential release from resin beads used for the synthetic process) to identify exactly which component(s) of the pool is/are active, so that they can be isolated and screened further for drug potential (Wilson-Lingardo et al. 1996). It is now being superseded by production of new c ompounds in parallel, with a single component in each well. Potential drug molecules can also be derived from natural sources, such as plant extracts, but these are less abundant as isolation and purification take time. They are often novel, complex molecules and can produce unexpected interactions. An example is artemisinin, an effective antimalarial drug developed from extracts from a Chinese plant; it has a highly unstable trioxane ring (Ploypradith 2004). There are so many compounds to be tested against a large range of potential drug targets that high throughput methods are essential to test the numerable combinations of drug and target interaction to find those that are biologically compatible. HIGH THROUGHPUT SCREENING ASSAYS In theory any assay that can be performed on the laboratory bench could be automated and scaled up to be used for HTS. In practice, however, some assays are intrinsically more suitable than others. High throughput screens require the automation of the entire process. This is best achieved if there are as few steps as possible in the assay; ideally the test should be able to be performed in a single well, with addition of the test sample the last key step. Obviously, it is important that the reaction between a target and biologically active compound must be readily detectable. It should ideally be detectable with high sensitivity while the products are still mixed together in the well, rather than needing further steps to separate or purify components of the reaction mixture. This can be difficult to achieve with automation and will increase the time taken per test, so becoming less efficient and cost effective. Assays used for chemical screening can be cell-free or cell-based (Silverman et al. 1998). Cell-free assays use solutions of relatively pure protein targets, such as receptors or enzyme substrates, which minimizes the number of steps required. It also allows for easy detection of biological activity in the wells of reaction mixture. Cell-based assays have the advantage that they are a closer representation of the normal physiology of the chemical environment inside a cell. Receptor-ligand interactions and enzyme inhibition reactions are more likely to be indicative of what will happen in vivo (Silverman et al. 1998), especially if ligand-gated ion channels are involved. Cell assays also allow specific processes to be studied and the output can be measured. Indirect effects of small molecule/protein binding which trigger secondary messenger systems, such as calcium ions or cAMP, can also be observed in their biological context. Cells can be manipulated to express target molecules on t he surface, so that they are available to bind to novel ligands, which may be tagged for detection. Cell assays can also provide additional information about cytotoxicity and bioavailability of a potential drug. Mammalian cells are expensive and can be difficult to culture in automated HT systems, but yeasts can provide a suitable alternative. Microorganisms such as yeasts are easy to propagate and have been demonstrated to have some homologous chemical processes, or can be easily genetically modified to express human processes accurately (Klein Geary 1997). HTS ASSAYS AND DETECTION FORMATS Fluorescence Fluorescence occurs when a fluorophore molecule absorbs a high-energy photon (often in the ultraviolet range) and emits a lower energy photon, which is typically in the visible range of the spectrum. There are many naturally occurring substances which have this intrinsic property, such as luciferin in fire-flies. There are a number of fluorescence – based assays available for use in HTS, to detect whether an interaction has occurred between target and potential drug molecule during random screening. Fluorescence assays are generally sensitive, versatile, stable, safe and easy to perform, which gives them a great advantage in automated systems for HTS. They have the disadvantage that quenchers can be present in the sample which dampen the light emission. There may also be background autofluorescence from free reagents in the reaction mixture (Grepin Pernelle 2000). Many of the assays have developed protocols that take these problems into account. Energy transfer formats: Homogeneous time resolved fluorescence (HTRF) uses the ion of the rare earth metal lanthamide (Eu3+ ), bound to crypate as a donor molecule. Following laser excitation (at a wavelength of 337nm), energy is transferred from this complex to an allophyocyanin (APC) acceptor molecule. This results in emission of light of 665nm, over a long period (milliseconds), which is recorded in a time resolved fashion so that any background fluorescence from free APC or media is not recorded. Peak emission of light occurs at 620nm for unbound Eu-cryptate, so the ratio of 620:665nm emissions can be used to quantify biological complexes in solution (see Figure 1). This technique can be widely applied to screening programs and has already been developed into a 1,536 well plate HTS, with plans to expand this to become ultra HTS (uHTS) and for use in cell-based assays. Figure 1: HRTF schematic explanation (from: Grepin Pernelle 2000) Fluorescence resonance energy transfer (FRET) is a slightly different form of detection, using the principle that excitation energy can be transferred between two fluorophore molecules. These can be different types of green fluorescent protein (GFP) or other bioluminescent molecules, such as luciferase (Hu et al. 2005). from: Becker et al. 2004 Fluorescence polarization (FP) FP can be used as the basis for homogeneous HTS assays for enzymatic and ligand-receptor binding interactions. The principle behind this detection assay is that when polarized light hits a small molecule that is binding to a larger (target) molecule, there will be rotational diffusion of the light beam. This change induced by binding can be detected by measuring the light emitted in orthogonal and normal planes of the polarized light. There is no interference from absorptive compounds in complex mixtures, as can occur with other fluorescence based techniques, and FP is quick and easy. Because of this it is used widely in high-throughput screening systems. Kim and colleagues (2004) developed a FP assay for the molecular chaperone Hsp90 (heat-shock protein), which is believed to have a role in cancer. They validated the assay for a high throughput format using molecules known to bind Hsp90, such as geldanamycin. The assay can now be used to screen for novel inhibitors of Hsp90, which m ay lead to a cancer drug being developed. Stricher and others (2005) have developed a high throughput FP assay for the CD4 binding site of HIV-1 glcoproteins, such as gp120, which are crucial targets to protect against HIV infection. Their assay used a 384-well plate and CD4M33, a mimic of host cell receptor antigen CD4, found on T helper lymphocytes. Some studies indicate that FP assay technology can also be developed as part of a HT structure-activity (SAR) study. Newman Josiah (2004) showed that FP is sufficiently sensitive to differentiate between high-affinity small molecule inhibitors interacting with the target and low-affinity ones, with Src kinase activity as a model. FP can also be used in cell-based assays, in conjunction with confocal microscopy (Heilker et al. 2005), as it shows high sensitivity even at minute volumes of reaction mixture, down to femtolitres. This type of assay can be described as fluorescence intensity distribution anaylsis (FIDA) and measures the absolute concentration of both bound and unbound ligand, thus providing the data with its own internal control. FIDA has been used to explore ligands which bind to G-protein coupled receptors (GPCR), which are widespread throughout the body and involved in signal transduction for numerous cell processes. They are therefore important therapeutic pharmaceutical targets, and can be studied in association with membrane fragments from cells over-expressing GPCR or associated with virus-like particles. Fluorescence correlation spectroscopy (FCS) FCS uses a two-photon excitation to measure the relative fluorescence of different molecules within a homogeneous mixture, from which the amount of each can be calculated. The technique can be applied to measure the relative amounts of ligand bound versus unbound receptor molecules, or cleaved versus intact enzyme substrates. FCS can be conducted using minute reaction volumes, less than 1 femtolitre (fl) is adequate for this sensitive, fast assay, which can study interactions of single molecules (Sterrer Henco 1997). FCS can also be used to study ligand-receptor interactions in live cells (Pramanik 2004), which allows reactions to be assessed, and to some extent the properties of the interaction quantified, in their biological context. The use of such live cell assays in a high throughput format will provide a wealth of information not observable in chemical solutions alone. Many applications of FCS are conducted in conjunction with confocal microscopy, which allows interaction kinetics to be examined on a molecular level, by the changes in diffusion patterns of the excitation. Confocal microscopy uses a high numerical aperture lens to focus the laser, to provide excitation and produces minimal background excitation, which allows such minute quantities to be studied. It can be used to detect spatial and temporal interactions in live cells, increasing the amount of information that can be obtained and used for drug development (such as interactions with other cell components or pH effects within the cell; Zemanova et al. 2003) The dual-colour cross- correlation spectroscopy method of FCS uses two different, spectrally separated, fluorophore molecules, which are attached to each of, for example, a receptor and possible ligand, or potential substrate to be cleaved. The two colours will be observed to fluoresce together if an interaction occurs, or separately if a substrate has been cleaved and the kinetics of this can then be assessed (Kettling et al. 1998). This can be demonstrated using, a DNA strand that has a red fluorophore molecule attached to one and and a green one to the opposing end. The strand is cleaved by restriction endonuclease enzyme ecoRI, which is detected by spectroscopy as a decrease in the quantity of DNA molecules with fluorescence at both ends. The method was shown to be suitable for this type of enzyme kinetics study, by accurate detection of catalytic activity down to an enzyme concentration of 1 pM (pico molar) and proper description of the reaction by the Michaelis-Menten equation. This method, dual-colour FCCS, therefore has great potential for HTS of enzyme and ligand binding reactions. Biomolecular fluorescence/reporters There are numerous molecules produced by plants and animals naturally that produce fluorescence, or what is sometimes called bioluminescence. Some of these have been adopted as research tools, such as green fluorescent protein (GFP), which produces green light at 509nm following excitation by blue light (Arun et al. 2005). The gene that encodes for this fluorescent protein has been elucidated and is now commonly inserted into the genomes of genetically modified microrganisms and cell lines. It is then expressed under the control of desired promoters, often as a fusion protein. In this way patterns of gene expression can be observed and changes in transcription detected. HTS for new drugs use this technology to detect changes in transcription that occur via secondary messenger systems following receptor-ligand binding in a live cell. For example, Changsen and others have validated a GPF microplate assay, using an acetamidase promoter associated with the gfp gene, to screen for antitub erculosis drugs (2003), and found it to be suitable for HTS for novel drugs. GFP reporter technology requires a detection system and most of those described for detecting fluorescence from synthetic fluorophores can also be applied, such as FRET (Zhang 2004), FCS and confocal microscopy. FITC (fluorescein – 5- isothiocyanate) FITC can be bound to other molecules as a marker and the fluorescence measured robotically in HTS systems. For example, FITC bound to heparin sulphate (HS) has been used to screen for heparanase inhibitors in a HT assay: 384-well microtitre plates are used, which are coated with fibroblast growth factor (FGF). This captures the FITC-HS, and labelled fragments are only released into the media when cleavage by heparanase has occurred. This is quantitatively measured by robotic detection of the amount of fluorescence in solution. Heparanase is believed to have roles in inflammation, tumour angiogenesis and metastasis, so is an important drug target in the treatment of cancer (Huang et al. 2004). Chemiluminescence Some assays using chemiluminescence have been adapted to use HT formats. These rely on chemical reactions to produce light emission as a side-product, which can be detected. One such HTS uses coupled reactions involving the enzymes acetylcholinesterase, choline oxidase and horse-radish peroxidase, in 96 and 384-well plate formats, to screen for novel acetylcholinesterase inhibitors to become new drugs to treat Alzheimer’s Disease (Andreani et al. 2005). Scintillation proximity assay (SPA) Scintillation proximity assays are used for quantitatively studying binding reactions. The receptor/target is bound to a surface such as a plastic bead. The ligand is labelled with radioactive isotype (typically H3 or I125 ) and emit electrons with a short range of about 10um. A scintillation counter under the surface to which the target is bound detects the ligand only when it is bound. When it is free in solution the media absorbs the electrons and they are not counted. This allows binding interactions to be quantified whilst at equilibrium. Zheng and others (2004) have used SPA as part of a HTS and have identified several novel inositol monophosphatase inhibitors, which may be developed as drugs fro bipolar disorder. Mass spectrometry Mass spectrometry is currently a popular option for HTS, as it is sensitive, selective and easily automated. It allows the activity, molecular weight (most drug-like molecules are 150-400 Da), elemental composition and structural features of a test compound to be analysed. This wealth of information is of great use for exploring the molecular interactions between target and potential drug compounds. A very high throughput can be achieved using flow injection analysis, which does not require any sample preparation. Solutions of the samples are sprayed, using electrospray or APCI (atmospheric pressure chemical ionization), which ionises the molecules in the sample, prior to analysis by the mass spectrometer. Sometimes tandem mass spectrometers are employed, to glean more structural information and elemental composition. The advantage of these techniques are that as well as being very high precision they can be conducted on the original sample, without the need the separate the compound out from a mixture. For LC-MS (liquid chromatography mass spectrometry), semipreparative HPLC (High Peformance Liquid Chromatography) is often used before the HTS to verify the structure and purity of each compound to be tested, especially those from a combinatorial library. Improving purity in this way facilitates more accurate observation of any biological interactions that occur between the target and the test compound, as well as easing interpretation of structural information about the test molecule or changes induced by the interaction (Abraham 2003). HPLC is easily automated and involves detection of a UV signal above a threshold level, which triggers collection of the fraction. Several fractions may be obtained from one sample, or the computers controlling sample collection can be programmed to detect only at peaks of desired molecular ions, following ionisation by a suitable technique, such as electrospray or MALDI (matrix-associated laser desorption/ionisation), which can be used as a gentle way of ionising more fragile molecules (Hillenkamp et al. 1991). LC-MS can be slower than other approaches but is sometimes necessary. Further developments to speed up the automated process include parallel LC-MS, in which multiple HPLC columns are interfaced to a single mass spectrometer (Kenseth Coldiron 2004), and fast HPLC. NMR NMR is a useful technique for exploring the 3-dimensional structure of biomacromolecules, in a concentrated solution. It is limited by the small size of molecule amenable to this technique; typically below 30kDa, so is more useful for small drug-like molecules than the molecular target they interact with. Structure-activity relationships (SAR) can be studied by observing alterations in a protein’s NMR spectrum. This not only indicates that ligand binding has occurred, but can give an indication of the location of the binding site (Shuker et al. 1996). X-ray crystallography X-ray crystallography enables the 3-dimensional structure of protein molecules to be studied, with resolution to the atomic level. The technique requires the molecule to be studied in its crystalline form, which is not a problem for the majority of biomacromolecules that are drug targets. Protein crystallization technology has also had to adapt to high throughput methods, so as not to become a bottleneck. Some fully automated systems can now produce as many as 2,500 to 140,000 crystallization experiments a day (Kuhn et al. 2002). Studying the 3-D structure of the target often produces clues to the type of ligand that will bind, which speeds up the time taken to find lead compounds in drug discovery. An example of this is the development of antiretroviral drugs used to treat AIDS (acquired immunodeficiency syndrome), such as amprenavir (‘Agenerase’), which followed from the study of the structure of the drug target, HIV (human immunodeficiency virus) viral protease. Another drug developed from such structure based studies is zanamivir (‘Relenza’); a flu treatment based on the crystal structure of the surface glycoprotein, neuraminidase, which is crucial for viral infectivity (Varghese 1998). This is likely to be an important weapon in the fight against an influenza pandemic. In X-ray crystallography, the macromolecular 3-D crystal is bombarded with X-rays, by a rotating-anode X-ray generator or a synchrotron, and the diffraction pattern produced is detected. Multiple measurements of diffracted waves generate much data, which can be analysed using calculations, such as Fourier synthesis and a structure revealed (Blundell et al. 2002). Advances in the structure determination process have aided the resolution of structures, for example, multiple-wavelength anomalous dispersion (MAD), in which selenomethionine is incorporated into proteins that are overexpressed by genetically modified micro-organisms, which simulates isomorphous replacement and allows the phases to be calculated (Hendrickson et al. 1990). Low-affinity binding reactions between ligand and target may have important properties and provide leads that would be missed by other HTS methods. Development of high throughput X-ray crystallography, by increased automation at all stages of the procedure, has lead to its growing use in lead discovery as well as its more traditional role in lead optimisation (Abola et al. 2000). This enables the technique to screen compound libraries, including those from combinatorial synthesis. Crystallographic screening for novel ligands in this way has already had some success; for example, a new class of urokinase inhibitors have been discovered, for treating cancer (Nienaber et al. 2000). Co-crystallization of receptor-ligand complexes allows the interaction between the molecules to be studied and conformational changes in the target, upon binding, to be discovered. This approach is known to be used by several industrial laboratories and has the capacity to compare the interactions of ‘hit’ ligands in the generation of a lead series. It also decreases the time taken to explore hits, which is a crucial factor for the pharmaceutical industry (Abraham 2003). Another way of achieving crystallized receptor-ligand interactions is to soak the ligand, often as molecular fragments dissolved in DMSO (dimethyl sulphoxide), into the receptor protein crystal (Nienaber et al. 2000), and observe changes in electron densities indicative of interaction. Structure based drug design in silico Three-dimensional structures can also be used in computer modelling programs to predict which ligands might bond/interact with targets or receptors, as an initial stage of drug design. This is truly a high throughput method as computing power allows the rate at which ligand-receptor interactions can be virtually screened to be incomparable to even the fastest high throughput methods involving physical experimentation. This is often termed virtual ligand screening (VLS), or in silico screening (Klebe 2000). Perrakis and his colleagues (1999) combined automated protein model building with iterative structure refinement, using ARP (automatic pattern recognition), which has been crucial for structure based drug design (SBDD). Diffraction data is fed directly into the computer program and a protein crystallization model produced automatically. Various programs have been developed to assess docking of virtual ligands into known target receptor sites and scoring of their suitability and fit, determined by energy. Some algorithms seem to have some bias towards certain chemical families; this can be reduced by using multiple docking algorithms simultaneously (Charifson et al. 1999). Software programmers and chemical modellers must remember to take into account the natural properties of protein molecules, as they are more flexible and accommodating of small changes than the rigidity suggested by traditional computer programs, although some programs now attempt to recreate this (Schapira et al 2000). Optimal results for structure based drug design are likely to be achieved by combining virtual and experimental methods, such as ‘SAR-NMR’ technology advocated by Shuker, Fesik and colleagues (1996). Microarrays DNA microarrays have been constructed following the sequencing of the human genome, using cDNA to study thousands of genes. From this has stemmed the growth of proteomics and protein biochips, as these are the functional molecules encoded by the genome. Protein arrays/biochips consist of immobilized proteins, which can be used, in the drug development context, to study ligand-receptor interactions (Lueking et al. 2005). Interactions of known pharmaceutical chemicals with proteins can also be explored. For example, Leflunomide (an isoxazole derivative) has been shown to have anti-inflammatory properties in vivo. Analysis of protein interactions using an array revealed that it was not only interacting with the suspected mitochondrial enzyme, but a number of other proteins in the cell, such as pyruvate kinase (Mangold et al. 1999). As the majority of drug targets are proteins, and many of the drugs themselves proteins too, protein arrays are likely to become more popular, as well as hig her throughput. CONCLUSION CHOOSING THE BEST HTS ASSAY: The literature reveals numerous modifications and validated systems of all the possible assays that are suitable for adaptation to high throughput screening in drug discovery. Many of the traditional weak points of each assay have therefore been addressed in this way, making critici

Religion and Politics Essay examples -- Papers Church State Separation

Religion and Politics Both liberals and conservatives have become quite adept at mixing religion and politics in our current society. One also continues to observe an ongoing practice of civil religion demonstrated by presidents and office-seekers on both the left and right. Generally, the leftist merger of religion and politics has received greater social acceptability because it has been cloaked in such rights' causes as civil rights, women's rights, or economic rights (the social distribution of wealth). The advocating of these rights issues have provided an appearance of transcending religion, keeping the left relatively free from criticism of any church and state overlap. Christian Conservatives, however, have found it more difficult to reasonably combine faith and politics because they have more overtly recognized that their political positions are grounded on faith assumptions. This has resulted in numerous attacks by both non-Christians and Christians alike against the conservative attempt to merge religion and politics. Three arguments have been used most frequently against the conservative mixture of religion and politics. In what follows each of these arguments is stated and then refuted. The first argument is that politics is too worldly. The essence of the argument is that politics is part of this world's system, and Christ clearly taught His followers to "love not the world," and to flee from worldly activities. There is a danger of becoming caught up in th... ...hermore, in the Bible there is much political activity by God's servants. The judges and kings ruled under God. The prophets and Moses were quite political. Daniel served in the civil governments of Babylon and Persia. Joseph governed in Egypt. The Apostles spoke of following God's rules rather than men's. In conclusion, to be obedient to Christ requires political activity. Jesus is quite clear about the need to overcome social injustices. If Christ tells us to confront the forces of evil, but society tells us not to, and even makes a law against bringing religion into politics, then who should we follow, the state or Christ? In the broadest sense, we are called to political activity because we are responsible to apply Christian principles and standards to all areas of our society, and politics is one of these areas.

The Character of Jurgid Rudkis in Upton Sinclairs The Jungle :: Upton Sinclair Jungle Essays

The Character of Jurgid Rudkis in The Jungle There are often many sides to a person's personality. Jurgis Rudkis of Upton Sinclair's novel, The Jungle, is no exception. Rudkis is a very determined and caring person. Conversely, he is also strickened with cupidity. He has both good and evil coexisting within him. Rudkis is a very determined and directed man. He is always eager to work. He does not let anything stop him and is "confident in his ability to get work for himself, unassisted by anyone(pg.35) ." Aware that he needed money, Rudkis does anything and everything to achieve his goals. No matter what he must endure, he always manages to keep his head high and keeps striving toward his dreams. Rudkis's determination is also displayed when he tries to make a good impression on his boss. He proves he is not lazy and "promptly reports for work in the morning(pg.46) ." Rudkis is also a caring man. His primary goal is to protect Ona, and when he reaches America, he has every confidence he can do so. He works in terrible conditions and endures many hardships merely to keep her happy. When he lost his job, he earned mony immoraly. He does not do this for himself, but for the welfare of Ona and the family. Eventhough he inevidably fails, he does everything in his power to be an ideal husband. Rudkis, like many other good-hearted people, had to circumb to the evil powers of greed. He buys an expensive house that he could not afford. He could settele for a house of lesser value that suits his needs just as well, but he doesn't. Eventhough he is somewhat conned into buying it, his greed still convinced him. Shortly after this, he is so eager to get more money, that he starts to behave immoraly. After he lost his job due to an injury, he sinks into a life of crime as a foe of society. He becomes a mugger and a grafter.

Racial Inclusivity and Social Media and The Souls of Black Folks by W.E

Modern innovation has made the infusion of racial inclusivity and social media a tightrope walking affair above a never-ending abyss. Social media when used has been a place for radicalized defense, sensitive humor and to cavalcade swagger. Simultaneously this tool that has been disposed to culture through telephones, computers, tablets and many other places has created a whole new world for inauthentic means of living. In particular in regards to the African American culture. The â€Å"new ‘New Negro,’† a term suggested by Marlo David has so much at their fingertips, yet do not know how to use them. She said, â€Å"the new New Negro of the millennial age has sought to escape the shadow†¦that has been more real to him than his personality.† The arbitrary nature that African Americans escape to social media networks to show themselves only serves to cover themselves from what their blackness is. Blackness rooted in the brutalization of systemic o bjectification of their minds, bodies and expressions in various walks of life. These issues are not new to the Black experience, they are found in the early 1900’s with W.E.B. Dubois in his work, The Souls of Black Folk. His prophetic work confronted the black person then, and resonates in the infusion of Social media today in everyday life. . He writes, â€Å"How does it feel to be a problem? I seldom answer a word.† He continues, â€Å"Being a problem is a strange experience - peculiar even fro one who has never been anything else, save perhaps in babyhood and in Europe.† Social media has only meliorated the way African American persons are viewed, for Dubois and today, as a problem. From Duboisian experience in 1903 to Social Media and the Black Experience today, progress and problems persist.... ...BIBLIOGRAPHY Congress, T. L., & Willis, D. L. A small nation of people : W.E.B. Du Bois and African-American portraits of progress. New York, NY: HarperCollins. David, M. (2007). Afrofuturism and Post-Soul Possibility in Black Popular Music. African American Review , 41 (4). Dubois, W. B. (2009). The Gift of Black Folk . Garden City Park, NY: Square One Publishers. DuBois, W. E. (1903). The souls of black folk: essays and sketches. Chicago: A.C. McClurg & Co.; [Cambridge]: University Press John Wilson and Son, Cambridge,. Neuhaus, R. (2008). "The public square: a continuing survey of religion, culture, and public life. First Things , 184, 57-72. Schwartz, D. (1989). Visual Ethnography. Qualatative Sociology , 12 (2), 119-154. Senft, T., & Noble, S. (2013). Race and Social Media . In T. M. Jeremy Hunsinger, Routledge Handbook of Social Media (pp. 107-120). Routledge.

Her Lifestory Essay

Now you can see how successful Concepcion Baylock is. At the age of 12 the young Concepcion was already away from her family and lived with her relatives in order to have a good education. Living with her relatives is not that easy, she had to do the household chores for them to let her stay, and she goes to school at the same time. At a very young age Concepcion showed her diligence in everything she does. When the time her grandparents took her, Concepcion’s life changed because they treat her nicely and they were good to her. However she still tried to help doing the chores because she wanted to thank them, in that simple way she showed her grandparents how thankful she is. As a teenager Concepcion supposed to be hanging out with her friends going to movies, parties, and outings. However she missed this, she would rather save her money that was given by her grandparents. She doesn’t even buy new things. When she was still in her senior years in high school she already worked by teaching grade school student. Later on she worked as a telephone operator in the United States Naval force in Subic. While she was working she married an irresponsible man, he just let Concepcion doing all the work. Good thing Concepcion successfully gets out of this marriage. She had a child with this unsuccessful marriage. Years later, Concepcion married again with an American who she had a four children. He is the one who helped her to put up her first business, they had a jeepney and taxi concession. When her business succeeded she put up her second business a four-storey hotel, which later on turned out to be a combined hotel, night club, and restaurant. Her ventures succeeded, but she remembers that before she married her second husband she faced many disapproval regarding in her plan f having a business. She never let this bring her down, despite she used this as challenge to pursue more. Concepcion was not still contented; she pursue her education in Manila. She managed to raise her children and run a business at the same time while she was studying. She had a very hectic schedule; she only had around four hours of sleep every day. After she finished her degree in commerce, she proceed to law, and then to a master’s in public administration, and a doctorate in commerce. Concepcion Blaylock is now a president and chairman of Diamond Motors Corporation. As an entrepreneur and a manager Conception knows how to deal with different type of people. She knew how to treat her people properly. She never hesitates to help them, especially those who showed loyalty to her and to the business. She never forgets to credit the companies who trust her. She always makes sure to maintain their trust to her. She never abused her creditor, who trusts her. Today, when Concepcion Blaylock looks back at her past she was very thankful for such an experience that she had. She was very grateful with the things that challenged her more to do more and thought her to be strong. A. Cultural Values| Manifestation of the Value| 1. Frugality (katipiran)| As a child, she saved money rather than buy new things; as an adult, did not immediately buy a car even though she can afford it. | 2. Risk taking (lakas ng loob)| She pursue her plan of having a business even though she knew that she don’t have any formal orientation in running a business. | 3. Amor Propio (utang na loob)| She never hesitates helping her staff especially those who have proven loyalty and commitment. 4. Harmonious labor management relations| She makes it to a point to compensate her people generously with profit sharing schemes and other benefits. | 5. Diligence (sipag)| At a young age, she already attributed this trait, she do the housemaid works and study at the same time. | 6. Endurance (pagkamtiisin)| She was already away with her family at an early age, for her to have a good educ ation. She never let this be a reason for not to achieve her goals, instead she makes this as her inspiration. | B. As a Filipino we were brought up by our parents to have a sense of adventure (pakikipagsapalaran) that is big help in venturing a business. Filipinos were not afraid of trying new things , we intend to be a risk taker. We usually put in our mind that God will help us in everything we do, that is a â€Å"bahala na† attitude. â€Å"Bahala na† attitude is not that bad because we do our part, but we just hope for the guidance and help of God. We Filipinos are well known of having a good relationship to people such as being family oriented and â€Å"pakikipagkapwa†. Filipinos are naturally have a close family ties. This trait is a good thing when you are in a business. Our family serves as our strength because we knew that they will be always be there to support us. They are the one who inspires us to do our best. Filipinos also exhibits the trait of being good to the people around us. This trait really plays a big role in how Filipino entrepreneur manages their people very well. Yes, the Filipino culture and values that were instill in us really help in building our entrepreneurial spirit.

Financial Analysis of Competition Bikes Essay

Financial Analysis of Competition Bikes Introduction   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In financial analysis a complete assessment of a business organization covering competitiveness, profitability, liquidity and stability concerns. Financial analysis of a business is undertaken by reviewing the business’ financial statements. Summarized financial statement reports are frequently presented to executives and top managers for setting up business goals as well as making decisions. Analysis of the financial statements of Competition Bikes demand evaluation of the internal operation focusing on vertical, horizontal, ratio and trend analyses and the working capital. These evaluations communicate profit margins enabling projection of budgets and restraining sales and costs potential. Annual comparison of production performance subject to profit versus overhead helps in forecasting of budgets for production ingredients on a monthly basis (Shim, J. and Siegel, J. 2009). Competition Bikes Horizontal Analysis   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   This is the examination of percentage changes in comparative statements of a business. In this case, it is the evaluation of Competition Bike’s comparative statements between the year 6 and 7 as well as 7 and 8. The horizontal analysis chart helps in indicating the value of accounts payable differential in year 6 and 7 as well as year 7 and year 8. The company’s net sales soared up by 33.3% between year 6 and 7 at $1,495,000. However, net sales differential between year 7 and 8 was a negative implying that sales decreased by 15% at $897,000. Therefore, it is essential that Competition Bikes increases annual sales to reap higher profits. The value of gross profit registered was a negative figure of $266,600 equivalent to 16.3% decrease. Interestingly, the company registered a 37.5% gross profits increase between year 6 and 7 at $447,000.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The time period between purchasing of raw materials, manufacturing and distribution of goods is referred to as the operating cycle. The net period in collection of receipts from payments and sales is the cash conversion cycle for the different ingredients consumed and produced by Competition Bikes. The company witnessed a decrease in the operating cycle between years 6 and 7 from 50.52 to 48.00 days. This is explained by the increased growth of sales relative to the inventories growth rate. The cash conversion period between year 6 and 8 was relatively negative. This is because Competition Bikes Inc has a high liquidity owing to the short receivables period supplemented by a lengthy payable deferral period. It is indicative of the efficient management of the company’s resources.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The aggregate of administrative and general expenses between year 6 and 7 increased at $156,440 equivalent to 20.4% increase. However, the increase between year 7 and 8 was significantly lower at $11,004 equivalent to 1.2% increase. Still, Competition Bikes Inc operating income between year 6 and 7 increased at $191,820 equivalent to 154.6% increase. However, this parameter decreased at $318,392 equivalent to 61.9% decrease. Higher profits were registered between year 6 and 7 relative to year 7 and 8 which registered a dcrease in profits.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In addition, the company’s cash account differential between 6 and 7 was a decrease of $142,451 equivalent to 54.6%. However, this differential increased between year 7 and 8 at $326,475 equivalent to 275.4%. The net liabilities difference between year 6 and 7 was $128,620 equal to 1.2% increase. According to horizontal analysis, the total liabilities differential from year 6 to 8 was a decrease at $35,500 or 1.9% (Brigham, E. and Houston, J. 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Still, Competition Bike’s common equity differential between year 6 and 7 was a 2.9% increase equating to $119,914 increase. Horizontal analysis of the same parameter indicates a fall between year 7 and 8 equal to $2,400 or 0.1% decrease. Since year 7 and 8 registered a lesser loss comparative to the gain between years 6 and 7, Competition Bikes Inc. broke even in the former years from the aggregate of year 6 and year 7. Competition Bikes Inc Vertical Analysis   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In vertical analysis, an exploration of a company’s statement of financial position is considered to validate each element comparative to the total assets as a percentage. For the income statement, vertical analysis involves exploration of the various variables subject to total sales. This analysis helps in evaluation of the financial performance of Competition Bikes Inc with time. The tabulation below indicates the Vertical Analysis of the Competition Bikes Inc’s Balance Sheet Account elements Year 6 Total assets ($4,199,303) Year 7 Total assets ($4,319,217) Year 8 Total assets ($4,316,817) Notes and accounts Payable 1.6% 4.5% 6.1% Accrued Salaries and other expenses 0.4% 0.3% 0.3% Accrued Expenses 0.5% 0.6% 0.6% Mortgage 42.9% 39.4% 37.1% Long term Liabilities 2.1% 2.0% 1.9% Stockholders Equity 52.5% 53.3% 54.1%   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Competition Bikes Inc Vertical Analysis assesses the liabilities, equities and assets of the company. Overall, the operating expenses fluctuated in little figures indicate a strong internal control policy. Therefore, there was little depreciation on the company subject to the operating sales versus costs. The proportion of liabilities decreased over the three years indicating an improved ability in Competition Bikes Inc to settle debts. The proportion of common equity relative to debts increased over the period signifying a growth in the net capital of the company. Competition Bikes Trend Analysis   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   This is the evaluation of the financial performance of a business over time. Firstly, Competition Bikes Inc balance sheet figures increased tremendously between years 6 and 8. This signifies growth and expansion trend in Competition Bikes. On average, the company grew at 3.3% which is a sustainable growth rate. Over the three years, the sales dropped significantly and especially between year 7 and 8. Nonetheless, the profit margin was relatively strong due to little fluctuations in overhead costs such as materials, productions costs and carrier fees. Therefore, it is potentially possible that the future sales in years 9, 10 and 11 high provided the company maintains the current growth and expansion rate.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Based on trend analysis, it is anticipated that the company’s sales in future will remain strong. This inspires the shareholder to invest more in the company over the next three years. Profits are anticipated to increase at 103.2%, 107.6% and 111.8% over the next three years respectively. In additional, further prodding of the company’s financial statements indicates a declining rate in sales growth rate. For instance, the company sales increase at 8.65% between year 6 and 7 as well as 9.85% between year 7 and year 8. Nonetheless, the significantly small sales growth rate is associative to higher boost in net income which rose by 12.82% and 14.46% in year 7 and 8 respectively. Competition Bikes Ratio Analysis   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   It is the determination of the past years financial performance relative to other companies ratios, trends as well as those of the company/business under review. These ratios include liquidity, profitability and efficiency ratios.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Liquidity ratios extracted from the statement of financial position determine the ability of the business to pay its debts at and as when they fall due. The fractions are significantly important in computation of the business ability to meet its short term and long term financial obligations and goals. Quick ratio is computed by dividing quick assets by current liabilities. The company registered a low quick ration of 3.11% and 3.21% for years 8 and 7 respectively. This is because as a motor bike retailer, the company must hold high levels of inventory meaning that most of the working capital ends up tied. Considering that the company enjoys a small inventory turnover ratio, this is not a worrying level.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Efficiency ratios include the inventory turnover ratio and the average collection period. The former is obtained by dividing total sales by total inventory. This ratio indicates the efficiency and the rapidity with which the company manages to sell its bikes. In year 7 and 8, the company’s inventory turnover fell from 46.7 to 45.9 indicating decrease strength in paying off debts. The latter ratio is the anticipated period of cashing owed receivables from clients. Competition Bikes Inc current average collection period is 102.6 days. It is not an ideal duration because it implies delayed conversion of receivables into cash for clearing debts and expenses.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Profitability ratios include return on assets and gross profit margin. The former ratio assesses the aptitude of Competition Bikes to raise revenue from its assets. The company’s return on asset parameter in year 7 and 8 was 4.52 and 4.25 respectively. The gross profit margin at the same period was 27.4% and 27% respectively. However, this was a 4.7% drop from the previous 5.3%. The fall in profits translates to poor operations and hence the need to evaluate the company’s strategies. Competition Bikes Working Capital   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   This is the difference between the current assets and the current liabilities. It is important to a business because it determines the available resources for increasing production, hiring additional staff, merging and buying out other companies as well as investing in expansion projects. The company had a working capital of $2,123,000 and $1,768,000 in year 7 and 6 respectively. The increased values in working capital indicate an advanced working capital over the three years. Internal Control Strengths and Weaknesses   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   These are predominant in the accounts departments. The company has adequate resources to finance its operations now and into the future. This is because all activities are adequately covered financially. Besides, the company boasts a readily available clientele with a potential to attract additional clients. The company maintains a check and balance system to control sales, purchase and cash management translates to a strong internal control system.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Corrective action in weaknesses lists changes to be made to enhance completion of targets and achieving of total significance in a business. The operations and management for implementation are executed by the management to ensure resolution of identified weaknesses. When the firms adopts a tracking system, execution of identified strategies top resolve the deficiencies is easily executed. Corrective actions were installed to improve production and purchasing deficiencies. This is to help in constant inquiry as well as cooperation among various departments in the business. Risks   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Businesses face constant risks and threats and therefore, it is important to identify, address and mitigate the risks. Competition Bikes is susceptible to numerous risks such as increased competition resonating to low profit margins. Therefore, the company must strategize on maintaining and attracting additional clients. Still, the internal controls are a threat to the company. Impromptu competition between purchasing unit and the accounting department may result to delay in payment of invoices. Proper communication lines must be set within the company to address broken communication. Compliance   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Competition Bikes Inc compliance with Sarbanes-Oxley is indicative of the stringent monitoring controls that the company has installed for internal auditing purposes. This assures stakeholders of the efficient management of the company as well as in compliance with different regulatory framework. Compliance entails provision of an admirable working framework such as motivation of employees, retention of skilled labor and recycling of products. Recommendation   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Considering the past performance of the company, it is recommended that the firm must maintain a sound internal control system. This will report deficiencies such as weaknesses in financial reporting. It will help in securing a lock tight financial recording and documentation. Closer monitoring and evaluation of the excess raw materials and manufacturing surpluses will be maintained in reasonable amounts reducing overspending and potential theft. References Bateman, T. S., & Snell, S. (2013). M: Management. New York, NY.: McGraw-Hill Companies. Internal Control Systems. (2011, July 4). Committee of Sponsoring Organizations of the Tread way Commission (COSO). Retrieved December 12, 2013, from http://www.coso.org/documents/COSO_ERM_ExecutiveSummary.pdf.Kieso, D. E., & Weygandt, J. J. (2012). Intermediate accounting (9th ed.). New York: Wiley. Shim, J. K., & Siegel, J. G. (2012). Schaum’s outline of financial management (2nd ed.). New York: McGraw-Hill. Source document