This Is Public Health - a Comparison Between Old and New...

As the term ‘health’ progresses to even more dynamic and ambiguous territories in the world today, health promotion and public health organisations have become increasingly important and prevalent in our society. As the World Health Organisation has tried to define health as ‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’, it is obvious that health is viewed from many perspectives today and this can help explain the trends and shifts in public health as it tries to address a more modern and relevant set of determinates of health. The determinates of health are the circumstances under which people live that can contribute to their health or ill health and can cause†¦show more content†¦Waste that is not properly managed can create serious health or social problems in a community- the spread of diseases, pests and poisons needs to be controlled by the minimisation of waste. Each organisation and council follows structured plans and frameworks to ensure the safety of the community-yet it is still only addressing the treatment of communicable disease. Although these public health systems are necessary in maintaining the health of the community, the fact that they only target communicable disease requires shift to a newer, broader outlook of public health, which is â€Å"distinguished by its basis in a comprehensive understanding of the ways in which lifestyles and living conditions determine health status† (WHO, Heath Promotion Glossary, p3). We see this shift clearly in policies and campaigns implemented in primary education and schools. With influences from many other public health organisations such as the ‘Go for your life’ campaign and the Healthy Kids Association, increasing amounts of healthy canteen policy action plans are being fully endorsed by the school community (Healthy Kids Association, 2010). These policies go hand in hand with initiatives put in place by Vic Health like the ‘Walking School Bus Initiative’. The Walking School Bus not only provides a safe environment and transport to school for children, it aims to educate in nutrition and the importance of a healthy active lifestyle, creating knowledge and powerful behaviouralShow MoreRelatedAn Article On The Health System Of The Indigenous Ashtray Lien Health Care966 Words   |  4 Pagesashtray lien health care. The article goes on to discuss how comparison of the indigenous Australian review against the Paris reference guide and suggests fledging but growing state of indigenous implementation research (McCalman et al., 2016). An article by Al-sharqi in 2012 it discusses the health system developments in Australia. The Contemporary health system in Australia evolved over two stages that are outlined as follows: the period was characterized by the development of health care servicesRead MoreThe Population Of The United States900 Words   |  4 Pagespopulation is beneficial to society has become widely debatable. While many believe that this top-heavy type of population distribution poses a colossal obstacle in terms of economic development in the long run, others maintain that it is a testament to the development of a society. 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Rachita Taneja. Professor Debashree Sinha. Aamn601 Minor

Rachita Taneja Professor Debashree Sinha AAMN601 Minor Project - I 10 March 2017 Ionesco’s Rhinoceros: The Exposition of Existentialism Eugene Ionesco’s first full-length play, Rhinoceros demonstrates the apprehension about the spread of inhuman totalitarian tendencies within the society. The drama written in 1959 is inspired by Ionesco’s personal experiences with fascism during World War II, this absurd drama depicts the struggle of a person to maintain his identity and integrity alone in a world where all others have yielded to the â€Å"beauty† of savage forces and violence This paper is going to talk about the idea behind Existentialism, the Existentialist struggle faced by Berenger and the unreliable resolution to a†¦show more content†¦A major concept in Ionesco s, Rhinoceros, is that the actual meaning is there in the action rather than in just words. A struggle one has to face rather than taking actions which results in an individual turning to be a rhinoceros. Berenger of all the individuals is the one who is truly in search for meaning in life, because he regards the life as meaningless, life as transient and it is nothing more than â€Å"a dream†. Through drinking Berenger slips into a realm of escapism and even questioned sometimes I wonder if I exist myself. Such comment reflects the existentialist concerns in the philosophical existence of an individual. As a result of this, Berenger looks to his friend Jean who always shown himself as self-righteous and â€Å"cultured†, and admired Jean’s rigid willpower which he thinks he lacks in. Despite of several clashes with Jean on matters they cannot agree on, he never questioned Jean but simply assumed that everything was too knowledgeable for his comprehension and he couldn’t understand it . Berenger unwillingly had to settle for some standards set by his friends because this was all he had to hope to become â€Å"smart† and â€Å"purposeful† like Jean and the logician. On one hand, Berenger desperately w ants to fit in with his friends yet on the other at the thought of becoming a rhinoceros, Berenger was appalled. When Jean turned into a rhinoceros, Berenger claimed I never would have thought it of him, never! Berenger then allocated

Pediatric Physical Therapy Children with Disabilities

Question: Describe about A case study is posted below for D.J., a child with Down Syndrome. Like many children with Down Syndrome, D.J. is overweight and generally inactive. He does not have an ongoing fitness routine. How might you help him develop a daily or weekly physical activity or conditioning program? What special considerations would you need to make considering D.J.s impairments including his educational level or cognitive status, and his family situation? Answer: In this case study, the major concern is the 10-year old child having Down syndrome. The Down syndrome is a genetic disorder and generally has an additional piece of chromosome 21. Symptoms include the birth defect, mental retardation, inactivity, hearing impairment, lack of activities. Therefore, these children need additional care. DJ has low muscle tone, hearing disability and frequently suffers from fatigue during hard work. Therefore, he needs additional care and proper treatment for combating with his health status(Campbell, Palisano Orlin, 2012). It has been noticed that DJ and his parents are not actively participating in the physical exercise; he is not involved in community sports programs or any recreation program. Therefore, his weekly physical activity program should include awareness about physical activities and sports. DJ was born with a ventricular-septal defect and suffered from a middle ear infection. Therefore, physical activities are important for him to improve his body strength. Therefore, DJ can be recommended to increase daily physical activity with the special sports program, for normalizing his growth and reducing weight. His exercise programs should be concerned about the movement skill development and should be focused on his interest. It has been addressed that, DJ spend his free time by watching television. His parents can be recommended to go for a short trip or arrange some entertainment program for his son, watching television will enhance his weight. Besides regular physical activity, these entertainment programs at the weekend will help in DJ's growth and help to keep him healthy and motivated. Incorporating them in community programs and resources will help him to achieve lifetime benefits (Campbell, Palisano Orlin, 2012). In the case of DJ, he is a Down syndrome patient and he has some special needs for making his exercise beneficial. He is having developmental disabilities and becoming overweight. Therefore, exercise plan will help DJ to reduce the risk of obesity-related secondary disorders. However, there are some barriers to physical activities. It has been revealed that he is more interested in watching television than playing in the garden; he is not confident about his sports skills. Additionally, his parents are not interested in regular exercise and this is affecting the cognitive perception of the child. Therefore, he and his family need a learning session for becoming aware of the importance of physical activity (Batshaw, Roizen Lotrecchiano, 2013). Exercise and recreation plan The priority of the exercise plan is to give a health promotion lesson to DJ and his family for making them aware of the physical activities and its benefits along with the benefits of healthy diet DJ's parents are recommended to participate in community activities and start regular exercise, including jogging, cycling and aerobic exercise. Participation of parents will have emotional influence on DJ to show interest in physical activities DJ's parents are also recommended to become members of indoor YMCA swimming pool in the community for encouraging their child in swimming Different community programs, mainly recreational program are recommended for his cognitive development (Shields, Synnot Barr, 2012) Weekly physical activity program Details Strengthening DJ has a low muscle tone; thus, he should strengthen his muscle. DJ should undergo formal exercise program, can join gym for four days a week in alternative days, he can use resistance bands and weights The therapist should focus on physical education and adaptive physical education class for developing his exercise plan Cardiovascular Cardiovascular exercise will help DJ to increase his ability to walk throughout the school day without fatigue, in this way he will not have to take more breaks while playing, it will improve his sports activities A swimming program can be recommended for him on the alternative days of gym During his free time in spite of watching TV, he can use trade mill, under supervision of a therapist On weekend, parents can have a walk with their child for refreshment; it will also motivate him and help in growth (Esposito et al., 2012) He has a tricycle by do not have a bicycle, so he has the interest in cycling. His parents are advised to provide a cycling lesson with the provision of a bicycle As he is starting PA, he should start slowly like 10 minutes walk per day (Wuang Su, 2012) Balancing Activities DJ's exercise plan should be developed by including balance tasks, as these are more enjoyable and helps to improve sports skills and mobility Stationary activities like balancing leg with hands on hip can be more entertaining and influence for him His exercise plan can be improved by including proper schedule, where 60 minutes exercise per day will be the aim per day. 10 minutes walk to school, 15 minutes basketball during recess, 30 aerobic exercise or swimming at evening and 5 minute warm up or skipping at morning can be scheduled with the proper diet plan. His therapist or dietician according to his age and weight should set his diet plan. This exercise plan will also help to lose weight (Murphy Carbone, 2012). Reference List Batshaw, M. L., Roizen, N. J., Lotrecchiano, G. R. (2013). Children with disabilities., Brookes Publishing Campbell, S. K., Palisano, R. J., Orlin, M. N. (Eds.). (2012). Physical therapy for children (4th ed.). st Louis, MO. Elsevier/ Saunders. Campbell, S. K., Palisano, R. J., Orlin, M. N. (Eds.). (2012). Physical therapy for children (4th ed.). st Louis, MO. Elsevier/ Saunders. Esposito, P. E., MacDonald, M., Hornyak, J. E., Ulrich, D. A. (2012). Physical activity patterns of youth with Down syndrome.Intellectual and developmental disabilities,50(2), 109-119. Murphy, N. A., Carbone, P. S. (2012). Promoting the participation of children with disabilities in sports, recreation, and physical activities.Pediatrics,121(5), 1057-1061. Shields, N., Synnot, A. J., Barr, M. (2012). Perceived barriers and facilitators to physical activity for children with disability: a systematic review.British Journal of Sports Medicine,46(14), 989-997. Wuang, Y., Su, C. Y. (2012). Patterns of participation and enjoyment in adolescents with Down syndrome.Research in developmental disabilities,33(3), 841-848.

The Rival as an Anti Sentimental Comedy free essay sample

Undoubtedly Sheridan’s purpose in writing â€Å"The Rivals† was to entertain the audience by making them laugh and not by making them shed tears. â€Å"The Rivals† was written as a comedy pure and simple. Though there are certainly a few sentimental scenes in this play yet they are regarded as a parody of sentimentality. The scenes between Faulkland and Julia are satire on the sentimental comedy which was in fashion in those days and against which Sheridan revolted. A brief examination of these sentimental scenes would clearly reveal that Sheridan’s intention was to poke fun at the sentimental comedy of the time. We find both Faulkland and Julia absurd. The true character of Faulkland is indicated to us by Absolute’s description of him as the â€Å"most teasing, captious, incorrigible lover†. Faulkland’s own description of his state of mind about his beloved Julia also makes him appear absurd. He says that every hour is an occasion for him to feel alarmed on Julia’s account. If it rains, he feels afraid lest some shower should have chilled her. If the wind is sharp, he feels afraid lest a rude blast should adversely affect her health. The heat of the noon and the dews of the evening may endanger her health. All this is funny and certainly no to be taken seriously. Sheridan is here ridiculing the excessive solicitude and concern which an over-sentimental lover like Faulkland experiences when separated from his beloved. Sheridan seems to be pleading for mental equilibrium even in the case of an ardent lover. Sheridan continues to portray Faulkland in the same satirical manner. When Acres appears and is questioned by Absolute regarding Julia’s activities in the countryside, Acres replied that Julia has been enjoying herself thoroughly and been having a gay time. Now, a normal lover would feel extremely happy to learn this. We expect the same reaction from Faulkland because he had assured Absolute that he would feel happy â€Å"beyond measure† if he were certain that Julia was hale and hearty. But his actual reaction is quite different and greatly amuses us by its absurdity. In both his interviews with Julia, Faulkland betrays the same absurdity. In the first interview, he complains to her of the mirth and gaiety that she as been enjoying during his absence. He wants to be loved for his own sake and for no particular reason and he also expects her love to be â€Å"fixed and ardent†. In short, his whole manner of talking to her and his soliloquy at the end of this scene reveals him in a still more comic light. The second interview again shows him a ridiculous light. He subjects Julia to a test in order to convince himself of the sincerity of her love. The author’s intention is to show the absurd length to which an over-sentimental lover can go, and the author expects us to laugh at this kind of lover. Even Julia suffers from an excessive sentimentality and she too is made to appear absurd and ridiculous for that reason. The manner in which she describes her lover to Lydia shows the kind of mentality that she has. In the two interviews with Faulkland, Julia is again over-flowing with emotion. We smile at the way she behaves; we are amused by her excess of emotion; we mock at the abject surrender to her lover and her repeated attempts to make up with him. Lydia too is an over-sentimental girl though in a different way; and she too becomes the subject of ridicule in the play. Her romantic ideas and her romantic planning appear absurd to us. She wants not the usual routine marriage but a runaway marriage. Now all this makes us laugh at her superficiality and silliness. These absurd notions have been derived by her from the sentimental and romantic stories to which she is addicted. The collapse of her romantic hopes disappoints her greatly but amuses us a good deal. The manner in which the other characters have been portrayed is also evidence of the anti-sentimental character of the play. Captain Absolute is a practical man and though he assumes the name and status of Ensign Beverley, he would not like to forfeit the rich dowry which Lydia will bring him. Mrs. Malaprop is a conventional, practical woman whose attitude to marriage is business-like. Sir Anthony to is a practical, worldly man. Bob Acres is a country boor with no romantic or sentimental pretensions but towards the end of the play he shows that he is more practical than anybody else by saying: If I cant get a wife without fighting for her, by any valour, I’ll live a bachelor. † Then there is Sir Lucius who is absurd but not because of nay sentimentality. One reason why he is absurd is because of his insistence on fighting duels. But he does not want to fight duels for the sake f any sentiment. When Sheridan himself fought a couple of duels for the sake of Miss Elizabeth Linley, there was a strong emotion behind them, but here we have a mockery of dueling and we are made to laugh at the manner in which these duels are arranged. pride and prejudice:irony Irony is the very soul of Jane Austen’s novels and â€Å"Pride and Prejudice† is steeped in irony of theme, situation, character and narration. Irony is the contrast between appearance and reality. As one examines â€Å"Pride and Prejudice†, one is struck with the fact of the ironic significance that pride leads to prejudice and prejudice invites pride and both have their corresponding virtues bound up within them. Each has its virtues and each has its defects. They are contradictory and the supreme irony is that intricacy, which is much deeper, carries with it grave dangers unknown to simplicity. This type of thematic irony runs through all of Jane Austen’s novel. In â€Å"Pride and Prejudice† there is much irony of situation too, which provides a twist to the story. Mr. Darcy remarks about Elizabeth that: â€Å"tolerable but not handsome enough to tempt me†¦Ã¢â‚¬  We relish the ironical flavour of this statement much later when we reflect that the woman who was not handsome enough to dance with was really good enough to marry. He removes Bingley from Netherfield because he considers it imprudent to forge a marriage alliance with the Bennet Family, but himself ends up marrying the second Bennet sister. Collins proposes to Elizabeth when her heart is full of Wickham and Darcy proposes to her exactly at the moment when she hates him most. Elizabeth tells Mr. Collins that she is not the type to reject the first proposal and accept the second but does exactly this when Darcy proposes a second time. The departure of the militia from Meryton was expected to put an end to Lydias flirtations, it brings about her elopement. The Lydia-Wickham episode may seem like an insurmountable barrier between Elizabeth and Darcy, but is actually instrumental in bringing them together. Lady Catherine, attempting to prevent their marriage only succeeds in hastening it. Irony in character is even more prominent than irony of situation. It is ironical that Elizabeth who prides herself on her perception is quite blinded by her own prejudices and errs badly in judging intricate characters. Wickham appears suave and charming but is ironically unprincipled rouge. Darcy appears proud and haughty but ironically proves to be a true gentleman when he gets Wickham to marry Lydia by paying him. The Bingley Sisters hate the Bennets for their vulgarity but are themselves vulgar in their behaviour. Darcy is also critical of the ill-bred Bennet Family but ironically his Aunt Catherine is equally vulgar and ill-bed. Thus, the novel abounds in irony of characters. The narrative of â€Å"Pride and Prejudice† too has an ironic tone which contributes much verbal irony. Jane Austen’s ironic tone is established in the very first sentence of the novel. â€Å"It is a truth universally acknowledged that a single man in possession of a good fortune must be in want of a wife. † As Dorothy Van Ghent remark, what we read in it is opposite – a single woman must be in want – of a man with a good fortune. There is much verbal irony in the witty utterances of Mrs. Bennet. He tells Elizabeth: â€Å"Let Wickham be your man. He is pleasant fellow and would jilt you creditable †¦Ã¢â‚¬  In the words ‘pleasant fellow’ is hidden a dramatic irony at the expense of Mr. Bennet, for Wickham is destined to make a considerable dent in Mr. Bennets complacency. Jane Austen did not show any cynicism or bitterness in using her irony to draw satirical portraits of whims and follies. Rather her irony can be termed comic. It implies on her side an acknowledgement of what is wrong with people and society. It is interesting to note that ironically, in â€Å"Pride and Prejudice†, it is the villainous character Wickham and lady Catherine – who are responsible for uniting Elizabeth and Darcy. She uses irony to shake her major figures of their self-deception and to expose the hypocrisy and pretentiousness, absurdity and insanity of some of her minor figures. It is definitely possible to deduce from her works a scheme of moral values. Andrew II Wright rightly points out that irony in her hands is ‘the instrument of a moral vision’. the rivals:comedy of manners Like typical comedy of manners, â€Å"The Rivals† has a complicated plot. There are three love-affairs in it – the Absolute-Lydia love-affair, the Faulkland-Julia love-affair, and the Mrs. Malaprop-Sir Lucius love-affair. All these love-affairs have a parallel development, so that the interest keeps shifting from one love-affair to the other quite rapidly. Again, like a typical comedy of manner, â€Å"The Rivals† abounds in wit. We have the wit of Captain Absolute, the wit of Sir Anthony, the wit of even Sir Lucius and Acres who are otherwise the targets of the play’s satire. â€Å"The Rivals† is an amusing satire on the fashionable upper-class of Sheridans time. The scene of this play is set in Bath. In the second half of the eighteenth century, Bath was a famous centre of fashionable life. The manner in which Fag dwells upon this life is quite amusing. The Faulkland-Julia love-affair is undoubtedly a parody of the sentimental comedy of the eighteenth century. Julia is portrayed as an excessively sentimental girl, while Faulkland is portrayed as the most whimsical and eccentric lover. Faulkland greatly amuses us by his account of the anxieties that fill his mind regarding Julia. Every hour he is alarmed on Julia’s account. If it rains, if the wind is sharp, he feels afraid. All this is very funny. Similarly, Faulkland’s feeling upset on hearing about the gay life that Julia has been leading also amuses us. Julia’s over-sentimentality in idealizing her lover and repeatedly forgiving his faults and silly suspicions is also funny. The portrayal of Lydia is a satire on the romantic notions which young, fashionable girls of upper-class families of the time entertained. She is fond of reading romantic novels and stories. Fed on such stories, she does not want a conventional and routine kind of wedding. When Captain Absolute’s real identity is revealed to Lydia, she feels terribly disappointed at the collapse of her romantic dreams and hopes. The manner in which she recalls her secret meetings with her lover during the cold nights of January is very amusing to us. The most amusing scenes in the play are those in which Captain Absolute comes face to face with his father, Sir Anthony. Sir Anthony is portrayed as a self-willed, dictatorial kind of father who demands implicit obedience from his son. He threatens to disinherit his son, to disown his son in case his son does not carry out his wishes. Sir Anthony in his own prime of life was a gay fellow. Sheridan also makes us laugh at some of the contemporary fashions. When Bob Acres comes to Bath, he decides to discard his country clothes and to dress himself according to the fashion prevailing in the city. Then he tries to practice some French dancing steps and discovers to his disappointment that his are â€Å"true-born English legs† which can never learn French dancing steps. He is also fond of swearing and has developed a new way of swearing. We find him swearing, by â€Å"Gods’ balls and barrels†, by â€Å"God’s bullets and blades†, by â€Å"God’s levels and aims† and so on. Then there is a satirical treatment of dueling. The manner in which Sir Lucius instigates Acres to send a challenge to Beverley is most amusing. Sir Lucius gives the following argument absurdly in favour of Acre’s sending a challenge to Beverley: â€Å"Can a man commit a more heinous offence against another than to fall in love with the same woman? † The portrayal of Sir Lucius is also satirical. Sir Lucius is an Irishman, easily duped by the maid-servant Lucy, who tells him that the love-letters which she brings for him have been sent by the seventeen-year old niece of Mrs. Malaprop. This wrong impression ultimately leads him to challenge Captain Absolute to a duel and the manner in which Sir Lucius picks up a quarrel with Captain Absolute is itself very funny. The portrayal of Lydias â€Å"tough old aunt† is also satirical. We laugh at the contradiction in this elderly woman who puts restrictions on her niece, while herself falling in love with a tall Irish baronet and writing letters to him under the assumed name of Delia. Beverley’s description of Mrs. Malaprop as an â€Å"old weather-beaten, she-dragon† is most amusing. One of the most striking features of â€Å"The Rivals† is witty dialogue. The manner in which Sir Anthony snubs and scolds his son for disobeying his wishes, the manner in which Captain Absolute deals with Mrs. Malaprop when he meets her first, Sir Lucius manner of dealing with Acres when he instructs Acres in the rules of dueling is also witty. Humorous and farcical situations are also generally found in a comedy of manner. Captain Absolute’s disguising himself as Ensign Beverley and then unmasking himself when finally he has to face Lydia in his true character are such situations. Then there are two more farcical situations. One is that in which Captain Absolute tricks his father into believing that his is going to make up his quarrel with Lydia when his is actually going to fight a duel. The second is when David shouts to Sir Anthony to stop Absolute because there is going to be fight, murder, bloodshed and so on. Instead of moral sentiments, Sheridan gives quick and witty dialogues, fast moving actions with its highly comic situations and above all the absence of any serious complication or conflict. Right from the beginning to the end, the play sends the audience into peals of laughter. The criticism that elements of sentimentality have penetrated into the play is based on misunderstanding.

Marxist Theory Essays (5467 words) - Marxist Theory,

Marxist Theory Introduction to Marxist theory on history Historical Materialism: the marxist view of history The history of all hitherto existing society is the history of class struggles. Freeman and slave, patrician and plebeian, lord and serf, guild-master and journeyman, in a word, oppressor and oppressed stood in constant opposition to each other, carried on an uninterrupted, now hidden, now open fight, a fight that each time ended, either in a revolutionary reconstitution of society at large or in the mutual ruin of the contending classes. Karl Marx and Frederick Engels: The Communist Manifesto Section A: How society works 1. Making sense of history: looking behind the 'story' The ruling class portrays history as the doings of "great men", the role of governors and explorers, lists of wars and invasions and other "important events". History in school books is like a story - a succession of events without any general pattern. Marxists say that in order to make sense of the story of history - what people, famous or not, actually did - we have to understand the overall economic and social context to show why they acted in the way they did. Take for example the American Civil War of 1861-65. What do most people know about this war? Northern Americans, the Union, fought against the Southern Confederates; Bluecoats fought Greycoats. Why? Most people would say, well, it was about slavery. The Union president, Abraham Lincoln, was against slavery, while the southerners were in favour of it. That's the myth; the northerners fighting slavery out of the goodness of their hearts. But Marxists would say there was a lot more to it than that. In fact the northern industrialists behind the Union were in bitter conflict with the big southern farmers who owned the slaves; most of these industrialists were racists and not very sympathetic to black slaves. The basic causes of the war were in this economic conflict between the to different sections of the US ruling class. Let's take the example of the English civil war of 1641-49. Most people know it was cavaliers against roundheads, parliament versus the crown, Oliver Cromwell versus Charles 1. But why? Who did parliament represent - whose interests? And who backed the king, and why? When we investigate this, we find that different class forces were involved. So, a Marxist analysis of the English civil war would try to explain the story of the war in terms of the class interests involved. This method of looking at things to discover the real class and social interests involved in events, of course is relevant to more contemporary events. Why did the US president George Bush start the Gulf war? To defend plucky little Kuwait against the monster Saddam? Marxists say no, this was just the propaganda; Bush started the war to defend the economic and political interests of the US, including the oil supplies from the area. Another example of how we try to look behind the surface events at the real story. So this is the first idea: Historical materialism is about discovering the class interests which determine how people act in history. Now read the following quote about the English civil war from someone who fought in it, and think how it relates to what we have discussed so far: "A very great part of the knights and gentlemen of England ... adhered to the King. And most of the tenants of these gentlemen, and also most of the poorest of the people, whom the others call the rabble, did follow the gentry and ere for the king. On the Parliament's side were (besides themselves) the smaller part of the gentry in most of the counties, and the greatest part of the tradesmen and freeholders and the middle sort of men, especially in those corporations and counties which depend on such manufactures". (Colonel Baxter: Autobiography) What Baxter is saying here is that the conflict was between the king and the aristocracy (supported by those most dependent on them) on the one hand: and the rising middle classes on the other. This of course is exactly the Marxist explanation of the Civil War. (See Christopher Hill: 'The English Revolution 1640'). 2. Different types of society The type of society we have now - capitalism - only started to come into existence about 350 years ago, first in Holland and England. But human society existed for hundreds of thousands of years before that. In societies before capitalism, the way people lived was different to what we know now. Before capitalism, in Western

Study into Drug discovery and Design The WritePass Journal

Study into Drug discovery and Design Introduction Study into Drug discovery and Design Introduction1. Background1.1 Target Identification and Validation1.2 Hit Identification and the Generation of a Lead Series 1.3 Lead Optimisation 1.4 Summary and Aims2. Case Studies2.1 Nuclear Magnetic Resonance in Fragment Based Library Screening and X of A G-Protein Coupled Receptor3. Conclusion3.1 Summary of Main Points and Advantages of Structure-Based Techniques3.2 The Limitations of Structure-Based Techniques3.3 Concluding Thoughts and Future AdvancesRelated Introduction 1. Background Drug discovery and design is fuelled by the need for appropriate and effective treatment for disease. Initially discovery was achieved via empirical screening of vast libraries of molecules, which was incredibly effective. The majority of drugs currently in clinical use were discovered this way. However with increased technology, and a greater need for newer more effective medicines, structural biology has become a prominent tool. The general principles behind drug discovery briefly discussed here include target identification and validation, and hit discovery or design to generate a lead which is then optimised. 1.1 Target Identification and Validation A target is often a protein, however it can also be RNA, DNA or a carbohydrate. People who suffer degenerative, autoimmune and genetic diseases can be screened for genetic differences through genome wide association studies (Grupe et al., 2007)or systematic meta-analysis (Bertram et al., 2007). Infective organisms have genes that are very different to human genes that may be essential in the life or infective cycle of the organism and are thus useful targets that can be identified through bioinformatics analysis or loss of function mutant phenotype studies (Crellin et al., 2011). A structure-based technique includes structural genomics, which is the study of the structures of all proteins in a genome. 1.2 Hit Identification and the Generation of a Lead Series Once a target has been identified and validated, small molecules that bind and in some way alter function must be discovered or designed, again there are a number of ways in which this can be done. Empirical screening has identified a number of drugs, however structure-based techniques are more and more commonly being used. 3D structures from X-ray crystallography data and, to a lesser extent, nuclear magnetic resonance (NMR) have been used to generate the information required for computational methods involving docking and screening. This has been useful, for example in the in-silico screening of G-protein coupled receptor (GPCR) binding molecules (Richardson et al., 2007), however most structure-based drug designs have come from the design of compounds based on the 3D structure obtained from X-ray crystallography or NMR, or via biophysical screening techniques involving surface plasmon resonance (SPR) or NMR. Structure based screening methods often require fragment based libraries. These encompass a greater number of potential molecules, within smaller libraries of compounds, this is possible because there are no large functional groups that would inhibit binding, and so result in attractive starting points for hit discovery (Nordstrà ¶m et al., 2008). To validate or measure the properties of the hits, crystal structures can be evaluated and additional information from secondary SPR screens, thermal information from isothermal titration calorimitry (ITC), and differential scanning fluorimitry (DSF) can be used to complement the data (Retra et al., 2010). 1.3 Lead Optimisation Once validated, the structure is optimised. This can be based on ligand binding structures in NMR and X-ray crystal structures, or increasingly, in-silico modelling based on the pharmocophore hypothesis involving the evaluation of chemical and functional groups that may bind important sites of the target molecule (Voet et al., 2011). The key structural techniques involved in structure-based drug design are X-ray crystallography and NMR, though mass spectrometry can also be used to observe proteins in multi-protein complex interactions. X-ray crystallography generates 3D structures of the protein of interest from crystals generated by altering conditions such as buffers, pH, temperature and the format; nanodrop, hanging drop as well as others (Giegà © Sauter, 2010). These crystals are homogenously packed and stored in cryo-protecting buffers so that they can be stored in liquid nitrogen which protects them from the X-rays used to generate the 3D structural information (Philippopoulos et al., 1999). Once obtained, if the ligand of interest is soluble and has relatively high affinity for the target protein, co-crystallisation studies can be used to look at interactions of the different ligands of interest with the target protein. This is not always possible; however there have been improvements since the advent of fragment based libraries. NMR based structures are more time consuming to construct, requiring the analysis of NMR peaks of different spectra to associate them with specific nuclei to generate restriction information to produce a structure. Though more time consuming, it is incredibly useful if other forms of structural information are not available (Zou, 2007). In structure-based drug design NMR has been more useful in ligand protein interaction studies (Pellecchia, 2005), but has also been used in screening libraries for hit molecules (C. Murray et al., 2010). Mass spectrometry can be used in each stage of drug discovery (Deng Sanyal, 2006), especially as technology advances, however it is much more limited (justification?) than those methods or techniques already mentioned and so will not be discussed in any great detail. To complement these techniques there are a vast array of technologies available, a few of which are   mentioned below. SPR measures interactions between the target protein and potential hits in biosensors, and can also be used in hit validation and optimisation in secondary screens (Retra et al., 2010). Since fragment based screening, SPR has become much more popular and will be discussed in greater detail later. Other complimentary techniques involves ITC which measures entropy and enthalpy to determine their contributions in ligand interaction, and therefore gives a clue as to what sorts of alterations would be required to optimise binding. DSF is also widely used, more often to measure where the hit compound is binding on the target molecule (Domigan et al., 2009). 1.4 Summary and Aims To summarise, the stages of drug design include target identification and validation; hit identification and generation of the lead molecule; and then the optimisation of the lead into a drug for testing and then clinical trials. Target identification may utilise such structural techniques as structural genomics. Hit identification makes better use of structural information from X-ray crystallography or NMR and the design of drugs and computational in-silico drug design, or screening methods including high throughput screening (HTS), SPR library screens, and in silico computational screening methods. Optimisation generally uses structural information taken from X-ray crystallography as well as computational methods and in some cases NMR aided by SPR, DSF and ITC to increase binding affinity and then the pharmacokinetic properties. To assess their usefulness in structure-based drug discovery and design, case studies will be analysed to look at how these techniques have been used to further the production of clinically used drugs, or at least increase our understanding so that we may be able to use it in future drug design attempts. 2. Case Studies 2.1 Nuclear Magnetic Resonance in Fragment Based Library Screening and X-ray Crystallography in the Design and Optimisation of Hsp90 Inhibitors The heat shock protein 90 (Hsp90) is a human chaperone which is involved in stress responses, but is also required in the essential process of client protein maturation. Many of its client proteins are involved in cell signalling, proliferation and growth (Biamonte et al., 2010), which have been associated with a number of different cancers. The overexpression or inappropriate activation of Hsp90 is also therefore associated with cancer, therefore a number of drugs have been produced which aim to inhibit the essential ATPase activity of Hsp90. Hsp90’s combinatorial in so many different client proteins makes it a good target for drug development, therefore many drugs are already available that target Hsp90. However there are a number of problems concerning bioavailability, toxicity and increased resistance and so newer more effective drugs are required (Van Montfort Workman, 2009). As can be seen in figure 1 Hsp90 is active as a dimer, and in the N terminal of each subunit is a functionally essential ATPase site (Prodromou et al., 1997), the middle domain regulates the interaction of Hsp90 with its client proteins (Meyer et al., 2003) and the C terminal region is responsible for dimerization (Minami et al., 1994). Initially drugs for Hsp90 were discovered using the binding and cell based assays, however more recently there have been drugs that have entered clinical trials that were generated using structure-based techniques. These have targeted the ATP binding site essential for function, and so required a good understanding of this site. As can be seen in figure 2 there are critical hydrogen bongs between the adenine of the ATP bound, and the side chain of the amino acid residues Thr184 and Asp93 . These would therefore be ideal targets in the design of an inhibitor molecule (Obermann, 1998). There are examples where inhibitors have been identified using NMR and X-ray crystallography screening methods of fragment libraries, and as has been described, fragment based libraries generate useful starting hits (Hartshorn et al., 2005). In an NMR fragment based library scan, the displacement of low concentrations of ADP (the product compound of the ATPase domain)was measured using NMRwaterLOGSY (Water-Ligand Observed Via Gradient SpectroscopY) (Dalvit et al., 2001), which indicated when a fragment had bound which could be chosen for further study (Murray et al., 2010). Murray et al. discovered a number of binding fragments, 2 of which became lead compounds. The first was compound 1 (fig3) which made extensive hydrogen bonding interactions with key residue Asp93 (as seen in figure 2) and a number of water molecules found deep within the binding pocket as can be seen in figure 4a. However, as can be seen in figure 4b the compound 1 doesn’t efficiently fill the lipophilic pocket defined by the residues Met98, Leu107, Val150, Phe138 and Val186, additionally it was found that compound 1 wasn’t particularly stable, as it was twisted about the bond between the pyridine and pyrimidine. Virtual screening for analogues was used initially to produce more stable forms of compound 1, and though this yielded higher affinity binding molecules, their torsion profiles indicated steric clashes between the methoxy group at position R2 (fig5a) would result in unfavourable binding. Instead using SAR (specific absorption rate) analysis, it was predicted that exchanging the methoxy for chloro improved it significantly, resulting in compound 9, the basis of further optimisation outline as a chemical structure in figure 5b, with the positions for optimisation labelled as R4 and R5. This was done using computer based modelling techniques, and illustrates how useful it can be when enough information regarding the target protein and the current ligands is available. The methoxy and chloro groups added to positions 4 and 5 of the upper phenyl ring increased binding affinity to the lipophilic binding pocket to 12nM. Once the affinity was increased, cellular activity had to be improved and this was achieved by adding a morpholine group to position 5 outlined in figure 5b, a decision based on the crystal structure, and this resulted in compound 14 which is currently going through clinical trials for the treatment of different cancers. As can be seen in figure 6, compound 14 in blue binds in much the same way as compound 1 in orange, but makes more extensive interactions with the lipophilic pocket via an extended phenyl ring. The second line of lead compounds Murray et al. followed initiated from compound 3 (fig7), which using their initial NMRwaterLOGSY screening method appeared to bind rather inefficiently. However, upon observation of the X-ray crystal structure of Hsp90 bound to compound 3 (fig8) it was decided that it provided a quick and attractive optimization route. It’s binding with water molecules and one of the key residues Thr184, though on its own provided a relatively weak interaction, if optimised could also make direct interactions with the alternative key residue Asp93, and also with additional endogenous water molecules. Using trial and error, the writers found that a tetra-butyl group filled the lipophilic pocket appropriately with fewer steric clashes, and this resulted in compound 18, the lead compound that was further optimized to make more effective interactions within the lipophilic pocket. Using modelling studies, interactions with the side chain of residue Lys58 was approved. Compound 24, an isoindoline filled the pocket with a phenyl ring which interacts with residues Ala55, Lys58 and Ile96 completely displacing Lys58 side chain as can be seen in figure 9a. In other inhibitors a position 2 OH (hydroxyl group) resulted in the greater affinities, however compound 18 had a position 4 OH, and a replacement with an OH at position 2 resulted in a lower affinity compound. Addition of an OH at position 2 to compound 24 as well as the OH at position 4 resulted in compound 31 which enabled interactions directly with Asp93, retaining interactions with Thr184 as well as increasing hydrogen bonding with water molecules as can be seen in figure 9b. It also , illustrates compound 31 in blue binding in much the same way as compound 3, but it fills the lipophilic pocket more efficiently, and makes more extensive interactions. This greatly increased binding affinity and compound 31 is now going through clinical trials. This helps illustrate the importance of structure-based approaches such as NMR and X-ray crystallography in the identification and optimization of lead compounds, as well as the input computer based methods can have. X-ray structures were particularly helpful in the case of compound 3, as without this structure compound 3 would have been dismissed as an inefficient binding compound. Additionally, all kinetic data which helped support the optimization and validation steps, was obtained using ITC. Further work on improvements to the pharmacokinetic properties as well as drug-tissue distribution should be concentrated on. 2.2 Crystal Structures from X-ray Crystallography and Nuclear Magnetic Resonance in In-Silico Drug Design, and 3D Drug Development Human Immunodeficiency Virus HIV (the human immunodeficiency Virus) is the causative agent of the acquired immune deficiency syndrome (AIDS) and statistics show that by 2005, approximately 38 million people worldwide were living with HIV (Beyrer, 2007). HAART (highly active anti-retroviral therapy) established in the 1990’s makes living with HIV bearable by keeping viraemia low, and CD4+ (cluster of differentiation 4) cells at a high enough level to protect from opportunistic pathogens. However, with increasing resistance and the negative side effects of current drugs, constant improvement and newer drugs are required. The protease inhibitors were revolutionary in HIV treatment, starting with the rationally designed Saquinavirapproved for use in 1995 (Roberts et al., 1990). HIV protease is a good target, essential in the life cycle of the virus, and though Saquinavir was very successful, resistance quickly arose, and so a greater understanding of the protease structure and biochemistry was required. This was necessary not only to try and target residues that would be less likely to result in resistance, but also to improve the pharmacokinetic properties, producing non-peptidic as opposed to peptidic drugs to reduce toxicity and improve half-life (Arung Ghosh et al., 2008). There have been multiple inhibitors designed with the use of X-ray crystallography, to enter clinical trials and be approved by the FDA (food and drug administration) for use in HAART. It was determined that by targeting the protease backbone residues, it would be possible to generate drugs that would be less likely to result in resistance because mutations are rare, and those that occur do not often distort the overall conformation. Such a site is therefore more conserved and a better drug target (Ghosh et al., 2011). Saquinavir, though a peptidic drug with poor pharmacokinetic properties did bind the backbone resides (though relatively weakly) it also bound outside of the binding envelope, the region which locates the gag-pol polyprotein for cleavage. Mutations are far more common and tolerated outside of the envelope region. Mutations would therefore not reduce virion viability but would prevent inhibitor binding (King et al., 2004). The development of Aprenavir, with a single-ringed tetrahydrofuran (THF) group was designed using Saquinavir as a scaffold, to generate a related, but non-peptidic cyclic compound that would bind and inhibit the active site of the protease, much in the same way as Saquinavir but with increased half-life, better pharmacokinetic properties, increased backbone binding and a more specific binding to the active site envelope. The chemical structure of Aprenavir as seen in figure 9, binds the S1S2 S1’S2’ binding envelope of the protease, closely interacting with the backbone residues Asp29 and Asp30, as well as many other residues (Kim, 1995). The interactions with Asp29/30 were relatively weak, and the THF group, believed to be involved in increasing favourable enthalpy interactions, if increased in size was thought to be able to improve backbone and hydrophobic interactions with the residues that make up the lipophilic flap. Using Aprenavir as a scaffold, Darunavir was developed, a bis-THF compound with a double ring, as can be seen in figure 10. This single ringed to double ringed evolution resulted in more extensive interactions with the key backbone residues (Tie et al., 2004) as can be seen in figure 10, as there are far more hydrogen bonds present between the bis-THF complex in pink with the backbone residues than there are between the single ringed THF complex in green. To measure the ability of Darunavir to withstand mutations in HIV protease, Tie et al. co-crystallised Darunavir with a wild type protease and a mutant version. As can be seen in figure 11, the wild type hydrogen bonds at 4.1 Ã… indicated by the purple dashed lines   is retained in the mutant distance of 3.8 Ã… in blue. This suggests that Darunavir is robust, and will continue to be active against resistant strains of HIV. The inherently high mutation rate of the HIV genome due to the accident prone polymerase means that there will be strains that will become resistant to Darunavir in the future, and it is always necessary to stay one step ahead. Darunavir has thus been used in modelling studies to design optimised structures which are incredibly potent, more so than Darunavir retaining the favourable pharmacokinetic and cellular properties (Ghosh et al., 2011). Figure 12 details the position of compound 1b in green– a Darunavir like compound in the hydrophobic pocket of the HIV-1 protease, and as can be seen, it makes a number of Van der Waals interactions with residues Ile47, Val32, Il84, Leu76 and Ile50’ which make up the hydrophobic flap as well as hydrogen bonds with Asp30 (3.5Ã… long) and Asp29 (2.9Ã… long). To improve the interaction distance with Asp30’s NH group, Ghosh et al. modelled an increase in phenyl ring size of the P2 ligand   in an attempt to also increase flexibility of the structure. This was achieved with the addition of an amide group which also increased the hydrophobic interactions with the lipophilic pocket residues. The pink structure of compound 35a as seen in figure 12 binds in much the same way as compound 1b, but makes more extensive interactions with the key residues and fills out the lipophilic pocket more effectively. This compound was then generated and its Ki and IC50 values cal culated to measure it against 1b, it was a far more efficient inhibitor, and thus a potential clinical candidate. There are many examples of proteins that cannot be crystallised, and to obtain structural information so rather than using X-ray crystallography, NMR can be used. As an example, the HIV protease structure was constructed using NMR (fig 13).An X-ray crystal structures is a static representation of a dynamic system in a relatively unnatural environment, whereas NMR is in solution and is believed to be more biologically relevant, and can in some circumstances be used to observe dynamic protein systems (Zou, 2007). NMR is far more time consuming however, and the inherent flexibility of proteins results in areas of low resolution in structures, more so than with X-ray crystallography. NMR has been used more successfully in hit identification, as has been discussed in the example of Hsp90 inhibitors. 2.3 The use of Surface Plasmon Resonance, Isothermal Titration Calorimetry and In-Silico Drug Design to Complement Structural Techniques Such as X-Ray Crystallography and Nuclear Magnetic Resonance As technology improves newer methods have evolved that complement the existing, this includes such techniques as SPR which detects the interactions between the target protein and ligand, used in primary fragment based library screens to identify hits, or secondary screens to identify or validate hits (Retra et al., 2010). As previously discussed, fragment based screening methods can result in attractive starting points for lead optimisation (Erlanson, 2006). SPR can be used in a number of ways, in chemical micro arrays, SPR imaging, secondary screens of hits found through high throughput screens and also in primary biosensor screens. In primary screens, a biosensor is set up with the target molecules immobilised on chips and this has been successfully used in the identification of hits without the requirement of other forms of structural information (Nordstrà ¶m et al., 2008). The hit molecules can then be integrated into lead series and optimised using other structural techniques such X-ray crystallography and NMR to obtain clinical candidates (Huber, 2005). The matrix metalloproteinases (MMPs) are a group of proteins found in many different species; in humans there are approximately 12 that are involved in tissue remodelling, and degrading extra cellular matrix molecules such as elastin, collagen and laminin (Demedts et al., 2006). MMP-12, involved in various human diseases such as emphysema and chronic obstructive pulmonary disease (COPD) is the target of a number of therapeutic drugs, all of which have harmful side effects and so new drugs are required (Nordstrà ¶m et al., 2008). Using SPR and ITC in conjunction with NMR or X-ray crystal structures Nordstrom et al. produced an in silico drug design based on the binding sites identified by the crystal structures, using pharmacophore properties to model a binding molecule. Mutant proteins were designed in silico and then generated, immobilised on chips along with wild type proteins as depicted in figure 14.   Molecules designed in silico could then be screened against the different p roteins on the chip. For screening purposes SPR is limited, the number of molecules screened against the biosensor is relatively small as the proteins become degraded; only a couple of hundred molecules can be screened, compared to thousands in HTS.   The library must therefore be carefully designed, using in silico modelling, docking and screening, or with a vast knowledge and understanding of the target. Alternatively, SPR can be used in hit validation for lead series initiation, assessing the enthalpy and kinetics of binding, as was the case for capstatin analogues to increase binding affinity for C3b in the treatment of multiple human disorders involving the over-activation of complement (Qu et al., 2010). C3b is an appropriate target because it is involved in so many disorders such as neurodegenerative, sepsis and has also been linked to stroke. Campstatin is a good peptidic protein inhibitor, binding and inhibiting C3b regardless of the initiation pathway. However, due to its peptidic nature, Campstatin is not very stable with a short half-life in vivo, and due to the low concentrations of C3b found in plasma, a higher affinity compound with better pharmacokinetic properties would be ideal. N-methylations were analysed at different positions on the Campstatin scaffold and changes in binding affinity measured using SPR, and confirmed using ITC to conclude that by generating a compound that retains a rigid structure both in solution and in a bound state, it would bind with increased enthalpy, without decreasing the entropy as had other previous designs (Qu et al., 2010). This demonstrates the powerful applications SPR and ITC can have in drug discovery or design, and how in conjunction with in-silico computer based techniques, they can complement X-ray crystallography and NMR techniques. 2.4 The Difficulties Associated with Membrane Protein – The B2 Adrenergic Receptor: an Example of A G-Protein Coupled Receptor Crystallisation seems to be at the heart of structural biology   and even with the option of NMR there are still severe limitations that mean many proteins, particularly membrane bound proteins, cannot be crystallised   and thus cannot be visualised as a 3D structure. This is particularly problematic for structure-based drug design, as some 50% of drugs target G-protein coupled receptors (GPCRs) alone, not including the many other families of membrane bound proteins.   GPCRs are a superfamily of proteins which all have 7 transmembrane helices found in eukaryotes important in many crucial signalling processes (Lundstrom, 2005). The problem with studying membrane proteins in general is the difficulties in solubilising them and getting enough protein to work with. To obtain this large amount of protein, recombinant protein is required and for human protein this is a particularly difficult task (Mancia et al., 2007). The lack of structural information limits our understanding of ligand binding, as well as allosteric control and active site location (Summers, 2010).   There have been major advances in obtaining the structures of GPCRs recently, with structural information on rhodopsin, A2A adenosine receptor, B1 adrenoreceptor and the B2 adrenergic receptor.   The problems to overcome were obtaining enough usable protein, thus an appropriate expression system, the intrinsic flexibility and therefore excessive instability, and obtaining the exact solubilising formula for each protein. Once achieved, the crystallisation process for membrane proteins is no different than for globular proteins (Velipekka et al, 2010). To stabilise the different GPCRs, mutagenesis was used in rounds for B1 adrenoreceptor (Warne et al., 2008), or in the case of the B2 adrenergic receptor and A2A adenosine receptor, the flexible intracellular loops were stabilised by replacing them with the easily crystallised and inherently stable T4 lysozyme (Rosenbaum et al., 2007). Therapeutics aimed at A2A adenosine receptor could help in the treatment of seizure, asthma, Parkinson’s, pain and many other neurological problems (Jaakola et al., 2009). The crystal structure of the A2A adenosine receptor with the antagonist ZM241385 enabled the determination of important residues in ligand binding, and thus generated the information required to use computational modelling studies to suggest residues that would be important in inhibitor binding. Figure 15 depicts the binding of the antagonist, hydrogen bonded to Asn253, aromatically stacked against Phe168 as well as hydrophibically interacting with Ile274. An understanding of these interactions greatly helps in the elucidation of therapeutically important binding molecules ( Jaakola et al., 2009). B2 adrenergic receptors, a class of GPCR are important in smooth muscle related diseases such as asthma (Cherezov et al., 2007). Cherezoc et al. made a B2-adrenergic receptor T4 lysozyme fusion protein to enable crystallisation with Carazolol at 2.4Ã…. Carazaole has high affinity for the receptor, lying adjacent to, and making significant interaction with the residues Phy289, phe290 and Trp286 as seen in figure 16b and reduces basal level of activity of the receptor via its interactions with phe289/290 which result in the inactive trp286 state as seen in figure 16. This understanding of agonist binding and an in depth knowledge of the residues involved, if expanded upon could increase the possibilities for structure-based drug design and modelling. 3. Conclusion 3.1 Summary of Main Points and Advantages of Structure-Based Techniques The power of structural biology is apparent; it provides a clear physical picture of the target protein. It enables the identification of hit compounds via X-ray crystallography and more commonly NMR, supported by the complimentary techniques – computational analysis, SPR, ITC and DSF. Such techniques can validate those hit compounds to enter them into lead series and they can then be used to optimise leads to generate clinically usable compounds. The importance of structural biology is therefore easy to see as it has been successful in generating clinically used drugs, Darunavir for the treatment of HIV as a protease inhibitor being just one of many examples. 3.2 The Limitations of Structure-Based Techniques Of course they are not without their limitations. X-ray crystal structures are static freeze frame shots of a dynamic system, so we cannot be certain that what we see is biologically relevant or simply artefacts. Both X-ray crystallography and NMR suffer with the inherent instability and flexibility of proteins. There are methods to improve the 3D structures, as seen in the crystallisation of membrane protein – the B2 adrenergic receptor (Rosenbaum et al., 2007), suggesting that these limitations are not permanent, and can be overcome. Many proteins cannot be crystallised, and though there has been recent breakthroughs as with the case of the GPCRs, the vast majority have not been visualised and yet 50% of drugs are aimed at them. Complementary techniques such as SPR, ITC and DSF have successfully been used to identify hit molecules (Nordstrà ¶m et al., 2008) and to validate or optimise leads (Huber, 2005). Unfortunately these too are not without their faults, requiring smaller screening libraries, and the proteins involved to be constantly replaced during screens. To overcome this there have been computer based in-silico screening and design processes, which under certain circumstances has been used efficiently as was the case with the optimization of Darunavir (Ghosh et al., 2011), however there have been huge limitations. The first human GPCR crystallised, rhodopsin was a model for all GPCRs and in-silico modelling studies utilised it to generate binding molecules, but with the visualisation of the A2A adenosine receptor via X-ray crystal images, it became apparent that this was a far too over-simplified view ( Jaakola et al., 2009). 3.3 Concluding Thoughts and Future Advances To conclude, there are clear limitations concerning the structure-based design of therapeutic drugs, requiring further advances in technology and understanding to be made before we can easily utilise every form of technology efficiently and in an integrated fashion. Structure-based techniques do not speed up the process of drug discovery, however, there are also clear advances that have been made through the use of such structural biology techniques. They should therefore continue to be used in conjunction with current technologies to ever improve the therapeutics in use. Future advances should include improved recombinant protein technologies and purification procedures to obtain the large quantities of protein required, improved detergent mixtures for membrane proteins as well as better crystallisation procedures in general to increase resolution. As well as finding hits for lead series of molecules, structural techniques should also focus on increasing the number of targets, so that whole new sets of drugs can be made to add to combinatorial drug therapies such as HAART in the treatment of HIV, in an attempt to overcome the problems of resistance.

International Energy Policies Essay Example | Topics and Well Written Essays - 2000 words

International Energy Policies - Essay Example The energy policies formulated by various nations throughout the globe chiefly focuses upon various important areas. The vital areas entail the mitigation of greenhouse gases, valuing the advantages which are obtained from various energy sources and most importantly investing particularly in the energy sectors of the developing nations (France, 2012). Structuring of energy policies is considered to be quite important as energy is known to serve as a vital factor in the financial as well as social activities in different industrialised nations. Moreover, the energy policies extensively pose an influence on the aspect of economic development and defending the safety of the citizen’s at large (Flavin & Aeck, n.d). In this discussion, the harmonisation of the 3 â€Å"E† which includes economic growth, energy supply security and environmental settings along with different factors relating to energy supply and demand will be taken into deliberation. Moreover, analysing the affect of the mentioned factors on the global energy policies, a balanced view of whether these procedures can be regarded as sustainable in the long-term will also to be depicted in the discussion. According to various realistic theories, it has been noted that the chief challenge of every energy policy decision remains to be the harmonisation of the 3 â€Å"E† which consists economic growth, energy security and environmental settings. A clean, affordable, resourceful and a reliable source of energy are supposed to be quite crucial for promoting worldwide prosperity. The developing nations requires to expand their access towards identifying modern as well as reliable energy sources in order to enhance public health, trim down the poverty level by a certain extent, augment productivity, improve competitiveness and most importantly to promote and boost financial growth. The existing modern energy systems are