Seven Wonders of the World

Seven Wonders of the World Centuries ago one man dreamed, designed and constructed a breathtaking monument and then, it went on to become a wonder. Wonders of the world are so many. No list can comprehend everything. But why they are actually the wonders and what are the factors which make them to call a wonders? Every wonder has its own history and importance, and they have some interesting facts related with them. However, the original seven wonders of the world are the most worthy of our praise and appreciation as they were constructed in an era that was devoid of any building machinery and done mostly by hand.The true wonder we can say is artistic, mysterious, magnificent, stunning or in other words it is really a master piece, and due to these qualities it attracts everyone towards itself. The most remarkable or amazing creations by mankind are included in the list of Seven Wonders of the World. The number 7 is said to symbolize perfection and hence is used to list the wonders. There are number of different lists of the Seven Wonders of the World: the seven wonders of the ancient world, seven natural wonders of the world, the new Seven Wonders of the World and the modern wonders.A campaign to name the new Seven Wonders of the World, launched in 1999, has just reached to its climax. Originally, there were nearly 200 nominations which were shortlisted and finally, in the largest ever poll of its kind, 100 million people voted across the world for the final seven. Voting was done through the internet, as well as by phone and text. The popularity poll was led by Canadian-Swiss Bernard Weber and organized by the new seven wonders foundation based in Zurich, Switzerland, with winners announced on July 7, 2007 in Lisbon.The New seven wonders foundation is regulated by the Swiss Federal Foundation Authority. 1. Seven Wonders of the Ancient World: In the recent past, people across the world were asked to vote for their favorite seven wonders of the world. The ancie nt Greeks loved art and architecture. They were the first people to compile the seven wonders of the ancient world list. These wonders were built-in the marvels of the 4th century BC. The Greeks had conquered much of the world and traveled far and wide.As they were patrons of beauty, they took fancy to the landmarks and unique architecture of various lands. 1. 1 Great Pyramid of Giza: The Great Pyramid of Giza is the only surviving member of the seven wonders of the ancient world list, which was built in 2584 BC. It is located at Giza Necropolis, Egypt. This pyramid is about 800 feet long, 450 feet high and is build from 2 million blocks of stone. It is said to have been built as the tomb of the 4th dynasty Egyptian Pharaoh Khufu. (Baxamusa) 1. 2 Hanging Gardens of Babylon: Hanging Gardens of Babylon is built around 600BC.It was built by King Nebuchandnezzar. He built the garden for his wife Amytis of Media to enjoy a private, terrace garden without any disturbance. It was built in Al-Hillah, Babil Province, Iraq. These gardens were said to be about 400 feet wide, 400 feet long and were over 80 feet in height. The garden is supposed to have been destroyed by a massive earthquake. 1. 3 Temple of Artemesium: The temple of Artemesium, at Ephesus, was one of great temple built by Croesus, king of Lydia, about 550 BC and was rebuilt after being burned by a madman named Herostratus in 356 BC.The Artemesium was famous not only for its great size over 350 by 180 feet but also for the magnificent works of art that adorned it. The temple was destroyed by invading Goths in 262 AD and was never rebuilt. 1. 4 Statue of Zeus at Olympia: Statue of Zeus at Olympia was built in 435 BC. The Greeks completed this building. The statue of Zeus was built in the temple to honor the Greek Olympic Game. The statue was a gigantic structure that occupied the whole width of the aisle of the temple. It was about 40 feet tall and was destroyed in a fire during the 5th and 6th century AD. B axamusa) 1. 5 Mausoleum of Halicarnassus: Mausoleum of Halicarnassus was built in 351 BC. King Mausolus ruled a small kingdom in Asia Minor. His queen Artemisia was a beautiful woman who loved the king a lot. After the death of King Mausolus, she got the most beautiful mausoleum built in the memory of her loving husband. It was known as the Mausoleum of Halicarnassus and people from far and wide came to visit it. By the year 1494 AD, it was destroyed by a flood. It was rebuilt but was damaged by an earthquake. 1. 6 Collosus of Rhodes: Collosus of Rhodes was built in 290 BC.Collosus of Rhodes was the colossal statue of the sun god Helios that stood in the ancient Greek city of Rhodes and was one of the Seven Wonders of the World. After about 56 years it was built, the statue was destroyed by an earthquake. It fell into the harbor and just the thumb of the statue was visible over the water surface. The king of Egypt offered to rebuild the statue, but the people of Rhodes refused. This is because they believed Helios himself threw the statue in water in a fit of rage. 1. 7 Lighthouse of Alexandria: Lighthouse of Alexandria was built in 280 BC.The Island of Pharos was a harbor in Alexandria, Egypt. This lighthouse was built in this harbor and helped ships enter the harbor safely. This lighthouse is said to have survived for 1500 long years and finally destroyed by an earthquake in the 1300's. During its era, it was the tallest man-made structure at about 380 to 440 feet high. So, these were some interesting facts about the 7 wonders of the ancient world. Just imagine, what an impact they may have created in the minds of the people of that age. Except the Pyramid of Giza, all the other wonders have long gone.We can just imagine more about these magnificent structures based on the writings by people of ancient Greece. These seven ancient wonders have something special thing in it, which creates curiosity between us to watch and study these wonders. Although, only on e ancient wonder is left today, but still they have attraction and by this force of attraction these wonders attract everyone towards itself. We can just imagine more about these magnificent structures based on the writings by people of ancient Greece. 2. New Seven Wonders of the World:The list of New Seven Wonders consists of man-made monuments from all over the world. These Seven Wonders of the World are spread across continents and were selected by people throughout the world using a voting method. The organizers thought that this will promote global harmony, along with increasing people's knowledge about these historical monuments some of which are not in their own continent. In 2001 an initiative was started by the Swiss corporation New Seven Wonders Foundation to choose the New Seven Wonders of the World from a selection of 200 existing monuments.Twenty-one finalists were announced January 1, 2006. Egyptians were not happy that the only surviving original wonder, the Great Pyr amid of Giza, would have to compete with the likes of the Statue of Liberty, the Sydney Opera House, and other landmarks. In response, Giza was named an honorary Candidate. The results were announced on July 7, 2007, in Lisbon, Portugal. Figure [ 1 ]: New seven Wonders of the World, Source: New7Wonders of the World,en. wikipedia. org/wiki/New7Wonders_of_the_World. 2. 1 Chichen Itza: The name ‘Chichen Itza' means ‘At the mouth of the well of Itza'.Here, Itza refers to a political clan of people, who were at their political and economical best in the northern peninsula (Saxena. Chaitra Suraj). Chichen Itza was the political focal point for a long time in the Mayan history. This winner of the seven wonders list is located in Yucatan, Mexico. The historical site consists of many stone buildings which are connected by a network of paved roads called Sacbeob. Most of these buildings have been restored and some are still under the process. These buildings have been grouped into sets of architectonic series (based on their architecture).And these sets are believed to be once separated by walls. The three famous sets out of them are, Great North Platform, the Osaario Group and the Central Group. These sets individually consist of various buildings, which are wonders in themselves. Chichen Itza consists of numerous temples, pyramids, and some interesting monuments like Steam Bath and the Great Ball Court. Each of the building had its own importance and was used for some specific purpose. One particular area of Chechen Itza is open to archeologists only, in a way it is still under observation and research. 2. 2 Christ the Redeemer:Christ the Redeemer is the statue of Jesus Christ, in Rio de Janeiro, Brazil. It is situated at a height of 700 meters on the Carcovado Mountain, in the Tijuca forest National Park. It weighs 635 tons and stands at a height of 39. 6 meters. It is built of reinforced concrete and soapstone and is the symbol of Christianity, as well a s Rio de Janeiro. The construction of a historical monument on Corcovado was suggested first in 1850, then again in 1921. A lot many designs were considered for the religious monument, which included, the representation of the Christian cross and the tatue of Jesus with a globe in his hand. The Christ the Redeemer was finalized and the construction began in 1922 and continued till 1931. The cost of construction is estimated to be $250,000. The statue was opened to public on 12th of October, 1931 and in 2007 it became a part of the Seven Wonders of the World. In February 2008, the statue was struck by lightning, during a storm but was saved because of the outer layer made of soapstone, which acted as an insulator. This particular storm is known to have caused a lot of damage in the city of Rio, but the statue stood unhurt. . 3 Colosseum: Colosseum, also known as the Roman Coliseum is situated in the city of Rome, Italy. Coming from such a strong background, it was a really strong con tender for a position in Seven Wonders of the World list. It is an elliptical amphitheater and was originally known as Flavian Amphitheater. It is said to be one of the largest buildings of the Roman Empire. Construction of this amphitheater took around 10 years, starting from 70 AD and once ready the Colosseum was used for various public events and fights between gladiators.Gladiatorial fights were the major source of entertainment during those times and the public events consisted of mock sea battles, animal hunts, executions, reenactments of famous battles, etc. The amphitheater was capable of seating a total of 50,000 spectators. It is estimated that some 500,000 people and over a million animals died in the events held at Colosseum. In the early medieval era, the building was stopped being used as a place of entertainment and then on, it is believed to have been used for various other purposes. The ancient building now stands partially ruined by earthquakes. . 4 Great Wall of C hina: The Great Wall of China was built between the 5th and 16th centuries BC. This wall was designed to protect the northern border from attacks. The Great Wall is over 4,000 miles long. The Great Wall of China also has the distinction of being one of the Wonders of the middle Ages as well. The Great Wall of China is a stone wall built from Shanhaiguan in the east to Lop Nur in the west of China and it stretches over a distance of 8,851. 8 kms. On land, the walls were made using earth or wood, but with the beginning of the Ming Dynasty, the walls were made using bricks.Other materials like lime, tiles and stones were also widely used. With the use of bricks the construction is believed to have fastened and the brick walls were much stronger. The wall is now in ruins at most of the places and only a few parts remain in good condition. Parts of it have sustained years of erosion, human attacks, modern-day construction and even graffiti at a lot of places, in order to find a place in the 7 wonders of the world. (Saxena) 2. 5 Machu Picchu: Machu Picchu is a pre Columbian Inca site in Cuzco, Peru.It is located at a height of 8000 feet above the sea level on the crest of the mountain Machu Picchu. The name Machu Picchu means ‘Old Peak' and is often referred to as ‘The Lost City of the Incas'. Its construction started in AD 1430 and the city was abandoned a hundred years later. It remained hidden from the outside world for hundreds of years, until it was discovered by Hiram Bingham, an American historian in the year 1911. Because of its location, Machu Picchu remained hidden from most of the world, including the Spanish conquerors.But now that it is in the seven wonders list, it is a famous tourist attraction and is visited by people from all across the world. Machu Picchu is believed to have been built at the peak of the Inca Empire and is the proof of their royalty and religious beliefs. Incas were basically sun worshipers. Inti in Peruvian means the S un and hence, it can be easily understood that one of its primary buildings is â€Å"The Temple of the Sun†. The other main buildings are the Intihuatana and the Room of the Three Windows. Most of the buildings in Machu Picchu are in some or the other way related and dedicated to their God, ‘The Sun'.Machu Picchu is on the list of endangered ‘World Heritage Sites'. And that is why tourism in Machu Picchu is of great concern. Scientists believe that more the People, more will be the damage. 2. 6 Petra: Petra is a historical and archaeological city in the Jordanian governorate of Ma'an that is famous for its rock cut architecture and water conduit system. Established sometime around the 6th century BC as the capital city of the Nabataeans, it is a symbol of Jordan as well as its most visited tourist attraction.It lies on the slope of Mount Hor in a basin among the mountains which form the eastern flank of Arabah (Wadi Araba), the large valley running from the Dead S ea to the Gulf of Aqaba. Petra has been a UNESCO World Heritage Site since 1985. The downfall of Petra began under the Roman Empire. The basic reason being was the change of trade routes. Most of the Petra was destroyed by earthquakes, which damaged buildings and fractured the lifeline of Petra; the water management system. 2. 7 Taj Mahal: Taj Mahal famously known as the ‘Symbol of Love' is a mausoleum, built by the Mughal emperor Shah Jahan for his wife Mumtaz Mahal.It is located in Agra, India. Taj Mahal's construction began around 1632 and it took around 21 years to be completed. It was constructed according to the Mughal architecture, which is a combination of Persian, Indian and Islamic architectural styles. The mausoleum was built solely in marble, while other buildings in the complex were made of red stone. For the decoration purposes, 28 types of precious and semi precious stones were used and the raw material is believed to be ordered from as far as Afghanistan in the North and Sri Lanka in the South.It is said that nearly 20,000 workers were employed from all across the country for the construction work. These include skilled artisans, carvers, sculptors and stone cutters of excellent rapport. All in all, 37 people formed the creative unit of the project. Some of them were from foreign countries too. The approximate cost of construction is estimated to some 32 million rupees (Indian currency). It is considered as one of the master pieces of Mughal Empire and attracts tourism from all over the world. Statistics suggest that approximately 2 to 4 million people visit Taj Mahal annually.So, according to the above discussion we can say that every wonder has its own importance in the present world according to their historical background and their construction. People from all over the world visit these wonders to satiate their curiosity. Now a day’s architectures are in the constant struggle to make the new wonders which are better than the a ncient and present wonders, but still the present wonders have great importance at the present time and architectures have to work very hard to defeat these wonders.Work Cited: 1. â€Å"Temple of Artemis. † Encyclopedia Britannica. Encyclopedia Britannica Online. Encyclopedia Britannica Inc. , 2012. Web. 27 Mar. 2012. <britannica. com/EBchecked/topic/36816/Temple-of-Artemis> 2. â€Å"Colossus of Rhodes. † Encyclopedia Britannica. Encyclopedia Britannica Online. Encyclopedia Britannica Inc. , 2012. Web. 28 Mar. 2012. <britannica. com/EBchecked/topic/501620/Colossus-of-Rhodes. > 3. Mish, Frederick C. , Editor in Chief. â€Å"Petra. † Webster’s Ninth New Collegiate Dictionary. 9th ed.Springfield, Massachusetts: Merriam-Webster Inc. , 1985 4. Graham Hancock and Robert Bauval, The Message of the Sphinx, Pyramidology, 4 volume, 1957-1972, Web. 5. Nakate. Shashank. Seven Wonders of the World. Web 3/16/2010. Buzzle. com 6. Baxamusa. Batul Nafisa. 7 Wo nders of the Ancient World List. Web. 2/25/2011. Buzzle. com 7. Marian K, Original Seven Wonders of the World. Web. 10/3/2011. Buzzle. com 8. Saxena. Chaitra Suraj, New 7 Wonders: What are the Seven Wonders of the World?. Web. 9/30/2011. Buzzle. com Seven Wonders of the World Seven Wonders of the Ancient World While the ancient world left little written record, the evidence that we do have depicts it as far more advanced and culturally rich than many would expect. From the Phoenicians in Mesopotamia to the Mayans in Central America, technological advancements and complex theories drove the ancient civilizations ahead. Great thinkers from that period like Socrates left huge marks on the literary world. Great scientists like Copernicus developed theories that provided the foundations for more modern thought. Juxtaposing their technology with our own, we find their accomplishments truly amazing.Their buildings, remarkably built without cranes, bulldozers, or assembly lines, rival our greatest and create great wonder among our culture. Chief among their architectural feats, the Seven Wonders of the Ancient World remind us constantly of the ancient cultures’ splendors and advancements. These landmarks, the Great Pyramid of Giza, the Hanging Gardens of B abylon, the Temple of Artemis at Ephesus, the Statue of Zeus at Olympia, the Mausoleum of Halicarnassus, the Colossus of Rhodes, and the Lighthouse of Alexandria or the Walls of Babylon according to the list, left evidence of the magnificence of the ancient world.Understanding the history of the whole group as well as the history of the individual places creates a gratitude and reverence for our ancient ancestors. Herodotus created the first list of wonders in the fifth century BC but gained little notoriety for the feat and inspired few subsequent lists. His written record, a list mirroring that above with the exception of substituting the Pharos of Alexandria for the Lighthouse, was destroyed with the exception of references in the burning of the Library of Alexandria (History Reference Center). In following centuries, however, Herodotus’s ideas began to catch on.Conquering vast empires in the name of Macedonia, Alexander the Great led a strategic military campaign througho ut the Balkans and much of the ancient world. Through these fourth century BC annexations, Alexander stimulated travel in the area, which in turn led to the Greeks gaining immense cultural knowledge about peoples like the Persians, Egyptians, and Babylonians. Alexander truly opened their world. With the influx of travel, the Greeks began and compile oral lists of ‘theamatas,’ a word translated to mean ‘the must-sees’. The lists, though they varied from person to person, lways contained a constant number of seven sites. Being neither a product nor factor of any number less than ten, seven is hard to separate into subdivisions and therefore provides an excellent number for indivisible things like the Seven Wonders, the Seven Deadly Sins, and the Seven Sages. After Herodotus, the next well-known list is that of Callimachus of Cyrene, a worker at the Library of Alexandria. He wrote a work entitled ‘A Collection of Wonders in Lands throughout the World,â⠂¬â„¢ but destroyed early on, the contents of the list remain unknown.De Septem Mundi Miraculous, or Of the Seven Wonders of the World, was written in 200 BC. Attributed to and supposedly written by Philo of Byzantium, many argue that it was actually written in the sixth century AD (Infoplease). Regardless, this work gives an excellent description of Seven Wonders, including the Hanging Gardens of Babylon, the Pyramids of Giza, the Statue of Zeus at Olympia, the Colossus at Rhodes, the Mausoleum of Halicarnassus, the Temple of Artemis and Ephesus, and the Lighthouse of Alexandria.While most lists agree on at least six of the seven wonders, some ancient and modern lists substitute the walls of Babylon for the Lighthouse of Alexandria. The most renowned ancient list, coming around 80 years later, belongs to Antipater of Sidon and does exactly this. A citizen of Alexandria, Egypt, Antipater compiled his list in a poem during the second century BC, saying   I have gazed on the walls o f impregnable Babylon, along which chariots may race, and on the Zeus by the banks of Alpheus.I have seen the Hanging Gardens and the Colossus of Helios, the great man-made mountains of the lofty pyramids, and the gigantic tomb of Maussollos. But when I saw the sacred house of Artemis that towers to the clouds, the others were placed in the shade, for the sun himself has never looked upon its equal outside of Olympus (History Reference Center)   These lists inspired others to not only explore but to tell of their explorations.After the works of Herodotus, Callimachus, Philo, and Antipater, people strove to make their own lists of wonders, almost always including the eight documented by Philo and Antipater. The oldest and only remaining of these eight wonders, the Pyramids of Giza took ancient Egypt by storm in 2560 BC. A remarkable architectural feat, they remained the tallest structures in the world until the nineteenth century. They originally stood at 481 feet tall but have shr unk to around 450 feet.Khufu’s pyramid, also known as the Great Pyramid, contains 2,300,000 blocks weighing around two and a half tons each. Every side of that pyramid is 756 feet long (Infoplease). Fourth-Dynasty Pharaoh Khufu, also known as Cheops, ordered the pyramids built as tombs for Pharaohs Khufu, Khafra, and Menkaure. Their splendor begins with their location. Cheops chose a plateau made of white limestone located southwest of Cairo. Surrounded by the Nile River, spacious green plains, astounding palm groves, and the magnificent skyline of Memphis, the area itself is a wonder.Originator of the concept of Seven Wonders, Herodotus became the first to describe the Pyramids when he visited Egypt around 450 BC. His account of the pyramids begins with an insult of Cheops, saying claiming â€Å"Cheops, who reigned over them, plunged the country into deep calamities† (History Reference Center). In Herodotus’s books, he asserts that Cheops employed over 100,000 slaves at a time, switching the men out every three months, but ancient historian Diodorus Siculus alleged that the pyramids actually required 360,000 slaves.Recent discoveries, however, have pinned the number of workers between 5,500 and 8,000 and declared that they worked willingly, not as slaves. Herodotus goes on to describe a magnificent causeway used to transport stones and marvelous underground rooms that took approximately ten years to build. With information gathered from his Egyptian guide, Herodotus chronicled the process used to build the pyramids, writing   This pyramid was constructed on the following plan.They began by building it in the shape of steps, having first made it in this form, they drew up the stones for the rest of the work by means of machines, consisting of short pieces of wood, when they had lifted them from the ground to the first tier of the steps; as soon as stone had reached so far, it was laid on another machine, placed on the first range; from t hence it was hauled up to the second [and from the second to the third,] by means of another machine, for as many as the tiers of the steps there were, there was the same amount of machines. This passage shows the technological advancements employed by the Egyptians.The architecture behind the underground rooms proved extremely innovative; Cheops used a canal from the Nile to create an insulation system (Books). Summing up his Egyptian encounter, he gives a brief account of the lesser two pyramids, built as tombs for Khafra and Menkaure, and moves on to new things. Though many people doubt its existence, the alleged regality of the Hanging Gardens of Babylon stupefies many. Herodotus, previously mentioned as the first big traveler of the era, gave a full description of the city of Babylon, making no mention of the Hanging Gardens.This causes speculation among many historians today (History Reference Center). For those who do believe, however, the Hanging Gardens stood in Mesopotamia , near the present location of Baghdad, Iraq. Berossus, a Babylonian priest, wrote the first account of the Gardens in 3rd century BC, but since then, the works have been lost. Strabo and Philo gave the next ancient descriptions. Philo wrote, The Hanging Garden has plants cultivated above ground level, and the roots of the trees are embedded in an upper terrace rather than in the earth. The whole mass is supported on stone columns.Streams of water emerging from elevated sources flow down sloping channels. These waters irrigate the whole garden saturating the roots of plants and keeping the whole area moist. Hence the grass is permanently green and the leaves of trees grow firmly attached to supple branches. This is a work of art of royal luxury and its most striking feature is that the labor of cultivation is suspended above the heads of the spectators. (Books)   While most of Mesopotamia lived up to its appellation the Fertile Crescent, Babylon differed, having a desert-like clim ate.According to ancient writers like Berossus, Philo of Byzantium, and Diodorus Siculus, King Nebuchadnezzar II ordered the Gardens built for his wife around sixth century BC (Infoplease). Amyitis, a native of the luscious green Persia, greatly missed the beautiful landscape of her home, and as any affectionate husband would do, Nebuchadnezzar built the Gardens to appease her. The King filled the Gardens with pears, plums, grapes, and many other colorful plants. Providing great shade among the sandy landscape, the Gardens served as a retreat for the royal family.For the scholars that believe that the Hanging Gardens actually existed, another argument arises over whether or not the Gardens actually â€Å"hang. † In their Seven Wonders of the Ancient World, Michael and Mary B. Woods argue that the description of the Gardens as â€Å"hanging† comes from a translation issue. They assert that the original Greek word can be translated into â€Å"hanging† or â€Å"ov erhanging† and claim that the original authors meant â€Å"overhanging†. Because its very existence remains disputed, no evidence of the date or method of destruction endures.Built in 560 BC, the Temple of Artemis at Ephesus paid homage to the Greek goddess Artemis, goddess of the hunt, childbirth, and virginity (History Reference Center). King Croesus of Lydia ordered the Temple built on a marshland in present-day Turkey, and one hundred and twenty years later it opened for worship. Towering above other structures in the land, the Temple, made of marble, stood 300 long by 150 wide and massive columns (Infoplease). Croesus chose the location in hopes of protecting it from volatile earthquakes.That natural disaster, however, would not cause the destruction of the Temple; instead, it would fall victim to arson committed by a power-hungry Herostratus in 356 BC, on the birthday of Alexander the Great. Greek legend holds that Artemis, busy assisting with Alexander’s c hildbirth, found herself too preoccupied to protect her Temple. Alexander, sympathetic to this story, offered to pay for the restoration of the Temple, but the Ephesian leaders rejected the request claiming it was â€Å"inappropriate for a god to dedicate offerings to the gods† (Books).Despite Alexander’s dismissal, the Ephesians, led by sculptor Scopas of Paros, rebuilt the Temple of Artemis at Ephesus, beginning almost immediately after the original’s destruction. The new Temple, the first made purely of marble, laid the foundation for extravagant building. Bigger than the original, it had 27 columns stretching 60 feet into the sky, spanning 425 feet long and 225 feet wide. Athens’s pride and joy, the Parthenon is believed to have only been a quarter of the size of the Temple of Artemis at Ephesus.Pliny the Elder provided a base ancient description of the Temple, along with many other Grecian works, in his Natural History, written in the 1st century AD. Of the Temple, he wrote, â€Å"The most wonderful monument of Grecian magnificence, and one that merits our genuine admiration, is the Temple of Diana at Ephesus† (Books). Some, like Pliny, referred to the Temple as the Temple of Diana, Artemis’s Roman form. As Christianity spread through the ancient world, the Temple slowly became obsolete and eventually met its demise through raids from the Goths in 268 AD.Dedicated Ephesians made a final attempt to rebuild the Temple after its destruction, but Roman Emperor Theodosius the Great’s decision to outlaw Christianity, eradicating the Temple’s purpose. Site of the earliest Olympics, Olympia wished to honor its supreme god, also patron of their games, for their prosperity and success. To do this, they commissioned Phidias, chief sculptor behind the Parthenon, to build a statue paying homage to this god, Zeus. Using an innovative method designed by Phidias himself, he built a wooden skeleton in the intended sh ape of the statue and ordered workers to adorn it.Sheets of iron and gold were cut and fashioned to cover the wooden structure. Looming over the Temple of Zeus, the statue rose 40 feet into the air and was a massive 22 feet wide. Zeus’s Statue features him sitting on a magnificent throne, with his head brushing the ceiling. The ancient historian Strabo criticized the proportions of the statue, claiming that Phidias â€Å"depicted Zeus seated, but with the head almost touching the ceiling, so that we have the impression that if Zeus moved to stand up he would unroof the temple. (History Reference Center). Citation Page 1. Scarre, Chris. â€Å"The Seven Wonders Of The Ancient World. † (2004): 125-127. History Reference Center. Web. 13 Nov. 2012. 2. Infoplease. Infoplease, n. d. Web. 13 Nov. 2012. . 3. â€Å"Books. † Seven Wonders of the Ancient World. N. p. , n. d. Web. 13 Nov. 2012. .

Moral Responsibility

Naina Navni Professor Adams UCWR 110 21 October 2010 Moral Responsibility America would not be where it is without the laws that have been placed and the citizens who follow the laws. In order for this to happen the knowledge and acceptance of the laws are needed to establish order. African Americans had been secluded in the past through harsh laws of segregation.Although many believe disobeying the law is morally wrong and if disobeyed a punishment should follow, Martin Luther King’s profound statement, â€Å"One has the moral responsibility to disobey unjust laws† (King 420) leads to greater justice for all which is also supported by King’s â€Å"Letter from Birmingham Jail,† Jefferson’s â€Å" The Declaration of Independence,† and Lincoln’s â€Å"Second Inaugural Address. † â€Å"I am in Birmingham because injustice is here,† wrote Dr. Martin Luther King, Jr. , in his â€Å"Letter from Birmingham Jail† (King 416 ).Eight Alabama clergymen composed a statement urging restraint in the Civil Rights movement and the discontinuance of demonstrations in Birmingham. The clergymen explained that progress could best be achieved through negotiation and through the court system and suggested that direct action would only make the situation worse. In response to this statement, Martin Luther King, Jr. composed his famous â€Å"Letter from Birmingham Jail† to explain why he was active in civil rights demonstrations, primarily because of the failure of the courts and negotiation to address the issue of civil rights effectively.One of King's most important and most extended arguments begins with the  distinction between just and unjust laws. He begins by stating one has a legal and a moral responsibility to obey just laws. Conversely, one has a moral responsibility to disobey unjust laws. â€Å"I would agree with St. Augustine that an unjust law is no law at all† (King 420). A distinction i s made that an unjust law is a human law that is not rooted in eternal law and natural law and by contrast, any law that uplifts human personality is just.Through these definition King can elaborate on his claim he developed earlier, â€Å"Segregation distorts the soul and damages the personality,† to draw a central conclusion which condemns segregation statutes as unjust (King 420). Any law that degrades human personality is unjust and all segregation statutes are unjust because segregation distorts the soul and damages the personality. Therefore this supports his conclusion, â€Å"Segregation gives the segregator a false sense of superiority and the segregated a false sense of inferiority† (King 420).Segregation is morally wrong and sinful, therefore action was needed to be taken to prevent it. In the second phase of this argument, King redefines â€Å"unjust law† in such a way as to intersect the democratic argument seen developed in Jefferson’s Declar ation of Independence. King begins his argument by stating what defines an unjust versus just law. â€Å"An unjust law is a code that a numerical or power majority group compels a minority group to obey but does not make binding on itself. This is difference made legal . . . a just law is a code that a majority compels a minority to follow and that it is willing to follow itself.This is sameness made legal . . . a law is unjust if it is inflicted on a minority that, as a result of being denied the right to vote, had no part in enacting or devising the law† (King 421). The segregation laws were enacted by the Alabama legislature, representatives to which Negroes did not vote for because they were denied the right to vote brings up a question â€Å"Can any law enacted under such circumstances be considered democratically structured? † (King 421). Such laws are not democratically structured, therefore such laws are unjust.After King clearly demonstrated that segregation l aws are unjust, it follows the immediate opening premise, â€Å"One has a moral responsibility to disobey unjust laws† that we are obliged to disobey segregation laws (King 420). King shines a new light on the disobedience of the law by expressing his belief that â€Å"An individual who breaks a law that conscience tells him is unjust, and who willingly accepts the penalty of imprisonment in order to arouse the conscience of the community over its injustice, is in reality expressing the highest respect for the law† (King 421).This therefore means that conscientious disobedience of an unjust law, especially with the intention of overturning injustice, shows the highest respect for the law, where just law is supposed to derive from natural law and God's moral order. King's language here echoes Jefferson, but particularly in the Declaration of Independence where Jefferson argues that governments exist to protect basic human rights, â€Å"Deriving their just powers from t he consent of the governed† (Jefferson 437).At time it appears that the letter might even surpass the Declaration of Independence in its importance and value, as the letter speaks on behalf of all Americans as a unified â€Å"we† (Ess). Lincoln’s famous â€Å"Second Inaugural Address† given in 1865, exemplifies what King tries to explain in his letter. The main message gained is that all men are created equal, therefore segregation laws should not exist (Ess). Lincoln’s speech laid the foundation for others, such as King, to continue to work hard to abolish segregation and discriminative treatment.King’s use of logos, appeals to our logic or reasoning and gives his own example of how segregation affected his life. Once, he was randomly arrested for walking around without a walking permit. Another example, an elderly black woman states, â€Å"My feets is tired but my soul is at rest† (King 430). He mentions that the old woman’s s tatement is grammatically incorrect, and emphasizes her lack of education and his awareness of it. He draws attention to this fact to point out that even the uneducated know and sense the magnitude of the injustice of segregation.Also, in quoting this elderly woman, King's appeal includes an appeal to the emotions. His use of imagery of this elderly woman with tired feet, we feel for her in that she is old and must endure this march to fight for something she should already have. The laws denied the rights of the elderly woman because of her race, hence the law being unjust, which King believes is fair not to follow. The main problem that was occurring in society was segregation. Similarities between King’s letter to the â€Å"The Declaration of Independence† and â€Å"Second Inaugural Address† are visible as both documents strive for the same goal: equality.If a law is morally wrong and unjust, then it is our responsibility to disobey it. King argues his point in a variety of ways, particularly the example of the elderly black woman complaining about the pain in her feet from the march and how King points out the grammatical errors in her speech which show her lack of education, yet still understands that segregation happening, knows it is wrong, and wants it to end.Works Cited Danner, Natalie, and Mary Kate. Paris. â€Å"King’s Letter from Birmingham Jail. † Mercury Reader: a Custom Publication. New York: Pearson Custom Pub. , 2009. 412-31. Print. Danner, Natalie, and Mary Kate. Paris. â€Å"Lincoln’s Second Inaugural Address. † Mercury Reader: a Custom Publication. New York: Pearson Custom Pub. , 2009. 434-35. Print. Danner, Natalie, and Mary Kate. Paris. â€Å"Jefferson’s The Declaration of Independence. † Mercury Reader: a Custom Publication. New York: Pearson Custom Pub. , 2009. 436-40. Print. Ess, Dr. Charles. â€Å"King's Letter from the Birmingham Jail. † Drury University, Springfie ld, Missouri. Web. 16 Oct. 2010. .

Competition in Healthcare

In the U. S. economy, when companies or organizations compete for consumers’ business, consumers usually win with lower prices and better quality product (Stossel, 2007). This idea has spread to the healthcare industry and is being encouraged as a way to increase value for patients (Rivers, 2008). With the healthcare industry being a very diverse industry, there are many different forms of competitions as well as benefits and shortfalls for competition in the healthcare market.Traditional competition in healthcare involves one more elements of price, quality, convenience, superior products or services, new technology and innovations (Rivers, 2008). There are different forms of healthcare competition. One form of healthcare competition is the competition that exists between individuals who provide healthcare such as physicians and other healthcare practitioners (Rivers, 2008). These entities compete for patients who are able to pay on their own, or who have their own health ins urance (Rivers, 2008). They also compete off of a non-price basis (Rivers, 2008).This means they are competing with their location, their colleague referrals, and their reputations (Rivers, 2008). Physicians and other healthcare practitioners may also compete in the medical market by reducing competition from non-physicians like psychologist (Rivers, 2008). The benefits for this type of competition are that it forces the healthcare practitioner and physicians to be more patient-orientated. It also encourages prices to competitive since some of these individuals are paying for the services out of their own pocket and is price conscious (Stossel, 2007).Another form of competition in the healthcare industry is healthcare organizations, such as hospitals (Rivers, 2008). These entities compete for physicians, third-party payers and patients (Rivers, 2008). They compete for patients by providing more services, better amenities and discounted prices (Rivers, 2008). They also compete for ph ysicians by trying to maintain a cutting edge of competition with their technology and new medical discoveries (Rivers, 2008). The final form of competition in the healthcare industry is between organizations that provide healthcare financing, insurance and plans.These entities compete with access, premiums, benefits, quality and different degrees of freedom in choosing a provider and the benefits or coverage services. The pitfall for this type of competition is that it can often be confusing for consumers who are comparing different insurance or financing plan. Competition in the healthcare industry is being encouraged to help better the quality of care patients receive as well as reduce medical costs. When patients have the choice of where they receive medical care, competition and having a competitive edge on opponents is important.Since the healthcare industry is so large and diverse, there are different forms of competition between healthcare entities. Ultimately competition is supposed to benefit the consumer and patients. resources: Rivers, P. (2008). Healthcare competition, strategic mission and patietn satisfaction:research models and propositions. Retrieved on October 13, 2012 from www. ncbi. nlm. nib/gov/pmc/articles/PMC2865678 Stossel, J (2007). The Competitive Advantage. http://abcnews. go. com/2020/story? id=36026262&page=1

Art Essay Example | Topics and Well Written Essays - 250 words - 15

Art - Essay Example The roofs of churches were vaulted and supported by thick stone walls, rounded arches and massive pillars. The creation of large churches during the Romanesque period was propagated by the strong devotion to Christianity and the church. There was a common belief among the Christians that the world was going to end a thousand years after Christ’s birth. This made people to have more commitment and devotion to church and so the churches had to be increased in size so that they could accommodate the large masses. The increase in size was also caused by political and cultural reasons. Flying buttresses is a masonry structure which typically consists of an inclined bar on an arch that extends from the top part of the wall to the pier which is some distance from the wall. Its main function is to carry the thrust of the vault. The pier is often crowned by a pinnacle which adds weight and enhances stability. The buttresses evolved during the gothic era as they allowed the building of high ceilinged churches (Kleiner 267). This changed the Notre-dame in Paris church architecture in general; it made the churches to have high vaults as they were strongly supported by the buttresses and pinnacles. They made churches to be bigger with high

The ideas and practices associated with marketing emerged in response Essay

The ideas and practices associated with marketing emerged in response to the challenges posed by mass production, and these idea - Essay Example In addition, the adoption of marketing strategies in the face of increasing competition is discussed. The evolution of marketing On the advent of the factory, new products began to emerge while old products appeared in strikingly new forms. With the flooding of the market with uniformly mass produced products that were virtually indistinguishable from one another, branding was introduced to differentiate the products. Competitive branding evolved to compensate for the product similarity, thereby, achieving image based difference. Essentially, advertising changed from delivering product news to developing an image around a branded version of a product. Design theorists assert that logos were introduced to evoke familiarity in an effort to address the new and unsettling similarity of packaged goods. Brand names replaced small shop keepers as the interface between the consumer and the product (Klein, 2001, p.12). In recent years, marketing has gone into an overdrive with increasing numb ers of ads and aggressive new formulas for reaching customers. The astronomical growth rate of the advertising industry is well reflected by the 1998 projection which set the total ad spending at $196.5 billion while the global estimate was $435 billion. This figure outpaces the growth of the global economy by a third. This trend is attributed to the firmly held belief that brands need to continuously and constantly increase advertising in response to increased competition. According to the law of diminishing returns, as more firms increase their ads firms are under increasing pressure to aggressively market their brands (Arvisdsson, 2006, p.178). As a result of the competition, marketers invented more strategies to attract customers. This caused marketers to introduce more clever and intrusive selling techniques. For instance, Calvin Klein stuck CK Be perfume strips on the back of Ticketmaster concert envelopes to attract customers to the CK Be brand. Proponents of branding claim t hat markets where producers compete based only on price, promotions and trade deals are susceptible to product duplication leading to decreased profits. Some companies have over time integrated their respective brands in the fabric of their companies. Such companies mould a corporate culture around the brand. Everything within such organizations is an ad for the brand; this includes branding employees with such tags as partners, superstar CEOs and design consistencies (Brownlie, et al, 1999, p.379). New media has revolutionised the interaction between consumers and organizations characterized by a shift in power where consumers have more influence on the product. The rise of consumer generated content has turned consumers into content producers. Consumers now possess greater control over what is provided in corporate communications. The shifts in power have not only changed consumer expectations but also have changed purchasing decisions (Bob, 2005, p.285). There is extensive eviden ce of a decline in traditional media usage among advertisers. In response to changes in technology, marketers are shifting expenditure to new media options. New media has transformed many aspects of brand marketing such as segmentation and targeting through positioning, distribution and customer relation management (Bob, 2005, p.285). Marketing strategies Marketing strategies evolved as a result of the need by marketers to deal

Dannon Company Research Paper Example | Topics and Well Written Essays - 1500 words

Dannon Company - Research Paper Example Dannon has since become the yoghurt founding company in America. Dannon is one of the leading producers of beverages, packaged foods and top selling yoghurt brands globally. The main value of the company is Health and Nutrition. The mission of the company is towards the provision of health through the food supply to the largest number of people possible (Dannon’s CSR 2009 Overview). The vision of the company is health for all people. The company is always looking for different ways of encouraging people to eat healthier and delightful tasting dairy products. Dannon produces and sells over 100 different products across the globe which varies in different sizes, styles and flavors of cultured dairy products. Transparency 1. Level of public disclosure. The company has a high level of public disclosure. That is, Dannon Company makes the information about its company public and makes it open to investors and shareholders. In every financial year, the company makes public its CSR re port, events and all annual reports. The company gives a press release of all activities taking place including company awards and all nutrition grants. All this is done with the aim of enhancing investor and shareholder confidence on the company. 2. Responsibility for environment/sustainable development. Dannon Company engages in Corporate Social Responsibility activities. ... nt, company has also increased its health and nutrition and nature of its produces which include packaging, energy consumption and manufacturing (Dannon’s CSR 2009 Overview). The company has also cut by 10% on its overall carbon footprint during the 2009 financial year. As part of its responsibility towards sustainable development, Dannon Company helps people in making informed food choices in order to improve their health and nutrition. Dannon Company also supports initiatives which encourage nutrition education, supports research and education which help in exploration of the relationship between better health and nutrition. To Dannon Company, its responsibility goes beyond the usual business of just producing yogurt products as it the company’s privilege to be an active partner in the provision of families with information and tools required for health lives. Dannon Company is committed to three core values in its corporate social responsibility activities, and they include health and nutrition, nature and people. The company is highly committed in the production of those products which are quite useful to the consumer (Laszlo, 2003). The company strives to makes nutritious products, engages families and children at the community level, and makes use of Dannon Next Generation Nutrition to help children in understanding the usefulness of healthy eating habits. The company also limits the kind of products to advertise to children and engages in childhood nutrition education programs. When it comes to nature, the company is highly committed to environmental sustainability as it has been saving on its carbon foot print, has reduced the quantity of its primary packaging and also saves fuel by re-inventing different ways of making energy saving bottles and cups. The

Will special programs for reconvicts reduce recidivism Essay

Will special programs for reconvicts reduce recidivism - Essay Example The study will focus on the area covered by the Metropolitan Police force and the State of Colorado in the U. S. A. it will compare and contrast the statistics relevant to the study. The convicts who have been reconvicted and those who have not been will also be compared and contrasted to study whether there is a class of persons more likely to reoffend than others. The histories of both the classes of convicts will be studied to determine the necessary steps to be taken for the prevention of recidivism. The results of this study will be utilized to identify the most representative of reconvicts will be formed. Experimental groups of the classes will be identified. The experimental groups will be given correctional lectures, incentives for good behavior including the shortening of the period of notification and a role in social aid for police forces (volunteering for traffic police duties etc.) apart from psychotherapy and counseling. Persons in each group will be selected randomly. The study will be done with the aid of secondary data in the form of the records maintained in the form of Violent and Sexual Crimes Register, Offenders Index and the National Police Register in the United Kingdom and the similar records in the U. S. A.

Cherished Love Essay Example | Topics and Well Written Essays - 750 words

Cherished Love - Essay Example He was taking the information so deeply it seemed my decision was so abrupt. I always told him about it before, preparing him for such a time as this as I knew pretty well that my departure is inevitable. My mother is in the United States and she wanted me to join her because things are really tough for us in Poland. My boyfriend said he was afraid I would stop loving him. Of course this was foolish. I know deep in my heart that I would always cherish him, adore and regard him with deep love and fidelity. I understood how he felt. I feel the same way however, I kept it unspoken. The atmosphere was so tense between us especially when he got testy, finding how I might take things if some unexpected events happened. To all his questions I said I will always remain loving him. How would I forget such a wonderful man? He was always romantic, always ready with something new to spice up our relationship. Expecting a surprise from him would never stop me from being surprised. He was just so witty, bright and fantastic. There never seemed to be a boring moment spent with him. He was always thoughtful. One of the treasures I brought along with me is a couple of brown bunnies my boyfriend gave me. He knew how I love animals and he just thought I might want to have something that would last for years, something that would not die, â€Å"like our love†, he said. That was so sweet of him and I treasure such memories. I find my boyfriend a wonderful man who is just so full of equally wonderful ideas to express how he felt towards me. This made me always feel comfortable with him even in the presence of his parents or friends. I knew I was genuinely loved and I in return, gave my generous love that seemed to have known no bounds. My days would always be fantastic after spending time with him, sharing a lazy moment when we did nothing but talk, laugh and enjoy each other’s company. He is a true debonair, I must say. He sure is the sunshine in my life, bringing che er to my gloomy days and encouragement when I am down. He is always energetic I always wonder where he finds all the strength to be so active in school and at home and yet would find much time to nurture the relationship that we shared. He is also funny and sometimes, he would go to an extreme and could almost be hilarious. There are also days that he would just simply be silly but not the kind of silly that is laughable. He sometimes just expresses himself weirdly like for instance, we are walking and he suddenly kneels in front of me to sing a song of love. I find that stupid and silly especially when he does that in front of other people but I guess that is how love would drive a person to madly indulge in. I consider my boyfriend mature and reflective. When he talks, he makes a lot of sense one would think he is speaking to a philosopher. He is a dreamer and in his plans and objectives, he always considers me. We were still teenagers then, and I think for a man to have such clea r perceptions of his future at such age, there is a certain maturity that is almost unseen from most of our age mates. He was always sincere with his words, expressing his love when he is at the summit of his emotions and saying just how bad he felt when something bad hit him. This is one of the attributes that has attracted me to my boyfriend because I find that in our world today, men who show their manliness through muscles and good looks and probably a string of women they attach to their character. However for me, I am more interested in the attitude than the physical attributes. He is also kind-hearted and sensitive. Sensitivity might be more appropriate for women, thought of as a feminine attribute yet, I find it attractive to be on a man especially

My Philosophy of Education Essay Example | Topics and Well Written Essays - 750 words

My Philosophy of Education - Essay Example From the video clip, the children learn by touching, seeing and feeling the concepts in the use of beads in understanding math. The child gets comfortable with all the materials that represent certain symbols. They can count the symbols from 0-9 by binding the spindle by a rubber band, to represent symbols. This is aimed at helping them manipulate numbers of any magnitude. Pestalozzian and Montessorian teaching techniques included the use of a special environment for learning, by using materials and activities that are based on the conservation of the children. Contrary to the conventional schools, children are not motivated to learn by rewards and subjected to punishments if they fail. Here children learn at their will. They concentrate on structure and play with objects, repeat the previous actions until they master a specific skill. Their capacity for learning lead to reading and writing skills on their own will. Ms. Williams used the same techniques as Pestalozzian and Montessorian. She gave children materials like small sticks and beads to play with. They tie the objects in the representation of symbols. They learn the concept of numbers and understand math. This is because children like playing with objects and enjoy touching everything. They learn by touching, feeling and gaining skills from it. Same as Pestalozzian and Montessorian, they are no t motivated by rewards. They learn at their convenience. Ms. Williams gives objects to children to learn by touching and playing with them. They acquire skills not by being told but by touching, seeing and understanding how everything works. For instance, a cat can scratch when handled carelessly, instead of telling them, they will experience it. So they will be careful next time, because they touched the cat, and learned how to handle it; where to touch it and where to avoid. That’s a skill they have learned through their own initiative.

Around the World Essay Example | Topics and Well Written Essays - 1000 words

Around the World - Essay Example Channel Access: Access of the alliance company to the various channels required for the business. Local Laws: Local laws with respect to formation of alliances need to be considered. Competency and Value of the Alliance Company: Competency of the alliance company and the value that it adds to the alliance is key to a successful alliance. The alliance must take the form of an international joint venture. International joint venture is an economically and legally separate organizational entity that has been created by 2 or more parent organizations with the objective to achieve strategic objectives. Parent companies invest both financial and other resources at disposal into the alliance (Schuler et al., 2004). A joint venture alliance has various advantages and is best suited in the current case. The major challenges for Around the World in establishing an international joint venture is shareholdings, human resource management, skills sharing and knowledge transfers. These challenges c an be overcome by effective and early planning. Share holdings and control structures of the partners need to be established and agreed upon before the alliance materializes. There are various ways to effectively manage the HR issues and, the knowledge and skill management issues. A four stage model of formation, development, implementation and advancement can be used to effectively to handle the challenges (Schuler & Tarique, 2004). Case Study 2 Following are the discussion points for the three questions at the end of the case study: 1. Aditya Birla Group adopted a growth strategy that made great business sense. The group exited from any business that did not offer them greater presence in the global market or the business which had registered losses. The group diversified and adopted businesses whose operations gave the group global presence and lead to acquiring of competencies in the market. The company built a business portfolio which is not limited to a single industry. The po rtfolio demonstrates the group’s ability to run different businesses efficiently and also has contributed to various revenue generating sources which has made the group immune to economic downturn in certain market or industries. 2. Various initiatives were taken by the group under the leadership of Kumar Mangalam Birla which has contributed to the group’s success. Gyanodaya was a great initiative which helped in the transfer of best practices. Appointment of new managers gave rise to a new dimension in the group’s leadership. Continuous learning and developing of human resources was one of main motive behind many of the initiatives. 3. Aditya Birla Group has addressed its second part of the mission – â€Å"Indian Values† by actively involving and contributing to the development of the country. It is presently working in 3700 villages. It is concentrating on health care, sustainable livelihood, infrastructure, education, social causes, etc through its Aditya Birla Centre for Community Initiatives and Rural Development. It is running around 18 hospitals and 14 schools. Case Study 3 In order for Aston Restaurant to extend their business to China, they have to consider various factors and the two important factors are the market and the localization. Market No two markets are same and there are numerous differences that have to be looked into. The following various issues/factors have to be addressed or considered for Aston to successfully expand to China: Language: Language is a primary barrier here and Aston has to ensure that language i.e., communication must not hinder the business. Chinese is the primary language used in China. Customs and Practices: The customs and practices in China are different from those in other countries. In

Sociological Analysis of the Crucible Essay Example for Free

Sociological Analysis of the Crucible Essay Sometimes, the person who should be the one wielding the power has none at all. In Arthur Miller’s play, The Crucible, he recounts the events of the Salem Witch Trials. As he tells the events that occurred, he clearly paints out who held the power and who should have been in power during the trials. In Miller’s play, the person who holds the most power in Salem during the Witch Trials is Abigail Williams. Despite being a child and an orphan, for her parents had died and she was sent to live her uncle Mr. Parris, she was able to gain unlimited power during this short span of time. When Mr. Parris caught her and other local girls out dancing at night, she threatened the others, â€Å"Let either of you breathe a word, or the edge of a word, about the other things, or I will come to you in the black of some terrible night†¦Ã¢â‚¬  (20), and they listened to her. None of the girls would speak against Abigail, and when Mary Warren did, the other girls did not join Mary; they protected Abigail and listened to her every word. As the play goes on, Abigail gains more and more power, accusing people in the town as witches. At the end of Act 1, Abigail cries out to Reverend Hale, â€Å"I want the light of God†¦ I saw Sarah Good with the Devil! I saw Goody Osburn with the Devil!†(48). Unfortunately for the accused, they were arrested and were tried by Judge Danforth, and were found to be guilty of witchcraft. Abigail becomes a saint in Salem, saving the villagers from the witches; however, little do they know, Abigail is using her newfound power for her own good. When she accuses Goody Proctor of being a witch, no one questions her; Abigail is helping the town out. But, the reason she accuses Goody Proctor is because Abigail secretly wants to be with John Proctor, Goody Proctor’s husband. When John Proctor defends his wife in court, he confesses to adultery with Abigail, and tells them that is why Abigail accused Goody Proctor in the first place. John Proctor tells Judge Danforth, â€Å"But it is a whore’s vengeance†¦ she thinks to dance with me on my wife’s grave!à ¢â‚¬ (110). Nether less, Abigail has power that John Proctor does not, she can ‘see’ the Devil, and Danforth believes her. Abigail Williams has the power in Salem, though she does not deserve it. Though Abigail has authority in Salem, the one who really deserves the power is John Proctor. Throughout the whole affair, Proctor is the only one who knows what is right and what is wrong. When Mr. Cheever comes to Proctor’s house to collect his wife, Goody Proctor, Proctor tells them, â€Å"Is the accuser always holy now? We are what we always were in Salem, but now the little crazy children are dangling the keys of the kingdom, and common vengeance writes the law!†(77). Proctor accurately sums up the situation in Salem, yet no one with any real power believes him, and they all discount him. Later on in the play, Proctor tells Judge Danforth, â€Å"I believe she means to murder,† (104). John Proctor was trying to tell the Judge that Abigail really was a bad person, not the saint she was painted out to be. But, Judge Danforth was under Abigail’s spell, and didn’t listen to John Proctor, even though he was the only person who actually was thinking clearly during this whole situation. John Proctor was the only who kept clear head during the Salem Witch Trials, and if he had held the power, not Abigail, things would have changed drastically. In The Crucible, by Arthur Miller, the events of the Salem Witch Trials are recounted. As the play continues, Miller accurately shows who has the power and who should have had the power. Abigail Williams, despite being an orphan, was hailed as a saint and everyone listened to what she said; however, she was a liar and a whore. John Proctor, who was accused of being a witch and was never listened to, had a clear head and understood what was happening unlike the other villagers. The Salem Witch Trials could have been avoided if the power had been taken out of Abigail’s hand and given to John.

The object of grammar Essay Example for Free

The object of grammar Essay Two types of grammar: normative, theoretical. Two parts of grammar: morphology, syntax. Grammar is a branch of Linguistics which studies the grammatical structure of language. The grammatical structure covers the rules of changing words and rules of arranging the forms of words into phrases and sentences. Grammar may study the gr. Structure of a language in different aspects. So? We distinguish: historical grammar which describes the str. of words, phrases, sentences in the process of their historical development; comparative gr. which deals with comparison of gr. systems of different languages; descriptive gr. analyses the gr. system of a language as it exists at a certain period of time. Grammar is divided into 2 types: Normative and Theoretical. Normative (Practical) Grammar gives rules how to build correct forms of words and syntactical constructions. It teaches to write and speak correctly. Theoretical (Scientific) Grammar describes the language as a system, studies the components of that system and relations between them. Theoretical gr. explains and analyses the most difficult phenomena of a language. It gives different concepts of these phenomena and helps linguists to be guided in linguistic literature in order to form a certain opinion of this or that theoretical form. Grammar is divided also into 2 parts: Morphology and Syntax. Morphology is a part of Grammar which studies the most characteristic features of classes of words. These classes are called parts of speech. Morphology studies not a single word, but the whole classes. Syntax is a part of Grammar which studies phrases and sentences, their structure, classification and combinations. Syntax is a system of 2 levels-that of phrases, that of sentences. It may be said that, in a way, morphology is more abstract than syntax, as it does not study connections between words actually used together in sentences, but connections between forms actually found in different sentences. In another way, however, morphology would appear to be less abstract than syntax, as it studies units of a smaller and more compact kind, whereas syntax deals with larger units, whose types and varieties are hard to number.

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

Procrastination Essay -- essays research papers

Procrastination Procrastination is the avoidance of doing a task that needs to be accomplished. Procrastination has a high potential for painful consequences. It may interfere with our personal or academic success. There are those of us who wait until the due date is a day away. I am not talking about making sure the money is in the bank. I am talking about putting it off because it is a tedious chore that we do not enjoy doing. Procrastination is a big problem for many, and one that can harm your career. Whether your procrastination causes you to arrive late at work or late for meetings, or keeps you from turning projects in on time, employers do not look positively upon it There are several reasons why we procrastinate. If a project is absolutely overwhelming, to the point where you don't even start it, break it down into small, specific steps. Do one or two each day. If you complete a step and are motivated to continue, fine. But if you're not, that's fine too because you have only committed to one small piece. Just don't stop before completing that piece. If there is no immediate payoff because the project is long term, build in mini-completion points. Design a reward system similar to what you do with a task you don't like. Creating instant gratification will motivate you until you reach the final destination. If you know you can handle the project but just don't know where to start, start anywhere. Just do something. Write a title on a piece of paper. Then write something else. Eventually you'll be led to where you need to go. But it takes a little bit of momentum to get the ball rolling. This doesn't mean that you'll use any of the material y ou start with. This is fine - you need a good finished product, not a good first draft. A final, common reason for procrastination is perfectionism. Be aware that there is a difference between doing something right and doing the right thing. Perfectionists can spend their time on the wrong thing, i.e. hanging and re-hanging a picture on the office wall. Looks great, but is it getting you anywhere? If the task is meaningless in the long run, it doesn't really matter if you do it perfectly. You can still do it well, just don't let it consume you. If perfectionism is keeping you from beginning a task, reevaluate whether the ... ...ntil the last minute to start a difficult task can also be used as a defense for poor performance. You can always claim that it would have been better if there was more time. (The report would have been more comprehensive if you had been given more time to do it.) It can shield you from the consequences that you expect to occur after the project is completed. For example, not accepting a high visibility special assignment will shield you from the consequences of a) being in the limelight and possibly failing or b) doing well and being offered more challenge. This could take the form of a new position as the office manager, a relocation or a new set of circumstances that may be frightening. If you are not feeling up to the rigorous standards that you have set for success, or are trying to live up to others have set that the expectations for your performance, delay can be used as a means of self-protection. When you find yourself blocked, unable to start a task and you have tried everything else, ask yourself: "Is there anything, no matter how small, that I am willing to do?" When you find that small thing, you are no longer procrastinating.