The Invasion of Canada in 1775
The invasion of Canada in 1775 saw the newly created Continental Army of the United States launch their first military action in the American Revolutionary War. It also marked the first major defeat of the Americans in the Revolutionary War. The invasion led by Colonel Benedict Arnold and General Richard Montgomery, was staged in the city of Quebec with the aim of protecting Canadians from British rule. Americans also hoped to persuade Canadians to join their campaign in revolting against England.
Events leading to the Invasion of Canada in 1775
After the forces led by Benedict Arnold and Ethan Allen captured Fort Ticonderoga in the spring of 1775, Americans got wind that a British Army was being created in Canada under the command of Sir Guy Carleton. Owing to the American resistance of British rule, they thought that by invading Canada, a rebellion would be triggered. Through the invasions, they hoped British plans for war with rebellious colonies would be disrupted.
With the approval of the Congress, George Washington authorized the attack on Canada in 1775 under General Philip Schuyler. The offensive was to be led by Richard Montgomery, advancing with troops from Ticonderoga.
How the 1775 American Invasion of Canada Occurred
Also known as the Battle of Quebec or Canadian Campaign, the invasion of Canada in 1775 started late August when Gen. Schuyler led American troops up Lake Champlain and captured St. Johns. However, the battle impacted ill health on the General, forcing him to wait for Montgomery’s forces before making further advancement.
Montgomery and Arnold finally met and joined their troops in early December 1775, outside Quebec City demanding the city to surrender. However, their demands were rejected by the then governor of the province of Quebec, General Guy Carleton.
With the looming expiry of the enlistment of American troops, they continued the march towards Quebec under snowfall cover in the wee hours of December 31. As the troops approached and surrounded the city, the British were ready and fire erupted between the two forces.
Montgomery was unable to make it through the first assault, and after several unfruitful attempts to penetrate through the British defenses, his troops were turned back.
At the time of Montgomery’s defeat, Arnold and his men were also taking heavy fire on the northern wall, forcing them to retreat. Apart from losing several troops, Arnold also got wounded on the leg. His role was taken up by Patriot Daniel Morgan who continued the assault but got held back at the second wall in wait for reinforcement. As Arnold’s men arrived, the British had reorganized and the Patriots were forced to discontinue the invasion.
Arnold and his men had to stay fortified outside the city amidst raging cold and lack of supplies. Thanks to their counterparts, reinforcements arrived in spring but there were no further orders to proceed with the invasion.
Instead, the American troops moved back to Montreal to team up with other forces, from where they all marched to Crown Point for safety. During this time, British forces and Carleton were still in pursuit. However, they later decided to return to Montreal after failing to capture the Americans who survived the battle.
Results and Significance of the Invasion of Canada in 1775
The greatest impact of the invasion of Canada in 1775 was on the Americans, considering their defeat. Of the about 1,200 American soldiers who took part in the war, more than 400 were taken into captivity, suffered wounds or died. Apart from losing a number of men, American troops also lost one of their Generals, Montgomery. Colonel Arnold left the battle filed with a broken leg while Morgan was captured.
Casualties on the side of the British were low
Canadians did not stage an uprising against the British as expected by the Americans. Canada remained as a British colony.
Americans had not planned well for the invasion of Quebec and this was clearly shown in their defeat. Besides, they had not properly analyzed the information about anti-British sentiments in Canada.
However, the actions of Arnold and his men while retreating to Montreal on Lake Champlain bore great impact by holding back the British Army from staging a counter-attack until 1777.
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After the conclusion of Samnite War , Pyrrhic war began when all of central Italy was put under Roman control. Roman territories were brought closer to Magna Graecia cities in Northern Italy, bringing about conflicting interests and subsequent fights.
An overview of Pyrrhic War
The pyrrhic war began shortly after the end of Samite wars with the Lucians and Brattain’s fighting in the early 3rd century BC. The continued attacks on Greek colonies did not deter them from appealing to Roman regional power for assistance. At that moment, the City of Magna Graecia, Tarentum was the most powerful.
The city of Magna Graecia and Tarentum signed a treaty with Rome clearly stating that it would not send any of her troops into the Gulf of Taranto. This situation led conflicts between Rome and Tarentum because the former started interfering with the affairs of Greek colonies in Southern Italy.
Soon, other states in Magna Graecia including Croton, Locris and Rhegum asked for Rome’s support in their struggles with their neighbors. Rome sent a troop to garrison town of Thurri in 282 BC since it had been attacked by Lucania. Tarentum saw this as a hostile act and responded by sinking the fleet and expelling roman troops from Thurii.
The city and states of Magna Graecia had sought help from mercenary kings during their struggles but now, Tarentum sought assistance from King Pyrrhus of Epirus, on the Greek Peninsula across the Adriatic Sea from southern Italy. Pyrrhus landed in Italy with 25, 000 men and twenty war elephants in 280 BC. His first move against the Romans took place at Heraclea, small coastal town.
Pyrrhic War first and second engagement
The first engagement of the war took place at Heraclea, a small coastal town. The romans had 50,000 thousand troops who drove to the Lucanian territory to prevent them from aligning with Pyrrhus. Romans technically lost at the battle at the small coastal town, Heraclea and Pyrrhus lost a large number of troops. The pattern became quite common during the fight between Pyrrhus and Romans. Despite winning main engagements, Pyrrhus could no longer keep up with the war without support.
After marching to northern parts of Latium, Pyrrhus was not happy with the domination of Romans. He hoped that many cities would join his cause. He misjudged the situation because Roman military alliances were more stable. Roman rule was evident as many states enjoyed roman protection. Leaders of the states also enjoyed their positions under the leadership of the romans. However, only a few Lucanians and Samnite’s sided with Pyrrhus.
This led to the second engagement took place at the battle of Ausculum. It took two days with massive fights between ancient armies. The Romans were led by Publious Dentius Mus and used the terrain of the area to their advantage thus, reducing the effect of the elephants and Epirote Calvary. The first day was a virtual draw and the second day of the fight was a stalemate. At the end of the battle, more than 6000 Romans and 3, 5OO Epirotes died. Pyrrhus was left in the command of the field. It was the results of this fight that was considered the Pyrrhic victory.
Pyrrhus upon receiving the congratulatory message said ‘’ that one other such victory, would utterly undo him’’. He acknowledged the costly victories and thought of signing peace treaties to Rome with no success and he remained in Italy. Appius Claudius who built the Appian Way refused the negotiations calling for the freedom of Tarentum and her allies.
Pyrrhus went to Sicily in 278 BC, aided the Greek city against Carthage and became quite victorious. Rome formed alliances with Carthage against Pyrrhus and later on, Rome’s interest became conflicts. Pyrrhus in 275 BC went back to Italy, faced the romans in Southern Italy, town of Malventum and was defeated. With the victory of him, Pyrrhus left Italy for good and went to Green mainland.
Results of the war
Pyrrhus lost in the war, more than a third of his army died in the fight and there was little to show for his efforts. Two years later, he died in a street battle in Argos.
Tarentum which was the third significant Greek city in the state of Italy finally accepted to sign an alliance with Rome in 272 BC. Rome became the mistress of the entire southern and central Italy.
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Battle of Bunker Hill
The battle of Bunker Hill occurred on June 17, 1775, after the American Revolutionary War. Thousands of American militia besieged Boston and the British were trying their best to control the city and its valuable sea ports. They also aimed at taking over the harbor in Boston, to keep it open to bring in their troops and supplies. Therefore, the British focused on two hills, the Breeds and the Bunker in order to achieve a tactical advantage. The American militia got the news and went ahead to defend the hills.
Location of Battle of the Bunker Hill
The British wanted to bombard the Americans from a distance and they thought of taking over two hills, the Bunker Hill and the Breed hill. Therefore, the battle took place on the Breeds hill, Charlestown, Massachusetts. The battle was followed by the battle of Chelsea Creek and an engagement during the 11 month of Siege of Boston in April 19, 1775 to March 17, 177. It ended with British victory.
An overview of the battle of Bunker Hill
The battle of Bunker Hill was one of the most significant battles of the American War of Independence. This followed the first Revolutionary War at the Battle of Lexington and The Battle of Concord, the militia which took over Boston. The Americans received intelligence reports that the British under General Thomas Gage were planning to control the hills, Dorchester Heights area and Charlestown to maintain Boston harbor and acted immediately.
With more than 1000 men, the colonial militia under the leadership of William Prescott constructed ramparts and fortifications on top of the Hills and Charlestown peninsula area. The British men of war opened fire and Colonel William Prescott walked over the ramparts while his men continued to dig.
General Thomas Gage sent three thousand men to attack the Americans across Charles River. They attacked and the first two assaults were repelled by the militia. More than 1000men were injured and killed. More British soldiers were sent to Boston and by the third assault, the militia had to retreat back to Cambridge due to lack of ammunition and powder.
Leaders during the war
The British army was led by General William Howe
The Americans were led by Colonel William Prescott
Major John Pitcairn was also one of the front leaders for the British army. He was in command of the troops that started the war or fight at Lexington and started the Revolutionary War.; Israel Putnam was the General in charge for the Americans. Leading the patriot was also Dr. Joseph Warren. He played an active role in the battle but died while fighting.
Results of the Battle of Bunker Hill war
Even though the British won during the war and took over the hill, they paid heavily. Many soldiers and officers lost their lives. The Americans on the other hand were filled with a lot of courage knowing that they could stand up to their enemies, the British in a fight. Many colonists also joined the army and the revolution grew in strength.
The American Revolutionary war which included the battle of Bunker Hill became strong as it was a culmination of the American Revolution. Many American colonists rejected the legitimacy of the British to govern the 13 colonies without representation. The other interesting facts about the war is that
- The Americans were low in ammunition and couldn’t fire until they could see the whites with their eyes
- Troops from America worked tirelessly especially at night to build up their defense. They build a redoubt which was nearly six feet high
- General William Howe from Britain was really astonished at the American defense and said ‘’The rebels have done more work in one night than my entire army and what it would have done in one month.’’
- The British also suffered the most with many casualties in a single fight during the American Revolutionary War.
- Inexperienced forces also build up their confidence and in their ability to fight the British in the war and more specifically, in the first war of the American War of Independence. This was the significance of the Battle of the Bunker Hill.
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SWOT Analysis of GAP Inc.
SWOT analysis of GAP is an effective method that the company applies in determining its ability to survive in the market, while also growing revenue base. GAP Inc. is a leading world-wide retailer that deals in clothing, accessories and personal care products for the whole family. It operates six globally recognized brands including, Old Navy, Banana Republic, Gap, Intermix, Athleta and Piperlime. GAP has several more than 3,200 stores across the world and also operates an e-commerce website from where customers can get products information and do their shopping.
What is SWOT Analysis of GAP Inc?
A SWOT analysis of GAP Inc. basically explores the strengths, weaknesses, opportunities and threats of the clothing giant, with regards to the global market which targets. By determining the company’s strengths and opportunities, the management will be able to come up with measures on where emphasis is required for continued success.
The weaknesses and threats of a business are indicators of failure and by knowing them, the company can easily make decisions and plans for eliminating mistakes and avoiding losses in the future. The following is a comprehensive SWOT analysis of GAP Inc.
With the six brands that it operates globally, GAP has been able to attain a strong product portfolio and brand recognition. Coupled with its wide range of products that target the whole family, GAP Inc. enjoys global customer recognition and loyalty.
Its’ presence over a wider geographical area is also another strength that has made several people across the globe to identify with the company’s products.
Because of the global reach of GAP Inc. the business is able to record a high inventory turnover ratio. In fact, this is one of the main reasons the company commands a strong financial position in the market.
GAP Inc’s dedicated section for baby products is also another feature that has kept the business afloat since such products are always in demand even when the market is not doing well.
Despite the global customer base that GAP Inc. has, the company heavily relies on vendors from outside to sell its products. This is an area of weakness since such vendors are susceptible to various kinds of mistakes that may hinder the successful operations of the company.
The high competition in the apparel and accessories industry is also another point of weakness since it implies many customers are learning of new brands that could shift their buying trends. Besides, it also limits the market share of the company.
GAP has not fully focused onto penetrating the emerging economy markets and this has limited its ability for expansion and revenue growth.
One of the opportunities that GAP Inc. can exploit is the emerging markets in Asia and Europe. These markets present an ideal platform for expansion and profitability.
The growing use of technology in business is also another opportunity. Through effective online campaigns and shopping, the company can easily attract new customers for its products and brands across the globe.
Considering the good performance of GAP Inc. in operating six major brands is proof that it can still form franchise units and joint ventures with other companies in the industry for greater development.
The readily available market for kids’ apparel and products is also another opportunity that the company can fully explore for maximum profits.
The clothing and accessories market is experiencing a very stiff completion between various brands, offering more fashionable products at better prices than GAP Inc.
The rapid change in fashion trends is also another threat that the company has to plan on how to handle.
Counterfeits is yet another issue that is threatening the existence and success of businesses today.
Another threat is the increased production and operational costs, which could water down profits.
Conclusion on SWOT Analysis of GAP Inc.
According to this SWOT analysis of GAP Inc., the company is strong enough to withstand market forces considering its wide selection of products and brand portfolio, which have ensured global recognition, loyalty and financial power. However, it still needs to focus on international expansion into the emerging economies and intensifying its online presence. Besides, GAP Inc. also needs to consider the shifting fashion trends in order to meet customer needs.
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SWOT Analysis of Costco
SWOT analysis of Costco is among the best methods used by the company in evaluating itself and making decisions for sustainability in the market. Costco Wholesale is considered one of the largest retailers in the world today. Based in Seattle, Washington, Costco operates membership warehouses in the United States, Canada, Japan, Mexico, Spain and Australia. Besides, it also has several subsidiaries in Korea and Taiwan.
What is SWOT Analysis of Costco?
SWOT analysis of Costco refers to the evaluation of the strengths, weaknesses, opportunities and threats of the company. Considering the majority of players and shifting trends in the retail warehousing industry, it is always advisable that a company conducts a SWOT analysis in order to determine areas of weakness that require fixing and potentialities that should be fully exploited.
By conducting a SWOT analysis, Costco Wholesale will be able to know how to package itself for continuous growth and development in the market. Below is a comprehensive SWOT analysis of Costco.
These are the outstanding features of Costco that makes it unique and different from other retailers in the sector. One of the strengths of Costco is its pricing authority. The company mainly focusses on offering its customers quality products at the most competitive prices. The fact that it does not emphasize on maximizing profits in the short term gives many customers the confidence of always obtaining high quality products.
Brand loyalty is another strength of the company, which it has been able to attain through its constant pursuit of high quality and great value. This has enabled it to attract customer loyalty too.
Costco often records high sales volumes, which contributes to increased revenues. As a result of this, the company is able to make high revenues even if its prices are than other retailers.
Although Costco is a renowned profitable retailer, it still suffers certain defects that if not solved on time, might negatively impact operations. One of them is the company’s business model which allows only the members of the club to use the warehouses. As much as this may encourage customers to buy at the company’s stores, it also limits the number since non-club members might not feel welcome.
Another weakness of Costco is that the stores do not offer a wide variety of goods and services like other retailers. This tends to send away many customers who will opt to shop from stores where they can easily find all the products they need at once.
One of the opportunities that Costco can exploit is the increasing number of younger customers. The recent months have seen the company’s management take measures aimed at attracting young customers, a move that can significantly help in driving long-term sales to the company.
The going numbers of people using e-commerce is yet another opportunity that Costco should look into tapping. Intensive online marketing could also be a great way of venturing into new markets and attracting more customers.
Costco has plans to continue growing its reach on the international map. There several foreign markets with better prospects like China, France among others.
The warehouse services industry is one which is quite competitive, considering the high number of players involved offering similar process, quality and selection. In the domestic market, Costco is facing stiff competition from companies like BJ’s Wholesale Club, Sam’s Club among others. Internationally, there are several other competitors like internet retailers and even others that do not require membership.
The intensive marketing by other retailers dealing in similar products as Costco is yet another threat that the company needs to challenge in order to avoid being edged out.
Conclusion on SWOT Analysis of Costco
Costco Wholesale is a business with high viability, the reason it has continued to expand even poor economic times. Its competitive prices is a key strength that has kept the business afloat for long. The above SWOT analysis of Costco also reveals that the company has several opportunities it can exploit in order to tame the threats in the market. Through the firm’s website, intensive internet marketing and network of suppliers, it can effectively reach out to a wider customer base and scare away competitors.
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Company Profile: SWOT analysis of Best Buy
Best Buy is an American with its stocks trading on the New York Stock Exchange. It specializes in consumer electronics, accounting for about 20% of America’s domestic market in technology-based products. Best Buy has 24 stores across the United States. Besides its presence in America, it also operates in the United Kingdom, Mexico and Turkey. By the year 2010, Best Buy and its subsidiaries had more than 1,050 stores in local markets. Today, Best Buy is position 45, according to Fortune’s top 1000 companies. What are the factors that keep Best Buy outshining its competitors in the market? What are its weaknesses and opportunities? Read this SWOT analysis of Best Buy to find out more.
Strengths: SWOT analysis of Best Buy
Best Buy enjoys dominating the market in retailing electronic products in America. For example, it is the leading retailer of electronic goods in the USA, accounting for about 20% of the market. As a result, the company has a unique market position, which favors its business operations, making it position 45 on global ranking.
Another reason why Best Buy excels is its enhanced presence across the United States, with outlets all over. With its strong network, Best Buy is able to maintain its economies of scale and strengthen its brand image. This network allows the company to reach more customers and penetrate the market effectively.
Best Buy has good practices in terms of growth, profitability and community involvement. This gives it a higher customer satisfaction index as compared to other players in the industry.
SWOT analysis of Best Buy further shows that it manages several stores in America, as a joint venture with various warehouses. This relationship helps consumer to buy and use its products with a lot of ease.
Weaknesses of Best Buy
Besides dominating the market in retailing electronic products and making good profits over the years, Best Buy has a range of weaknesses. Its main weakness is over dependence on a few suppliers. By the end of 2007, Best Buy maintained only 25 suppliers, who accounted for the company’s 60% of purchases.
Additionally, Best Buy does not maintain strong ties its suppliers. It does not favor long-term contracts. This approach exposes the Best Buy to risks of shortages especially in the event one of the suppliers turns its back on them.
Another weakness is the endless lawsuits against its operations. In one of the suits, Best Buy was accused of charging higher prices more than what is advertised. In 2000, Best Buy was also charged for concealing warrantees of products with the aim of selling their labeled merchandise. Lastly, its overdependence on the US domestic market could affect sales with low economic growth.
Opportunities: SWOT Analysis of Best Buy
From this SWOT Analysis of Best Buy, it is clear that the company has a bright future with a range of opportunities to expand and diversify its operations. First, Best Buy can make major acquisitions. From its recent acquisitions, the company was able to increase its customer base and strengthen brand image in the market. Such will allow Best Buy to enter new market and develop new products under the same brand name and increase sales.
Secondly, Best Buy plans to expand its business in other countries. By expanding its operations geographically, this will guarantee the company more opportunities and a higher market share.
Threats of Best Buy Inc
The first threat is cutthroat competition from three main players, Amazon, Apple and Wal-Mart. The competition is stiff as the leading giants increase inventory of products related to electronics. In addition, these retailers offer installation services and focus on increasing their market penetration. With increasing competition, this many exert pressure on the company’s margins and harm its operating results.
Another threat is the increase in prices of rental equipment in America. If this trend escalates, it may increase Best Buy’s operating cost, which is likely to affect its profitability. The company also faces a risk of low sales because of low desire for Americans to make purchases. This SWOT analysis of Best Buy has explained the business environment, which favors and threatens the company’s optimal operations.
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Mark to Model
Mark to model is one of the most popular accounting practices that have been used across the globe. It is a practice that involves sharing of assets based on a mathematical model as opposed to market price.
In many cases, the accounting model is used on assets whenever there is no active market. However, it is good to note that Level 3 assets are often valued depending on a financial model used in an economy. Therefore, mark to model is the opposite of mark to market model where asset values are recorded based on the last price recorded on public exchange.
Mark to model takes into consideration the payout for specific assets. It also takes into consideration the risks involved when trading in the assets as well as their expiration date. In addition, it has a wide array of inputs that are very subjective and have been often criticized for providing a value that is more of illusion than real value.
In mark to model, an insurer may provide a policy that covers oil refineries. Therefore, oil refiners will have to pay an insurer over a specified of time. The periodic payments will however be paid back by an insurer in the event of a major disaster. The contracts in mark to model may not be traded publicly as in the case of market to market.
Contracts in mark to model are also highly specialized. This means that it can be very hard to find the real value of assets. A model that will help traders to find the expected payout, probability of finding a market, premiums and the probability of a disaster will have to be created.
In the case of an insurance company, an insurer can report an asset or a liability in a balance sheet. An insurer will also have to record its real value based on mark to model rather than the asset’s real market value.
Why mark to model matters
Mark to model has been considered a risky method of finding the value of assets and liabilities by economists. It is even more risky if it is used to price assets that are traded in a liquid and the market is declining. This is based on the fact that the model is always subjective at an individual level.
Mark to model does not put into account the number of buyers and sellers in the market who are willing to value an asset. Individuals therefore, may not agree on the accuracy if the price of assets priced using mark to model method.
The system also matters bearing in mind that it was used during the credit crisis in late 2000s. Mortgages and securities lost a lot of their values within a very short time. Federal Accounting Standards Board suspended mark to market accounting in favor of the model only to provide way to financial institutions to put up a value for their mortgages.
With mark to model, financial institutions were also able to place a value on MBSs in an old and tumultuous market. The model is similarly used in private bond market whenever it goes liquid.
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Nicotinamide Adenine Dinucleotide
Nicotinamide adenine dinucleotide simply called NAD refers to a coenzyme that is found in every living cell. This compound is the dinucleotide and since it has two nucleotides that are joined via phosphate groups. One of the nucleotides has a nicotinamide and the other an adenine. Nicotinamide adenine dinucleotide is usually found in two forms. These are the reduced form and in the oxidized forms abbreviated as NADH and NAD respectively.
Nicotinamide adenine dinucleotide is usually involved in the redox reactions in metabolism. It carries electrons across different reactions. Therefore, the coenzyme is found in two different forms in the living cells. These are the oxidizing agent NAD+ which accepts electrons from the other molecules becoming reduced. The reaction forms the NADH with is then possible to reduce as the reducing agent that donates electrons.
The electron transfer reactions are the major role of the NAD. Nevertheless, NAD is also used in cellular processes with enzyme substrate being the most notable that removes or add chemical groups from the proteins in the posttranslational modifications. Due to the crucial role of the functions of NAD, the enzymes that are involved in its metabolism are the targets of drug discovery.
In living organisms, synthesis of NAD can result from the simple building blocks the de novo. This is from amino acids aspartic acid and tryptophan. In the alternative fashion, complex components of coenzymes are usually taken up from the food in form of a vitamin known as niacin.
There are similar compounds that are released by the reactions that break NAD’s structure down. The preformed components pass via salvage pathway recycling them into an active form. There is also NAD that is converted to Nicotinamide adenine dinucleotide phosphate, simplified as NADP. Chemistry of the coenzyme is like that of the NAD. However, its roles in the metabolism process are different.
Despite NAD+ being written with the sign of superscript plus due to its formal charge in a certain nitrogen atom, for most part at the physiological pH is a singly-charged anion. The charge is that of minus 1. On the other hand, NADH is doubly-charged anion. For Haemophilus influenza growth, NAD is considered as the V factor. Just like other dinucleotides, Nicotinamide adenine dinucleotide has the two nucleotides that are joined by phosphate groups as their bridge. They also have ribose rings with one having adenine that is attached to first atom of carbon while the other is with the nicotinamide.
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Multidrug Resistance Protein 3
Multidrug resistance protein 3 is a protein belonging to the ABC subfamily C [ABCC]3) and it plays a significant role in the protection of hepatocytes as well as other tissues through extreation of different toxic organic conjugates of anion including the bile salts. Expression of multidrug resistance protein 3 or ABCC3 increases in a liver of individuals who are cholestatic but this molecular mechanism of the up-regulation stays elusive.
Basically, multidrug resistance protein 3 is a member of adenosine triphosphate binding cassette, the ABC transporter super-family. It expresses itself in different tissues including kidney, liver, adrenal gland, bladder and intestine of rodents and humans. Multidrug resistance protein 3 is localized in the basolateral membrane of the cells and it excretes sulfated, taurine-conjugated bile salts, glycine and bilirubin glucuronides, leukorienes, 17 x- glucuronosyl, and several drugs.
Hepatic multidrug resistance protein 3 expression under normal physiological circumstances is low. However, this expression is up-regulated significantly as adaptive and protective response when an individual is suffering from cholestasis. The up-regulation is also observed in the liver of a patient during the advance stages of primary biliary cirrhosis. It is also the case for parient with the extrahepatic cholestasis that is caused by pancreatic malignancy. However, it is not the case with patients in their early stages of progressive familial intra-hepatic cholestasis or PBC.
According to these revelations, it has been concluded that the distribution of multidrug resistance protein 3 and the basolateral position that it occupies in polarized cells suggests that the protein play an important role in metabolism when it comes to intestinal uptake of the organic anions as well as removal of the organic acids from liver cells and bile under cholestasic conditions.
The study revealed that multidrug resistance protein 3 up-regulation is high in the liver of the rats that were made cholestatic through litigation of the bile duct. It is also the case in the cholestatic liver of humans. Multidrug resistance protein 3 is also present in adrenal cortex in high levels. This has increased the possibility of multidrug resistance protein 3 being responsible for the secretion of certain hydrophilic steroid home derivatives including the dehydroepiandrosterone sulfate.
Despite being a member of the MRP subfamily that is involved in the development of multi-drug resistance, specific function of multidrug resistance protein 3 is yet to be determined. Nevertheless, it has been proven to play a significant role in the intestinal organic anions excretion and biliary transport.
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Multidrug Resistance-Associated Protein 2
Multidrug resistance-associated protein 2 [MRP2] or ATP-binding cassette sub-family C members 2 is a protein that in humans is programmed by the ABCC2 gene. The MRP2 is a known member of the ATP-binding cassette [ABC] transporters. ABC transporters are members of protein superfamily that is one of the largest and oldest in the families with members from extant phyla from prokaryotes to human beings. The term multidrug resistance has been used to elaborate the mechanism of resistance that cells [Eukaryotic and prokaryotic] have in response to the many chemotherapeutic drugs.
ABC proteins transport various molecules across extra and intra-cellular membranes. ABC genes are divided into seven unique subfamilies that include ABC1, MDR, TAP, MRP, GCN20, OABP and White. The ABC protein is a member of the MRP subfamily which is involved in multi-drug resistance. The protein is also exceptionally exhibited in the canalicular [apical] section of the hepatocyte and aids in biliary transport. The known substrate include anticancer drugs such as vinblastine. Thus, the multidrug resistance-associated protein 2 [MRP2] appears to contribute to drug resistance in mammalian cells.
Multidrug resistance-associated protein was incorporated into the drug resistance scene in 1992 when Susan Cole and Rodger Deeley cloned the Multidrug resistance-associated protein gene, the MRP1. The Multidrug resistance-associated protein 2 [MRP2] followed in 1996 and more MRP members followed. The MRP2 was characterized as the canalicular multispecific organic anion transporter [cMOAT] from its cloning. Homology is also high in MRP2 as it is in the Multidrug resistance-associated protein 1 [MRP1] 3 and 6. On top of this, these MRPs also share the characteristics of TMD0L0 segment. They are also seen in glutathione-drug conjugate [GS-X] and aid pump from eukaryotes like leishmania and yeast.
Within the ABC transporters in mammalians, the MRPs form a group that is clearly defined from the other known groups. MRP2 are able to transport methotrexate. MRP1,4 AND 5 RNAs are widely spread in the body while for MRP2, 3 and 6 mainly appear to function in kidney, liver and gut. While gathering more information on Multidrug resistance-associated proteins, there are a few problems encounter in the study. For instance;
- The MRPs are characterized and so they are organic anion transporters. Most of the substrates for these transporters are extremely charged and do not penetrate the cell membrane.
- Antibodies that work against MRP are often cross-react with another member of multidrug resistance-associated protein family. This issue can be solved by generating monoclonal antibodies against the non-conserved parts of the MRP family.
- The body cells chosen for drug resistance often overexpress multiple transporter genes. The use of certain inhibitors or transfected cells has helped solve this problem.
- It is challenging to get the multidrug resistance-associated protein transfectants giving high expression and products channeled to cell membrane. Most of the cells contain organic anion and this result to background transport activity.
Multidrug resistance-associated protein 2 is helpful in protection against exogenous toxic compounds. The presence of many ABC transporters available offer defense against toxic compounds. The discovery of MRP family has improved the study of MDR in tumor cells and led into interest in the functions of the MRP family members in normal metabolism.
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The genotype is the genetic character of a cell, organism or an individual and it is referenced with certain characteristics being considered. The genotype of an organism is usually the inherited instructions that it carries within its genetic code. Genetic variation in populations can be analyzed and quantified by the frequency of alleles [same genes or same genetic locus]. Population genetics is determined by two great and imperative calculations and these are the genotype frequencies and allele frequencies. Genotype frequency in a population is the number of individuals with a given genotype that is divided by the total number of individuals in the population.
Genotype frequency is the proportion of the genotypes in a population. Although the allele and genotype proportions relate, there are differences to hold in your fingertips especially if conducting research on genetic variation in populations. Genotype frequency has also been effective and it guarantees a bright future when it comes to genomic profiling and making it easy to predict someone is having a disease or a birth disorder. Testing of different gene variants for prediction of diseases such as Type 2 diabetes or coronary heart disease will become easier. More so, genotype frequency can also aid in determining ethnic diversity.
Genotyping is the process of revealing the genotype an individual with a biological assay. The techniques involved include Polymerase chain reaction [PCR], DNA fragment analysis, allele specific oligonucleotide , DNA sequencing, nucleic acid hybridization and DNA microarrays or beads. DNA fragment analysis is a technique that can be used to ascertain certain disease causing genetic abnormalities such as microsatellite instability [MSI], aneuploidy, or loss of heterozygosity [LOH].
When determining genotype or allele frequency, keep in mind that the sum is always less than or equal to one [it is less than or equal to 100%]. The Hardy-Weinberg principle or law is useful in describing the relationship between genotype frequencies and allele frequencies especially when a population is not evolving. There are several factors that are known to affect genotype frequency and they include;
- Selective sexual selection- There are certain genotypes and phenotypes that get choose by mates. The alleles of the chosen mates increase in frequency while the alleles that are not chosen will decrease.
- Differential migration- Here if a certain phenotype moves out of an area, the frequency of those alleles will decrease while those that stay in a chosen area will increase.
- Assortative mating- This is a kind of mating that affects genotype frequencies expected under the Hardy-Weinberg equilibrium. This is because when an individual mate favorably with other individuals that are phenotypically similar, this leads to an overabundance of homozygous individuals occurs since similar phenotypes are likely to share akin genotypes. When mating of similar phenotypes takes place more frequently than random mating, the possibility of offspring receiving two copies of an identical allele increase perturbing the Hardy-Weinberg outlooks.
- Natural selection- certain phenotypes survive and those alleles increase in frequency whereas the alleles of the unsuccessful ones decrease.
- Isolation [Founder effect] – This is a form of genetic drift that affects genotype frequency. Here, if a small group of individuals is separated from main group, they may have a different frequency of alleles in the gene group. As population grows, these frequencies may differ from the main group.
Genotype frequencies and gene frequency are related variables and thus affected by similar factors. Besides the aforementioned factors affecting genotype frequencies, mutation and random genetic drift are the other notable factors. Genotype frequencies are easy to measure and the simplest case is working on a case where you have one genetic locus with two alleles and three genotypes. To learn more on representations of the genotype frequencies, the De Finetti diagram can aid as it is useful in population genetics presentations.
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Inbreeding refers to the process of producing offspring by mating or breeding organisms or individuals that are related closely genetically. The opposite of inbreeding is out-crossing which is breeding or mating individuals or organisms that are not related. Analogically, the term inbreeding is used in reproduction in human although it commonly refers to genetic disorders as well as other consequences that arise from constanguinity and incestuous sexual relationships.
Homozygosity results from inbreeding. This can increase changes of the offspring suffering the effects of deleterious or recessive traits. Generally, this leads to decreased fitness biologically in a population. This is known as inbreeding depression and the ability of a population to reproduce and survive is greatly reduced.
Individuals that inherit the deleterious traits are called inbred. The main reason for selective out-crossing is avoidance of the deleterious recessive traits or alleles that result from inbreeding. For many years, inbreeding has been used as a technique for selective breeding. Breeders, for instance use inbreeding in livestock when they want to establish a desirable and new trait in their stock. However, they always watch for the undesirable characteristics in the offspring that can be eliminated later through culling or further breeding selectively.
Inbreeding is basically used in revealing the deleterious recessive alleles that can be eliminated via culling or assortative breeding. Inbred lines in breeding of plants are used as the hybrid lines creation stocks. This makes it possible to use heterosis effects. In plants, inbreeding occurs naturally in form of the self-pollination process.
In human beings, offspring of persons that are closely related are likely to suffer the effects of inbreeding including congenital birth defects. Chances of the disorders occurring are increased by the closeness of the relationships of biological parents. This can be attributed to the fact that pairing increases proportion of the homozygous zygotes being produced in the offspring, particularly, the deleterious recessive alleles that produce the disorders.
In populations, majority of recessive alleles are not common. It is highly unlikely for marriage partners who are unrelated to carry the alleles. Nevertheless, due to the fact that close relatives have a large portion of alleles, there is a dramatically high probability that such deleterious alleles will be inherited from common ancestor via both parents.
This is contrary to the common belief that allele frequencies are not altered by inbreeding but instead, it increases relative homozygote to the heterozygote proportion. However, its frequency decreases rapidly in an inbred population due to the increased proportion of the deleterious homozygote allele exposed to natural selection.
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Genetic drift is also called allelic drift. It is change that occurs in the frequency of gene variant or allele in the population. Genetic drift is caused by random sampling. Alleles that are found in an offspring are samples of the ones found in the parents. In addition, chance plays a role in determining if an individual offspring survives and successfully reproduces.
Allele frequency of a population refers to a fraction of copies of a gene sharing a particular form. Gene variants can disappear completely due to genetic drift. This reduces genetic variation. In cases where allele copies are few, genetic drift’s effect is larger. When allele copies are many, there is a smaller effect.
Vigorous debates have occurred over relative importance of the natural selection process versus the neutral processes such as genetic drift. Some scientists such as Ronald Fisher are of the view that the entire process of genetic drift plays a minor role in the evolution process. This has remained a dominant view over the years.
Motoo Kimura in 1968 rekindled this debate with the neutral theory of the molecular evolution. The claims are that most instances of genetic change spread across the population. However, these are not necessarily phenotypes’ changes. They result from genetic drift.
Many scientists view genetic drifts in statistical drift in a population over time due to the effects that random sampling have in successive generations’ formation. In a narrower sense, genetic drift can be seen as expected dynamics of a population of the neutral alleles. Neutral alleles are the ones that are defined as comprising negative and positive impact on the reproductive fitness. They are predicted to becoming fixed at 100 percent or zero frequency eventually in absence of other mechanisms that affect the distribution of allele.
Genetic drift can cause a loss of genetic traits in a population. A genetic trait can also become widespread in the population irrespective of the reproductive or survival value of the involved alleles. Random statistical effect of genetic drift can be seen in small and isolated populations where there is small gene pool that is sufficient to allow chance to change its makeup significantly.
In a larger population, specific allele can be carried by many individuals making it almost certain that it will be transmitted by some organisms of the population unless if it is unfavorable biologically. Nevertheless, genetic drift, mutation, migration and natural selection are the basic mechanisms that facilitate evolution.
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Nucleic Acid Sequence
Nucleic acid sequence is determination of nucleotide bases sequence in a RNA or DNA fragment. This type of sequencing is an indispensable tool for carrying out basic biological research and it is also applied in varying fields like molecular diagnostics, forensics, systems biology, pharmacogenomics and genetic engineering.
By principle sequences are presented from the five inch to the three inch end. Normally, nucleic acids are linear (unbranched) polymers specification of the sequence is equivalent to definition of covalent structure of the complete molecule. Precisely for this reason, sequence and nucleic acid is also termed as the primary structure.
Sequence also has the capacity of representing information. Biological DNA also represents the information that is needed to direct functions of a living thing and in such context, the term genetic sequence is used often. Sequences can also be read from biological raw material though DNA sequencing techniques.
Nucleic acids also have a tertiary and secondary structure. The primary structure of often mistakenly known as the primary sequence. Equally, there is no parallel concept of tertiary and secondary sequence. The analysis of DNA sequence was traditionally accomplished through use of two varying techniques:
- The ddNTP mediated chain termination technique if Sanger (1997
- The chemical degradation technique of Gilbert and Maxam (1997).
Numerous next generation sequencing technologies for DNA have been developed and while this is the case, the traditional nucleic sequence techniques are routinely used in majority of life science laboratories. Obtaining optimal results with the conventional sequencing techniques requires careful reagents selection.
Nucleic acids is comprised of a chain of units that are linked known as nucleotides. Each nucleotide is made of 3 subunits which include, a sugar (ribose in RNA case and in DNA case deoxyribose) which makes up the backbone of nucleic acid strand, phosphate group and a set of nucleobases attached to the sugar. The nucleobases are especially important in the base pairing of strands to form tertiary and secondary structure like the famed double helix.
Possible letters in this case include A, C, G and T which represent the 4 nucelotide bases of DNA strand adenine, cytosine, guanine, thymine-covalently linked to a phosphodiester backbone. I n typical cases, the sequence are printed adjoining one another without any gaps as in the sequence AAAGTCTGAC which is read left to right in the 5 inch to 3 inch direction.
Current methods of sequencing rely on discriminatory ability of DNA polymerases and as such can only distinguish 4 bases. When using current technology, it is difficult to sequence small amounts of DNA because the signal is usually too weak t be measured and this can be overcome by polymerase chain reaction (PCR) amplification.
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Gene expression refers to the process through which genetic instructions are used for purposes of synthesizing gene products. The purpose of genes is information storage as such, each gene contains information that is needed to make a protein or in other cases, RNA non-coding. Genes are expressed in order to produce functional protein molecules and RNA in the cells.
Gene expression can occur in two stages which include transcription and protein synthesis:
In this case, the gene is copied so it can produce RNA molecule (primary transcript) with basically similar sequence as the gene. In most cases, human genes can be divided into introns and exons. Only exons carry information needed for protein synthesis. The most primary transcripts are consequently processed through splicing in order to remove intron sequence and as such, generate mature messenger RNA (mRNA) or transcript that is comprised of exons only.
This is the second stage and it is also known as translation for the simple reason it does not have any direct correspondence between the sequence of amino acids in the protein and nucleotide sequence in DNA (RNA). As a matter of fact, there are three nucleotides which are needed in order to specify one amino acid. The amino acid chain must also fold up in order to generate final tertiary structure of protein.
All genes in human genome are not expressed in the same manner. There are those that expressed in all cells at all times and they are known as housekeeping genes. They are essential for the purposes of carrying out basic cellular functions.
There are other genes that are expressed in specific cell types or at particular development stages. For instance, genes that encode protein muscle like myosin and actin are expressed in muscle cells only not in brain cells. Still, there are other genes that are inhibited or activated by signals circulation in the body like hormones.
Differential gene expression is achieved through regulation translation and transcription. All genes are also surrounded by DNA sequences that control expression. Proteins known as transcription factors bind the sequences and can switch genes off and on. As such, gene expression is controlled by activity and availability of different kinds of transcription factors.
Note transcription factors are in themselves, proteins as such, they must be produced by genes as well and the genes should be regulated through other transcription factors. In such a manner, all proteins and genes can be linked into regulatory hierarchy starting with transcription factors in the egg at the start of development. There are some diseases that are caused by malfunction or absence of transcription factors as such, they cause gene expression interruption.
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