title: Redditch

text: The parliamentary constituency of Redditch is represented by Rachel Maclean of the Conservatives, elected in the 2017 General Election.


title: Redditch

text: Redditch has a Borough Council with councillors elected from the Wards of Redditch, which manages lower-tier local government services. Worcestershire County Council manages upper-tier services.


title: Redditch

text: The foundation stone for Redditch Town Hall was laid in 1981. It cost £7.5 million to build and it was opened in 1982.


title: Redditch

text: Redditch is in Worcestershire, just south of the West Midlands urban area. It is north of Evesham on the A435, which skirts it to the east. The main access routes are the A441 via junction 2 of the M42 Motorway, the A435 from junction 3 of the M42 and the A448 via junctions 4 or 5 of the M5. The Roman Road known as Icknield Street is prominent, running north to south through the eastern side of the town.


title: Redditch

text: The Borough of Redditch is divided into several districts. To the east of the town are "New Town Districts" built in the 1970s and 1980s. To the west of the Borough are older "Former Village Districts" that dominate the south and west.


title: Redditch

text: Since 2011, Redditch has participated in the Greater Birmingham & Solihull Local Enterprise Partnership along with neighbouring authorities Birmingham, Bromsgrove, Cannock Chase, East Staffordshire, Lichfield, Solihull, Tamworth, and Wyre Forest.


title: Redditch

text: Redditch is within a green belt region that extends into the wider surrounding counties, and is in place to reduce urban sprawl, prevent the towns in the nearby West Midlands conurbations centred around Birmingham and Coventry, discouraging further convergence, protect the identity of outlying communities, encourage brownfield reuse, and preserve nearby countryside. This is achieved by restricting inappropriate development within the designated areas, and imposing stricter conditions on permitted building.


title: Redditch

text: The main urban area up to the Webheath, Walkwood, and Hunt End suburbs, Astwood Bank, and the southernmost extent of the borough are exempt from the green belt area, bar small adjacent green belt 'wedges', but surrounding smaller villages, hamlets, and rural areas such as Feckenham, Littleworth, Old Yarr, and Ham Green up to the B4090 Salt Way road are 'washed over' by the designation. The green belt was first drawn up under Worcestershire County Council, and the size in the borough in 2017 amounted to some .


title: Redditch

text: The M42 motorway is a short drive away and it is linked by dual carriageways and A-class roads to surrounding towns such as Bromsgrove and Evesham. There are regular bus services to Studley, Bromsgrove, Catshill, and Birmingham.


title: Redditch

text: The Cross-City Line provides a regular train service via Birmingham New Street to Four Oaks and Lichfield. Redditch railway station, the southern terminus of the line, was first opened as the terminus of the Redditch Railway on 19 September 1859, alongside what is now Clive Road. This first station stayed until 4 May 1868 when the last section from Alcester to Redditch of the Redditch and Evesham Railway was closed, at which point a second station was built alongside the junction of Bromsgrove Road and Plymouth Road. This station was provided with a standard Midland Railway design and two platforms. The current station was built in 1993.


title: Redditch

text: There is an extensive network of local bus services run by Diamond West Midlands and other operators (including Stagecoach and a community run bus). Many services run from the bus station in the town centre, a postcard of which was voted Britain's most boring postcard in a competition run by the photographer Martin Parr. The bus station was rebuilt as part of the 2002 shopping centre expansion.


title: Redditch

text: Some areas of Redditch have dedicated bus routes; however, there have been issues with safety on these routes and 3 children have died over the past 15 years.


title: Redditch

text: Redditch is occasionally noted for its confusing road system dominated by a system of dual carriageways built when it became a New Town, including the only cloverleaf interchange in England at the junction of the A441 and the Bromsgrove-bound A448. The system is designed to allow rapid flow of large volumes of traffic around the various districts and into the town centre, whilst keeping fast moving vehicles separated from residential streets. Redditch was briefly famous (via The Graham Norton Show) for a tongue-in-cheek calendar featuring its "picturesque" roundabouts created by a local printing company. The calendar was called, unsurprisingly, 'Roundabouts of Redditch' and it proved so successful that it sparked a national series. This self-similar pattern is found on a smaller scale in many of the modern estates in the town, which follow a Radburn style of planned community.


title: Redditch

text: Redditch is one of the few areas of the country where the three-tier system of first, middle, and high schools still exists. Students attend first school from the age of 4, middle school from the age of 9, and secondary school at the age of 13. Other areas of Worcestershire adopted this system at the same time as Redditch (in the 1970s), but many have reverted to the traditional 5–7 infant, 7–11 junior and 11-16/18 secondary schools.


title: Redditch

text: Redditch currently has four high schools (RSA Academy Arrow Vale, Saint Augustine's Catholic High School, Tudor Grange Academy, Trinity High School) and six middle schools.


title: Redditch

text: Heart of Worcestershire College (often referred to locally as "HOW College") is a large general further education college: one of its four campuses is in central Redditch; the other three are in Bromsgrove, Worcester, and Malvern.


title: Redditch

text: Since June 2013, the swimming pool at Abbey Stadium Leisure Centre has been heated using waste heat diverted from Redditch Crematorium. Redditch Borough Council expects the scheme to reduce the leisure centre's gas bill by more than 40%, equivalent to an annual saving of about £15,000.


title: Redditch

text: Malcolm Bradbury's novel "The History Man", which was dramatised by the BBC in 1981, contained a reference to Redditch when Flora Beniform, a sociologist, mentioned to the hero Howard Kirk that she was studying an outbreak of troilism in Redditch.


title: Redditch

text: It is also sometimes reported as being mentioned in the John Cooper Clarke song, 'Burnley', however Reddish (a district in Greater Manchester) is the more likely interpretation.


title: Redditch

text: Redditch is featured in a section heading in "An Utterly Impartial History of Britain" by John O'Farrell.


title: Redditch

text: Birmingham and national TV comedian Jasper Carrott makes Redditch a repeated butt of his jokes, for example over the difficulty of escaping the Redditch ring road.


title: Redditch

text: Kingfisher Shopping Centre was opened in 1976 by the then Prime Minister James Callaghan and now forms the town's primary retail centre.


title: Redditch

text: The centre has over of retail space, with stores including Primark, Next plc, Boots UK, H&M, The Perfume Shop, and Warren James Jewellers. It is one of the largest covered shopping centres in the United Kingdom. In 2007, a cinema opened on the new upper floor and is now owned by Vue Cinemas.


title: Redditch

text: Redditch has of public open space in Arrow Valley Country Park. This incorporates the Arrow Valley Lake, fed by the River Arrow. The park incorporates a Local Nature Reserve, Proctor's Barn Meadow.


title: Redditch

text: The Arrow Valley Countryside centre, opened in 2000 in the Country Park, has a lakeside café, gift shop and an interactive exhibition. The lake is also used for water sports. There are four waymarked trails for walking and cycling around the lake and through the Country Park. There is a skate park in the south of the park with walks along the river Arrow through the Country Park to the Forge Mill Museum in the north. There are interactive events and family activities at the Countryside Centre and a comprehensive children's play area.


title: Redditch

text: Redditch was the home of the Royal Enfield motorcycle. This is where the main factory of the original company was located and the business continued manufacturing until the 1960s, the last model being the Interceptor. The Redditch factory was closed in 1967 and production was moved to the Bradford on Avon factory, which closed in 1970, ending English Enfield manufacturing. In the mid 1950s, the company established a partner, Madras Motors, in Madras, India, who manufactured the Bullet 350 model. The Indian factory is producing new models and has taken Royal Enfield into its third century of manufacturing. Some of the original factory buildings in Redditch still remain, most are in a derelict state and can be seen from Hewell Road. Some buildings have been taken over and now make the old part of Enfield Industrial Estate close to the town centre on Hewell Road.


title: Redditch

text: In 1956, Redditch was twinned with Auxerre in Burgundy, France. This twinning proved sufficiently popular to form an organisation named The Friends of Auxerre (FoA). At the beginning of June each year the coupling of these two towns is officially celebrated.


title: Redditch

text: In 1986, Redditch was twinned with Mtwara in Tanzania. Frequent events are organised with assistance from the community of Tanzanian students at Birmingham University and Selly Oak College.


title: Redditch

text: Redditch has an oceanic climate (Köppen climate classification "Cfb") similar to almost all of the United Kingdom.


title: Kermit Roosevelt

text: Kermit Roosevelt MC (October 10, 1889 – June 4, 1943) was an American businessman, soldier, explorer, and writer. A son of Theodore Roosevelt, the 26th President of the United States, Kermit graduated from Harvard College, served in both World Wars (with both the British and U.S. Armies), and explored two continents with his father. He fought a lifelong battle with depression and died by suicide while serving in the US Army in Alaska during World War II.


title: Kermit Roosevelt

text: Kermit was born at Sagamore Hill, the family estate in Oyster Bay, New York, the second son of Theodore Roosevelt, (1858–1919) and Edith Kermit Carow (1861–1948). He had an older half-sister Alice Lee Roosevelt (1884–1980), from his father's first marriage to Alice Hathaway Lee (1861–1884), an elder brother, Theodore Roosevelt III (1887–1944), a younger sister, Ethel Carow Roosevelt (1891–1977), and two younger brothers; Archibald Bulloch "Archie" Roosevelt (1894–1979) and Quentin Roosevelt (1897–1918).


title: Kermit Roosevelt

text: As a child, he had little resistance to illness and infection. He had a flair for language, however, and read avidly. He showed a talent for writing that led to recording his experiences in World War I in a book.


title: Kermit Roosevelt

text: After attending the Groton School, he enrolled at Harvard. In 1909, as a freshman, he and his father (recently out of office as president)—both of whom loved nature and outdoor sports—went on a year-long expedition in Africa funded by the Smithsonian Institution. After this trip and a swing through Europe, Roosevelt returned to Harvard and completed four years of study in two and a half years, graduating with the Class of 1912. He was a member of the Porcellian Club, as was his father.


title: Kermit Roosevelt

text: Roosevelt became active in the Boone and Crockett Club, a wildlife conservation organization that had been co-founded by his father. One commentator wrote that Kermit embodied the ideals of the club perhaps more purely than anyone, including his father.


title: Kermit Roosevelt

text: One of Theodore Roosevelt's most popular books, "Through the Brazilian Wilderness", recounted the expedition into the Amazon Basin Brazilian jungle in 1913–14. The father and son went on what would become known as the Roosevelt-Rondon Scientific Expedition, exploring the Brazilian jungle with explorer Colonel Cândido Rondon. During this expedition, they explored the River of Doubt, later renamed Rio Roosevelt in honor of the President, as well as a branch of that river named the Rio Kermit in his honor. The source of the river had been discovered by Rondon earlier, but it had never been fully explored or mapped.


title: Kermit Roosevelt

text: At the time of the expedition, Roosevelt was newly engaged to Belle Wyatt Willard, daughter of the U.S. ambassador to Spain. His mother Edith was concerned about her husband's health and the difficulties of a new expedition, and asked Kermit to accompany his father. He did so, reluctantly delaying his marriage.


title: Kermit Roosevelt

text: The scope of the expedition expanded beyond the original plans, leaving the participants inadequately prepared for a trip tracing the River of Doubt from its source through hundreds of kilometers of uncharted rainforest. The climate and terrain, inadequate gear and food, and two deaths (one drowning, the other murder) turned a scientific expedition into an ordeal. Roosevelt's father contracted malaria and a serious infection resulting from a minor leg wound, weakening him to the point that he considered taking a fatal dose of morphine rather than being a burden to his companions. Roosevelt told his father that he was bringing him back literally "dead or alive" and if he died, he would be an even bigger burden to the expedition. Although Roosevelt contracted malaria as well, he downplayed his sickness to save quinine for TR, nearly dying himself before the physician insisted on giving him the medication by injection. Roosevelt's determination and his rope- and canoe-handling skills were instrumental in saving his father's life. Nonetheless, TR was plagued by flareups of malaria and inflammation so severe that they required hospitalization.


title: Kermit Roosevelt

text: Besides the newly named Rio Roosevelt, one branch of the river was named the Rio Kermit in his honor. Today, the Rio Roosevelt is commonly called the Rio Teodoro by Portuguese-speaking Brazilians because of pronunciation difficulties they have with the name 'Roosevelt'.


title: Kermit Roosevelt

text: Although Kermit and TR faced skepticism about their claims of navigating a completely uncharted river over 1000 km long, they eventually silenced their critics through TR's oratory and one of his most popular books, "Through the Brazilian Wilderness." The 1913–14 expedition was later recounted in "The River of Doubt" by Candice Millard (Doubleday 2005).


title: Kermit Roosevelt

text: After the Amazon trip, in 1914 Kermit married Belle Wyatt Willard (1892–1968), daughter of the U.S. Ambassador to Spain, Joseph Edward Willard. They had four children: Kermit Roosevelt Jr. (1916–2000), Joseph Willard Roosevelt (1918–2008), Belle Wyatt "Clochette" Roosevelt (1919–1985), and Dirck Roosevelt (1925–1953). His daughter, Clochette Roosevelt, married John Gorham Palfrey, who was dean of Columbia College and a member of the United States Atomic Energy Commission.


title: Kermit Roosevelt

text: In 1917, as he was about to be transferred to a Russian branch, the U.S. entered the World War. He attended the Plattsburg School for officers from May to July 1917 but resigned from the U.S. Army to join the British Army. On August 22, 1917, Roosevelt was appointed an honorary captain in the British Army. He saw hard fighting in the Near East, later transferring to the United States Army. While his other brothers had had summer training at Plattsburgh, New York, Roosevelt had missed out on this training.


title: Kermit Roosevelt

text: Roosevelt joined the British Army to fight in the Mesopotamia (modern-day Iraq) theater of World War I. He was attached to the 14th Light Armoured Motor Battery of the Machine Gun Corps, but the British High Command decided they could not risk his life and so they made him an officer in charge of transport (Ford Model T cars). Within months of being posted to Mesopotamia, he mastered spoken as well as written Arabic and was often relied upon as a translator with the locals. He was awarded a Military Cross on August 26, 1918.


title: Kermit Roosevelt

text: Roosevelt relinquished his British commission on April 28, 1918, and was transferred to the AEF in France. In 1918, he learned that his youngest brother Quentin, a pilot, had been shot down over France and had been buried by the Germans with full military honors.


title: Kermit Roosevelt

text: He was commissioned a captain in the United States Army on May 12, 1918, and commanded Battery C, 7th Artillery of the 1st Division. He participated in the Meuse-Argonne Offensive near the end of the war. He returned to the United States on March 25, 1919, and was discharged from the Army two days later.


title: Kermit Roosevelt

text: After the war, Roosevelt went into business; he founded the Roosevelt Steamship Company and the United States Lines. He continued to enjoy outdoor activities with his brothers. In 1919, he joined the Empire State Society of the Sons of the American Revolution, to which both his father and elder brother belonged.


title: Kermit Roosevelt

text: In 1925, Roosevelt accompanied his brother Ted on a hunting expedition across the Himalayas, over uncharted mountain passes rising from the Vale of Kashmir through the ancient Silk Route into China, in search of the legendary bighorn wild sheep called "Ovis poli". He and his brother Ted documented the trip in their book "East of the Sun and West of the Moon". Several trophies collected during this expedition are on display in the Field Museum of Natural History in Chicago. This expedition, financed by Museum trustee James Simpson, is sometimes called the "James Simpson-Roosevelt Asiatic Expedition of the Field Museum of Natural History".


title: Kermit Roosevelt

text: In 1928–1929, Kermit Roosevelt and his brother Ted were members of the Kelley-Roosevelts Asiatic Expedition. The Roosevelt brothers told the story of their part in the expedition in their book "Trailing the Giant Panda".


title: Kermit Roosevelt

text: By October 14, 1939, when Britain was at war with Germany, Roosevelt had negotiated a commission as a Second Lieutenant in the Middlesex Regiment with the assistance of his friend, Winston Churchill, who was by then First Lord of the Admiralty. His first task was to lead a contingent of British volunteers for the Winter War in Finland. According to a contemporary story published in Picture Post, he had resigned from the British Army to lead the expedition. However, before the expedition could be launched, Finland made peace with Russia. Roosevelt served with distinction in a raid into Norway and was later sent to North Africa, where there was little action at the time. While in Norway, he was injured during the Battle of Narvik. He resumed drinking and was debilitated by an enlarged liver complicated by a resurgence of malaria. At the end of 1940, he returned to England and was discharged from the army on health grounds on May 2, 1941, by which time he had once again reached the rank of captain. Roosevelt appealed this discharge all the way to the British Prime Minister, Winston Churchill, who upheld the medical discharge.


title: Kermit Roosevelt

text: When he returned to the US, he turned to drinking to forget his problems. His wife enlisted the help of his cousin, President Franklin Delano Roosevelt, who ordered the FBI to track him down, and he was brought back to his family. In late April 1942, his brother Archibald sought to have him committed to a sanitarium for a year; at month's end, he agreed to a four-month stay at an institution in Hartford. To extricate him from his current situation, the President gave him a commission as a major in the United States Army, and had him transferred and posted to Fort Richardson, Alaska, where he worked as an intelligence officer and helped establish a territorial militia of Eskimos and Aleuts.


title: Kermit Roosevelt

text: Roosevelt died in Alaska on June 4, 1943, in his room at Fort Richardson, from suicide by a gunshot to the head. He was discovered by Dr. Sanford Couch Monroe, who later filed the autopsy report. His death was reported to his mother, Edith, as a heart attack. He was interred in Fort Richardson National Cemetery near Anchorage, where a memorial stone gateway was erected in his honor in 1949.


title: Kermit Roosevelt

text: The town of Kermit, Texas, was named for him (he had visited Winkler County, Texas, a few months earlier to hunt antelope). The town of Kermit, West Virginia, is also named after him.


title: Kermit Roosevelt

text: The "Luzon"-class repair ship was named in his honor. The town of Kermit, North Dakota was also named after him.


title: Kermit Roosevelt

text: There is an annual lecture series given in the United States by a British Army general officer and in the United Kingdom by a U.S. Army general officer named in memory of Kermit Roosevelt.


title: Kermit Roosevelt

text: Kermit Roosevelt appears as a minor character in the Wilbur Smith novel "Assegai" on safari in East Africa with his father.


title: Kermit Roosevelt

text: Kermit Roosevelt appears in the second episode of 1992's "The Young Indiana Jones Chronicles" television series.


title: Kermit Roosevelt

text: The book "Roosevelt's Beast" by Louis Bayard is a fictitious story of the Rondon-Roosevelt expedition, narrated by Kermit Roosevelt.


title: Kermit Roosevelt

text: Kermit Roosevelt appears as a main character in the James Ross historical fiction "Hunting Teddy Roosevelt" about the safari in East Africa with his father.


title: Kermit Roosevelt

text: Kermit Roosevelt appears in the fiction book "The President's Daughter" by Kimberly Brubaker Bradley which is based on Kermit's sister Ethel Roosevelt Derby and their time in the White House.


title: Enzyme inhibitor

text: An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.


title: Enzyme inhibitor

text: An enzyme inhibitor stops ("inhibits") this process, either by binding to the enzyme's active site (thus preventing the substrate itself from binding) or by binding to another site on the enzyme such that the enzyme's catalysis of the reaction is blocked. Enzyme inhibitors may bind reversibly or irreversibly. Irreversible inhibitors form a chemical bond with the enzyme such that the enzyme is inhibited until the chemical bond is broken. By contrast, reversible inhibitors bind non-covalently and may spontaneously leave the enzyme, allowing the enzyme to resume its function. Reversible inhibitors produce different types of inhibition depending on whether they bind to the enzyme, the enzyme-substrate complex, or both.


title: Enzyme inhibitor

text: Enzyme inhibitors play an important role in all cells, since they are generally specific to one enzyme and serve to control that enzyme's activity. For example, enzymes in a metabolic pathway may be inhibited by molecules produced later in the pathway, thus curtailing the production of molecules that are no longer needed. This type of negative feedback is an important way to maintain balance in a cell. Enzyme inhibitors also control essential enzymes such as proteases or nucleases that, if left unchecked, may damage a cell. Many poisons produced by animals or plants are enzyme inhibitors that block the activity of crucial enzymes in prey or predators.


title: Enzyme inhibitor

text: Many drug molecules are enzyme inhibitors that inhibit an aberrant human enzyme or an enzyme critical for the survival of a pathogen such as a virus, bacterium or parasite. Examples include methotrexate (used in chemotherapy and in treating rheumatic arthritis) and the protease inhibitors used to treat HIV/AIDS. Since anti-pathogen inhibitors generally target only one enzyme, such drugs are highly specific and generally produce few side effects in humans, provided that no analogous enzyme is found in humans. (This is often the case, since such pathogens and humans are genetically distant.) Medicinal enzyme inhibitors often have low dissociation constants, meaning that only a minute amount of the inhibitor is required to inhibit the enzyme. A low concentration of the enzyme inhibitor reduces the risk for liver and kidney damage and other adverse drug reactions in humans. Hence the discovery and refinement of enzyme inhibitors is an active area of research in biochemistry and pharmacology.


title: Enzyme inhibitor

text: Enzyme inhibitors are a chemically diverse set of substances that range in size from organic small molecules to macromolecular proteins.


title: Enzyme inhibitor

text: Small molecule inhibitors include essential primary metabolites that inhibit upstream enzymes that produce those metabolites. This provides a negative feedback loop that prevents over production of metabolites and thus maintains cellular homeostasis (steady internal conditions). Small molecule enzyme inhibitors also include secondary metabolites, which are not essential to the organism that produces them, but provide the organism with a evolutionary advantage, in that they can be used to repel predators or competing organisms or immobilize prey. In addition, many drugs are small molecule enzyme inhibitors that target either disease-modifying enzymes in the patient or enzymes in pathogens which are required for the growth and reproduction of the pathogen.


title: Enzyme inhibitor

text: In addition to small molecules, some proteins act as enzyme inhibitors. The most prominent example are serpins (serine protease inhibitors) which are produced by animals to protect against inappropriate enzyme activation and by plants to prevent predation. Another class of inhibitor proteins is the ribonuclease inhibitors, which bind to ribonucleases in one of the tightest known protein–protein interactions. A special case of protein enzyme inhibitors are zymogens that contain an autoinhibitory N-terminal peptide that binds to the active site of enzyme that intramolecularly blocks its activity as a protective mechanism against uncontrolled catalysis. The N-terminal peptide is cleaved (split) from the zymogen enzyme precursor by another enzyme to release an active enzyme.


title: Enzyme inhibitor

text: The binding site of inhibitors on enzymes is most commonly the same site that binds the substrate of the enzyme. These active site inhibitors are known as orthosteric ("regular" orientation) inhibitors. The mechanism of orthosteric inhibition is simply to prevent substrate binding to the enzyme through direct competition which in turn prevents the enzyme from catalysing the conversion of substrates into products. Alternatively, the inhibitor can bind to a site remote from the enzyme active site. These are known as allosteric ("alternative" orientation) inhibitors. The mechanism of allosteric inhibition are varied and include changing the conformation (shape) of the enzyme such that it can no longer bind substrate (kinetically indistinguishable from competitive orthosteric inhibition) or alternatively stabilise binding of substrate to the enzyme but lock the enzyme in a conformation which is no longer catalytically active.


title: Enzyme inhibitor

text: Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the enzyme active site combine to produce strong and specific binding.


title: Enzyme inhibitor

text: In contrast to irreversible inhibitors, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be easily removed by dilution or dialysis. A special case are covalent reversible inhibitors that form a chemical bond with the enzyme, but the bond can be cleaved so the inhibition is fully reversible.


title: Enzyme inhibitor

text: Reversible inhibitors are generally categorized into four types, as introduced by Cleland in 1963. They are classified according to the effect of the inhibitor on the "V" (maximum reaction rate catalysed by the enzyme) and "K" (the concentration of substrate resulting in half maximal enzyme activity) as the concentration of the enzyme's substrate is varied.


title: Enzyme inhibitor

text: In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time. This usually results from the inhibitor having an affinity for the active site of an enzyme where the substrate also binds; the substrate and inhibitor "compete" for access to the enzyme's active site. This type of inhibition can be overcome by sufficiently high concentrations of substrate ("V" remains constant), i.e., by out-competing the inhibitor. However, the apparent "K" will increase as it takes a higher concentration of the substrate to reach the "K" point, or half the "V". Competitive inhibitors are often similar in structure to the real substrate (see for example the "methotrexate versus folate" figure in the "Drugs" section).


title: Enzyme inhibitor

text: In uncompetitive inhibition, the inhibitor binds only to the enzyme-substrate complex. This type of inhibition causes "V" to decrease (maximum velocity decreases as a result of removing activated complex) and "K" to decrease (due to better binding efficiency as a result of Le Chatelier's principle and the effective elimination of the ES complex thus decreasing the "K" which indicates a higher binding affinity). Uncompetitive inhibition is rare.


title: Enzyme inhibitor

text: In non-competitive inhibition, the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate. As a result, the extent of inhibition depends only on the concentration of the inhibitor. "V" will decrease due to the inability for the reaction to proceed as efficiently, but "K" will remain the same as the actual binding of the substrate, by definition, will still function properly.


title: Enzyme inhibitor

text: In mixed inhibition, the inhibitor may bind to the enzyme whether or not the substrate has already bound. Hence mixed inhibition is a combination of competitive and noncompetitive inhibition. Furthermore, the affinity of the inhibitor for the free enzyme and the enzyme-substrate complex may differ. By increasing concentrations of substrate [S], this type of inhibition can be reduced (due to the competitive contribution), but not entirely overcome (due to the noncompetitive component). Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition generally results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation (that is, the tertiary structure or three-dimensional shape) of the enzyme so that the affinity of the substrate for the active site is reduced.


title: Enzyme inhibitor

text: These four types of inhibition can also be distinguished by the effect of increasing the substrate concentration [S] on the degree of inhibition caused by a given amount of inhibitor. For competitive inhibition the degree of inhibition is reduced by increasing [S], for noncompetitive inhibition the degree of inhibition is unchanged, and for uncompetitive (also called anticompetitive) inhibition the degree of inhibition increases with [S].


title: Enzyme inhibitor

text: Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme-substrate complex, and its effects on the kinetic constants of the enzyme. In the classic Michaelis-Menten scheme (shown in the "inhibition mechanism schematic" diagram), an enzyme (E) binds to its substrate (S) to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release product P and free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation constants "K" or "K"', respectively.


title: Enzyme inhibitor

text: When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered. This results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with substrate A for the first binding site, but be a non-competitive inhibitor with respect to substrate B in the second binding site.


title: Enzyme inhibitor

text: Traditionally reversible enzyme inhibitors have been classified as competitive, uncompetitive, or non-competitive, according to their effects on "K" and "V". These three types of inhibition result respectively from the inhibitor binding only to the enzyme E in the absence of substrate S, to the enzyme–substrate complex ES, or to both. The division of these classes arises from a problem in their derivation and results in the need to use two different binding constants for one binding event. It is further assumed that binding of the inhibitor to the enzyme results in 100% inhibition and fails to consider the possibility of partial inhibition. The common form of the inhibitory term also obscures the relationship between the inhibitor binding to the enzyme and its relationship to any other binding term be it the Michaelis–Menten equation or a dose response curve associated with ligand receptor binding. To demonstrate the relationship the following rearrangement can be made:


title: Enzyme inhibitor

text: This rearrangement demonstrates that similar to the Michaelis–Menten equation, the maximal rate of reaction depends on the proportion of the enzyme population interacting with its substrate.


title: Enzyme inhibitor

text: the effect of the inhibitor is a result of the percent of the enzyme population interacting with inhibitor. The only problem with this equation in its present form is that it assumes absolute inhibition of the enzyme with inhibitor binding, when in fact there can be a wide range of effects anywhere from 100% inhibition of substrate turn over to no inhibition. To account for this the equation can be easily modified to allow for different degrees of inhibition by including a delta "V" term.


title: Enzyme inhibitor

text: This term can then define the residual enzymatic activity present when the inhibitor is interacting with individual enzymes in the population. However the inclusion of this term has the added value of allowing for the possibility of activation if the secondary "V" term turns out to be higher than the initial term. To account for the possibly of activation as well the notation can then be rewritten replacing the inhibitor "I" with a modifier term (stimulator or inhibitor) denoted here as "X".


title: Enzyme inhibitor

text: While this terminology results in a simplified way of dealing with kinetic effects relating to the maximum velocity of the Michaelis–Menten equation, it highlights potential problems with the term used to describe effects relating to the "K". The "K" relating to the affinity of the enzyme for the substrate should in most cases relate to potential changes in the binding site of the enzyme which would directly result from enzyme inhibitor interactions. As such a term similar to the delta "V" term proposed above to modulate "V" should be appropriate in most situations:


title: Enzyme inhibitor

text: An enzyme inhibitor is characterised by its dissociation constant "K", the concentration at which the inhibitor half occupies the enzyme. In non-competitive inhibition, the inhibitor can also bind to the enzyme-substrate complex, and the presence of bound substrate can change the affinity of the inhibitor for the enzyme, resulting in a second dissociation constant "K"'. Hence "K" and "K"' are the dissociation constants of the inhibitor for the enzyme and to the enzyme-substrate complex, respectively. The enzyme-inhibitor constant "K" can be measured directly by various methods; one especially accurate method is isothermal titration calorimetry, in which the inhibitor is titrated into a solution of enzyme and the heat released or absorbed is measured. However, the other dissociation constant "K"' is difficult to measure directly, since the enzyme-substrate complex is short-lived and undergoing a chemical reaction to form the product. Hence, "K"' is usually measured indirectly, by observing the enzyme activity under various substrate and inhibitor concentrations, and fitting the data via nonlinear regression to a modified Michaelis–Menten equation.


title: Enzyme inhibitor

text: where the modifying factors α and α' are defined by the inhibitor concentration and its two dissociation constants


title: Enzyme inhibitor

text: Thus, in the presence of the inhibitor, the enzyme's effective "K" and "V" become (α/α')"K" and (1/α')"V", respectively. However, the modified Michaelis-Menten equation assumes that binding of the inhibitor to the enzyme has reached equilibrium, which may be a very slow process for inhibitors with sub-nanomolar dissociation constants. In these cases, the inhibition becomes effectively irreversible, hence it is more practical to treat such tight-binding inhibitors as irreversible (see below).


title: Enzyme inhibitor

text: The effects of different types of reversible enzyme inhibitors on enzymatic activity can be visualised using graphical representations of the Michaelis–Menten equation, such as Lineweaver–Burk, Eadie-Hofstee or Hanes-Woolf plots. An illustration is provided by the three Lineweaver–Burk plots depicted in the "Lineweaver–Burk diagrams" figure. In the top diagram, the competitive inhibition lines intersect on the "y"-axis, illustrating that such inhibitors do not affect "V". In the bottom diagram, the non-competitive inhibition lines intersect on the "x"-axis, showing these inhibitors do not affect "K". However, since it can be difficult to estimate "K" and "K"' accurately from such plots, it is advisable to estimate these constants using more reliable nonlinear regression methods.


title: Enzyme inhibitor

text: The mechanism of partially competitive inhibition is similar to that of non-competitive, except that the EIS complex has catalytic activity, which may be lower or even higher (partially competitive activation) than that of the enzyme–substrate (ES) complex. This inhibition typically displays a lower "V", but an unaffected "K" value.


title: Enzyme inhibitor

text: Substrate or product inhibition is where either an enzymes substrate or product also act as an inhibitor. This inhibition may follow the competitive, uncompetitive or mixed patterns. In substrate inhibition there is a progressive decrease in activity at high substrate concentrations, potentially from an enzyme having two competing substrate-binding sites. At low substrate, the high-affinity site is occupied and normal kinetics are followed. However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the enzyme. Product inhibition (either the enzyme's own product, or a product to an enzyme downstream in its metabolic pathway) is often a regulatory feature in metabolism and can be a form of negative feedback.


title: Enzyme inhibitor

text: Slow-tight inhibition occurs when the initial enzyme–inhibitor complex EI undergoes conformational isomerism (a change in shape) to a second more tightly held complex, EI*, but the overall inhibition process is reversible. This manifests itself as slowly increasing enzyme inhibition. Under these conditions, traditional Michaelis–Menten kinetics give a false value for "K", which is time–dependent. The true value of "K" can be obtained through more complex analysis of the on ("k") and off ("k") rate constants for inhibitor association with kinetics similar to irreversible inhibition.


title: Enzyme inhibitor

text: Multi-substrate analogue inhibitors are high affinity selective inhibitors that can be prepared for enzymes that catalyse reactions with more than one substrate by capturing the binding energy of each of those substrate into one molecule. For example, in the formyl transfer reactions of purine biosynthesis, a potent Multi-substrate Adduct Inhibitor (MAI) to glycinamide ribonucleotide (GAR) TFase was prepared synthetically by linking analogues of the GAR substrate and the N-10-formyl tetrahydrofolate cofactor together to produce thioglycinamide ribonucleotide dideazafolate (TGDDF), or enzymatically from the natural GAR substrate to yield GDDF. Here the subnanomolar dissociation constant (KD) of TGDDF was greater than predicted presumably due to entropic advantages gained and/or positive interactions acquired through the atoms linking the components. MAIs have also been observed to be produced in cells by reactions of pro-drugs such as isoniazid or enzyme inhibitor ligands (for example, PTC124) with cellular cofactors such as nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP) respectively.


title: Enzyme inhibitor

text: As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in structure to the substrates of their targets. Inhibitors of dihydrofolate reductase (DHFR) are prominent examples. Other examples of these substrate mimics are the protease inhibitors, a therapeutically effective class of antiretroviral drugs used to treat HIV/AIDS. The structure of ritonavir, a peptidomimetic (peptide mimic) protease inhibitor containing three peptide bonds, as shown in the "competitive inhibitor examples" figure. As this drug resembles the peptide that is the substrate of the HIV protease, it competes with the substrate in the enzyme's active site.


title: Enzyme inhibitor

text: Enzyme inhibitors are often designed to mimic the transition state or intermediate of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding affinity (lower "K") than substrate-based designs. An example of such a transition state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the reaction of the viral enzyme neuraminidase.


title: Enzyme inhibitor

text: However, not all inhibitors are based on the structures of substrates. For example, the structure of another HIV protease inhibitor tipranavir is not based on a peptide and has no obvious structural similarity to a protein substrate. These non-peptide inhibitors can be more stable than inhibitors containing peptide bonds, because they will not be substrates for peptidases and are less likely to be degraded.


title: Enzyme inhibitor

text: In drug design it is important to consider the concentrations of substrates to which the target enzymes are exposed. For example, some protein kinase inhibitors have chemical structures that are similar to ATP, one of the substrates of these enzymes. However, drugs that are simple competitive inhibitors will have to compete with the high concentrations of ATP in the cell. Protein kinases can also be inhibited by competition at the binding sites where the kinases interact with their substrate proteins, and most proteins are present inside cells at concentrations much lower than the concentration of ATP. As a consequence, if two protein kinase inhibitors both bind in the active site with similar affinity, but only one has to compete with ATP, then the competitive inhibitor at the protein-binding site will inhibit the enzyme more effectively.


title: Enzyme inhibitor

text: Irreversible inhibitors covalently bind to an enzyme, and this type of inhibition can therefore not be readily reversed. Irreversible inhibitors often contain reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates. These electrophilic groups react with amino acid side chains to form covalent adducts. The residues modified are those with side chains containing nucleophiles such as hydroxyl or sulfhydryl groups; these include the amino acids serine (that reacts with DFP, see the "DFP reaction" diagram), and also cysteine, threonine, or tyrosine.


title: Enzyme inhibitor

text: Irreversible inhibition is different from irreversible enzyme inactivation. Irreversible inhibitors are generally specific for one class of enzyme and do not inactivate all proteins; they do not function by destroying protein structure but by specifically altering the active site of their target. For example, extremes of pH or temperature usually cause denaturation of all protein structure, but this is a non-specific effect. Similarly, some non-specific chemical treatments destroy protein structure: for example, heating in concentrated hydrochloric acid will hydrolyse the peptide bonds holding proteins together, releasing free amino acids.


title: Enzyme inhibitor

text: Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterised by an IC value. This is because the amount of active enzyme at a given concentration of irreversible inhibitor will be different depending on how long the inhibitor is pre-incubated with the enzyme. Instead, "k"/["I"] values are used, where "k" is the observed pseudo-first order rate of inactivation (obtained by plotting the log of % activity versus time) and ["I"] is the concentration of inhibitor. The "k"/["I"] parameter is valid as long as the inhibitor does not saturate binding with the enzyme (in which case "k" = "k") where "k" is the rate of inactivation.


title: Enzyme inhibitor

text: Irreversible inhibitors first form a reversible non-covalent complex with the enzyme (EI or ESI). Subsequently a chemical reaction occurs between the enzyme and inhibitor to produce the covalently modified "dead-end complex" EI* (an irreversible covalent complex). The rate at which EI* is formed is called the inactivation rate or "k". Since formation of EI may compete with ES, binding of irreversible inhibitors can be prevented by competition either with substrate or with a second, reversible inhibitor. This protection effect is good evidence of a specific reaction of the irreversible inhibitor with the active site.


title: Enzyme inhibitor

text: The binding and inactivation steps of this reaction are investigated by incubating the enzyme with inhibitor and assaying the amount of activity remaining over time. The activity will be decreased in a time-dependent manner, usually following exponential decay. Fitting these data to a rate equation gives the rate of inactivation at this concentration of inhibitor. This is done at several different concentrations of inhibitor. If a reversible EI complex is involved the inactivation rate will be saturable and fitting this curve will give "k" and "K".


title: Enzyme inhibitor

text: Another method that is widely used in these analyses is mass spectrometry. Here, accurate measurement of the mass of the unmodified native enzyme and the inactivated enzyme gives the increase in mass caused by reaction with the inhibitor and shows the stoichiometry of the reaction. This is usually done using a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass fingerprinting involves digestion of the native and modified protein with a protease such as trypsin. This will produce a set of peptides that can be analysed using a mass spectrometer. The peptide that changes in mass after reaction with the inhibitor will be the one that contains the site of modification.


title: Enzyme inhibitor

text: Not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so tightly to their target enzyme that they are essentially irreversible. These tight-binding inhibitors may show kinetics similar to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly bind to the enzyme in a low-affinity EI complex and this then undergoes a slower rearrangement to a very tightly bound EI* complex (see the "irreversible inhibition mechanism" diagram). This kinetic behaviour is called slow-binding. This slow rearrangement after binding often involves a conformational change as the enzyme "clamps down" around the inhibitor molecule. Examples of slow-binding inhibitors include some important drugs, such methotrexate, allopurinol, and the activated form of acyclovir.


title: Enzyme inhibitor

text: Diisopropylfluorophosphate (DFP) is an example of an irreversible protease inhibitor (see the "DFP reaction" diagram). The enzyme hydrolyses the phosphorus–fluorine bond, but the phosphate residue remains bound to the serine in the active site, deactivating it. Similarly, DFP also reacts with the active site of acetylcholine esterase in the synapses of neurons, and consequently is a potent neurotoxin, with a lethal dose of less than 100 mg.


title: Enzyme inhibitor

text: Suicide inhibition is an unusual type of irreversible inhibition where the enzyme converts the inhibitor into a reactive form in its active site. An example is the inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), which is an analogue of the amino acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness). Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of ornithine (see the "DFMO inhibitor mechanism" diagram). However, this decarboxylation reaction is followed by the elimination of a fluorine atom, which converts this catalytic intermediate into a conjugated imine, a highly electrophilic species. This reactive form of DFMO then reacts with either a cysteine or lysine residue in the active site to irreversibly inactivate the enzyme.


title: Enzyme inhibitor

text: Since irreversible inhibition often involves the initial formation of a non-covalent enzyme inhibitor (EI) complex, it is sometimes possible for an inhibitor to bind to an enzyme in more than one way. For example, in the figure showing trypanothione reductase from the human protozoan parasite "Trypanosoma cruzi", two molecules of an inhibitor called "quinacrine mustard" are bound in its active site. The top molecule is bound reversibly, but the lower one is bound covalently as it has reacted with an amino acid residue through its nitrogen mustard group.


title: Enzyme inhibitor

text: Enzyme inhibitors are found in nature and also produced artificially in the laboratory. Naturally occurring enzyme inhibitors regulate many metabolic processes and are essential for life. In addition, naturally produced poisons are often enzyme inhibitors that have evolved for use as toxic agents against predators, prey, and competing organisms. These natural toxins include some of the most poisonous substances known. Artificial inhibitors are often used as drugs, but can also be insecticides such as malathion, herbicides such as glyphosate, or disinfectants such as triclosan. Other artificial enzyme inhibitors block acetylcholinesterase, an enzyme which breaks down acetylcholine, and are used as nerve agents in chemical warfare.


title: Enzyme inhibitor

text: Enzyme inhibition is a common feature of metabolic pathway control in cells. Metabolic flux through a pathway is often regulated by a pathway's metabolites acting as inhibitors and enhancers for the enzymes in that same pathway. The glycolytic pathway is a classic example. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6-bisphosphate and ADP are examples of metabolites that are allosteric activators.


title: Enzyme inhibitor

text: Physiological enzyme inhibition can also be produced by specific protein inhibitors. This mechanism occurs in the pancreas, which synthesises many digestive precursor enzymes known as zymogens. Many of these are activated by the trypsin protease, so it is important to inhibit the activity of trypsin in the pancreas to prevent the organ from digesting itself. One way in which the activity of trypsin is controlled is the production of a specific and potent trypsin inhibitor protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the trypsin activity that would otherwise be detrimental to the organ. Although the trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the protease by excluding water from trypsin's active site and destabilising the transition state. Other examples of physiological enzyme inhibitor proteins include the barstar inhibitor of the bacterial ribonuclease barnase.


title: Enzyme inhibitor

text: Animals and plants have evolved to synthesise a vast array of poisonous products including secondary metabolites, peptides and proteins that can act as inhibitors. Natural toxins are usually small organic molecules and are so diverse that there are probably natural inhibitors for most metabolic processes. The metabolic processes targeted by natural poisons encompass more than enzymes in metabolic pathways and can also include the inhibition of receptor, channel and structural protein functions in a cell. For example, paclitaxel (taxol), an organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and inhibits their assembly into microtubules in the cytoskeleton.


title: Enzyme inhibitor

text: Many natural poisons act as neurotoxins that can cause paralysis leading to death and function for defence against predators or in hunting and capturing prey. Some of these natural inhibitors, despite their toxic attributes, are valuable for therapeutic uses at lower doses. An example of a neurotoxin are the glycoalkaloids, from the plant species in the family Solanaceae (includes potato, tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter, muscular paralysis and then death. Neurotoxicity can also result from the inhibition of receptors; for example, atropine from deadly nightshade ("Atropa belladonna") that functions as a competitive antagonist of the muscarinic acetylcholine receptors.


title: Enzyme inhibitor

text: Although many natural toxins are secondary metabolites, these poisons also include peptides and proteins. An example of a toxic peptide is alpha-amanitin, which is found in relatives of the death cap mushroom. This is a potent enzyme inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing DNA. The algal toxin microcystin is also a peptide and is an inhibitor of protein phosphatases. This toxin can contaminate water supplies after algal blooms and is a known carcinogen that can also cause acute liver haemorrhage and death at higher doses.


title: Enzyme inhibitor

text: Proteins can also be natural poisons or antinutrients, such as the trypsin inhibitors (discussed in the "metabolic regulation" section above) that are found in some legumes. A less common class of toxins are toxic enzymes: these act as irreversible inhibitors of their target enzymes and work by chemically modifying their substrate enzymes. An example is ricin, an extremely potent protein toxin found in castor oil beans. This enzyme is a glycosidase that inactivates ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single molecule of ricin to kill a cell.


title: Enzyme inhibitor

text: The most common uses for enzyme inhibitors are as drugs to treat disease. Many of these inhibitors target a human enzyme and aim to correct a pathological condition. For instance, aspirin is a widely used drug that acts as a suicide inhibitor of the cyclooxygenase enzyme. This inhibition in turn suppresses the production of proinflammatory prostaglandins and thus aspirin may be used to reduce pain, fever, and inflammation.


title: Enzyme inhibitor

text: An example of the structural similarity of some inhibitors to the substrates of the enzymes they target is seen in the figure comparing the drug methotrexate to folic acid. Folic acid is the oxidised form of the substrate of dihydrofolate reductase, an enzyme that is potently inhibited by methotrexate. Methotrexate blocks the action of dihydrofolate reductase and thereby halts thymidine biosynthesis. This block of nucleotide biosynthesis is selectively toxic to rapidly growing cells, therefore methotrexate is often used in cancer chemotherapy.


title: Enzyme inhibitor

text: A common treatment for erectile dysfunction is sildenafil (Viagra). This compound is a potent inhibitor of cGMP specific phosphodiesterase type 5, the enzyme that degrades the signalling molecule cyclic guanosine monophosphate. This signalling molecule triggers smooth muscle relaxation and allows blood flow into the corpus cavernosum, which causes an erection. Since the drug decreases the activity of the enzyme that halts the signal, it makes this signal last for a longer period of time.


title: Enzyme inhibitor

text: Drugs are also used to inhibit enzymes needed for the survival of pathogens. For example, bacteria are surrounded by a thick cell wall made of a net-like polymer called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit the enzymes that produce and then cross-link the strands of this polymer together. This causes the cell wall to lose strength and the bacteria to burst. In the figure, a molecule of penicillin (shown in a ball-and-stick form) is shown bound to its target, the transpeptidase from the bacteria "Streptomyces" R61 (the protein is shown as a ribbon diagram).


title: Enzyme inhibitor

text: Antibiotic drug design is facilitated when an enzyme that is essential to the pathogen's survival is absent or very different in humans. Humans do not make peptidoglycan, therefore antibiotics that inhibit this process are selectively toxic to bacteria. Selective toxicity is also produced in antibiotics by exploiting differences in the structure of the ribosomes in bacteria, or how they make fatty acids.


title: Enzyme inhibitor

text: Drugs that inhibit enzymes needed for the replication of viruses are effective in treating viral infections. Antiviral drugs include protease inhibitors used to treat HIV/AIDS and Hepatitis C, reverse-transcriptase inhibitors targeting HIV/AIDS, neuraminidase inhibitors targeting influenza, and terminase inhibitors targeting human cytomegalovirus.


title: Enzyme inhibitor

text: Many pesticides are enzyme inhibitors. Acetylcholinesterase (AChE) is an enzyme found in animals, from insects to humans. It is essential to nerve cell function through its mechanism of breaking down the neurotransmitter acetylcholine into its constituents, acetate and choline. This is somewhat unusual among neurotransmitters as most, including serotonin, dopamine, and norepinephrine, are absorbed from the synaptic cleft rather than cleaved. A large number of AChE inhibitors are used in both medicine and agriculture. Reversible competitive inhibitors, such as edrophonium, physostigmine, and neostigmine, are used in the treatment of myasthenia gravis and in anaesthesia to reverse muscle blockade. The carbamate pesticides are also examples of reversible AChE inhibitors. The organophosphate pesticides such as malathion, parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase.


title: Enzyme inhibitor

text: The herbicide glyphosate is an inhibitor of 3-phosphoshikimate 1-carboxyvinyltransferase, other herbicides, such as the sulfonylureas inhibit the enzyme acetolactate synthase. Both enzymes are needed for plants to make branched-chain amino acids. Many other enzymes are inhibited by herbicides, including enzymes needed for the biosynthesis of lipids and carotenoids and the processes of photosynthesis and oxidative phosphorylation.


title: Enzyme inhibitor

text: New drugs are the products of a long drug development process, the first step of which is often the discovery of a new enzyme inhibitor. There are two principle approaches of discovering these inhibitors.


title: Enzyme inhibitor

text: The first general method is rational drug design based on mimicking the transition state of the chemical reaction catalysed by the enzyme. The designed inhibitor often closely resembles the substrate, except that the portion of the substrate that undergoes chemical reaction is replaced a chemically stable functional group that resembles the transition state. Since the enzyme has evolved to stabilise the transition state, transition state analogues generally possess higher affinity for the enzyme compared to the substrate, and therefore are effective inhibitors.


title: Enzyme inhibitor

text: The second way of discovering new enzyme inhibitors is high-throughput screening of large libraries of structurally diverse compounds to identify hit molecules that bind to the enzyme. This method has been extended to include virtual screening of databases of diverse molecules using computers, which are then followed by experimental confirmation of binding of the virtual screening hits. Complementary approaches that can provide new starting points for inhibitors include fragment-based lead discovery and screening of DNA-encoded chemical libraries.


title: Enzyme inhibitor

text: Hits from any of the above approaches can be optimised to high affinity binders that efficiently inhibit the enzyme. Computer-based methods for predicting the binding orientation and affinity of an inhibitor for an enzyme such as molecular docking and molecular mechanics can be used to assist in the optimisation process. New inhibitors are used to obtain crystallographic structures of the enzyme in an inhibitor/enzyme complex to show how the molecule is binding to the active site, allowing changes to be made to the inhibitor to optimise binding in a process known as structure-based drug design. This test and improve cycle is repeated until a sufficiently potent inhibitor is produced.


title: Bulk carrier

text: A bulk carrier or bulker is a merchant ship specially designed to transport unpackaged bulk cargo — such as grains, coal, ore, steel coils, and cement — in its cargo holds. Since the first specialized bulk carrier was built in 1852, economic forces have led to continued development of these ships, resulting in increased size and sophistication. Today's bulk carriers are specially designed to maximize capacity, safety, efficiency, and durability.


title: Bulk carrier

text: Today, bulk carriers make up 21 percent of the world's merchant fleets, and they range in size from single-hold mini-bulk carriers to mammoth ore ships able to carry 400,000 metric tons of deadweight (DWT). A number of specialized designs exist: some can unload their own cargo, some depend on port facilities for unloading, and some even package the cargo as it is loaded. Over half of all bulk carriers have Greek, Japanese, or Chinese owners, and more than a quarter are registered in Panama. South Korea is the largest single builder of bulk carriers, and 82 percent of these ships were built in Asia.


title: Bulk carrier

text: On bulk carriers, crews are involved in operation, management, and maintenance of the vessel, taking care of safety, navigation, maintenance, and cargo care, in accordance with international maritime legislation. Crews can range in size from three people on the smallest ships to over 30 on the largest.


title: Bulk carrier

text: Cargo loading operations vary in complexity, and loading and discharging of cargo can take several days. Bulk carriers can be gearless (dependent upon terminal equipment) or geared (having cranes integral to the vessel).


title: Bulk carrier

text: Bulk cargo can be very dense, corrosive, or abrasive. This can present safety problems that can threaten a ship: problems such as cargo shifting, spontaneous combustion, and cargo saturation. The use of old ships that have corrosion problems — as well as the bulk carriers' large hatchways — has been linked to a spate of bulk carrier sinkings in the 1990s. These large hatchways, important for efficient cargo handling, can allow the entry of large volumes of water in storms or if the ship is endangered by sinking. New international regulations have since been introduced to improve ship design and inspection and to streamline the process of a crew's abandoning ship.


title: Bulk carrier

text: The term bulk carrier has been defined in varying ways. As of 1999, the International Convention for the Safety of Life at Sea defines a bulk carrier as "a ship constructed with a single deck, top side tanks and hopper side tanks in cargo spaces and intended to primarily carry dry cargo in bulk; an ore carrier; or a combination carrier." Most classification societies use a broader definition, by which a bulk carrier is any ship that carries dry unpackaged goods. Multipurpose cargo ships can carry bulk cargo, but can also carry other cargoes and are not specifically designed for bulk carriage. The term "dry bulk carrier" is used to distinguish bulk carriers from bulk liquid carriers such as oil, chemical, or liquefied petroleum gas carriers. Very small bulk carriers are almost indistinguishable from general cargo ships, and they are often classified based more on the ship's use than its design.


title: Bulk carrier

text: A number of abbreviations are used to describe bulk carriers. "OBO" describes a bulk carrier that carries a combination of ore, bulk, and oil, and "O/O" is used for combination oil and ore carriers. The terms "VLOC", "VLBC", "ULOC", and "ULBC" for very large and ultra-large ore and bulk carriers were adapted from the supertanker designations very large crude carrier and ultra-large crude carrier.


title: Bulk carrier

text: Before specialized bulk carriers were developed, shippers had two methods to move bulk goods by ship. In the first method, longshoremen loaded the cargo into sacks, stacked the sacks onto pallets, and put the pallets into the cargo hold with a crane. The second method required the shipper to charter an entire ship and spend time and money to build plywood bins into the holds. Then, to guide the cargo through the small hatches, wooden feeders and shifting boards had to be constructed. These methods were slow and labor-intensive. As with the container ship, the problem of efficient loading and unloading has driven the evolution of the bulk carrier.


title: Bulk carrier

text: Specialized bulk carriers began to appear as steam-powered ships became more popular. The first steam ship recognized as a bulk carrier was the British collier "John Bowes", built in 1852. She featured a metal hull, a steam engine, and a ballasting system which used seawater instead of sandbags. These features helped her succeed in the competitive British coal market. The first self-unloader was the lake freighter "Hennepin" in 1902 on the Great Lakes. This greatly decreased the unloading time of bulk carriers by using conveyor belt to move the cargo. The first bulk carriers with diesel propulsion began to appear in 1911.


title: Bulk carrier

text: Before World War II, the international shipping demand for bulk products was low—about 25 million tons for metal ores—and most of this trade was coastal. However, on the Great Lakes, bulk carriers hauled vast amounts of iron ore from Minnesota and Michigan's northern mines to the steel mills. In 1929, 73 million tons of iron ore was transported on the Lakes, and an almost equal amount of coal, limestone, and other products were also moved. Two defining characteristics of bulk carriers were already emerging: the double bottom, which was adopted in 1890, and the triangular structure of the ballast tanks, which was introduced in 1905. After World War II, an international bulk trade began to develop among industrialized nations, particularly between the European countries, the United States and Japan. Due to the economics of this trade, ocean bulk carriers became larger and more specialized. In this period, Great Lakes freighters increased in size, to maximize economies of scale, and self-unloaders became more common to cut turnaround time. The thousand-footers of the Great Lakes fleets, built in the 1970s, were among the longest ships afloat, and, in 1979, a record 214 million tons of bulk cargo were moved on the Great Lakes.


title: Bulk carrier

text: Bulk carriers are segregated into six major size categories: small, handysize, handymax, panamax, capesize, and very large. Very large bulk and ore carriers fall into the capesize category but are often considered separately.


title: Bulk carrier

text: Categories occur in regional trade, such as Kamsarmax, Seawaymax, Setouchmax, Dunkirkmax, and Newcastlemax also appear in regional trade.


title: Bulk carrier

text: Mini-bulk carriers are prevalent in the category of small vessels with a capacity of under . Mini-bulk carriers carry from 500 to 2,500 tons, have a single hold, and are designed for river transport. They are often built to be able to pass under bridges and have small crews of three to eight people.


title: Bulk carrier

text: Handysize and Handymax ships are general purpose in nature. These two segments represent 71% of all bulk carriers over and also have the highest rate of growth. This is partly due to new regulations coming into effect which put greater constraints on the building of larger vessels. Handymax ships are typically 150–200 m in length and 52,000 with five cargo holds and four cranes. These ships are also general purpose in nature.


title: Bulk carrier

text: The size of a Panamax vessel is limited by the Panama canal's lock chambers, which can accommodate ships with a beam of up to 32.31 m, a length overall of up to 294.13 m, and a draft of up to 12.04 m.


title: Bulk carrier

text: Capesize ships are too large to traverse the Panama canal and must round Cape Horn to travel between the Pacific and Atlantic oceans. Earlier, capesize ships could not traverse the Suez and needed to go around the Cape of Good Hope. Recent deepening of the Suez canal to 66 ft (20 m) permits most capesize ships to pass through it.


title: Bulk carrier

text: Capesize bulk carriers are specialized: 93% of their cargo is iron ore and coal. Some ships on the Great Lakes Waterway exceed Panamax dimensions but they are limited to use on the Great Lakes as they cannot pass through the smaller St. Lawrence Seaway to the ocean. Very large ore carriers and very large bulk carriers are a subset of the capesize category reserved for vessels over . Carriers of this size are almost always designed to carry iron ore.


title: Bulk carrier

text: In October 2022, Mitsui O.S.K. Lines (MOL)'s bulk carrier "Shofu Maru" arrived in Newcastle on its maiden voyage, becoming the first bulk carrier to be partially powered by hard sail wind power propulsion technology. A five percent fuel savings was anticipated.


title: Bulk carrier

text: The world's bulk transport has reached immense proportions: in 2005, 1.7 billion metric tons of coal, iron ore, grain, bauxite, and phosphate was transported by ship. Today, the world's bulk carrier fleet includes 6,225 ships of over 10,000 DWT, and represent 40% of all ships in terms of tonnage and 39.4% in terms of vessels. Including smaller ships, bulk carriers have a total combined capacity of almost 346 million DWT. Combined carriers are a very small portion of the fleet, representing less than 3% of this capacity. The lake freighters of the Great Lakes, with 98 ships of 3.2 million total DWT, despite forming a small fraction of the total fleet by tonnage and only operating 10 months a year, carried a tenth of the world's bulk cargo because of the short trip distance and fast turnarounds.


title: Bulk carrier

text: As of 2005, the average bulk carrier was just over 13 years old. About 41% of all bulk carriers were less than ten years old, 33% were over twenty years old, and the remaining 26% were between ten and twenty years of age. All of the 98 bulk carriers registered in the Great Lakes trade are over 20 years old and the oldest still sailing in 2009 was 106 years old.


title: Bulk carrier

text: As of 2005, the United States Maritime Administration counted 6,225 bulk carriers of or greater worldwide. More bulk carriers are registered in Panama, with 1,703 ships, more than any four other flag states combined. In terms of the number of bulk carriers registered, the top five flag states also include Hong Kong with 492 ships, Malta (435), Cyprus (373), and China (371). Panama also dominates bulk carrier registration in terms of deadweight tonnage. Positions two through five are held by Hong Kong, Greece, Malta, and Cyprus.


title: Bulk carrier

text: Greece, Japan, and China are the top three owners of bulk carriers, with 1,326, 1,041, and 979 vessels respectively. These three nations account for over 53% of the world's fleet.


title: Bulk carrier

text: Several companies have large private bulk carrier fleets. The multinational company Gearbulk Holding Ltd. has over 70 bulk carriers. The Fednav Group in Canada operates a fleet of over 80 bulk carriers, including two designed to work in Arctic ice. Croatia's Atlantska Plovidba d.d. has a fleet of 14 bulk carriers. The H. Vogemann Group in Hamburg, Germany operates a fleet of 19 bulk carriers. Portline in Portugal, owns 10 bulk carriers. Dampskibsselskabet Torm in Denmark and Elcano in Spain also own notable bulk carrier fleets. Other companies specialize in mini-bulk carrier operations: England's Stephenson Clarke Shipping Limited owns a fleet of eight mini-bulk carriers and five small Handysize bulk carriers, and Cornships Management and Agency Inc. in Turkey owns a fleet of seven mini-bulk carriers.


title: Bulk carrier

text: Asian companies dominate the construction of bulk carriers. Of the world's 6,225 bulk carriers, almost 62% were built in Japan by shipyards such as Oshima Shipbuilding and Sanoyas Hishino Meisho. South Korea, with notable shipyards Daewoo and Hyundai Heavy Industries, ranked second among builders, with 643 ships. The People's Republic of China, with large shipyards such as Dalian, Chengxi, and Shanghai Waigaoqiao, ranked third, with 509 ships. Taiwan, with shipyards such as China Shipbuilding Corporation, ranked fourth, accounting for 129 ships. Shipyards in these top four countries built over 82% of the bulk carriers afloat.


title: Bulk carrier

text: Several factors affect the cost to move a bulk cargo by ship. The bulk freight market is very volatile, and it fluctuates, along with the type of cargo, the ship's size, and the route traveled all affect the final price. Moving a capesize load of coal from South America to Europe cost anywhere from $15 to $25 per ton in 2005. Hauling a panamax-sized load of aggregate materials from the Gulf of Mexico to Japan that year could cost as little as $40 per ton to as much as $70 per ton.


title: Bulk carrier

text: Some shippers choose instead to charter a ship, paying a daily rate instead of a set price per ton. In 2005, the average daily rate for a Handymax ship varied between $18,000$30,000. A Panamax ship could be chartered for $20,000$50,000 per day, and a Capesize for $40,000$70,000 per day.


title: Bulk carrier

text: Generally, ships are removed from the fleet by going through a process known as ship breaking or scrapping. Ship-owners and buyers negotiate scrap prices based on factors such as the ship's empty weight (called light ton displacement or LDT) and prices in the scrap metal market. In 1998, almost 700 ships were scrapped in places like Alang, India and Chittagong, Bangladesh. This is often done by 'beaching' the ship on open sand, then cutting it apart by hand with gas torches, a dangerous operation that results in injuries and fatalities, as well as exposure to toxic materials such as asbestos, lead, and various chemicals. Half a million deadweight tons worth of bulk carriers were scrapped in 2004, accounting for 4.7% of the year's scrapping. That year, bulk carriers fetched particularly high scrap prices, between $340 and $350 per LDT.


title: Bulk carrier

text: The crew on a bulk carrier typically consists of 20 to 30 people, though smaller ships can be handled by 8. The crew includes the captain or master, the deck department, the engine department, and the steward's department. The practice of taking passengers aboard cargo ships, once almost universal, is very rare today and almost non-existent on bulk carriers.


title: Bulk carrier

text: During the 1990s, bulk carriers were involved in an alarming number of shipwrecks. This led ship-owners to commission a study seeking to explain the effect of various factors on the crew's effectiveness and competence. The study showed that crew performance aboard bulk carriers was the lowest of all groups studied. Among bulk carrier crews, the best performance was found aboard younger and larger ships. Crews on better-maintained ships performed better, as did crews on ships where fewer languages were spoken.


title: Bulk carrier

text: Fewer deck officers are employed on bulk carriers than on similarly sized ships of other types. A mini-bulk carrier carries two to three deck officers, while larger Handysize and Capesize bulk carriers carry four. Liquid natural gas tankers of the same size have an additional deck officer and unlicensed mariner.


title: Bulk carrier

text: A bulk carrier's voyages are determined by market forces; routes and cargoes often vary. A ship may engage in the grain trade during the harvest season and later move on to carry other cargoes or work on a different route. Aboard a coastal carrier in the tramp trade, the crew will often not know the next port of call until the cargo is fully loaded.


title: Bulk carrier

text: Because bulk cargo is so difficult to discharge, bulk carriers spend more time in port than other ships. A study of mini-bulk carriers found that it takes, on average, twice as much time to unload a ship as it does to load it. A mini-bulk carrier spends 55 hours at a time in port, compared to 35 hours for a lumber carrier of similar size. This time in port increases to 74 hours for Handymax and 120 hours for Panamax vessels. Compared with the 12-hour turnarounds common for container ships, 15-hour turnarounds for car carriers, and 26-hour turnarounds for large tankers, bulk carrier crews have more opportunities to spend time ashore.


title: Bulk carrier

text: Loading and unloading a bulk carrier is time-consuming and dangerous. The process is planned by the ship's chief mate under the direct and continued supervision of ship's captain. International regulations require that the captain and terminal master agree on a detailed plan before operations begin. Deck officers and stevedores oversee the operations. Occasionally loading errors are made that cause a ship to capsize or break in half at the pier.


title: Bulk carrier

text: The loading method used depends on both the cargo and the equipment available on the ship and on the dock. In the least advanced ports, cargo can be loaded with shovels or bags poured from the hatch cover. This system is being replaced with faster, less labor-intensive methods.


title: Bulk carrier

text: Double-articulation cranes, which can load at a rate of 1,000 tons per hour, represent a widely used method, and the use of shore-based gantry cranes, reaching 2,000 tons per hour, is growing. A crane's discharge rate is limited by the bucket's capacity (from 6 to 40 tons) and by the speed at which the crane can take a load, deposit it at the terminal and return to take the next. For modern gantry cranes, the total time of the grab-deposit-return cycle is about 50 seconds.


title: Bulk carrier

text: Conveyor belts offer a very efficient method of loading, with standard loading rates varying between 100 and 700 tons per hour, although the most advanced ports can offer rates of 16,000 tons per hour. Start-up and shutdown procedures with conveyor belts, though, are complicated and require time to carry out. Self-discharging ships use conveyor belts with load rates of around 1,000 tons per hour.


title: Bulk carrier

text: Once the cargo is discharged, the crew begins to clean the holds. This is particularly important if the next cargo is of a different type. The immense size of cargo holds and the tendency of cargoes to be physically irritating add to the difficulty of cleaning the holds. When the holds are clean, the process of loading begins.


title: Bulk carrier

text: It is crucial to keep the cargo level during loading in order to maintain stability. As the hold is filled, machines such as excavators and bulldozers are often used to keep the cargo in check. Leveling is particularly important when the hold is only partly full, since cargo is more likely to shift. Extra precautions are taken, such as adding longitudinal divisions and securing wood atop the cargo. If a hold is full, a technique called tomming is used, which involves digging out a hole below the hatch cover and filling it with bagged cargo or weights.


title: Bulk carrier

text: A bulk carrier's design is largely defined by the cargo it will carry. The cargo's density, also known as its stowage factor, is the key factor. Densities for common bulk cargoes vary from 0.6 tons per cubic meter for light grains to 3 tons per cubic meter for iron ore.


title: Bulk carrier

text: The overall cargo weight is the limiting factor in the design of an ore carrier, since the cargo is so dense. Coal carriers, on the other hand, are limited by overall volume, since most bulk carriers can be completely filled with coal before reaching their maximum draft.


title: Bulk carrier

text: For a given tonnage, the second factor which governs the ship's dimensions is the size of the ports and waterways it will travel to. For example, a vessel that will pass the Panama Canal will be limited in its beam and draft. For most designs, the ratio of length-to-width ranges between 5 and 7, with an average of 6.2. The ratio of length-to-height will be between 11 and 12.


title: Bulk carrier

text: The engine room on a bulk carrier is usually near the stern, under the superstructure. Larger bulk carriers, from Handymax up, usually have a single two-stroke low-speed crosshead diesel engine directly coupled to a fixed-pitch propeller. Electricity is produced by auxiliary generators and/or an alternator coupled to the propeller shaft. On the smaller bulk carriers, one or two four-stroke diesels are used to turn either a fixed or controllable-pitch propeller via a reduction gearbox, which may also incorporate an output for an alternator. The average design ship speed for bulk carriers of Handysize and above is . The propeller speed is relatively low, at about 90 revolutions per minute, although it depends on the size of the propeller.


title: Bulk carrier

text: As a result of the 1973 oil crisis, the 1979 energy crisis, and the resulting rise in oil prices, experimental designs using coal to fuel ships were tested in the late 1970s and early 1980s. The Australian National Lines (ANL) constructed two 74,700-ton coal-burner ships called "River Boyne" and "River Embely". along with two constructed by TNT called "TNT Capricornia" and "TNT Capentaria" and renamed "Fitzroy River" and "Endeavor River". These ships were financially effective for the duration of their lives, and their steam engines were able to generate a shaft-power of . This strategy gave an interesting advantage to carriers of bauxite and similar fuel cargoes, but suffered from poor engine yield compared to higher maintenance cost and efficient modern diesels, maintenance problems due to the supply of ungraded coal, and high initial costs.


title: Bulk carrier

text: A hatch or hatchway is the opening at the top of a cargo hold. The mechanical devices which allow hatches to be opened and closed are called hatch cover. In general, hatch covers are between 45% and 60% of the ship's breadth, or beam, and 57% to 67% of the length of the holds. To efficiently load and unload cargo, hatches must be large, but large hatches present structural problems. Hull stress is concentrated around the edges of the hatches, and these areas must be reinforced. Often, hatch areas are reinforced by locally increasing the scantlings or by adding structural members called stiffeners. Both of these options have the undesired effect of adding weight to the ship.


title: Bulk carrier

text: As recently as the 1950s, hatches had wooden covers that would be broken apart and rebuilt by hand, rather than opened and closed. Newer vessels have hydraulic-operated metal hatch covers that can often be operated by one person. Hatch covers can slide forwards, backwards, or to the side, lift up or fold up. It is essential that the hatch covers be watertight: unsealed hatches lead to accidental cargo hold flooding, which has caused many bulk carriers to sink.


title: Bulk carrier

text: Regulations regarding hatch covers have evolved since the investigation following the loss of the . The Load Line Conference of 1966 imposed a requirement that hatch covers be able to withstand load of 1.74 tons/m due to sea water, and a minimum scantling of 6 mm for the tops of the hatch covers. The International Association of Classification Societies then increased this strength standard by creating its "Unified Requirement S21" in 1998. This standard requires that the pressure due to sea water be calculated as a function of freeboard and speed, especially for hatch covers located on the forward portion of the ship.


title: Bulk carrier

text: Bulk carriers are designed to be easy to build and to store cargo efficiently. To facilitate construction, bulk carriers are built with a single hull curvature. Also, while a bulbous bow allows a ship to move more efficiently through the water, designers lean towards simple vertical bows on larger ships. Full hulls, with large block coefficients, are almost universal, and as a result, bulk carriers are inherently slow. This is offset by their efficiency. Comparing a ship's carrying capacity in terms of deadweight tonnage to its weight when empty is one way to measure its efficiency. A small Handymax ship can carry five times its weight. In larger designs, this efficiency is even more pronounced: Capesize vessels can carry more than eight times their weight.


title: Bulk carrier

text: Bulk carriers have a cross-section typical of most merchant ships. The upper and lower corners of the hold are used as ballast tanks, as is the double bottom area. The corner tanks are reinforced and serve another purpose besides controlling the ship's trim. Designers choose the angle of the corner tanks to be less than that of the angle of repose of the anticipated cargoes. This greatly reduces side-to-side movement, or "shifting," of cargo which can endanger the ship.


title: Bulk carrier

text: The double bottoms are also subject to design constraints. The primary concern is that they be high enough to allow the passage of pipes and cables. These areas must also be roomy enough to allow people safe access to perform surveys and maintenance. On the other hand, concerns of excess weight and wasted volume keep the double bottoms very tight spaces.


title: Bulk carrier

text: Bulk carrier hulls are made of steel, usually mild steel. Some manufacturers have preferred high-tensile steel recently in order to reduce the tare weight. However, the use of high-tensile steel for longitudinal and transverse reinforcements can reduce the hull's rigidity and resistance to corrosion. Forged steel is used for some ship parts, such as the propeller shaft support. Transverse partitions are made of corrugated iron, reinforced at the bottom and at connections. The construction of bulk carrier hulls using a concrete-steel sandwich has been investigated.


title: Bulk carrier

text: Double hulls have become popular in the past ten years. Designing a vessel with double sides adds primarily to its breadth, since bulk carriers are already required to have double bottoms. One of the advantages of the double hull is to make room to place all the structural elements in the sides, removing them from the holds. This increases the volume of the holds, and simplifies their structure which helps in loading, unloading, and cleaning. Double sides also improve a ship's capacity for ballasting, which is useful when carrying light goods: the ship may have to increase its draft for stability or seakeeping reasons, which is done by adding ballast water.


title: Bulk carrier

text: A recent design, called Hy-Con, seeks to combine the strengths of single-hull and double-hull construction. Short for Hybrid Configuration, this design doubles the forward-most and rear-most holds and leaves the others single-hulled. This approach increases the ship's solidity at key points, while reducing the overall tare weight.


title: Bulk carrier

text: Since the adoption of double hull has been more of an economic than a purely architectural decision, some argue that double-sided ships receive less comprehensive surveys and suffer more from hidden corrosion. In spite of opposition, double hulls became a requirement for Panamax and Capesize vessels in 2005.


title: Bulk carrier

text: Freighters are in continual danger of "breaking their backs" and thus longitudinal strength is a primary architectural concern. A naval architect uses the correlation between longitudinal strength and a set of hull thicknesses called scantlings to manage problems of longitudinal strength and stresses. A ship's hull is composed of individual parts called "members." The set of dimensions of these members is called the ship's scantlings. Naval architects calculate the stresses a ship can be expected to be subjected to, add in safety factors, and then can calculate the required scantlings.


title: Bulk carrier

text: These analyses are conducted when traveling empty, loading and unloading, when partially and fully loaded, and under conditions of temporary overloading. Places subject to the largest stresses are studied carefully, such as hold-bottoms, hatch-covers, bulkheads between holds, and the bottoms of ballast tanks. Great Lakes bulk carriers also must be designed to withstand springing, or developing resonance with the waves, which can cause fatigue fractures.


title: Bulk carrier

text: Since 1 April 2006, the International Association of Classification Societies has adopted the "Common Structural Rules." The rules apply to bulk carriers more than 90 meters in length and require that scantlings' calculations take into account items such as the effect of corrosion, the harsh conditions often found in the North Atlantic, and dynamic stresses during loading. The rules also establish margins for corrosion, from 0.5 to 0.9 mm.


title: Bulk carrier

text: The 1980s and 1990s were a very unsafe time for bulk carriers. Many bulk carriers sank during this time; 99 were lost between 1990 and 1997 alone. Most of these sinkings were sudden and quick, making it impossible for the crew to escape: more than 650 sailors were lost during this same period. Due partly to the sinking of , a series of international safety resolutions regarding bulk carriers were adopted during the 1990s.


title: Bulk carrier

text: Cargo shifting poses a great danger for bulk carriers. The problem is even more pronounced with grain cargoes, since grain settles during a voyage and creates extra space between the top of the cargo and the top of the hold. Cargo is then free to move from one side of the ship to the other as the ship rolls. This can cause the ship to list, which, in turn, causes more cargo to shift. This kind of chain reaction can capsize a bulk carrier very quickly.


title: Bulk carrier

text: The 1960 SOLAS Convention sought to control this sort of problem. These regulations required the upper ballast tanks designed in a manner to prevent shifting. They also required cargoes to be leveled, or trimmed, using excavators in the holds. The practice of trimming reduces the amount of the cargo's surface area in contact with air which has a useful side-effect: reducing the chances of spontaneous combustion in cargoes such as coal, iron, and metal shavings.


title: Bulk carrier

text: Another sort of risk that can affect dry cargoes is absorption of ambient moisture. When very fine concretes and aggregates mix with water, the mud created at the bottom of the hold shifts easily and can produce a free surface effect. The only way to control these risks is by good ventilation practices and careful monitoring for the presence of water.


title: Bulk carrier

text: In 1990 alone, 20 bulk carriers sank, taking with them 94 crewmen. In 1991, 24 bulk carriers sank, killing 154. This level of loss focused attention on the safety aspects of bulk carriers, and a great deal was learned. The American Bureau of Shipping concluded that the losses were "directly traceable to failure of the cargo hold structure" and Lloyd's Register of Shipping added that the hull sides could not withstand "the combination of local corrosion, fatigue cracking and operational damage."


title: Bulk carrier

text: Previous practices had required ships to withstand the flooding of a single forward hold, but did not guard against situations where two holds would flood. The case where two after (rear) holds are flooded is no better, because the engine room is quickly flooded, leaving the ship without propulsion. If two holds in the middle of the ship are flooded, the stress on the hull can become so great that the ship snaps in two.


title: Bulk carrier

text: The new rules adopted in the 1997 annexes to the SOLAS convention focused on problems such as reinforcing bulkheads and the longitudinal frame, more stringent inspections (with a particular focus on corrosion) and routine in-port inspections. The 1997 additions also required bulk carriers with restrictions (for instance, forbidden from carrying certain types of cargoes) to mark their hulls with large, easy-to-see triangles.


title: Bulk carrier

text: Since December 2004, Panamax and Capesize bulk carriers have been required to carry free-fall lifeboats located on the stern, behind the deckhouse. This arrangement allows the crew to abandon ship quickly in case of a catastrophic emergency. One argument against the use of free-fall lifeboats is that the evacuees require "some degree of physical mobility, even fitness" to enter and launch the boat. Also, injuries have occurred during launches, for example, in the case of incorrectly secured safety belts.


title: Bulk carrier

text: In December 2002, Chapter XII of the SOLAS convention was amended to require the installation of high-level water alarms and monitoring systems on all bulk carriers. This safety measure quickly alerts watch standers on the bridge and in the engine room in case of flooding in the holds. In cases of catastrophic flooding, these detectors could speed the process of abandoning ship.


title: Mel Robbins

text: Melanie Robbins (née Schneeberger on October 6, 1968) is an American lawyer, television host, author, and motivational speaker. Robbins is known for covering the George Zimmerman trial for CNN; her TEDx talk, "How to Stop Screwing Yourself Over"; and her books, "The 5 Second Rule" and "The High 5 Habit".


title: Mel Robbins

text: Robbins was born in Kansas City, Missouri, and grew up in North Muskegon, Michigan. She attended Dartmouth College. She received a J.D. degree from Boston College Law School in 1994.


title: Mel Robbins

text: Prior to joining CNN as a legal analyst, Robbins worked as a criminal defense attorney and hosted Cox Media Group's "The Mel Robbins Show", A&E's "Monster In-Laws", and Fox's "Someone's Gotta Go".


title: Mel Robbins

text: In 2011, Robbins published "Stop Saying You're Fine: Discover a More Powerful You". She spoke at TEDx San Francisco about a psychological trick that she termed "the five second rule". Her talk, viewed more than 20 million times on YouTube , launched her public speaking career.


title: Mel Robbins

text: On February 28, 2017, Robbins released her second book, "The 5 Second Rule: Transform Your Life, Work, and Confidence with Everyday Courage". It was the top non-fiction book on Audible and sixth most-read book on Amazon in 2017.


title: Mel Robbins

text: She collaborated with Audible to release the Audible Original programs "Kick Ass with Mel Robbins" in June 2018 and "Take Control of Your Life" in 2019.


title: Mel Robbins

text: Her syndicated daytime talk show with Sony Pictures Television, "The Mel Robbins Show," premiered on September 16, 2019. On January 29, 2020, Sony announced that the show would be canceled following its first season due to low ratings.


title: Richard Harris (anaesthetist)

text: Richard "Harry" Harris, , is an Australian anaesthetist and cave diver who played a crucial role in the Tham Luang cave rescue. He and Craig Challen were jointly awarded 2019 Australian of the Year as a result of that rescue.


title: Richard Harris (anaesthetist)

text: After completing school at St Peter's College in Adelaide, South Australia, Harris completed a Bachelor of Medicine and Bachelor of Surgery at Flinders University in 1988. He subsequently completed anaesthetics training in the United Kingdom and New Zealand.


title: Richard Harris (anaesthetist)

text: Harris has worked on medical assistance teams in natural disasters in the Pacific region and taken part in Australian Aid missions to Vanuatu. he works as an aeromedical consultant and anaesthetist for the South Australian Ambulance Service's medical retrieval service.


title: Richard Harris (anaesthetist)

text: Harris is a cave diver with over 30 years of experience. Harris's cave diving experiences include leading a team of Australian divers to record depths of in 2011 and 2012 whilst searching for the source of New Zealand's Pearse River, the mission was filmed for "National Geographic". In 2011, Harris was requested by the South Australian Police to participate in the recovery of the body of his close friend Agnes Milowka, who had died whilst exploring a cave near Tantanoola in the south east of South Australia.


title: Richard Harris (anaesthetist)

text: In 2009 Harris was awarded the "Outstanding Achievement" award at the Australian technical diving conference Oztek, to mark his exceptional contributions to cave diving exploration, in 2017 he was awarded the "Australasian Technical Diver of the Year" at Oztek.