title: Frank Whittle

text: Whittle demonstrated an aptitude for engineering and an interest in flying from an early age. At first he was turned down by the RAF but, determined to join the force, he overcame his physical limitations and was accepted and sent to No. 2 School of Technical Training to join No 1 Squadron of Cranwell Aircraft Apprentices. He was taught the theory of aircraft engines and gained practical experience in the engineering workshops. His academic and practical abilities as an Aircraft Apprentice earned him a place on the officer training course at Cranwell. He excelled in his studies and became an accomplished pilot. While writing his thesis he formulated the fundamental concepts that led to the creation of the turbojet engine, taking out a patent on his design in 1930. His performance on an officers' engineering course earned him a place on a further course at Peterhouse, Cambridge, where he graduated with a First.


title: Frank Whittle

text: Without Air Ministry support, he and two retired RAF servicemen formed Power Jets Ltd to build his engine with assistance from the firm of British Thomson-Houston. Despite limited funding, a prototype was created, which first ran in 1937. Official interest was forthcoming following this success, with contracts being placed to develop further engines, but the continuing stress seriously affected Whittle's health, eventually resulting in a nervous breakdown in 1940. In 1944 when Power Jets was nationalised he again suffered a nervous breakdown, and resigned from the board in 1946.


title: Frank Whittle

text: In 1948, Whittle retired from the RAF and received a knighthood. He joined BOAC as a technical advisor before working as an engineering specialist with Shell, followed by a position with Bristol Aero Engines. After emigrating to the U.S. in 1976 he accepted the position of NAVAIR Research Professor at the United States Naval Academy from 1977 to 1979. In August 1996, Whittle died of lung cancer at his home in Columbia, Maryland. In 2002, Whittle was ranked number 42 in the BBC poll of the 100 Greatest Britons.


title: Frank Whittle

text: Whittle was born in a terraced house in Newcombe Road, Earlsdon, Coventry, England, on 1 June 1907, the eldest son of Moses Whittle and Sara Alice Garlick. When he was nine years old, the family moved to the nearby town of Royal Leamington Spa where his father, a highly inventive practical engineer and mechanic, purchased the Leamington Valve and Piston Ring Company, which comprised a few lathes and other tools and a single-cylinder gas engine, on which Whittle became an expert. Whittle developed a rebellious and adventurous streak, together with an early interest in aviation.


title: Frank Whittle

text: After two years attending Milverton School, Whittle won a scholarship to a secondary school which in due course became Leamington College for Boys, but when his father's business faltered there was not enough money to keep him there. He quickly developed practical engineering skills while helping in his father's workshop, and being an enthusiastic reader spent much of his spare time in the Leamington reference library, reading about astronomy, engineering, turbines, and the theory of flight. At the age of 15, determined to be a pilot, Whittle applied to join the RAF.


title: Frank Whittle

text: In January 1923, having passed the RAF entrance examination with a high mark, Whittle reported to RAF Halton as an Aircraft Apprentice. He lasted only two days: just five feet tall and with a small chest measurement, he failed the medical. He then put himself through a vigorous training programme and special diet devised by a physical training instructor at Halton to build up his physique, only to fail again six months later, when he was told that he could not be given a second chance, despite having added three inches to his height and chest. Undeterred, he applied again under an assumed name and presented himself as a candidate at the No 2 School of Technical Training RAF Cranwell. This time he passed the physical and, in September that year, 364365 Boy Whittle, F, started his three-year training as an aircraft mechanic in No. 1 Squadron of No. 4 Apprentices Wing, RAF Cranwell, because RAF Halton No. 1 School of Technical Training was unable to accommodate all the aircraft apprentices at that time.


title: Frank Whittle

text: Whittle hated the strict discipline imposed on apprentices and, convinced there was no hope of ever becoming a pilot, he at one time seriously considered deserting. However, throughout his early days as an aircraft apprentice (and at the Royal Air Force College Cranwell), he maintained his interest in model aircraft and joined the Model Aircraft Society, where he built working replicas. The quality of these attracted the eye of the Apprentice Wing commanding officer, who noted that Whittle was also a mathematical genius. He was so impressed that in 1926 he recommended Whittle for officer training at RAF College Cranwell.


title: Frank Whittle

text: For Whittle, this was the chance of a lifetime, not only to enter the commissioned ranks but also because the training included flying lessons on the Avro 504. While at Cranwell he lodged in a bungalow at Dorrington. Being an ex-apprentice amongst a majority of ex-public schoolboys, life as an officer cadet was not easy for him, but he nevertheless excelled in the courses and went solo in 1927 after only 13.5 hours instruction, quickly progressing to the Bristol Fighter and gaining a reputation for daredevil low flying and aerobatics.


title: Frank Whittle

text: A requirement of the course was that each student had to produce a thesis for graduation: Whittle decided to write his on potential aircraft design developments, notably flight at high altitudes and speeds over 500 mph (800 km/h). In "Future Developments in Aircraft Design" he showed that incremental improvements in existing propeller engines were unlikely to make such flight routine. Instead he described what is today referred to as a motorjet; a motor using a conventional piston engine to provide compressed air to a combustion chamber whose exhaust was used directly for thrust – essentially an afterburner attached to a propeller engine. The idea was not new and had been talked about for some time in the industry, but Whittle's aim was to demonstrate that at increased altitudes the lower outside air density would increase the design's efficiency. For long-range flight, using an Atlantic-crossing mailplane as his example, the engine would spend most of its time at high altitude and thus could outperform a conventional powerplant. According to Whittle, "...I came to the general conclusion that if very high speeds were to be combined with long range, it would be necessary to fly at very great height, where the low air density would greatly reduce resistance in proportion to speed."


title: Frank Whittle

text: Of the few apprentices accepted into the Royal Air Force College, Whittle graduated in 1928 at the age of 21 and was commissioned as a pilot officer in July. He ranked second in his class in academics, won the Andy Fellowes Memorial Prize for Aeronautical Sciences for his thesis, and was described as an "exceptional to above average" pilot. However, his flight logbook also showed numerous red ink warnings about showboating and overconfidence, and because of dangerous flying in an Armstrong Whitworth Siskin he was disqualified from the end of term flying contest.


title: Frank Whittle

text: Whittle continued working on the motorjet principle after his thesis work but eventually abandoned it when further calculations showed it would weigh as much as a conventional engine of the same thrust. Pondering the problem he thought: "Why not substitute a turbine for the piston engine?" Instead of using a piston engine to provide the compressed air for the burner, a turbine could be used to extract some power from the exhaust and drive a similar compressor to those used for superchargers. The remaining exhaust thrust would power the aircraft.


title: Frank Whittle

text: On 27 August 1928, Pilot Officer Whittle joined No. 111 Squadron, Hornchurch, flying Siskin IIIs. His continuing reputation for low flying and aerobatics provoked a public complaint that almost led to his being court-martialled. Within a year he was posted to Central Flying School, at Wittering, for a flying instructor's course. He became a popular and gifted instructor, and was selected as one of the entrants in a competition to select a team to perform the "crazy flying" routine in the 1930 Royal Air Force Air Display at RAF Hendon. He destroyed two aircraft in accidents during rehearsals but remained unscathed on both occasions. After the second incident an enraged Flight Lieutenant Harold W. Raeburn said furiously, "Why don't you take all my bloody aeroplanes, make a heap of them in the middle of the aerodrome and set fire to them – it's quicker!"


title: Frank Whittle

text: Whittle showed his engine concept around the base, where it attracted the attention of Flying Officer Pat Johnson, formerly a patent examiner. Johnson, in turn, took the concept to the commanding officer of the base. This set in motion a chain of events that almost led to the engines being produced much sooner than actually occurred.


title: Frank Whittle

text: Earlier, in July 1926, A. A. Griffith had published a paper on compressors and turbines, which he had been studying at the Royal Aircraft Establishment (RAE). He showed that such designs up to this point had been flying "stalled", and that by giving the compressor blades an aerofoil-shaped cross-section their efficiency could be dramatically improved. The paper went on to describe how the increased efficiency of these sorts of compressors and turbines would allow a jet engine to be produced, although he felt the idea was impractical, and instead suggested using the power as a turboprop. At the time most superchargers used a centrifugal compressor, so there was limited interest in the paper.


title: Frank Whittle

text: Encouraged by his commanding officer, in late 1929 Whittle sent his concept to the Air Ministry to see if it would be of any interest to them. With little knowledge of the topic they turned to the only other person who had written on the subject and passed the paper on to Griffith. Griffith appears to have been convinced that Whittle's "simple" design could never achieve the sort of efficiencies needed for a practical engine. After pointing out an error in one of Whittle's calculations, he went on to comment that the centrifugal design would be too large for aircraft use and that using the jet directly for power would be rather inefficient. The RAF returned his comment to Whittle, referring to the design as being "impracticable".


title: Frank Whittle

text: Pat Johnson remained convinced of the validity of the idea, and had Whittle patent the idea in January 1930. Since the RAF was not interested in the concept they did not declare it secret, meaning that Whittle was able to retain the rights to the idea, which would have otherwise been their property. Johnson arranged a meeting with British Thomson-Houston (BTH), whose chief turbine engineer seemed to agree with the basic idea. However, BTH did not want to spend the £60,000 it would cost to develop it, and this potential brush with early success went no further.


title: Frank Whittle

text: In January 1930, Whittle was promoted to flying officer. In Coventry, on 24 May 1930, Whittle married his fiancée, Dorothy Mary Lee, with whom he later had two sons, David and Ian. Then, in 1931, he was posted to the Marine Aircraft Experimental Establishment at Felixstowe as an armament officer and test pilot of seaplanes, where he continued to publicise his idea. This posting came as a surprise for he had never previously flown a seaplane, but he nevertheless increased his reputation as a pilot by flying some 20 different types of floatplanes, flying boats, and amphibians.


title: Frank Whittle

text: While at Felixstowe, Whittle met with the firm of Armstrong Siddeley, and their technical advisor W.S. Farren. The firm rejected Whittle's proposal, doubting material was available to sustain the required very high temperatures. Whittle's turbojet proposal required a compressor with a pressure ratio of 4:1, while the best current supercharger only had half that value. Besides publishing a paper on superchargers, Whittle wrote The Case for the Gas Turbine. According to John Golley, "The paper contained example calculations which showed the big increase in efficiency which could be obtained with the gas turbine at great height due to the beneficial effects of low air temperature. It also contained calculations to demonstrate the degree to which range would depend on height with turbojet aircraft."


title: Frank Whittle

text: Every officer with a permanent commission was expected to take a specialist course, and as a result Whittle attended the Officers School of Engineering at RAF Henlow in 1932. He obtained an aggregate of 98% in all subjects in his entrance exam, which allowed him to complete a shortened one-year course. Whittle received a Distinction in every subject, except mechanical Drawing, noting he was "A very able student. He works hard and has originality. He is suitable for experimental duties."


title: Frank Whittle

text: His performance in the course was so exceptional that in 1934 he was permitted to take a two-year engineering course as a member of Peterhouse, the oldest college of Cambridge University, graduating in 1936 with a First in the Mechanical Sciences Tripos. In February 1934, he had been promoted to the rank of flight lieutenant.


title: Frank Whittle

text: Still at Cambridge, Whittle could ill afford the £5 renewal fee for his jet engine patent when it became due in January 1935, and because the Air Ministry refused to pay it the patent was allowed to lapse. Shortly afterwards, in May, he received mail from Rolf Dudley-Williams, who had been with him at Cranwell in the 1920s and Felixstowe in 1930. Williams arranged a meeting with Whittle, himself, and another by-then-retired RAF serviceman, James Collingwood Tinling. The two proposed a partnership that allowed them to act on Whittle's behalf to gather public financing so that development could go ahead. Whittle thought improvements to his original idea could be patented, noting, "Its virtue lies entirely in its extremely low weight, and that it will work at heights where atmospheric density is very low." This led to three provisional specifications being filed, as the group sought to develop a jet-propelled airplane.


title: Frank Whittle

text: The agreement soon bore fruit, and in 1935, through Tinling's father, Whittle was introduced to Mogens L. Bramson, a well-known independent consulting aeronautical engineer. Bramson was initially sceptical but after studying Whittle's ideas became an enthusiastic supporter. Bramson introduced Whittle and his two associates to the investment bank O.T. Falk & Partners, where discussions took place with Lancelot Law Whyte and occasionally Sir Maurice Bonham-Carter. The firm had an interest in developing speculative projects that conventional banks would not touch. Whyte was impressed by the 28-year-old Whittle and his design when they met on 11 September 1935:


title: Frank Whittle

text: However O.T. Falk & Partners specified they would only invest in Whittle's engine if they had independent verification that it was feasible. They financed an independent engineering review from Bramson (The historic "Bramson Report"


title: Frank Whittle

text: ), which was issued in November 1935. It was favourable and Falk then agreed to finance Whittle. With that the jet engine was finally on its way to becoming a reality.


title: Frank Whittle

text: On 27 January 1936, the principals signed the "Four Party Agreement", creating "Power Jets Ltd" which was incorporated in March 1936. The parties were O.T. Falk & Partners, the Air Ministry, Whittle and, together, Williams and Tinling. Falk was represented on the board of Power Jets by Whyte as chairman and Bonham-Carter as a director (with Bramson acting as alternate). Whittle, Williams and Tinling retained a 49% share of the company in exchange for Falk and Partners putting in £2,000 with the option of a further £18,000 within 18 months. As Whittle was still a full-time RAF officer and currently at Cambridge, he was given the title "Honorary Chief Engineer and Technical Consultant". Needing special permission to work outside the RAF, he was placed on the Special Duty List and allowed to work on the design as long as it was for no more than six hours a week. However he was allowed to continue at Cambridge for a year doing post-graduate work which gave him time to work on the turbojet.


title: Frank Whittle

text: The Air Ministry still saw little immediate value in the effort (they regarded it as long-range research), and having no production facilities of its own, Power Jets entered into an agreement with steam turbine specialists British Thomson-Houston (BTH) to build an experimental engine facility at a BTH factory in Rugby, Warwickshire. Work progressed quickly, and by the end of the year 1936 the prototype detail design was finalised and parts for it were well on their way to being completed, all within the original £2,000 budget. However, by 1936, Germany had also started working on jet engines (Herbert A. Wagner at Junkers and Hans von Ohain at Heinkel) and, although they too had difficulty overcoming conservatism, the German Ministry of Aviation (Reichsluftfahrtministerium) was more supportive than their British counterpart. Von Ohain applied for a patent for a turbojet engine in 1935 but having earlier reviewed and critiqued Whittle's patents, had to narrow the scope of his own filing. In Spain, air-force pilot and engineer Virgilio Leret Ruiz had been granted a patent for a jet engine in March 1935, and Republican president Manuel Azaña arranged for initial construction at the Hispano-Suiza aircraft factory in Madrid in 1936, but Leret was executed months later by Francoist Moroccan troops after commanding the defence of his seaplane base near Melilla at the onset of the Spanish Civil War. His plans were hidden from the Francoists and secretly handed to the British embassy in Madrid a few years later when his wife, Carlota O'Neill, was released from prison.


title: Frank Whittle

text: Despite lengthy delays in their own programme, the Luftwaffe beat the British efforts into the air by nine months. A lack of cobalt for high-temperature steel alloys meant the German designs were always at risk of overheating and damaging their turbines. The low-grade alloy production versions of the Junkers Jumo 004, designed by Dr. Anselm Franz and which powered the Messerschmitt Me 262 would typically last only 10–25 hours (longer with an experienced pilot) before burning out; if it was accelerated too quickly, the compressor would stall and power was immediately lost, and sometimes it exploded on their first startup. Over 200 German pilots were killed during training. Nevertheless, the Me 262 could fly far faster than allied planes and had very effective firepower. Although Me 262s were introduced late in the war they shot down 542 or more allied planes and in one allied bombing raid downed 32 of the 36 Boeing B-17 Flying Fortresses.


title: Frank Whittle

text: Earlier, in January, when the company formed, Henry Tizard, the rector of Imperial College London and chairman of the Aeronautical Research Committee (ARC), had prompted the Air Ministry's Director of Scientific Research to ask for a write-up of the design. The report was once again passed on to Griffith for comment, but was not received back until March 1937 by which point Whittle's design was well along. Griffith had already started construction of his own turbine engine design and, perhaps to avoid tainting his own efforts, he returned a somewhat more positive review. However, he remained highly critical of some features, notably the use of jet thrust. The Engine Sub-Committee of ARC studied Griffith's report, and decided to fund his effort instead. Given this astonishing display of official indifference, Falk and Partners gave notice that they could not provide funding beyond £5,000.


title: Frank Whittle

text: Nevertheless, the team pressed ahead, and the Power Jets WU (Whittle Unit, or W.U.) engine began test runs on 12 April 1937. Initially, the W.U. showed an alarming tendency to race out of control, due to issues with the fuel injection, before stable speeds were reached. However, by August, Whittle acknowledged a major reconstruction effort was needed to solve the combustion problem and compressor efficiency.


title: Frank Whittle

text: On 9 July, Falk & Partners gave the company an emergency loan of £250. On 27 July, Falk's option expired, but they agreed to continue financing Power Jets by loan. Also in July, Whittle's post-graduate stay at Cambridge was over, but then he was placed on the Special Duty List so he could work full-time on the engine. On 1 November, Williams, Tinling and Whittle took control of Power Jets. Whittle was promoted to squadron leader in December. Tizard pronounced it "streaks ahead" of any other advanced engine he had seen, and managed to interest the Air Ministry enough to fund development with a contract for £5,000 to develop a flyable version. However, it was not until March 1938 that a contract was signed, when Power Jets became subject to the Official Secrets Act, limiting the ability to raise additional funds. In January 1938, BTH invested £2,500.


title: Frank Whittle

text: In December 1937, Victor Crompton became Power Jets first employee, as an assistant to Whittle. Because of the dangerous nature of the work being carried out, development was moved largely from Rugby to BTH's lightly used Ladywood foundry at nearby Lutterworth in Leicestershire in 1938. Tests with a reconstructed W.U. engine commenced on 16 April 1938, and proceeded until a catastrophic failure of the turbine on 6 May. Yet, the engine ran for 1 hour and 45 minutes, and generated a thrust of at 13,000 rpm. Another W.U. engine reconstruction was started on 30 May 1938, but using ten combustion chambers to match the ten compressor discharge ducts. Avoiding a single large combustion chamber made the engine lighter and more compact. Tests commenced with this third W.U. on 26 October 1938.


title: Frank Whittle

text: These delays and the lack of funding slowed the project. In Germany, Hans von Ohain had filed for a patent in 1935, which in 1939, led to the world's first flyable jet aircraft, the Heinkel He 178, powered by the Heinkel HeS 3. There is little doubt that Whittle's efforts would have been at the same level or even more advanced had the Air Ministry taken a greater interest in the design. When war broke out in September 1939, Power Jets had a payroll of only 10 and Griffith's operations at the RAE and Metropolitan-Vickers were similarly small.


title: Frank Whittle

text: Whittle's smoking increased to three packs a day and he suffered from various stress-related ailments such as frequent severe headaches, indigestion, insomnia, anxiety, eczema and heart palpitations, while his weight dropped to nine stone (126 lb / 57 kg). To keep to his 16-hour workdays, he sniffed Benzedrine during the day and then took tranquillizers and sleeping pills at night to offset the effects and allow him to sleep. He admitted later he had become addicted to benzedrine. Over this period he became irritable and developed an "explosive" temper.


title: Frank Whittle

text: On 30 June 1939, Power Jets could barely afford to keep the lights on when yet another visit was made by Air Ministry personnel. This time Whittle was able to run the third reconstructed W.U. at 16,000 rpm for 20 minutes without any difficulty. One of the members of the team was the Director of Scientific Research, David Randall Pye, who walked out of the demonstration utterly convinced of the importance of the project. The Ministry agreed to buy the W.U. and then loan it back to them, injecting cash, and placed an order for a flyable version of the engine, referred to as the Power Jets W.1 and Power Jets W.2. By then, the Ministry had a tentative contract with the Gloster Aircraft Company for a simple aircraft specifically to flight-test the W.1, the single-engine Gloster E.28/39.


title: Frank Whittle

text: Whittle had already studied the problem of turning the massive W.U. into a flyable design, with what he described as very optimistic targets, to power a little aeroplane weighing 2,000 lb with a static thrust of 1,389 lb. The designed maximum thrust for the W.1 was , while that for the W.2, was The W.2 was to be flown in the twin-engine Gloster Meteor fighter, designated F.9/40, but the engine was replaced with the W.2B, having


title: Frank Whittle

text: a designed static thrust of . An experimental version of the W.1, designated W.1X, was used as a mock-up for the E.28 installation. A second E.28 was powered by the W.1A, that incorporated W.2 features such as air cooling of the turbine and a different compressor intake. On 26 March 1940, the jet engine was listed as a potential war winner by Air Marshal Tedder, and given the associated priority.


title: Frank Whittle

text: Power Jets also spent some time in May 1940 drawing up the W.2Y, a similar design with a "straight-through" airflow that resulted in a longer engine and, more critically, a longer driveshaft but having a somewhat simpler layout. To reduce the weight of the driveshaft as much as possible, the W.2Y used a large diameter, thin-walled, shaft almost as large as the turbine disc, "necked down" at either end where it connected to the turbine and compressor.


title: Frank Whittle

text: In April, the Air Ministry issued contracts for W.2 production lines with a capacity of up to 3,000 engines a month in 1942, asking BTH, Vauxhall and the Rover Company to join. However, the contract was eventually taken up by Rover only. In June, Whittle received a promotion to wing commander.


title: Frank Whittle

text: On 19 July 1940, Power Jets abandoned effort to vaporize fuel, and adopted the controlled atomising burner for the combustion chamber, developed by Isaac Lubbock of Asiatic Petroleum Company. In the words of Whittle, "the introduction of the Shell system may be said to mark the point where combustion ceased to be an obstacle to development." The size of Power Jets also increased with the WWII effort, increasing from 25 employees in January 1940 to 70 in September 1940.


title: Frank Whittle

text: Meanwhile, work continued with the W.U., which eventually went through nine rebuilds in an attempt to solve the combustion problems that had dominated the testing. On 9 October the W.U. ran once again, this time equipped with Lubbock or "Shell" atomising-burner combustion chambers. Combustion problems ceased to be an obstacle to development of the engine although intensive development was started on all features of the new combustion chambers.


title: Frank Whittle

text: By this point it was clear that Gloster's first airframe would be ready long before Rover could deliver an engine. Unwilling to wait, Whittle cobbled together an engine from spare parts, creating the W.1X ("X" standing for "experimental") which ran for the first time on 14 December 1940. Shortly afterwards an application for a US patent was made by Power Jets for an "Aircraft propulsion system and power unit"


title: Frank Whittle

text: The W.1X engine powered the E.28/39 for taxi testing on 7 April 1941 near the factory in Gloucester, where it took to the air for two or three short hops of several hundred yards at about six feet from the ground.


title: Frank Whittle

text: The definitive W.1 of 850 lbf (3.8 kN) thrust ran on 12 April 1941, and on 15 May the W.1-powered E.28/39 took off from Cranwell at 7:40 pm, flying for 17 minutes and reaching a maximum speed of around 340 mph (545 km/h). At the end of the flight, Pat Johnson, who had encouraged Whittle for so long said to him, "Frank, it flies." Whittle replied, "Well, that's what it was bloody well designed to do, wasn't it?"


title: Frank Whittle

text: Within days the aircraft was reaching 370 mph (600 km/h) at 25,000 feet (7,600 m), exceeding the performance of the contemporary Spitfires. Success of the design was now evident, and in 1941, Rolls-Royce, Hawker Siddeley, the Bristol Aeroplane Company, and de Havilland became interested in gas turbine aircraft propulsion.


title: Frank Whittle

text: In mid-1941, relations between Power Jets and Rover had continued to deteriorate. Rover had established a version of Power Jet's set-up at Waterloo Mill, associated with their Barnoldswick factory, near Clitheroe. Rover was working on an alternative to Whittle's "reverse-flow" combustion chambers, by developing a "straight-through" combustion chamber and turbine wheel. Rover referred to the engine as the B.26, sanctioned by the Directorate of Engine Development, but kept secret until April 1942, from Power Jets, the Controller of Research and Development, and the Director of Scientific Research.


title: Frank Whittle

text: Earlier, in January 1940, Whittle had met Dr Stanley Hooker of Rolls-Royce, who in turn introduced Whittle to Rolls-Royce board member and manager of their Derby factory, Ernest Hives (later Lord Hives). Hooker was in charge of the supercharger division at Rolls-Royce Derby and was a specialist in fluid dynamics. He had already increased the power of the Merlin piston engine by improving its supercharger. Such a speciality was naturally suited to the aero-thermodynamics of jet engines in which the optimisation of airflow in compressor, combustion chambers, turbine and jet pipe, is fundamental. Hives agreed to supply key parts to help the project. Also, Rolls-Royce built a compressor test rig which helped Whittle solve the surging problems (unstable airflow in the compressor) on the W.2 engine.


title: Frank Whittle

text: On 10 December 1941 Whittle suffered a nervous breakdown, and left work for a month. However, by the end of January 1942, Power Jets had three W.2B engines, two built by Rover. In February 1942, flight trials of the W.1A engine began in the E.28, which reached 430 mph (690 km/h) at 15,000 feet (4,600 m). On 13 March 1942, Whittle started work on a redesign of the W.2B, referred to as the W.2/500.


title: Frank Whittle

text: On 13 September 1942, W.2/500 performance tests matched predictions, showing a thrust of at full speed. In October 1941, the Ministry approved a new factory to be built outside Whetstone, Leicestershire.


title: Frank Whittle

text: From 3 June until 14 August 1942 Whittle visited the United States. At the General Electric's Lynn Factory, Whittle reviewed the Type I Supercharger, GE's code name for their jet engine, based on Power Jets' W.1X. An improved version of the W.2B would also be built, called the I-16, incorporating features of the W.2/500. Whittle also toured the Bell Aircraft, and the three Bell XP-59A Airacomets, a twin-engine fighter powered by the General Electric I-A jet engines. This fighter took flight in October 1942, one year and one day after GE received Power Jets' W.1X.


title: Frank Whittle

text: On 11 December 1942 Whittle had a meeting with Ministry of Aircraft Production Wilfrid Freeman and Air Marshal Linnell. According to Whittle, "He made it clear that he had definitely decided to transfer Barnoldswick and Clitheroe to Rolls-Royce management." Spencer Wilks of Rover met with Hives and Hooker at the "Swan and Royal" pub, in Clitheroe, near the Barnoldswick factory. By arrangement with the Ministry of Aircraft Production they traded the jet factory at Barnoldswick for Rolls-Royce's tank engine factory in Nottingham.


title: Frank Whittle

text: Testing and production ramp-up was immediately accelerated. By January 1943, Rolls-Royce had achieved 400 hours of run time, ten times Rover's number of the previous month, and in May 1943, the W.2B passed its first 100-hour development test at of thrust.


title: Frank Whittle

text: When Rolls-Royce became involved, Ray Dorey, the manager of the company's Flight Centre at Hucknall Airfield on the north side of Nottingham, had a Whittle W.2B engine installed in the rear of a Vickers Wellington bomber. The installation was done by Vickers at Weybridge.


title: Frank Whittle

text: Whittle wanted to improve the efficiency of the jet engine at lower speeds. According to Whittle, "I wanted to 'gear down the jet', ie to convert a low-mass high-velocity jet into a high-mass low-velocity jet. The obvious way to do this was to use an additional turbine to extract energy from the jet and use this energy to drive a low-pressure compressor or fan capable of 'breathing' far more air than the jet engine itself and forcing this additional air rearwards as a 'cold jet'. The complete system is known as a 'turbofan'." The first embodiment was referred to as a No 1 Thrust Augmentor, which consisted of an "aft fan", or additional turbine, in the exhaust of the main engine. In 1942, No 2 Augmentor, a conventional two-stage system with the fan blades external to the turbine blades, was used by GE in the Convair 990 Coronado. A No 3 Augmentor, known as the "tip turbine", had the turbine blades outside the fan. A No 4 Augmentor, in combination with the W2/700, included an afterburner, was the design powerplant for the Miles M.52 project. According to Whittle, "The first attempt at the turbofan proper, ie having the fan ahead of and supercharging the core engine, was the LR1 intended as the power plant of a four-engined bomber for operations in the Pacific. The mass flow through the fan of the LR1 was to have been 3-4 times that through the core engine, ie the 'bypass ratio' was 2-3." Filed in March 1936, Whittle's main turbofan patent 471368, expired in 1962.


title: Frank Whittle

text: Whittle's work had caused a minor revolution within the British engine manufacturing industry and, even before the E.28/39 flew, most companies had set up their own research efforts. In 1939, Metropolitan-Vickers set up a project to develop an axial-flow design as a turboprop but later re-engineered the design as a pure jet known as the Metrovick F.2. Rolls-Royce had already copied the W.1 to produce the low-rated WR.1 but later stopped work on this project after taking over Rover's efforts. In 1941, de Havilland started a jet fighter project, the Spider Crab — later called Vampire — along with their own engine to power it, Frank Halford's Goblin (Halford H.1). Armstrong Siddeley also developed a more complex axial-flow design with an engineer called Heppner, the ASX but reversed Vickers' thinking and later modified it into a turboprop instead, the Python. The Bristol Aeroplane Company proposed to combine jet and piston engines but dropped the idea and concentrated on propeller turbines instead.


title: Frank Whittle

text: During a demonstration of the E.28/39 to Winston Churchill in April 1943, Whittle proposed to Stafford Cripps, Minister of Aircraft Production, that all jet development be nationalised. He pointed out that the company had been funded by private investors who helped develop the engine successfully, only to see production contracts go to other companies. Nationalisation was the only way to repay those debts and ensure a fair deal for everyone, and he was willing to surrender his shares in Power Jets to make this happen. In October, Cripps told Whittle that he decided a better solution would be to nationalise Power Jets only.


title: Frank Whittle

text: Whittle believed that he had triggered this decision, but Cripps had already been considering how best to maintain a successful jet programme and act responsibly regarding the state's substantial financial investment, while at the same time wanting to establish a research centre that could use Power Jets' talents, and had come to the conclusion that national interests demanded the setting up of a Government-owned establishment. On 1 December Cripps advised Power Jets' directors that the Treasury would not pay more than £100,000 for the company.


title: Frank Whittle

text: In January 1944 Whittle was appointed a Commander of the Order of the British Empire in the New Year Honours. By this time he was a group captain, having been promoted from wing commander in July 1943. Later that month after further negotiations the Ministry made another offer of £135,500 for Power Jets, which was reluctantly accepted after the Ministry refused arbitration on the matter. Since Whittle had already offered to surrender his shares he would receive nothing at all, while Williams and Tinling each received almost £46,800 for their stock, and investors of cash or services had a threefold return on their original investment. Whittle met with Cripps to object personally to the nationalisation efforts and how they were being handled, but to no avail. The final terms were agreed on 28 March, and Power Jets officially became Power Jets (Research and Development) Ltd, with Roxbee Cox as chairman, Constant of RAE Head of Engineering Division, and Whittle as Chief Technical Advisor. On 5 April 1944, the Ministry sent Whittle an award of only £10,000 for his shares.


title: Frank Whittle

text: From the end of March, Whittle spent six months in hospital recovering from nervous exhaustion, and resigned from Power Jets (R and D) Ltd in January 1946. In July the company was merged with the gas turbine division of the RAE to form the National Gas Turbine Establishment (NGTE) at Farnborough, and 16 Power Jets engineers, following Whittle's example, also resigned.


title: Frank Whittle

text: In 1946, Whittle accepted a post as Technical Advisor on Engine Design and Production to Controller of Supplies (Air); was made a Commander of the US Legion of Merit; and was appointed a Companion of the Order of the Bath in 1947. During May 1948 Whittle received an ex-gratia award of £100,000 from the Royal Commission on Awards to Inventors in recognition of his work on the jet engine, and two months later he was made a Knight Commander of the Order of the British Empire.


title: Frank Whittle

text: During a lecture tour in the US, Whittle again broke down and retired from the RAF on medical grounds on 26 August 1948, leaving with the rank of air commodore. He joined BOAC as a technical advisor on aircraft gas turbines and travelled extensively over the next few years, viewing jet engine developments in the United States, Canada, Africa, Asia and the Middle East. He left BOAC in 1952 and spent the next year working on a biography, "Jet: The Story of a Pioneer". He was awarded the Royal Society of Arts' Albert Medal that year.


title: Frank Whittle

text: Returning to work in 1953, he accepted a position as a Mechanical Engineering Specialist with Shell, where he developed a new type of self-powered drill driven by a turbine running on the lubricating mud that is pumped into the borehole during drilling. Normally a well is drilled by attaching rigid sections of pipe together and powering the cutting head by spinning the pipe from the surface, but Whittle's design removed the need for a strong mechanical connection between the drill and the head frame, allowing for much lighter piping to be used. He gave the Royal Institution Christmas Lectures in 1954 on "The Story of Petroleum".


title: Frank Whittle

text: Turbine drilling is best used for drilling hard rocks at high bit RPMs with diamond impregnated bits, and can be used with an angled drive shaft for directional drilling and horizontal drilling. It competes though with moyno motors and increasingly with rotary steerable systems and is again out of favour.


title: Frank Whittle

text: Whittle left Shell in 1957 to work for Bristol Aero Engines who picked up the project in 1961, setting up "Bristol Siddeley Whittle Tools" to further develop the concept. In 1966 Rolls-Royce purchased Bristol Siddeley, but the financial pressures and eventual bankruptcy because of cost overruns of the RB211 project led to the slow wind-down and eventual disappearance of Whittle's "turbo-drill". The concept eventually re-appeared in the west in the late 1980s, imported from Russian designs. (Russia needed the technology because it lacked high strength drill pipe.)


title: Frank Whittle

text: As part of his socialist ideals, he proposed that Power Jets be nationalised; in part because he saw that private companies would profit from the technology freely given during the war. By 1964 he had deserted his previously socialist beliefs, going so far as to launch a fierce attack on the Labour candidate in Smethwick.


title: Frank Whittle

text: In 1960 he was awarded an honorary degree, doctor techn. honoris causa, at the Norwegian Institute of Technology, later part of Norwegian University of Science and Technology.


title: Frank Whittle

text: In 1967, he was awarded an Honorary Degree (Doctor of Science) by the University of Bath. That year, he was inducted into the International Air & Space Hall of Fame.


title: Frank Whittle

text: Whittle received the "Tony Jannus Award" in 1969 for his distinguished contributions to commercial aviation.


title: Frank Whittle

text: In 1976, his marriage to Dorothy was dissolved and he married American Hazel S. Hall ("Tommie"). He emigrated to the US and the following year accepted the position of NAVAIR Research Professor at the United States Naval Academy (Annapolis, Maryland). His research concentrated on the boundary layer before his professorship became part-time from 1978 to 1979. The part-time post enabled him to write a textbook entitled "Gas turbine aero-thermodynamics: with special reference to aircraft propulsion", published in 1981.


title: Frank Whittle

text: Having first met Hans von Ohain in 1966, Whittle again met him at Wright-Patterson Air Force Base in 1978 while von Ohain was working there as the Aero Propulsion Laboratory's Chief Scientist. Initially upset because he had believed von Ohain's engine had been developed after seeing Whittle's patent, he eventually became convinced that von Ohain's work was, in fact, independent. The two became good friends and often toured the US giving talks together.


title: Frank Whittle

text: In a conversation with Whittle after the war, von Ohain stated: "If you had been given the money you would have been six years ahead of us. If Hitler or Goering had heard that there is a man in England who flies 500 mph in a small experimental plane and that it is coming into development, it is likely that World War II would not have come into being."


title: Frank Whittle

text: In 1986, Whittle was appointed a member of the Order of Merit (Commonwealth). He was made a Fellow of the Royal Society, and of the Royal Aeronautical Society, and in 1991 he and von Ohain were awarded the Charles Stark Draper Prize for their work on turbojet engines.


title: Frank Whittle

text: Whittle died of lung cancer on 9 August 1996, at his home in Columbia, Maryland. He was cremated in America and his ashes were flown to England where they were placed in a memorial in a church in Cranwell. Lady Hazel Whittle died on 30 July 2007 aged 91.


title: Five Power Defence Arrangements

text: The Five Power Defence Arrangements (FPDA) are a series of bilateral defence relationships established by a series of multi-lateral agreements between Australia, Malaysia, New Zealand, Singapore, and the United Kingdom, all of which are Commonwealth members that once belonged to the British Empire.


title: Five Power Defence Arrangements

text: Signed in 1971, the FPDA consists of the five powers consulting each other "immediately" in the event or threat of an armed attack on any of the FDPA members for the purpose of deciding what measures should be taken jointly or separately in response.


title: Five Power Defence Arrangements

text: There is no specific commitment to intervene militarily, and the agreement is merely consultative. The Five Powers Defence Arrangements do not refer to exclusive economic zones (EEZ), and the enforcement of a state's EEZ rights is a matter for that state, which may request the assistance of other states in so doing.


title: Five Power Defence Arrangements

text: The FPDA was set up following the termination of the United Kingdom's defence guarantees of Malaya under the Anglo-Malayan Defence Agreement, as a result of the UK's decision in 1967 to withdraw its armed forces east of Suez. Under the Five Powers Defence Arrangements, the five 'powers' (Australia, Malaysia, New Zealand, Singapore and the United Kingdom) are to consult each other "immediately" in the event or threat of an armed attack, although there is no specific commitment to intervene militarily. The FPDA provides defence co-operation between the countries, establishing an Integrated Air Defence System (IADS) for Peninsular Malaysia and Singapore based at RMAF Butterworth under the command of an Australian Air Vice-Marshal (2-star). RMAF Butterworth, was under the control of the Royal Australian Air Force until 1988, and is now run by the Royal Malaysian Air Force but hosts rotating detachments of aircraft and personnel from all five countries.


title: Five Power Defence Arrangements

text: In 1981, the five powers organised the first annual land and naval exercises. Since 1997, the naval and air exercises have been combined. In 2001, HQ IADS was redesignated Headquarters Integrated "Area" Defence System. It now has personnel from all three branches of the armed services, and co-ordinates the annual five-power naval and air exercises, while moving towards the fuller integration of land elements. An annual FPDA Defence Chiefs' Conference (FDCC) is hosted by either Malaysia or Singapore, and is the highest military professional forum of the FPDA and serves as an important platform for dialogue and exchange of views among the Defence Chiefs. There is also a Five Powers Defence Arrangements Ministerial Meeting (FDMM).


title: Five Power Defence Arrangements

text: John Moore, then Minister of Defence of Australia said, "As an established multilateral security framework, the FPDA has a unique role in Asia. It is of strategic benefit to all member nations and, in Australia's view, to the wider Asia-Pacific region." Malaysia's CDF, former General (GEN) Tan Sri Dato' Sri Zulkifeli Bin Mohd Zin concurred: "We can help each other... and cooperate with one another."


title: Five Power Defence Arrangements

text: In the latest New Zealand defence White Paper released in June 2016, it was outlined that given New Zealand was a longstanding member of the Five Power Defence Arrangements, it would, "meet its commitments should Malaysia or Singapore be subject to a military attack."


title: Five Power Defence Arrangements

text: On 1 November 2011, Singapore hosted FPDA's 40th anniversary celebrations, with the defence ministers, aircraft and servicemen from all five signatory countries converging on Changi Air Base (East) to participate in the event. Later, a gala dinner was hosted by Singaporean Defence Minister Ng Eng Hen at Singapore's Istana whereupon they called on the Prime Minister of Singapore—Mr Lee Hsien Loong to discuss a multitude of issues. Codenamed "Exercise Bersama Lima", the three days joint exercise tested the readiness and co-operation between all participating countries and concluded on 4 November 2011.


title: Five Power Defence Arrangements

text: On 18 October 2021, FPDA celebrated its 50th anniversary with joint air and naval displays involving the ships and aircraft of the member countries. These were observed by Singaporean Defence Minister Ng Eng Hen and the High Commissioners of Australia, Malaysia, New Zealand and the United Kingdom. Prior to this, a two-week joint exercise had taken place, known as Exercise Bersama Gold in honour of the FPDA's golden jubilee. It was the first FPDA exercise held since the start of the COVID-19 pandemic and involved 2,600 military personnel, air and maritime sea training exercises, and a virtual jungle warfare workshop. Participating ships included the Australian amphibious assault ship and New Zealand's replenishment tanker. The British destroyer also took part in the exercise but missed the final days due to technical issues. Whilst in the region at the time, did not participate in the exercise, likely due to the presence of United States Marine Corps on the aircraft carrier.


title: Five Power Defence Arrangements

text: The United Kingdom has the following personnel and facilities based in Malaysia and Singapore in support of the FPDA:


title: Five Power Defence Arrangements

text: Since its formation, the FPDA has conducted multilateral military exercises involving all five member states with operational command alternating between Singapore and Malaysia. These began as intermittent Air Defence Exercises (ADEX) in the 1970s before land and sea components were added in the 1980s. They have since become yearly fixtures and have grown in complexity, combining air, sea and land components to address both conventional and non-conventional threats. Whilst most exercises take place off the coast of Malaysia and Singapore, they have also extended into the South China Sea. Non-FPDA representatives are often invited to observe the drills.


title: Toyota Wish

text: The is an automobile produced by the Japanese automaker Toyota from 2003 to 2017. It is a compact MPV with standard three-row seating, and was positioned between the Corolla Spacio and the Ipsum in Toyota's minivan lineup. In Japan, it was available at "Toyota Netz" dealerships.


title: Toyota Wish

text: Apart from Japan, the Wish was also assembled in Thailand (for Malaysia and Singapore) and Taiwan. It was also sold in Hong Kong, where it was imported from Japan.


title: Toyota Wish

text: The Wish was developed under code name "760N" by the team, led by chief engineer named Takeshi Yoshida and was introduced to the public for the first time at Tokyo Motor Show in October 2002 (Commercial vehicles & welcab show) and then launched in Japan in January 2003, under a massive publicity campaign with Japanese singer Hikaru Utada. The television commercial features her song Colors, which coincides with the launch of her new CD single. The car was marketed under the "Wish Comes True" slogan.


title: Toyota Wish

text: Codenamed ZNE10G (FWD) and ZNE14G (4WD), it uses a 1.8 L 1ZZ-FE engine, producing (JIS) 132 PS and . It is only available with four-speed automatic. A 2.0 L version (codenamed ANE11W for the six-seater version and ANE10G for the seven-seater version) was launched in March 2003. Equipped with the 1AZ-FSE direct-injection engine, it has (JIS) 155 PS (114 kW) and 192 N·m (142 lb·ft). Variants with the 2.0 D-4 engine are only available with a CVT gearbox.


title: Toyota Wish

text: The WISH was extremely successful in its home market, and is frequently seen on the Top 5 on the 30 bestseller list each month. It has also made shockwave to its competitors, such as the Honda Stream and Mazda Premacy/Mazda5 to changing its market positioning.


title: Toyota Wish

text: The Toyota Wish was also launched as a locally assembled model in Thailand in December 2003 following the compact MPV trend of Thailand at that time. The Wish in Thailand is available with 3 trim levels including 2.0 S, 2.0 Q and 2.0 Q Limited (with sunroof) and is very similar to the Japanese version, except for a few differences:


title: Toyota Wish

text: The Wish was launched in Taiwan as a left-hand drive vehicle in November 2004. For this market, the car is marketed under the "No Rules!" slogan and the TVCM is shot in New York. The Taiwanese version shares the same engine as the Thailand model, which means missing out on Toyota's D-4 technology. The Taiwanese assembled version have some styling differences: a new front end, redesigned rear LED tail lights, reflectors recessed into the rear bumper, body color/chrome side rubbing strips and a cleaner chrome rear plate garnish. The WISH badging is not an integral part of the garnish, unlike the Japanese-spec model. Equipment may include parking sensors, dual moonroof and leather seats. Another aspect unique to the Taiwanese Wish is that it can be specified with a beige interior color scheme unlike its Japanese and Thai-built counterparts. The Wish was also made available in Indonesia as a CBU import, where many were offered as prizes by Bank Mandiri.


title: Toyota Wish

text: The Wish was updated at the end of 2005 with the introduction of a facelifted model. The original car was fundamentally well designed and that meant that few changes were necessary. Cosmetic changes to the headlights, bumpers, LED tail lights and dashboard were made, together with revised switchgear for the climate control and automatic transmission (The 2.0 Z received a seven-gear transmission.) As the changes were minor the fuel consumption figures, which are the best in the compact MPV class, remain the same. The 2005 Wish was also the third model to be sold exclusively at Toyota NETZ dealerships, hence the replacement of the Wish's signature "W" front emblem with a generic NETZ oval as seen on the 2005 Vitz and Ist. Feedback on the electronic throttle control has been mixed, with claims that the original throttle system used in the 2003 car is quicker off the mark. The drivetrain and engines remained the same.


title: Toyota Wish

text: For model year 2007 on Japanese models only, G-BOOK, a subscription telematics service, is offered as an option.


title: Toyota Wish

text: In Singapore, the local distributor brought in the Toyota Wish later in 2008 as a compact MPV to buyers there. Instead of the generic NETZ oval emblem found on the parallel imported Wish, the local distributor replaced the oval NETZ emblem with the Toyota one. Sold as the Wish "Aero Tourer" to distinguish itself from the parallel import Wish; additional, accessories such as a 5-piece bodykit inclusive of a high mounted rear LED brake light, touchscreen DVD head unit, reverse camera, side mirror indicators, illuminated scuff plates, window visors, chrome muffler tip are featured as standard equipment. Previously, the Wish was only sold by parallel importers.


title: Toyota Wish

text: The second-generation Wish has been available for the Japanese market since March 2009. It is powered by Toyota's Dual VVT-i "2ZR-FAE" and "3ZR-FAE" engines. All models come with Toyota's 7-speed Super CVT-i transmission. The exterior dimensions remain similar to the previous generation, except for the length which has increased slightly.


title: Toyota Wish

text: The second generation Wish continued to be sold outside of the Japanese market in Hong Kong, Singapore and Taiwan. These models had speedometer clusters that were slightly different from the Japanese market model in the km/h dials section.


title: Toyota Wish

text: The Wish received a facelift in April 2012. Cosmetic changes to the headlights and rear lamps featured LED insets, revised front grille, rear tailgate garnish and dashboard meter cluster were made.


title: Toyota Wish

text: All models include safety features such as ABS with EBD and BA. Additional features include TCS and VSC. All models include front ventilated and rear disc brakes with the exception of 1.8X 2WD (which include rear drums).


title: Toyota Wish

text: Sales of the Wish was discontinued in Taiwan in 2016, where it was replaced by the Sienta, and was also discontinued in Japan on 13 October 2017 and in Singapore in mid 2018, where Prius α and the Sienta replaced the outgoing Wish. In Japan, the role of the Wish as a three-row compact MPV is effectively replaced by the Sienta, the Prius α and the tall-bodied Noah/Voxy/Esquire triplets.


title: Nina Conti

text: Conti was born and raised in Hampstead, London, the daughter of actors Tom Conti and Kara Wilson. She attended King Alfred School, London, and graduated with a first class honours degree in philosophy from the University of East Anglia in 1995. She trained with Ken Campbell.


title: Nina Conti

text: Conti has worked as an actress since 1996. She appeared in several roles in Daisy and Ken Campbell's 1999 and 2000 productions of "The Warp", Neil Oram's 24-hour play cycle, and was a member of the RSC's 2000/01 company in Stratford and London. Ken Campbell subsequently devised the ventriloquist play "Let Me Out!!!" for her, which she took to the 2001 Edinburgh Festival Fringe. She appeared as half-Afghan camera operator Azadine in Henry Naylor's play "Finding Bin Laden" at the 2003 Edinburgh Festival Fringe. In 2005, Conti voiced Latrina in the animated comedy series "Bromwell High".


title: Nina Conti

text: Conti has appeared in several television shows, including "Black Books", "Holby City", "Single", and the Australian panel show "Spicks and Specks". Her radio performances include characters in Radio 4 comedy "Clare in the Community".


title: Nina Conti

text: Conti and Monkey portrayed a morning weather team on the fictional "Wake Up L.A." in Christopher Guest's 2006 film, "For Your Consideration".


title: Nina Conti

text: Conti was awarded joint "Best Performance" in the Maverick Movie Awards for "Her Master's Voice", a 2012 film.


title: Nina Conti

text: In 2013, she portrayed the part of Bea Chadwick in Christopher Guest's HBO mockumentary "Family Tree".


title: Nina Conti

text: In 2002, Conti won the BBC New Comedy Awards, came second in the Hackney Empire New Act of the Year and came third in "Laughing Horse New Act of the Year" competitions.


title: Nina Conti

text: She took her first solo full-length show, "Complete and Utter Conti", to the Edinburgh Festival Fringe in 2007, where she introduced some new characters as well as performing familiar routines. In 2008 she won the Barry Award for this show at the Melbourne International Comedy Festival, tying with Kristen Schaal.


title: Nina Conti

text: At the Melbourne Comedy Festival 2010 she debuted a new puppet, an elderly woman who is her "Granny". Conti and Granny appeared in episode six of the ninth series of the BBC comedy quiz show "QI" in 2011. On that episode, Conti noted that she inherited the Granny puppet from Ken Campbell on Campbell's death.


title: Nina Conti

text: In 2012, Conti appeared in "Russell Howard's Good News" with Granny. She also used a mask on an audience member to persuade him to dance. On the series 8 premiere of "Live at the Apollo", Conti expanded the act to provide voices for two audience members in masks.


title: Nina Conti

text: In March 2013, Conti appeared on "Let's Dance for Comic Relief" with Monk. She danced to "I Like to Move It" by Reel 2 Real.


title: Nina Conti

text: Conti appeared as a guest host on the final episode of the ninth series of the BBC stand-up comedy programme, "Live at the Apollo", performing her act with Monkey and an additional dummy-mask routine.


title: Nina Conti

text: In October 2014, Conti appeared on Channel 4's "The Feeling Nuts Comedy Night" raising awareness of testicular cancer.


title: Nina Conti

text: In 2015, Nina appeared on BBC Four's "Clowning Around", where she trained to be a giggle doctor and clown, and performed to children in hospitals.


title: Nina Conti

text: In May 2015, Nina appeared on "8 Out of 10 Cats Does Countdown" in Dictionary Corner and used Fabio, the show's regular prop guy, as a dummy.


title: Nina Conti

text: Conti's radio work includes "Clare in the Community", "Sneakiepeeks" and guesting on "Parsons and Naylor's Pull-Out Sections".


title: Nina Conti

text: In 2003 she starred as Mary in a series called "Single", then in 2005 voiced characters in another series entitled "Bromwell High". She played a part in "Blunder", "The Golf War" and featured in "Comedy Cuts" in 2006, 2007 and 2008 respectively.


title: Nina Conti

text: Conti has appeared on "Pointless Celebrities" twice: 10 November 2018 with Sally Phillips and 30 October 2021 partnering Tim Vine.


title: Nina Conti

text: Conti has appeared in a number of diverse forms of media including films, television shows, and shorts, listed below.


title: Nina Conti

text: Monkey is a cynical monkey who is continually insulting Conti and swearing when he does not have his demands fulfilled. He often deconstructs ventriloquism by pointing out that he has no microphone, or that all of his ideas are Conti's, and calls it a "dead art". He sometimes shows irritation towards performing on stage and makes Conti laugh at his words.


title: Nina Conti

text: Granny is an elderly Scotswoman to whom Conti refers as someone who is a lot like her own grandmother. Granny often chides Conti for the simplest things Conti has done; for instance, when Conti reveals she has two legs, Granny responds by saying "Oh, two legs? You're spoiling me!" Her main act is to telepathically guess numbers or words, which she always guesses correctly. She also talks about her dead husband, Frank. Granny refers to people with words like "dear", "child" or "my daughter". The original prop was donated to Vent Haven Museum in July 2009, in memory of Ken Campbell, from whom Conti received her, but Conti had a replica made which she continues to use in her acts.


title: Nina Conti

text: The face mask, rather than an actual puppet with a personality, is a mask that covers the lower half of an audience participant's face and can be manipulated by a hand-piece held by Conti to make it look like the participant is talking. Conti often uses this to put the participant in awkward and embarrassing situations, such as making them say that they want nothing more than to dance in front of the audience, while their body language suggests the opposite.


title: Nina Conti

text: Conti was in a relationship with the comedian and actor Ken Campbell, from whom she inherited his collection of ventriloquist dummies after he died. She has two sons from her marriage with fellow comedian Andrew "Stan" Stanley, from whom she is separated.


title: Miconazole

text: Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin (jock itch), and feet (athlete's foot). It is applied to the skin or vagina as a cream or ointment.


title: Miconazole

text: Common side effects include itchiness or irritation of the area in which it was applied. Use in pregnancy is believed to be safe for the baby. Miconazole is in the imidazole family of medications. It works by decreasing the ability of fungi to make ergosterol, an important part of their cell membrane.


title: Miconazole

text: Miconazole was patented in 1968 and approved for medical use in 1971. It is on the World Health Organization's List of Essential Medicines.


title: Miconazole

text: Miconazole is mainly used externally for the treatment of ringworm including jock itch and athlete's foot. Internal application is used for oral or vaginal thrush (yeast infection). This oral gel may also be used for the lip disorder angular cheilitis and other associated systems.


title: Miconazole

text: In the UK, miconazole may be used to treat neonatal oral thrush, while the alternative nystatin is only licensed for patients over the age of one month, but drug interactions are possible.


title: Miconazole

text: Miconazole is generally well tolerated. The oral gel can cause dry mouth, nausea and an unpleasant taste in about 1–10% of people. Anaphylactic reactions are rare. The drug prolongs the QT interval.


title: Miconazole

text: The substance is partly absorbed in the intestinal tract when used orally, as with the oral gel, and possibly when used vaginally. This can lead to increased concentrations of drugs that are metabolized by the liver enzymes CYP3A4 and CYP2C9, because miconazole inhibits these enzymes. Such interactions occur for example with anticoagulants of the warfarin type, phenytoin, some newer atypical antipsychotics, ciclosporin, and most statins used to treat hypercholesterolemia.


title: Miconazole

text: Miconazole is contraindicated for people who use certain drugs that are metabolized by CYP3A4, for the reasons mentioned above:


title: Miconazole

text: Miconazole inhibits the fungal enzyme 14α-sterol demethylase, resulting in a reduced production of ergosterol. In addition to its antifungal actions, miconazole, similarly to ketoconazole, is known to act as an antagonist of the glucocorticoid receptor.


title: Miconazole

text: After application to the skin, miconazole can be measured in the skin for up to four days, but less than 1% is absorbed into the bloodstream. When applied to the oral mucosa (and possibly also for vaginal use), it is significantly absorbed. In the bloodstream, 88.2% are bound to plasma proteins and 10.6% to blood cells. The substance is partly metabolized via the liver enzyme CYP3A4 and mainly eliminated via the faeces.


title: Miconazole

text: The solubilities of miconazole nitrate powder are 0.03% in water, 0.76% in ethanol and up to 4% in acetic acid. Miconazole crystallises as colourless prisms in the monoclinic space group P2/c.


title: Miconazole

text: Miconazole is also used in Ektachrome film developing in the final rinse of the Kodak E-6 process and similar Fuji CR-56 process, replacing formaldehyde. Fuji Hunt also includes miconazole as a final rinse additive in their formulation of the C-41RA rapid access color negative developing process.


title: Miconazole

text: In 2010, the U.S. Food and Drug Administration approved Oravig (miconazole) buccal tablets once daily for the local treatment of oropharyngeal candidiasis, more commonly known as thrush, in adults and children age 16 and older. Oravig is the only local, oral prescription formulation of miconazole approved for this use in the U.S.


title: Miconazole

text: External skin treatment (brand names Desenex and Zeasorb in US and Canada, Micatin, Monistat-Derm, Daktarin in India, UK, Australia, Belgium and the Philippines, Daktar in Norway, Fungidal in Bangladesh, Decocort in Malaysia)


title: Dead Pixels

text: Dead Pixels is a British television sitcom, which began airing on E4 on 28 March 2019. It focuses on the obsession of three friends, Meg, Nicky and Usman, for a fictional massive multiplayer online role-playing game (MMORPG) called "Kingdom Scrolls".


title: Dead Pixels

text: In July 2019, E4 renewed the programme for a second series which filmed later that year, for an intended spring 2020 broadcast that was delayed until 26 January 2021.


title: Dead Pixels

text: "Dead Pixels" started as "Avatards", which was a part of the Comedy Blaps series on Channel 4's website in 2016, and has since expanded to what it is now. The series creators have been cited as wanting to create a more well-rounded portrayal of the lives of some gamers, noting that mainstream television does not have the best reputation for how it presents gamers on screen. It hopes to do this by showing both the funny and the thought provoking side of gaming and gaming culture. Both the writer of the series, Jon Brown, and the director, Al Campbell, have been described as "massive gamers".


title: Dead Pixels

text: The series has been described by "The Guardian" as "wickedly entertaining" and "the sharpest new sitcom of 2019". Chortle said that the first episode of the show is "certainly funny and involving enough to entice any viewer". The Arts Desk noted that the action shifts are "cleverly visualised".


title: Dead Pixels

text: In May 2020, The CW acquired the broadcast rights for the series. Originally procured to plump up the network's autumn 2020 schedule in light of production breakdowns during the COVID-19 pandemic, the series was later shifted to the network's summer 2020 slate instead, with its autumn slot being filled by "Devils".


title: Robyn Hilton

text: Robyn Hilton is an American film and television actress and model. Hilton was active in the 1970s and 1980s following her debut supporting role as Miss Stein, the secretary to Governor William J. Le Petomane, in Mel Brooks' 1974 comedy film "Blazing Saddles".


title: Robyn Hilton

text: Hilton grew up on a farm near Twin Falls, Idaho. She graduated from Jerome High School in 1958. Hilton attended Boise Junior College and Utah State University before becoming a weather forecaster in her home town.


title: Robyn Hilton

text: In addition to other film and television work, Hilton appeared as a guest on "The Tonight Show Starring Johnny Carson" on January 17, 1974. Her last credited role was in 1985.


title: Tommy Henriksen

text: Tommy Henriksen (born February 21, 1964) is an American musician from Port Jefferson, New York, best known for his work as a guitarist, bassist and songwriter with Alice Cooper, Hollywood Vampires and German metal band Warlock. He has also fronted punk rockers P.O.L. and released several albums as a solo artist. In addition, Henriksen is a songwriter, arranger, producer and mixer who has worked with artists such as Lady Gaga, Meat Loaf, Lou Reed, Halestorm, Kesha, and Daughtry. Henriksen is currently based out of Zurich, Switzerland where he lives with his family.


title: Tommy Henriksen

text: Henriksen got his start on the New York scene with the band Ruffkut which also featured his brother Gene on drums. After playing mostly covers initially, the group began writing their own material and issued the "Fight for the Right" mini-LP in 1984. In 1986, Henriksen joined German metal band Warlock and was featured on their 1987 album "Triumph and Agony" which went gold in Germany; the videos for the singles "All We Are" and "Für immer" were in regular rotation on MTV's heavy metal program Headbangers' Ball. Henriksen stuck around co-writing several songs as lead vocalist Doro Pesch lost the rights to the name Warlock and issued her next album "Force Majeure", which also went gold, under the name Doro. Eventually, Henriksen, guitarist Jon Levin, and drummer Bobby Rondinelli all left the Doro camp and formed their own band, Big Trouble, with future Burning Rain and Montrose vocalist Keith St. John rounding out the line-up; another incarnation featured Eric St. Michaels (China, Criminal Minds) on vocals. Although signed to Atlantic Records the band split up without ever releasing an album. Henriksen left New York and moved to Los Angeles. After a brief stint with C.C. DeVille's ill-fated band Needle Park he joined former Dokken bassist Jeff Pilson's band War & Peace, appearing on the band's 1993 debut album, "Time Capsule", along with guitarist Russ Parrish, aka Satchel of Steel Panther, and future Enuff Z'nuff drummer Ricky Parent.


title: Tommy Henriksen

text: In 1994, Henriksen, taking on the alias Da Skunk, formed punk rock outfit P.O.L., short for Parade of Losers, signing a major label deal with Warner Bros. imprint Giant Records. The band's Garth Richardson produced self-titled debut was released in 1995 and the group appeared on "The Jon Stewart Show" playing their top 5 alternative single, "Stupid". P.O.L. issued their sophomore effort, "Sprockett", on their own Junkrock label in 1996 before the album saw a wider release via Entourage Records. The song "Sixteen and Confused" would later become the alternate closing theme to "Is It Fall Yet?", the first Daria TV film.


title: Tommy Henriksen

text: After the breakup of P.O.L., Henriksen began working Keith Forsey on a more pop oriented full-length solo album. Released by Capitol Records in 1999, the self-titled album included the hit single "I See the Sun", which reached #34 on the Adult Top 40 that year and was also included in the "Blast from the Past" movie soundtrack. In 2000, Henriksen released the follow-up, "Selected Songs for a New Beginning", on his own ZuZu Ltd label. He also collaborated with former War & Peace bandmate Jeff Pilson in Underground Moon whose sole album was issued on the Nuclear Blast subsidiary Rebelution Entertainment in 2002.


title: Tommy Henriksen

text: In 2001, Henriksen teamed up with P.O.L. drummer and future Alice Cooper bandmate Glen Sobel to form girl-fronted sugar-punk band Boink!. They achieved popularity in LA, releasing a single and video, "Punk Break Beat", followed up by a 5-track EP, "Walk of Fame". A huge Sex Pistols fan, Henriksen unleashed DiS ViciOuS in 2006, described by Tommy as being "another side of Sid Vicious". A few tracks were released via social networking, most of which were an anarchic rant against society, albeit rather tongue-in-cheek.


title: Tommy Henriksen

text: 2007 saw Henriksen, in a silent member producer/singer/songwriter role, join forces with Rehab's Brooks Buford and Ashley Alan-Lee in The Audio Club. The trio independently produced a music video for the single, "Sumthin' Serious", which gained airplay on a number of North American radio stations. Signed to Interscope Records, the group disbanded after disputes with their label. During this time Henriksen also continued to hone his skills as a producer and engineer working with a wide variety of artists.


title: Tommy Henriksen

text: Henriksen has worked as a songwriter, arranger, producer and mixer for such artists as Lady Gaga, Kesha, Krace, Daughtry, Kumi Koda, Porcelain Black, Meat Loaf, Cavo, Allison Iraheta, Atom Smash, Steel Magnolia, Alice, Tohoshinki, Kimberly Caldwell, Hyper Crush, The Canadian Tenors, Fefe Dobson, Lou Reed, Christian Kane, Alice Cooper, Longview, Reamonn, Revis, Runner Runner, Clear Static, Framing Hanley, Halestorm, China, Camera Can't Lie, New Medicine, Angels Fall, The Audio Club, Syndicate, Safety Suit, Brooks Buford, Emphatic, BC Jean, Kristin Chenoweth, Bowling for Soup, Capra, Simple Plan, Future Boy, Wes Carr, Fighting with Wire, The Rouge, David Cook, Beasto Blanco, Fugufish, The 3 Dudes, Annie-Rose and The All New Josie and the Pussycats.


title: Tommy Henriksen

text: In March 2011, while being associate producer, guitar player, bass player, programmer, mixer and engineer on the new Alice Cooper "Welcome 2 My Nightmare" record, Henriksen was asked by Alice to join his live band on guitar, which he continues to be a member of. He can also be seen playing bass guitar in the "Heaven in This Hell" video by fellow Cooper bandmate Orianthi.


title: Tommy Henriksen

text: On October 31, 2014, Henriksen released the digital single "Give'm Hell" off his solo album "Tommy! Tommy!! Tommy!!!", out on the Blue Martin/K-tel label in Switzerland, Germany and Austria. A promotional video for "Give 'Em Hell" was shot around Zurich, Switzerland. A limited edition vinyl version of the album was released in 2015 on Bellyache Records.


title: Tommy Henriksen

text: Henriksen is also an auxiliary member of the Cooper-fronted rock supergroup Hollywood Vampires, appearing on the band's eponymous 2015 debut studio album and playing rhythm guitar at the band's Rock in Rio show on September 24, 2015, as well as warm-up shows at The Roxy on September 16 and 17. Henriksen played with the Hollywood Vampires during their February 2016 Grammy Award Performance.


title: Tommy Henriksen

text: In March 2017, Henriksen digitally released his latest solo album, "StarStruck", on his own label Dis Vicious Music; a limited edition vinyl release followed in late May via Bellyache Records. Henriksen also had a significant role in the making of the Alice Cooper album, "Paranormal", co-producing, playing guitar, and co-writing 3 songs.


title: Enix

text: The company was founded by Yasuhiro Fukushima on September 22, 1975, as . The name "Enix" is a play on the words "phoenix", a mythical bird that is reborn from its own ashes, and "ENIAC", the world's first digital computer.


title: Enix

text: Enix was founded on September 22, 1975, as Eidansha Boshu Service Center by Japanese architect-turned-entrepreneur Yasuhiro Fukushima. The company initially published tabloids that advertised real estate.


title: Enix

text: On February 5, 1980, Eidansha Boshu Service created a wholly owned subsidiary Eidansya Fudousan for the purpose of specializing in real estate trading and brokerage. Eidansya Fudousan took the name Eidansha Systems on August 18. 1981. The following year, on August 30, 1982, Eidansha Systems was renamed Enix Corporation.


title: Enix

text: After a failed attempt of Eidansha Boshu Service to go nationwide in 1982, its newly established Enix subsidiary began a foray into the gaming market by holding a personal computer game programming contest. One of the winners was "Love Match Tennis", created by Yuji Horii. It would go on to become one of the company's first PC releases. Another winner was the puzzle game "Door Door" by Koichi Nakamura, which would become one of the company's better known home computer titles. The game was subsequently ported to the Nintendo Family Computer, but never saw any form of release outside Japan. Nakamura would stay on board as one Enix's key programmers.


title: Enix

text: Over the next few years, Enix published several video games for various Japanese home computer systems. Rather than developing games within its own company, Enix would continue to outsource the production of its games to other developers through the use of royalties. Enix is perhaps most famous for publishing the "Dragon Quest" series of console games (released as "Dragon Warrior" in North America until 2005) developed by Chunsoft. Key members of the developer's staff consisted of director Koichi Nakamura, writer Yuuji Horii, artist Akira Toriyama, and composer Koichi Sugiyama, among others. The first game in the Famicom-based RPG series was released in 1986, and would eventually sell 1.5 million copies in Japan, establishing "Dragon Quest" as the company's most profitable franchise.


title: Enix

text: On April 1, 1989, the original Enix Corporation along with two sister companies (Konika Enix and Enix Products) were unified and merged into their parent Eidansha Boshu Service who then renamed itself Enix Corporation.


title: Enix

text: In 1991, Enix registered its stock with the Japan Securities Dealers Association, later known as JASDAQ. Enix soon began publishing manga from its shonen magazine "Monthly Shōnen Gangan". The company established ties with more video game developers and would go on to publish several games for fourth, fifth, and sixth generation game consoles. Despite the announcement that Enix's long-time competitor Square Co., Ltd. would develop exclusively for Sony PlayStation, Enix announced in January 1997 that it would release games for both Nintendo and Sony consoles. This caused a significant rise in stock for both Enix and Sony. By November 1999, Enix was listed in the Tokyo Stock Exchange's 1st section, indicating it as a "large company."


title: Enix

text: In June 2001, Enix expressed interest in partnering with both Square and Namco in online ventures to deal with mounting development costs. That same month, Enix invested in the company Game Arts, acquiring ¥99.2 million worth of stock shares in order to publish the latter's "Grandia" series. Despite Enix's marketing of "Dragon Quest VII" in 1999, the game was delayed numerous times and not released until 2000. As a result, the game didn't (as had been expected) contribute to the fiscal year 1999, cutting the company's previous profit-to-sales ratio in half and causing its stock value to drop by 40% in early 2000. Enix was further hurt by a delay of "Dragon Quest Monsters 2" in Japan in 2001, dropping its first-half 2001 fiscal year profit by 89.71%.


title: Enix

text: Enix's competitor Square also suffered financially in 2001, mainly from the box office failure of its feature film "". This made Enix hesitant to join with the company. However, it was announced on November 26, 2002, that the two companies would merge the following year in order to mutually decrease development costs and to compete with foreign developers. The merge was delayed until April 1, 2003, when the new merged entity Square Enix came into being, with Enix as the surviving company. As part of the merger, former Square president Yoichi Wada was appointed the president of the new corporation, while former Enix president Keiji Honda became its vice president.The founder of Enix and the largest shareholder of the newly combined corporation, Yasuhiro Fukushima, was made its honorary chairman.


title: Enix

text: On October 1, 2008, Square Enix (the former Enix Corporation) renamed itself Square Enix Holdings and became a pure holding company. On that same date, a new video game company called Square Enix was created as a subsidiary of Square Enix Holdings.


title: Enix

text: Digital Entertainment Academy Co., Ltd. was established as a partially owned subsidiary in 1991. Originally called Toshima Ku Hokkaido University, the school was founded to teach game development. As of April 2008, it is funded by 20 gaming corporations, including Square Enix.


title: Enix

text: Square Enix Webstar Network Technology (Beijing) Co., Ltd. was a company formed between Enix and Mauritius Webstar Inc. in 2001 to develop online and mobile phone games in China and, later, other parts of Asia. One of the products includes the MMORPG "Cross Gate". The subsidiary was carried over after the merger between Square and Enix, but was dissolved in 2005 after the establishment of Square Enix China.


title: Enix

text: Enix America Corporation was the corporation's first American localization subsidiary based in Redmond, Washington. It was organized after the release of "Dragon Warrior" by Nintendo of America in 1989. The subsidiary came into existence in 1990, but closed in November 1995 when the parent company decided to no longer release products in North America due to poor sales. One of the games they published, "King Arthur & the Knights of Justice", was Enix's first and only North America exclusive game.


title: Enix

text: Enix America, Inc., Enix's last American localization subsidiary, was organized in 1999 after the release of "Dragon Warrior Monsters" through a joint venture with Eidos. Paul Handelman, who was part of Enix America Corporation's staff, returned to lead Enix America, Inc. as president. The corporation was in existence until 2003, ceasing to exist after the merger with Square Co., Ltd. It was based in Seattle, Washington.


title: Enix

text: From 1983 to 1993, Enix published games for Japanese home computers including the NEC PC-8801, MSX, Sharp X68000, and FM-7. Beginning on the Famicom, Enix published the very successful "Dragon Quest" series, which, after the formation of Square Enix, had already sold over 78 million copies worldwide. Although the first few titles were developed by Chunsoft, other companies would also develop main installments, spin-offs, and remakes for the series including Heartbeat, ArtePiazza, TOSE, and Level-5. The "Dragon Quest" franchise would carry over as one of Square Enix's most important assets. Other notable franchises published by Enix include the acclaimed "Star Ocean" and "Valkyrie Profile" series by tri-Ace, both of which would also continue with Square Enix. The company Quintet developed several role-playing games for Enix such as "ActRaiser", "Robotrek", "Soul Blazer", "Illusion of Gaia", and "Terranigma" for the Super NES.


title: Enix

text: Enix began publishing manga in 1991 in its own Gangan Comics publications, which originally consisted of Monthly Shōnen Gangan, Monthly Gangan Wing, and Monthly GFantasy.


title: Enix

text: In November 2000, Enix set up a subsidiary titled BMF in Kawasaki, Kanagawa Prefecture to handle a fingerprint identification systems operation. Enix took a 68% stake in 200 million yen capitalization. The subsidiary was expected to post a pretax profit of 12 million yen on sales of 135 million yen in the first five months of operation. In September 2002, Enix entered a joint venture with Waseda University to distribute broadband sports content. The subsidiary, Sports BB, was owned 80% by Enix and 20% by the college.


title: Regulation of gene expression

text: Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.


title: Regulation of gene expression

text: Gene regulation is essential for viruses, prokaryotes and eukaryotes as it increases the versatility and adaptability of an organism by allowing the cell to express protein when needed. Although as early as 1951, Barbara McClintock showed interaction between two genetic loci, Activator ("Ac") and Dissociator ("Ds"), in the color formation of maize seeds, the first discovery of a gene regulation system is widely considered to be the identification in 1961 of the "lac" operon, discovered by François Jacob and Jacques Monod, in which some enzymes involved in lactose metabolism are expressed by "E. coli" only in the presence of lactose and absence of glucose.


title: Regulation of gene expression

text: In multicellular organisms, gene regulation drives cellular differentiation and morphogenesis in the embryo, leading to the creation of different cell types that possess different gene expression profiles from the same genome sequence. Although this does not explain how gene regulation originated, evolutionary biologists include it as a partial explanation of how evolution works at a molecular level, and it is central to the science of evolutionary developmental biology ("evo-devo").


title: Regulation of gene expression

text: Any step of gene expression may be modulated, from signaling to transcription to post-translational modification of a protein. The following is a list of stages where gene expression is regulated, the most extensively utilized point is Transcription Initiation:


title: Regulation of gene expression

text: In eukaryotes, the accessibility of large regions of DNA can depend on its chromatin structure, which can be altered as a result of histone modifications directed by DNA methylation, ncRNA, or DNA-binding protein. Hence these modifications may up or down regulate the expression of a gene. Some of these modifications that regulate gene expression are inheritable and are referred to as epigenetic regulation.


title: Regulation of gene expression

text: Transcription of DNA is dictated by its structure. In general, the density of its packing is indicative of the frequency of transcription. Octameric protein complexes called histones together with a segment of DNA wound around the eight histone proteins (together referred to as a nucleosome) are responsible for the amount of supercoiling of DNA, and these complexes can be temporarily modified by processes such as phosphorylation or more permanently modified by processes such as methylation. Such modifications are considered to be responsible for more or less permanent changes in gene expression levels.


title: Regulation of gene expression

text: Methylation of DNA is a common method of gene silencing. DNA is typically methylated by methyltransferase enzymes on cytosine nucleotides in a CpG dinucleotide sequence (also called "CpG islands" when densely clustered). Analysis of the pattern of methylation in a given region of DNA (which can be a promoter) can be achieved through a method called bisulfite mapping. Methylated cytosine residues are unchanged by the treatment, whereas unmethylated ones are changed to uracil. The differences are analyzed by DNA sequencing or by methods developed to quantify SNPs, such as Pyrosequencing (Biotage) or MassArray (Sequenom), measuring the relative amounts of C/T at the CG dinucleotide. Abnormal methylation patterns are thought to be involved in oncogenesis.


title: Regulation of gene expression

text: Histone acetylation is also an important process in transcription. Histone acetyltransferase enzymes (HATs) such as CREB-binding protein also dissociate the DNA from the histone complex, allowing transcription to proceed. Often, DNA methylation and histone deacetylation work together in gene silencing. The combination of the two seems to be a signal for DNA to be packed more densely, lowering gene expression.


title: Regulation of gene expression

text: Regulation of transcription thus controls when transcription occurs and how much RNA is created. Transcription of a gene by RNA polymerase can be regulated by several mechanisms.


title: Regulation of gene expression

text: Specificity factors alter the specificity of RNA polymerase for a given promoter or set of promoters, making it more or less likely to bind to them (i.e., sigma factors used in prokaryotic transcription).


title: Regulation of gene expression

text: Repressors bind to the Operator, coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase's progress along the strand, thus impeding the expression of the gene. The image to the right demonstrates regulation by a repressor in the lac operon.


title: Regulation of gene expression

text: General transcription factors position RNA polymerase at the start of a protein-coding sequence and then release the polymerase to transcribe the mRNA.


title: Regulation of gene expression

text: Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene. Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.


title: Regulation of gene expression

text: Enhancers are sites on the DNA helix that are bound by activators in order to loop the DNA bringing a specific promoter to the initiation complex. Enhancers are much more common in eukaryotes than prokaryotes, where only a few examples exist (to date).


title: Regulation of gene expression

text: Silencers are regions of DNA sequences that, when bound by particular transcription factors, can silence expression of the gene.


title: Regulation of gene expression

text: RNA can be an important regulator of gene activity, e.g. by microRNA (miRNA), antisense-RNA, or long non-coding RNA (lncRNA). LncRNAs differ from mRNAs in the sense that they have specified subcellular locations and functions. They were first discovered to be located in the nucleus and chromatin, and the localizations and functions are highly diverse now. Some still reside in chromatin where they interact with proteins. While this lncRNA ultimately affects gene expression in neuronal disorders such as Parkinson, Huntington, and Alzheimer disease, others, such as, PNCTR(pyrimidine-rich non-coding transcriptors), play a role in lung cancer. Given their role in disease, lncRNAs are potential biomarkers and may be useful targets for drugs or gene therapy, although there are no approved drugs that targert lncRNAs yet. There number of lncRNAs in the human genome remains poorly defined, but some estimates range from 16,000 to 100,000 lnc genes.


title: Regulation of gene expression

text: Epigenetics refers to the modification of genes that is not changing the DNA or RNA sequence. Epigenetic modifications are also a key factor in influencing gene expression. They occur on genomic DNA and histones and their chemical modifications regulate gene expression in a more efficient manner. There are several modifications of DNA (usually methylation) and more than 100 modifications of RNA in mammalian cells.” Those modifications result in altered protein binding to DNA and a change in RNA stability and translation efficiency.


title: Regulation of gene expression

text: In vertebrates, the majority of gene promoters contain a CpG island with numerous CpG sites. When many of a gene's promoter CpG sites are methylated the gene becomes silenced. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see regulation of transcription in cancer). Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs. In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-expressed microRNA-182 than by hypermethylation of the BRCA1 promoter (see Low expression of BRCA1 in breast and ovarian cancers).


title: Regulation of gene expression

text: One of the cardinal features of addiction is its persistence. The persistent behavioral changes appear to be due to long-lasting changes, resulting from epigenetic alterations affecting gene expression, within particular regions of the brain. Drugs of abuse cause three types of epigenetic alteration in the brain. These are (1) histone acetylations and histone methylations, (2) DNA methylation at CpG sites, and (3) epigenetic downregulation or upregulation of microRNAs. (See Epigenetics of cocaine addiction for some details.)


title: Regulation of gene expression

text: Chronic nicotine intake in mice alters brain cell epigenetic control of gene expression through acetylation of histones. This increases expression in the brain of the protein FosB, important in addiction. Cigarette addiction was also studied in about 16,000 humans, including never smokers, current smokers, and those who had quit smoking for up to 30 years. In blood cells, more than 18,000 CpG sites (of the roughly 450,000 analyzed CpG sites in the genome) had frequently altered methylation among current smokers. These CpG sites occurred in over 7,000 genes, or roughly a third of known human genes. The majority of the differentially methylated CpG sites returned to the level of never-smokers within five years of smoking cessation. However, 2,568 CpGs among 942 genes remained differentially methylated in former versus never smokers. Such remaining epigenetic changes can be viewed as “molecular scars” that may affect gene expression.


title: Regulation of gene expression

text: In rodent models, drugs of abuse, including cocaine, methamphetamine, alcohol and tobacco smoke products, all cause DNA damage in the brain. During repair of DNA damages some individual repair events can alter the methylation of DNA and/or the acetylations or methylations of histones at the sites of damage, and thus can contribute to leaving an epigenetic scar on chromatin.


title: Regulation of gene expression

text: In mammals, methylation of cytosine (see Figure) in DNA is a major regulatory mediator. Methylated cytosines primarily occur in dinucleotide sequences where cytosine is followed by a guanine, a CpG site. The total number of CpG sites in the human genome is approximately 28 million. and generally about 70% of all CpG sites have a methylated cytosine.


title: Regulation of gene expression

text: In a rat, a painful learning experience, contextual fear conditioning, can result in a life-long fearful memory after a single training event. Cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the hippocampus neuron DNA of a rat that has been subjected to a brief fear conditioning experience. The hippocampus is where new memories are initially stored.


title: Regulation of gene expression

text: Methylation of CpGs in a promoter region of a gene represses transcription while methylation of CpGs in the body of a gene increases expression. TET enzymes play a central role in demethylation of methylated cytosines. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene.


title: Regulation of gene expression

text: When contextual fear conditioning is applied to a rat, more than 5,000 differentially methylated regions (DMRs) (of 500 nucleotides each) occur in the rat hippocampus neural genome both one hour and 24 hours after the conditioning in the hippocampus. This causes about 500 genes to be up-regulated (often due to demethylation of CpG sites in a promoter region) and about 1,000 genes to be down-regulated (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain.


title: Regulation of gene expression

text: After the DNA is transcribed and mRNA is formed, there must be some sort of regulation on how much the mRNA is translated into proteins. Cells do this by modulating the capping, splicing, addition of a Poly(A) Tail, the sequence-specific nuclear export rates, and, in several contexts, sequestration of the RNA transcript. These processes occur in eukaryotes but not in prokaryotes. This modulation is a result of a protein or transcript that, in turn, is regulated and may have an affinity for certain sequences.


title: Regulation of gene expression

text: Three prime untranslated regions (3'-UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3'-UTRs often contain both binding sites for microRNAs (miRNAs) as well as for regulatory proteins. By binding to specific sites within the 3'-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3'-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA.


title: Regulation of gene expression

text: The 3'-UTR often contains miRNA response elements (MREs). MREs are sequences to which miRNAs bind. These are prevalent motifs within 3'-UTRs. Among all regulatory motifs within the 3'-UTRs (e.g. including silencer regions), MREs make up about half of the motifs.


title: Regulation of gene expression

text: As of 2014, the miRBase web site, an archive of miRNA sequences and annotations, listed 28,645 entries in 233 biologic species. Of these, 1,881 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target mRNAs (affecting expression of several hundred genes). Freidman et al. estimate that >45,000 miRNA target sites within human mRNA 3'-UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.


title: Regulation of gene expression

text: Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs. Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).