In the first millennium BC, Iranian nomads established irrigation systems along the rivers of Central Asia and built towns at Bukhara and Samarqand. These places became wealthy points of transit on what became known as the Silk Road between China and Europe. In the seventh century AD, the Soghdian Iranians, who profited most visibly from this trade, saw their province of Transoxiana overwhelmed by Arabs, who spread Islam throughout the region. Under the Arab Abbasid Caliphate, the eighth and ninth centuries were a golden age of learning and culture in Transoxiana; as Turks began entering the region from the north, they established new states, many of which were Persianate in nature. After a succession of states dominated the region, in the twelfth century, Transoxiana was united in a single state with Iran and the region of Khwarezm, south of the Aral Sea. In the early thirteenth century, that state was invaded by Mongols, led by Genghis Khan. Under his successors, Iranian-speaking communities were displaced from some parts of Central Asia.
Under Timur, Transoxiana began its last cultural flowering, centered in Samarqand. After Timur the state began to split, by 1510 Uzbek tribes had conquered all of Central Asia. In the sixteenth century, the Uzbeks established two strong rival khanates and Khorazm. In this period, the Silk Road cities began to decline as ocean trade flourished; the khanates were weakened by attacks from northern nomads. Between 1729 and 1741 all the Khanates were made into vassals by Nader Shah of Persia. In the early nineteenth century, three Uzbek khanates—Bukhoro and Quqon —had a brief period of recovery. However, in the mid-nineteenth century Russia, attracted to the region's commercial potential and to its cotton, began the full military conquest of Central Asia. By 1876 Russia had incorporated all three khanates into its empire, granting the khanates limited autonomy. In the second half of the nineteenth century, the Russian population of Uzbekistan grew and some industrialization occurred. At the beginning of the twentieth century, the Jadidist movement of educated Central Asians, centered in present-day Uzbekistan, began to advocate overthrowing Russian rule.
In 1916 violent opposition broke out in Uzbekistan and elsewhere, in response to the conscription of Central Asians into the Russian army fighting World War I. When the tsar was overthrown in 1917, Jadidists established a short-lived autonomous state at Quqon. After the Bolshevik Party gained power in Moscow, the Jadidists split between supporters of Russian communism and supporters of a widespread uprising that became known as the Basmachi Rebellion; as that revolt was being crushed in the early 1920s, local communist leaders such as Faizulla Khojayev gained power in Uzbekistan. In 1924 the Soviet Union established the Uzbek Soviet Socialist Republic, which included present-day Tajikistan and Uzbekistan. Tajikistan became the separate Tajik Soviet Socialist Republic in 1929. In the late 1920s and early 1930s, large-scale agricultural collectivization resulted in widespread famine in Central Asia. In the late 1930s, Khojayev and the entire leadership of the Uzbek Republic were purged and executed by Soviet leader Joseph V.
Stalin and replaced by Russian officials. The Russification of political and economic life in Uzbekistan that began in the 1930s continued through the 1970s. During World War II, Stalin exiled entire national groups from the Caucasus and the Crimea to Uzbekistan to prevent "subversive" activity against the war effort. Moscow’s control over Uzbekistan weakened in the 1970s as Uzbek party leader Sharaf Rashidov brought many cronies and relatives into positions of power. In the mid-1980s, Moscow attempted to regain control by again purging the entire Uzbek party leadership. However, this move increased Uzbek nationalism, which had long resented Soviet policies such as the imposition of cotton monoculture and the suppression of Islamic traditions. In the late 1980s, the liberalized atmosphere of the Soviet Union under Mikhail S. Gorbachev fostered political opposition groups and open opposition to Soviet policy in Uzbekistan. In 1989 a series of violent ethnic clashes involving Uzbeks brought the appointment of ethnic Uzbek outsider Islam Karimov as Communist Party chief.
When the Supreme Soviet of Uzbekistan reluctantly approved independence from the Soviet Union in 1991, Karimov became president of the Republic of Uzbekistan. In 1992 Uzbekistan adopted a new constitution, but the main opposition party, was banned, a pattern of media suppression began. In 1995 a national referendum extended Karimov’s term of office from 1997 to 2000. A series of violent incidents in eastern Uzbekistan in 1998 and 1999 intensified government activity against Islamic extremist groups, other forms of opposition, minorities. In 2000 Karimov was reelected overwhelmingly in an election whose procedures received international criticism; that year, Uzbekistan began laying mines along the Tajikistan border, creating a serious new regional issue and intensifying Uzbekistan’s image as a regional hegemon. In the early 2000s, tensions developed with neighboring states Kyrgyzstan and Turkmenistan. In the mid-2000s, a mutual defense treaty enhanced relations between Russia and Uzbekistan. Tension with Kyrgyzstan increased in 2006 when Uzbekistan demanded extradition of hundreds of refugees who had fled from Andijon into Kyrgyzstan after the riots.
A series of border incidents inflamed tensions with neighboring Tajikistan. In 2006 Karimov continued arbitrary dismissals and shifts of subordinates in the government, including one deputy prime minister. In 1938 A. Okladnikov discovered th
The Potter House is a historic building located in Rock Island, United States. It was designated a Rock Island Landmark in 1987, listed individually on the National Register of Historic Places in 1989, the house was included as a contributing property in the Broadway Historic District in 1998; the home was built by Minnie Potter, the president of J. W. Potter Company, which owned the Rock Island Argus newspaper, her husband had bought the newspaper in 1882. He died at the age of 36 in 1898. Minnie was a mother of three young children, she raised her family. She never remarried; the Argus prospered under her leadership and she directed the construction of a new newspaper plant on Fourth Avenue in 1925. Mrs. Potter had the home built in 1907 and lived there until her death, the home remained in the family until 1983; the Potter family sold the newspaper in 1985. The home was designed by Rock Island architect George Stauduhar in the Colonial Revival style, it includes elements of the Prairie School style.
The Colonial Revival style is found in the main façade’s symmetry, door sidelights, the elliptical fanlight above the door, in the multiple panes of glass of the upper sashes on the windows. Many of the widows, are characteristic of the Prairie style, they are topped with a smaller upper sash. The exterior of the house is covered in stucco; the texture on the lower half of the wall is rough. The interior features leather embossed wall coverings in the front entrance, a grand central staircase, mahogany paneling, stained glass, six fireplaces
Marvel 2099: One Nation Under Doom was a cancelled game for the PlayStation developed by Mindscape Inc. It was to be loosely based on the "One Nation Under Doom" storyline in Marvel's Doom 2099 comic, it was envisioned as a 2D side-scroller with 3D rendered characters. In February 1996, Mindscape announced they would produce a video game based on the Marvel 2099 universe. Promoted as one of their top five games for the year, the game would be released on December 1, 1996, just in time for the Christmas rush. Two versions were announced: PlayStation and Windows 95. By May 1996, CD-ROM and VHS video demos were being shipped to game magazines for pre-release reviews, along with a one-page color brochure; the first public demo was shown at the E3 show, featured a playable single level of the Punisher 2099 fighting SHIELD troops, opening menus and some cut scenes. Electronic Gaming Monthly had a quarter-page preview of the game in their July 1996 issue and a half page preview in their August 1996 issue, showing screenshots of actual gameplay with Punisher 2099, claiming that Spider-Man 2099, X-Men 2099, Ghost Rider 2099, Fantastic Four 2099, Hulk 2099 would all be player characters as well, in addition 40 other characters from the comic books would appear as non-player characters.
At the 1996 San Diego Comicon, the Mindscape booth handed out brochures, raffled off One Nation Under Doom pins and posters. Some attendees were allowed to play the demo at the booth, although no copies of the demo were distributed. September 1996 issue of 3D Design magazine had a cover story on the Marvel 2099 game. Following a round of layoffs of development staff in November 1996, Mindscape maintained that the game was still in the works. After July, due to financial troubles, ongoing production of the game slowed down, stopped, though the game was never canceled
The 1950 Grand National was the 104th renewal of the Grand National horse race that took place at Aintree Racecourse near Liverpool, England, on 25 March 1950. Nearly 500,000 people packed into Aintree for the first royal National since the Second World War. In attendance were King George VI, Queen Elizabeth, their daughter Princess Elizabeth, a number of other members of the royal family. Royal interest centred on Monaveen, the co-third-favourite, jointly owned by the Queen and Princess Elizabeth. Despite leading the field, Monaveen made a bad mistake at The Chair, nearly unseating his jockey, losing significant ground; the race was won by Freebooter, the 10/1 joint-favourite ridden by Irish jockey Jimmy Power and trained by Bobby Renton for owner Lurline Brotherton. In second place was Wot No Sun, Acthon Major finished third, Rowland Roy fourth. Forty-nine horses ran and all returned safely to the stables
Carbonic anhydrase IX is an enzyme that in humans is encoded by the CA9 gene. It is one of the 14 carbonic anhydrase isoforms found in humans and is a transmembrane dimeric metalloenzyme with an extracellular active site that facilitates acid secretion in the gastrointestinal tract. CA IX is overexpressed in many types of cancer including clear cell renal cell carcinoma as well as carcinomas of the cervix and lung where it promotes tumor growth by enhancing tumor acidosis. Carbonic anhydrases are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide, they participate in a variety of biological processes, including respiration, acid-base balance, bone resorption, the formation of aqueous humor, cerebrospinal fluid and gastric acid. They show extensive diversity in their subcellular localization. CA IX is expressed in the gastrointestinal tract where it facilitates acid secretion; the CA IX enzyme, along with the CA II enzyme, binds to Anion Exchanger 2 which increases bicarbonate transport and maximizes the rate of acid secretion by gastric parietal cells.
CA IX is a transmembrane glycoprotein with an extracellular active site. The cytoplasmic tail of the enzyme contains three residues that may be phosphorylated and participate in signal transduction. Phosphorylated tyrosine 449 can interact with PI3K which activates protein kinase B to affect cellular glucose metabolism. Under physiological conditions, the enzyme exists as two nearly identical dimers. Both dimers are stabilized by two hydrogen bonds between Arg-137 and the Ala-127 carbonyl oxygen as well as many Van der Waals interactions. One dimer, has additional stabilization due to a disulfide bridge formed by two Cysteine residues. One face of the dimer contains proteoglycan domains-a feature, unique from other CA enzymes- and the opposite face contains the C-termini which help the enzyme attach to the cell membrane. CA IX contains an N-linked glycosylation site bearing mannose-type glycan structures on Asn-309 as well as an O-linked glycosylation site on Thr-78. Expression of CA IX is regulated at the transcriptional level.
The promoter region of the CA9 gene contains an HRE where HIF-1 can bind, which allows hypoxic conditions to increase CA IX expression. Expression can be regulated post-translationally by metalloproteinases which cause shedding of the enzyme's ectodomain. Unlike other CA isozymes, CA IX is not inhibited by high lactate concentrations. However, it is inhibited by bicarbonate. CA IX is a tumor-associated carbonic anhydrase isoenzyme, it is over-expressed in VHL mutated clear cell renal cell carcinoma and hypoxic solid tumors, but is low-expressed in normal kidney and most other normal tissues. It may be involved in cell transformation; this gene is mapped to 9p13-p12. CA IX is a cellular biomarker of hypoxia. Furthermore, recent studies examining the association between CA IX levels and various clinicopathological outcomes suggest that CA IX expression may be a valuable prognostic indicator for overall survival although this association has been questioned. CA IX shows high expression in carcinomas of the uterine cervix, oesophagus, breast, colon and vulva compared to expression in few noncancerous tissues.
Its overexpression in cancerous tissues compared to normal ones is due to hypoxic conditions in the tumor microenvironment caused by abnormal vasculature and subsequent transcriptional activation by HIF-1 binding. In clear cell renal carcinomas, CA IX shows high expression under normoxia due to a mutation in the VHL gene that negatively regulates HIF-1; because of its overexpression in many types of cancer and low expression in normal tissues, CAIX has become a useful target for clear cell RCC and breast cancer tumor imaging in mice. CA IX plays a significant role in tumor acidification as it has high catalytic activity with the highest rate of proton transfer of the known CAs; the enzyme converts carbon dioxide outside of the tumor into bicarbonate and protons, contributing to extracellular acidosis and promoting tumor growth by regulating the pH of the cytosol. Because of its low expression in normal tissues and overexpression in many cancer tissues, CA IX has become a desirable drug target.
Girentuximab, an antibody that binds to CA IX, failed to improve disease-free as well as overall survival of patients with clear cell RCC in Phase III clinical trials. However, a number of small molecules have been used to inhibit CA IX; the main classes of these inhibitors are inorganic anions, sulfonamides and coumarins. Anions and sulfonamides inhibit CA IX by coordinating the zinc ion within CA IX while phenols bind to the zinc-coordinated water molecule. Coumarins serve as mechanism-based inhibitors that are hydrolyzed by the enzyme to form a cis-2-hydroxy-cinnamic acid derivative that binds to the active site
Woodside Plaza is a 29-storey skyscraper in Perth, Western Australia. The 137-metre tower serves as the headquarters for Woodside Petroleum and incorporates several energy-efficient design features; when completed in 2004, the building was the first premium-grade skyscraper completed in Perth since Central Park in 1992. It is the sixth tallest skyscraper in Perth. Woodside Petroleum experienced strong growth in its business during the 1990s. However, there had been no major expansion in office space in the Perth central business district since the opening of Exchange Plaza and Central Park in 1992; as a result, by 1998 Woodside had its Perth staff spread across six sites, including Central Park and the headquarters at 1 Adelaide Terrace. Woodside Petroleum called for tenders for a tower to be constructed for the company. Perron Group put forward a proposal to leave Woodside in its existing headquarters on Adelaide Terrace and build a tower beside it to house the other staff. Meanwhile, Consolidated Press Holdings and Multiplex proposed to build a tower on CPH's Westralia Square site.
Jones Lang Wootton proposed a new tower on the Bishop's See site. However, it was announced in April 1999 that the winning tenderer was Hai Sun Hup Group subsidiary Knoxville Group; this proposal was to develop Hai Sun Hup's site at the corner of St Georges Terrace and Milligan Street into an office tower and hotel project. This 9,000-square-metre site stretches all the way from St Georges Terrace to Hay Street, had been bought by Alistair McAlpine for $100 million, before being sold to Hai Sun Hup in 1996 for just $20 million; the vacant site was occupied by small buildings fronting Hay Street and vacant land fronting all three streets. The corner of Milligan Street and St Georges Terrace featured the eight-storey AWA Computer House; the development necessitated the demolition of the building on Hay Street which housed the Matsuri Japanese Restaurant, which moved to new premises in QV.1. Approval of the office tower was delayed due to a dispute with the Department of Transport about the number of car parking bays which could be included in the development, it was rumoured that the building may not proceed due to difficulties in Hai Sun Hup securing financing.
However, the construction was made viable by the booming resources industry in Western Australia. Planning approval was received from the City of Perth in December 2000, with plot ratio concessions awarded to the development in return for allowing pedestrian thoroughfare and providing a public square at the base of the tower similar to that at the base of the Central Park tower; the $250 million development contract was signed on 30 January 2001. Under this deal, Deutsche Asset Management paid Hai Sun Hup $23 million for the building site and development contract, Woodside agreed to lease 32,500 square metres of the tower for 15 years, with two five-year options to extend. Hai Sun Hup retained ownership of the Hay Street side of the site. Site works began on 31 January 2001, with a groundbreaking ceremony held on 27 February 2001. Construction on the tower by builder Baulderstone Hornibrook began in March 2001. Although the building would add 46,000 square metres of office space to the central business district and raise the premium-grade office floor space in the central business district by 24 per cent, Woodside was to occupy so much of it that only 13,500 square metres would be available to other tenants.
By October 2003, building manager CB Richard Ellis had leased all but three floors of the building, after securing law firm Corrs Chambers Westgarth and the joint venture alliance between Transfield, Worley Limited and Woodside. This was reduced to less than two floors unleased in April 2004 when accounting firm Deloitte Touche Tohmatsu signed on as tenant, vacating its office in Central Park; the building was completed in early 2004, was opened in March 2004. It became Perth's third largest building by total floor area, was the city's first new high-rise office building in eight years and the first premium-grade tower since the completion of Central Park in 1992, it was thought that the move of Woodside to the western end of the central business district would draw other resources companies to the area. The plans included the construction of a hotel adjacent to the new office tower on the Hay Street side of the site; the 13-storey hotel was to be a 220-room 5-star Stamford Hotel. The hotel, expected to cost $50 million, was put on hold by Stamford Land Corporation in 2001 and construction would only proceed if the local hotel market became strong enough.
A 13-level, 13,000-square-metre A-grade office tower was proposed for the site by Stamford Land Corporation in 2008. The tower was designed by architects Kann Finch Group, it features 251 basement car parking bays, a bar on the ground floor, shops, a 120-seat auditorium on the mezzanine level and a equipped gym. The structure is of concrete frame, with a conventionally reinforced jump-formed core containing all of the lifts and service risers; the office floors are formed from post-tensioned band beams supporting conventional reinforced slabs. The perimeter of the building has columns spaced 8.2 metres apart and supporting post-tensioned edge beams. The support columns were formed from 80 MPa concrete to minimise the column size at ground level. Woodside Plaza has two basement levels, two plant floor levels, 23 office floor levels, a mezzanine and the ground floor, giving a total of 29 floors; the building has a total floor area of 77,000 m2. The building is divided into three elevator zones: low-