Table football in particular is quite awful. The Wii mini-games are also just plain rubbish. Best of all is the inclusion of the Manager Mode, similar to Pro Evo’s Master League, where you get to play full seasons through a career as well as managing the team off and on the pitch, making decisions from ticket pricing to employing new medical staff. You can also compete in one of a boatload of league and cup tournaments or create your own, although the apparent lack of an international tournament is a bit of a surprise here. I’ve lost count of how many times I’ve heard him say someone’s got to come off after they injured themselves during a slide tackle, when clearly no-one even challenged for the ball.Įvery football league you’d ever want to play in is present, including all four English leagues. Clive Tyldesley’s familiar tones make for a great atmosphere but poor old Andy Gray must have only recorded a few lines as they regularly crop up time and time again, often in a somewhat nonsensical fashion. Commentary however is, as is often the case with footy sims, a mixed bag. You can also choose to use your classic controller or a GameCube controller but it’s surprising how hollow that feels once you’ve played it using the Wii remote.Īs expected with any FIFA game the attention to visual detail is pretty impressive with a host of players and stadiums having been reproduced and while the graphics won’t stand up against other consoles they’re pretty good for the Wii. The whole control mechanism makes for a far simpler gaming experience than last year’s Pro Evo and for a much more compelling one that last year’s FIFA, and it’s one that’s so much fun to boot. ![]() It can occasionally take longer than you’d like for the game to register the exact player you want to control, especially if they’re all close too each other, but this isn’t a major problem. The control system also works well when it comes to defending as you can select any one of your defenders by pointing your Wii remote at the screen and then moving them with the Nunchuck’s control stick. You can instruct players to make forward runs and point them in the right direction to run by passing the ball into space for someone to pick it up but other than that the player AI looks after everything. Whereas in Pro Evo you controlled where all the players moved on the pitch, in FIFA 09 this is all looked after by the game’s AI engine. However, there is one massive difference between the two that turns FIFA 09 into what is the best football game on the console, and one of the best footy games I’ve ever played full stop. Controlling players is done via the control joystick on the Nunchuck, just like in Pro Evo 2008. Shooting is carried out by flicking the Wii remote, just like in Pro Evo 2008. Passing on FIFA 09 All-Play is done by pointing your Wii remote at the player you want to pass to and pressing the A button, just like in Pro Evo 2008. That brings us to the Advanced Play system and here’s where FIFA owes an awful lot to Konami. However, for serious football gamers this will be quickly dismissed. ![]() Using this, you control key aspects such as passing and shooting while the AI does everything else. The All-Play control system referred to in the title makes it easy for anyone to pick up and play the game, as EA have tried to make all their sports titles this year. The reason I mention last year’s Pro Evo in this review is because, to be blunt, FIFA 09 All-Play has nicked the good things about the control system in Pro Evo 2008 and showed them how it should have been done in the first place.
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These include the JAK/STAT, the Hedgehog and Wingless signalling pathways as well as inputs from the Hox genes. Using the snail gland specific enhancer as a proxy for gland formation, we show that the glands are specified by the same inputs specifying the trachea. One key difference between glands and trachea is that the endocrine primordia activate the Epithelial to Mesenchymal inducer gene snail. All three organs derive from a primordium arising at similar locations along the cephalic and trunk segments, they activate common developmental genes using the same cis-regulatory elements, and can be transformed into each other by modifying Hox expression. Genetic experiments in Drosophila melanogaster suggested that, despite their extremely different morphology and function, the corpora allata and the prothoracic glands are homologous to the respiratory trachea. The main endocrine organs controlling insect moulting and metamorphosis are the corpora allata and the prothoracic glands. Our results show that the same upstream regulators are required for the early gland and tracheal primordia specification, reinforcing the hypothesis that they originated from a segmentally repeated organ present in an ancient arthropod. Here we show that the expression of a key regulator of early gland development, the snail gene, is controlled by the Dfd and Scr Hox genes and by the Hedgehog and Wnt signalling pathways that induce localised transcription of upd, the ligand of the JAK/STAT signalling pathway, which lies at the heart of gland specification. ![]() While much is known about tracheal specification, there is limited information about corpora allata and prothorathic gland specification. Glands and trachea can be homeotically transformed into each other suggesting that all three evolved from a metamerically repeated organ that diverged to form glands in the head and respiratory organs in the trunk. ![]() These endocrine glands are specified in the maxillary and labial segments at positions homologous to those forming the trachea in more posterior segments. The corpora allata and the prothoracic glands control moulting and metamorphosis in insects. ![]() By this point, Ubisoft has perfected the core formula of exploring, fighting, gathering and crafting. There’s lots of new ideas here, most of the good, but the rhythm of the experience is familiar and remains compelling. Far Cry Primal is a serious game, for the most part, but the moments of levity are welcome.Īll in all then, Far Cry Primal is a good game that does enough to differentiate itself from its predecessors. One character in particular was responsible for most of them, his missions playfully taking the piss out of established series tropes. Oh and it’s funny too! Without spoiling too much, Far Cry Primal made me laugh out loud on a few different occasions. It’s a decent fit for a game all about freedom. Far Cry Primal doesn’t offer up a linear narrative, instead providing a handful of storylines to follow in whatever order you fancy. There’s even a new approach to the story, which gives you a degree of freedom over what order you take on missions. You can ride some of the land’s bigger animals, like bears and mammoths. In the northern reaches of the map it’s icy and cold, dictating that Takkar has to avoid prolonged exposure to the elements by ducking into caves and searching out fire. You can even get the owl to swoop down and take out weaker enemies, or drop little handmade bombs to give you a further advantage. This allows you to make more informed decisions about where and when to move, essential if you’re planning on taking everyone down stealthily. Before wading into enemy encampments, you can now scope out the area and tag all of the different enemy types to get the lay of the land. Similarly, the ability to control an owl is a good new addition, giving outpost attacks a slightly different flavour. Wandering around with one of the most badass, visually distinctive beasts at your side is a great feeling and vital to your progress. They’re pretty fun, these missions, each one ranging across a number of locations and calling on you to build traps to either stall or damage. The most useful companion animals can be found via Beast Master quests, which see you track, hunt and tame the land’s most fearsome nasties in long, multi-part missions. Rather go in stealthy and pick people off one by one? The wolf is probably your best bet. Want to burst into an outpost and mess shit up? You’ll be wanting a bear. ![]() Each animal type has its own stats, across stealth, speed and power, allowing you to pick a companion that suits your playstyle. The headline new addition is Takkar’s Beastmaster abilities, which allow the character to tame and control some of the game’s wildlife, from wolves all the way up to sabretooth tigers. Rescue an NPC and they’ll join your community, swelling its ranks and allowing you access to greater perks. It’s essentially the same in Primal, but instead of being represented by just numbers, your actions now have an impact on your village. ![]() In the last couple of Far Crys, if you bumped into someone being held hostage or in a running battle with an enemy, you could rescue them for XP. The village even adds a bit of meaning to some of the encounters you’ll stumble across out in the wild. It’s all represented in a hub area that you can explore, a nice way of visually representing your progress. Use your gathered resources (wood, rocks, skins) and you can upgrade the hut in which the character lives, unlocking further abilities. Bring a character skilled in crafting back to your village, for example, and you’ll gain access to new crafting abilities. As you progress you’ll encounter a handful of new story characters, each with their individual area of expertise. One big change is the addition of your tribe’s village. But as you play, the new stuff becomes apparent. It’s Far Cry in a pair of hairy Speedos, basically. There’s skinning and crafting, flower picking, side-missions, grappling hooks and a squillion collectibles. Wildlife roams around causing trouble for the locals and interfering with your adventures. There are outposts to liberate, either with stealthy take-downs, noisy battles or a messy combination of the two. There’s an exotic location with a big map that reveals itself as you explore. Prowling the land are mammoths, sabretooth tigers and a plethora of higher-up-the-food-chain prehistoric nasties, as well as rival tribes that want to eat Takkar’s face, burn him to a crisp and otherwise see him extinct. Set in the Stone Age, Far Cry Primal sees you take the role of Takkar, a great big lump of a caveman intent on reuniting his tribesmen and creating a safe haven for them to thrive. ![]() I am getting a new hockey stick on friday so i thought i could do a review on my. Any questions? Please ask! :)Taxes: Canadian Buyers: GST/HST tax is due and payable by the buyer on all items we sell calculated automatically at checkout. WARRIOR Covert DT4 Grip Composite Hockey Stick Int (2012). Please allow approximately 5-14 days for delivery. ![]() BRAND NEW WARRIOR DT4 HOCKEY STICK!!!Dagger T2 Technology – Enhanced Super Low KickTrue1 LT Construction – 20g Lighter Blade, Better BalanceUniSpar EXT – Engineered Internal Structure EXTends to Dagger Taper12K BladeSoftCoreX Blade CoreGrip Finish60"BRAND NEW! Senior Warrior One Piece Stick, 85 Flex, Grip, Left Hand, W03 HenriqueSUGGESTED RETAIL PRICE ON THIS STICK IS $149.99 USD! THIS IT THE LT MODEL aka The Best Model!SHIPS SAME BUSINESS DAY AND WEEKENDS!!! BUY MULTIPLE STICKS AND SAVE HUGE ON SHIPPINGShipping is via Canada Post Expedited Parcel within Canada and to the USA. ![]() By aggregating listings from multiple websites, Rent By Owner offers an immense amount of choice of the best RBO properties in Fawn Creek.Item: 262440617826 Warrior Covert DT4 LT Grip SR Hockey Stick! W03 Henrique, 85 Flex Left LH DT4LT. How many RentByOwner vacation rentals are available in Fawn Creek?Ĭurrently, the total number of properties listed by Rent By Owner in 2022 is over 203 in the Fawn Creek area, and still counting. Pastoral Log Cabin with Trails about 1Mi to Grand Lake.If you are looking for a family-friendly vacation home in Fawn Creek, check out one of the following properties as all are highly-rated places to stay with excellent review for families or groups staying in Fawn Creek: Which vacation homes in Fawn Creek are best for families? Top-rated RBO homes that have access to a swimming pool include: There are 29 vacation rentals with private pools near Fawn Creek. How many vacation rentals have private pools in Fawn Creek? TownePlace Suites by Marriott Tulsa North/Owasso.El juego te llevará a numerosas aventuras en el modo de un jugador o multijugador. Cada uno de ellos tiene su propia arma y habilidades. Holiday Inn Express & Suites - Coffeyville, an IHG Hotel ¡Stick Warrior Hero Battle comienza en muchas arenas peligrosas llenas de superhéroes Serán monigotes disfrazados de superhéroes.Fairfield Inn & Suites by Marriott Tulsa Catoosa.If you plan on staying in the Fawn Creek area, consider making a reservation for a few nights at one of these properties as these have been rated the Top Vacation Rentals in Fawn Creek: There are a lot of options in Fawn Creek. Just search for your destination and secure your reservation today.įrequently Asked Questions About Fawn Creek What are the top vacation rentals in Fawn Creek? RentByOwner makes it easy and safe to find and compare vacation rentals in Fawn Creek with prices often at a 30-40% discount versus the price of a hotel. Popular Airbnb-style properties in Fawn Creek. Huge master suite bedrooms and have large screen televisions? You can find vacation rentals by owner (RBOs), and other Looking for an RBO with the best swimming pools, hot tubs, allows pets, or even those with Homes? With RentByOwner Fawn Creek, you have the flexibility of comparing different options of variousĭeals with a single click. ![]() Looking for last-minute deals, or finding the best deals available for cottages, condos, private villas, and large vacation Get more value and more room when you stay at an RBO property in Fawn Creek. These rentals, including vacation rentals, Rent By Owner Homes (RBOs) and other short-term private accommodations, have top-notch amenities with the best value, providing you with comfort and luxury at the same time. There are more than 203 vacation rentals that are available in Fawn Creek. ![]() The nation that needed their help in a time of crisis, it seems, was not yet ready for the greater social equality that would slowly come in the decades to follow. Women veterans encountered roadblocks when they tried to take advantage of benefit programs for veterans, like the G.I. Nurses were in Normandy on D-plus-four.Īt the war’s end, even though a majority of women surveyed reported wanted to keep their jobs, many were forced out by men returning home and by the downturn in demand for war materials. More than 1,600 nurses were decorated for bravery under fire and meritorious service, and 565 WACs in the Pacific Theater won combat decorations. Sixty-eight American service women were captured as POWs in the Philippines. Some women served near the front lines in the Army Nurse Corps, where 16 were killed as a result of direct enemy fire. They also drove trucks, repaired airplanes, worked as laboratory technicians, rigged parachutes, served as radio operators, analyzed photographs, flew military aircraft across the country, test-flew newly repaired planes, and even trained anti-aircraft artillery gunners by acting as flying targets. Women in uniform took office and clerical jobs in the armed forces in order to free men to fight. “The contribution of the women of America, whether on the farm or in the factory or in uniform, to D-Day was a sine qua non of the invasion effort.” (Ambrose, D-Day, 489) General Eisenhower felt that he could not win the war without the aid of the women in uniform. Nearly 350,000 American women served in uniform, both at home and abroad, volunteering for the newly formed Women’s Army Auxiliary Corps (WAACs, later renamed the Women’s Army Corps), the Navy Women’s Reserve (WAVES), the Marine Corps Women’s Reserve, the Coast Guard Women’s Reserve (SPARS), the Women Airforce Service Pilots (WASPS), the Army Nurses Corps, and the Navy Nurse Corps. ![]() When men left, women “became proficient cooks and housekeepers, managed the finances, learned to fix the car, worked in a defense plant, and wrote letters to their soldier husbands that were consistently upbeat.” (Stephen Ambrose, D-Day, 488) Rosie the Riveter helped assure that the Allies would have the war materials they needed to defeat the Axis. In New Orleans, as the demand for public transportation grew, women even became streetcar “conductorettes” for the first time. As the men fought abroad, women on the Home Front worked in defense plants and volunteered for war-related organizations, in addition to managing their households. When the war began, quickie marriages became the norm, as teenagers married their sweethearts before their men went overseas. The role of German women, he said, was to be good wives and mothers and to have more babies for the Third Reich. Hitler derided Americans as degenerate for putting their women to work. The Axis powers, on the other hand, were slow to employ women in their war industries. That commitment included utilizing all of America’s assets-women included. Reluctant to enter the war when it erupted in 1939, the United States quickly committed itself to total war after the Japanese attack on Pearl Harbor. Not only did they give their sons, husbands, fathers, and brothers to the war effort, they gave their time, energy, and some even gave their lives. American Women in World War II: On the Home Front and BeyondĪmerican women played important roles during World War II, both at home and in uniform. ![]() ![]() ![]() Army Men: 3D Army Men: Air Attack Army Men: Air Attack 2 Army Men: Green Rogue Army Men: Sarge's Heroes 2 Army Men: World War Army Men: World War - Final Front / Lock 'n' Load Army Men: World War - Land Sea Air Army Men: World War - Team Assault Assault: Retribution Asteroids Atlantis: The Lost Empire Auto Destruct Azure Dreams B Ballistic Baldur's Gate Batman & Robin Batman Beyond: Return of the Joker Batman Forever Batman: Gotham City Racer Battle Arena Toshinden Battle Arena Toshinden 2 Plus Battle Arena Toshinden 3 Battle Hunter Battle Stations BattleTanx: Global Assault beatmania Beyblade Bishi Bashi Special Black Dawn Blade Blazing Dragons Blood Omen: Legacy of Kain Bloody Roar Bloody Roar II Block Buster Bob the Builder: Can We Fix It? Bomberman Fantasy Race Bomberman: Party Edition Brave Fencer Musashi Breath of Fire III Breath of Fire IV Broken Sword: The Shadow of the Templars Broken Sword: The Smoking Mirror Bug's Life Bugs Bunny & Taz: Time Busters Bugs Bunny: Lost in Time Burning Road Burstrick: Wake Boarding!! Bushido Blade Bushido Blade 2 Bust-A-Groove Bust-A-Groove 2 Bust-A-Move 4 Buzz Lightyear of Star Command C C: The Contra Adventure C-12: Final Resistance Capcom vs. 123 007: Racing 007: The World Is Not Enough 007: Tomorrow Never Dies 101 Dalmatians II: Patch's London Adventure 102 Dalmatians: Puppies to the Rescue 2002 FIFA World Cup 2Xtreme 3Xtreme 5 Star Racing A A-Train Ace Combat 2 Ace Combat 3: Electrosphere Aces of the Air Action Man: Operation Extreme Actua Soccer 2 Actua Soccer: Club Edition Actua Tennis ADVAN Racing Advanced Variable Geo Advanced Variable Geo 2 Adventure of Little Ralph Adventures of Lomax Air Hockey / Hooockey!! Akuji: The Heartless Agent Armstrong Air Combat Air Race Championship Aladdin in Nasira's Revenge Alien Trilogy Alien: Resurrection All Star Racing All Star Racing 2 All Star Tennis 2000 Allied General Alone in the Dark: One-Eyed Jack's Revenge Alone in the Dark: The New Nightmare Alundra American Pool Andretti Racing Ape Escape Apocalypse Aquanaut's Holiday Arc the Lad Arc the Lad II Arc the Lad III Armored Core Armored Core: Master of Arena Armored Core: Project Phantasma Armorines: Project S.W.A.R.M. Find Key Decision Makers Of Qube Gaming Networks Email, Phone, LinkedIn Profile. 2 and Toxic Games logos are trademarks or registered trademarks of Toxic Games. Qube Gaming Networkss Overview, Revenue, Employee Size, Location For Free. Original musical score composed by BAFTA nominated composer, David HousdenĬopyright © Toxic Games 2010 - 2018.Experience an all new adventure and brand new characters.Interact with new and improved game mechanics:įull colour blind support, using symbols as a colour aid: Master eleven puzzle areas and solve over 80 individual puzzles:Įxplore diverse environments that expand the Q.U.B.E. Play online, access classic NES and Super NES games, and more with a. ![]() Use your manipulation gloves to change and adapt the architectural structure in your search to rendezvous with another survivor, finding a way off the planet.Īs you explore and solve puzzles to progress, thought-provoking questions about your true purpose and the origins of the structure you are navigating will need to be considered, forcing you to come to terms with a devastating truth that will shake your world. Qube Qross is a challenging and logical puzzle game, like Nonogram in 3D. Super silent with intelligen thermal fan controler technology. SLi Ready and support Intel & AMD Dual & Multi core. Awaiting you is a maze-like monolith, a structure that you must navigate, solving mind-bending puzzles. FAN speed auto control by thermal sensor inside power supply. Waking up wearing a strange suit with attached gloves, you have no prior knowledge on how you came to be in this environment. Together with the distant help of another survivor, Commander Emma Sutcliffe, you must traverse and manipulate the structure of this forgotten world to find a way back home. You are Amelia Cross, a stranded archaeologist who has mysteriously awoken among the sand swept ruins of an ancient alien landscape. 2, players step into the shoes of Amelia Cross, a British archaeologist, who has awoken on a strange alien planet. ![]() ![]() 2 is the sequel to the hit first-person puzzle game Q.U.B.E. ![]() ![]() Pace/iLok no longer required for AAX choose Pace/iLok or Wave Arts licensing for all formats. AAX formats support Wave Arts licensing.Only 64-bit formats are supported on MacOS. Dropping support for VST2, DX, MAS, RTAS, AAX DSP, and 32-bit builds on Mac OS-X.Power Suite 6 supports VST3, AU, and AAX (native) formats. MacOS installers are properly notarized.Plug-ins work on latest Mac DAWs such as Cubase 10, WaveLab 10, Premiere 2020, and Audition 2020. To receive the discount coupon, visit the Upgrade Coupon page. The price to upgrade any individual plug is $52.15, the full Power Suite upgrade is $174.65. The discount can be used to purchase Power Suite 6 or individual Power Suite 6 plug-ins (TrackPlug 6, MasterVerb 6, FinalPlug 6, MultiDynamics 6, Panorama 6). Wave Arts are offering a 65% discount to owners of Power Suite 5 plug-ins. The Power Suite 6 plug-ins do not replace Power Suite 5 plug-ins, they will co-exist on the same system. Power Suite 5 installers are still available in the Archive section. You can download Power Suite 6 plug-ins from their Downloads page and try out the demos. On these DAWs, the v5 plug-ins do not draw properly. This was necessary to maintain compatibility with MacOS and the latest MacOS DAWs, such as Cubase 10, WaveLab 10, Premiere 2020, and Audition 2020. However, under the hood, the plug-ins have been completely rewritten to use the latest development tools and SDKs. The signal processing algorithms and user-interface functions are largely unchanged from Power Suite 5. Power Suite 6 is a significant update to the Power Suite line, featuring compatibility with MacOS Catalina, support for VST3 format, improved licensing and improved preset management. ![]() Author Brandon Sanderson is a fantasy and science fiction writer from Utah. Pictured is “Words of Radiance” which is part of the Stormlight Archive series. This event started a war between the two races, and the series takes you through the events of the war, the secrets behind its circumstances, and the individual stories of each character. It all begins when a race of humanoid creatures sends an assassin after a human king who was attempting to establish a peace treaty between the two races before he died. The story follows the adventures of Kaladin, Shallan, and Dalinar in a fantasy world full of magic, monsters, and more. This series currently has three books out, each considerably thick. The Stormlight Archive by Brandon Sanderson is a wonderful fantasy series to occupy your long summer hours. With so many free hours ahead, it is the perfect chance to embrace the world of epic fantasy and begin a long series. A great way to pass the hours is sitting down and reading a good book. "Enjoyable, adventurous read.Being quarantined over the summer is leaving many with a lot of free time on their hands. ![]() "Highly recommended to anyone hungry for a good read." - Robin Hobb on Mistborn "Intrigue, politics, and conspiracies mesh complexly in a world Sanderson realizes in satisfying depth and peoples with impressive characters." - Booklist on Mistborn The magic system is perfectly detailed, the world, though not completely revealed, has a great sense of natural logic to it, and the characters are a reflection of both." - SFF World "Sanderson is crafting an extremely well-thought out saga with Mistborn, one that looks to stand above the pack of his literary peers. Sanderson is astonishingly wise." - Orson Scott Card "It's rare for a fiction writer to have much understanding of how leadership works and how love really takes root in the human heart. There is simply no other way to describe what he's managed to pull off in this transcendent final volume of his Mistborn trilogy." - RT Book Reviews (Gold Medal, Top Pick!) on The Hero of Ages ![]() Unless all the nations of Roshar can put aside Dalinar’s blood-soaked past and stand together-and unless Dalinar himself can confront that past-even the restoration of the Knights Radiant will not prevent the end of civilization. And Dalinar realizes that his holy mission to unite his homeland of Alethkar was too narrow in scope. Nestled in the mountains high above the storms, in the tower city of Urithiru, Shallan Davar investigates the wonders of the ancient stronghold of the Knights Radiant and unearths dark secrets lurking in its depths. While on a desperate flight to warn his family of the threat, Kaladin Stormblessed must come to grips with the fact that the newly kindled anger of the parshmen may be wholly justified. In Oathbringer, the third volume of the New York Times bestselling Stormlight Archive, humanity faces a new Desolation with the return of the Voidbringers, a foe with numbers as great as their thirst for vengeance.ĭalinar Kholin’s Alethi armies won a fleeting victory at a terrible cost: The enemy Parshendi summoned the violent Everstorm, which now sweeps the world with destruction, and in its passing awakens the once peaceful and subservient parshmen to the horror of their millennia-long enslavement by humans. The eagerly awaited sequel to the #1 New York Times bestselling Words of Radiance, from epic fantasy author Brandon Sanderson at the top of his game. ![]() ![]() The AF-2 domain of the protein associates with corepressor molecules in the absence of ligand. ![]() RARs modulate transcription through interaction with cofactors. The C-terminal E domain of RARα contains the AF2 ligand-dependent transcriptional activation domain as well as a dimerization interface for RXR. 42, 43 Through alternative promoter usage, the RARα protein can have two different A domains (A1 or A2). 42 AF-1, contained within the N-terminal A/B domain, is a ligand-independent transcriptional activation domain that works in a promoter context-dependent manner. 41 RARα and other nuclear receptors contain two domains, AF-1 (A/B domains) and AF2 (E domain), which can cooperate to activate transcription. 39, 40RARα is a ligand-dependent transcription factor stimulated by ATRA, whereas its partner, RXR, responds to ATRA or 9- cis retinoic acid. 36-38 Heterodimerization is mediated both by the DNA binding and ligand binding domain of RARα. RARα binds as a heterodimer to this site along with the related retinoid X receptor protein (RXR). ![]() 35 RAREs consist of a direct repeat (A/G)G(G/T)TCA separated by 2 or 5 nucleotides. Through this domain, RARα binds to retinoic acid response elements (RARE) located in the promoters of many genes, including those of RARα, 31, 32 RARβ, 33, 34and RARγ. The most highly conserved domain among nuclear receptors and retinoid receptors is the C domain, which contains two C 2C 2 zinc finger motifs (reviewed in Chambon 30). RARα structure parallels that of other nuclear receptors and is divided into 6 evolutionarily conserved domains (A through F Fig 2). We will also examine how the recent explosion of knowledge in APL has led to the development of new therapeutic agents such as arsenic trioxide 16, 17 and sodium butyrate. Finally, we will reconstruct the disease of APL and examine the leukemogenic functions of the RARα fusion proteins in cell culture models, animal models, and patients. We will examine each of the genes fused to the RARα in APL, searching for similarities and differences among the four partner proteins that may explain the distinct clinical outcome some patients with variant forms of APL. In this review, we will deconstruct the APL problem by evaluating the role of RARα in normal and neoplastic myeloid development. This again highlights the importance of retinoid metabolism, but also suggests that partner genes with RARα could also play important roles. Although this hypothesis is essentially correct, 7 years of intense investigation of the APL model have begun to uncover a more complicated picture.ĪPL is now associated with four different gene rearrangements, fusing RARα to the PML, promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), or nuclear matrix associated (NuMA) genes (Fig 1), leading to the formation of reciprocal fusion proteins (N-RARα and RARα-N). According to this line of reasoning, retinoic acid in pharmacological doses could then overcome this pathology, leading to in vivo differentiation and clinical remission. 10-15 These data suggested that disruption of RARα function was the major cause of APL. In 1991, it was discovered that the consistent chromosomal translocation of APL, t(15:17), 9fused the retinoic acid receptor α (RARα) gene to the promyelocytic leukemia (PML) gene on chromosome 15, yielding the fusion protein PML-RARα. At that time, it became apparent that APL was, among the forms of acute myeloid leukemia, uniquely sensitive to all- transretinoic acid (ATRA) 1, 2 and clinical trials indicated that ATRA induced complete remissions by differentiation and eventual elimination of the malignant clone (reviewed previously 3-8). IN THE LATE 1980s and early 1990s, the elucidation of the molecular basis of acute promyelocytic leukemia (APL) emerged as a paradigm for the connection between the bench and bedside. |
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