![]() ![]() There, along with Rena Lanford, he must investigate a recent surge of demons coming from a meteorite. Kenny is accidentally transported to the mysterious planet Expel. Twenty years after the events of the original Star Ocean, Pangalactic Federation Army Ensign Claude C. ![]() And IMO the original SFC title really is the better one to play if you can tolerate the old-school gaming experience. If you’d rather experience the original Star Ocean in its purest form, an English patch for the game’s ROM is just one Google search away. Nowadays, such things have become more common in gaming.īut they remain key parts of the experience for all SO titles. Members of a town’s defense force after a mission to find an antidote for a mysterious disease goes completely off-course and sends them on a larger-than-life space adventure.īack when the original Super Famicom game came out, its character affinity system and multiple endings were revolutionary and added a lot of depth to an already complex game. The story follows Roddick, Millie, and Dorne. So in 2008 tri-Ace decided to bring the story and its characters to the West through Star Ocean: First Departure, a complete remake on the PSP with enhanced graphics and an entirely new engine. The original Star Ocean for the Super Famicom never made it out of Japan. Still, I found the characters to be charming and quite lovable.Īnd the fact that the protagonist Fidel isn’t a whiny kid that spends half the game complaining was refreshing for me. The combat system also caught a lot of flak for being chaotic thanks to its inclusion of every single party member at the same time, which might seem desirable at first… but ultimately dilutes the strategic experience. The game can be finished in under 20h at a leisurely pace! While the game has a charming art-style that’s true to the franchise and boasts some of the most beautiful graphics ever seen on an RPG of its kind, it comes at the cost of a lackluster plot and a criminally short length. The fifth main entry in the Star Ocean franchise gets a lot of bad press from long-time fans and some media outlets for a variety of reasons.Īnd even though I enjoyed my time with the game, I can’t possibly rank it higher than previous releases. ![]() Star Ocean: Integrity and Faithlessness (2016) Whether you just want to reminisce or are looking for something new to scratch your space-faring itch, have a peek at our list ranking ever Star Ocean game ever released in the West. Tri-Ace’s very influential action-RPG deals with the impact of spacefaring technology and what it can mean for societies in different stages of social, cultural, and technological development in a way that few other franchises even attempt.Īll of this couple with some of the most dynamic combat seen in RPGs, excellent storytelling, a big focus on character interactions, and giving the player freedom to make choices that would ultimately affect the outcome of the story, all make the first Star Ocean games completely vanguard.Īnd they gave way to a very well-loved series still running well today. This is a franchise with a unique narrative style that brings together elements from different genres to create an enthralling experience. Fans of Sci-Fi and Fantasy RPGs have always found common ground in Star Ocean. ![]()
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![]() When autocomplete results are available use up and down arrows to review and enter to select. Check out our selection of Beer Brand Costumes, Liquor Bottle Costumes, Beer Girl Costumes, Funny Adult Drinking Costumes, and more. Discover (and save!) your own Pins on Pinterest We would like to show you a description here but the site won’t allow us.Our latest costumes for 2017 are available to ship out today! Grab a few costumes to take advantage of our FREE SHIPPING on orders over $50, shipping in the US. The officially licensed Sam costume features a one-piece jumpsuit and a hooded mask a burlap trick-or-treat sack is.This Pin was discovered by Kirsten Cairns. Etsy Search for items or shops Close search Skip to Content Sign in 0 Cart Home Favourites Jewellery & Accessories Clothing & ShoesGreen Gatorade water bottle Halloween costume with hand painted G and crocheted beanie! 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There are many tutorials on painting mountain landscapes, and they are relatively easy to follow. You can paint from memory, in an abstract style, or look at a real mountain and paint what you see. Mountains have so many dimensions and colors that make them easy to paint. ![]() Therefore, there are no boundaries on the number of colors you use, no rules on which technique you use to apply the paint to your canvas, and no right or wrong.Ībstract art is one of the easiest things you could choose to paint on your canvas. One of the most delightful things about an abstract artwork is that each person who views it interprets its meaning differently. It is an art style that lets you channel your deepest inner feelings through creativity and sets you free. Abstract ArtĪbstract art allows you to express yourself without structure. Like pixel art, a geometric tiger has the same concept, but you use geometric shapes to create your picture. Color Shift Drip ArtĬolor shift drip art is similar to pour art, but when you create this artwork, you pour one or more colors of paint on one edge, and when you lift the same side, allowing the paint to drip down, so it looks like your painting is melting. When you get more confident with judging scale and proportion, start defining the details of the objects to look a bit more life-like. You can also apply the abstract approach by painting the still life with overlapping lines and different colors to the actual items. You can also choose your difficulty level by painting basic or intricate objects. It also allows you to practice painting in dimensions and scale. Painting a still life on canvas might seem tricky, but it is one of the easiest things you can paint on canvas. Still Life Closeup male artist painting red shallot, acrylic color on canvas Pour paint art is an expressionist’s dream! It requires no planning, and all you do is pour your chosen colors onto the canvas and tilt the canvas in any direction(s) to cover the entire canvas. Use a contrasting color to paint the background so that the flower can stand out and become the main focus of the painting. Instead, try to paint an object such as a flower with different shades of color and overlapping lines. Abstract Flowerĭon’t try to paint intricate and elaborate details yet if you are new at this. You can recreate your version of the “Starry Night” by Vincent Van Gogh, or you could create your starry night painting by looking up at the sky for inspiration. The acrylic provides some texture, and the watercolor is flat, emphasizing the acrylic texture. Mixing these two mediums on canvas has a beautiful effect. You can paint pumpkins or create an entire scene with trees and falling leaves. Painting a fall day can be expressed in various scenarios. Painting abstract forms mean using these primary forms as the platform of your artwork, but they can overlap or be asymmetric, and you don’t need to create a picture that makes sense you are playing around with shapes and colors. Abstract FormsĪbstract forms can be anything from a square, triangle, and circle to a rectangle or parallelogram. Sunflowers look pretty with contrasting blue backgrounds. Instead, you can apply your paint thicker using a palette knife to give your sunflower more definition. ![]() Abstract SunflowerĪbstract sunflowers are easy to paint on canvas because you don’t have to paint them picture-perfect. You can also draw an umbrella on the beach on a sunny day or people walking with umbrellas on the street on a rainy day with water dripping from it. The fun thing about painting them is that you can make them each a solid color or color every umbrella with multiple colors. Umbrellas have a shape that is easy to recreate. Scrape art is a form of abstract art, and instead of using regular brush strokes to apply paint, you are using a scraping tool or palette knife to scrape the colors onto your canvas. The great thing about painting a quote on canvas is that you can create emotion with a background painted in colors that emphasize the quote’s meaning.įor example, if you are writing love quotes, you could paint a background with colors representing love, such as red, pink, purple, gold, white, or any other colors that you associate with love.Īfter you have painted the background, plan where you want to paint the quote and try to choose a color that stands out. There are so many easy things to paint on canvas, and we will explore them in detail below. An artist uses different mediums and painting techniques to create captivating and expressive artworks that show the world who they are. The ability to express yourself through art is a quintessential trait of an artist. ![]() Conclusion Which Things Are Easy To Paint On Canvas? ![]() ![]() ![]() ![]() Pixa Tool will help you make a pixel art sprite from any picture that you have. The final sprite will appear as a pixel art sprite ready to be used in any game Pixel Art allows you to use the tool with any image editing program. The application is very easy to use, as it does not require an introduction or even a configuration.Īllows you to create pixel art from any image-editing software The tool can be used with any image editing software and is compatible with any image format. The process is straightforward, but in order to save the final outcome, you must save the current project.īest of all, you can even use the tool with your iPhone, iPad and iPod touch. You can now choose the desired pixel art style and layout.Īfter that, you can choose the desired settings and make adjustments as needed. Then the software shows you the open screen, which is divided into three areas: preset, image and advanced. You need to first load the image or video you want to use. What’s more, you can load and apply presets from the photos you have already prepared with any photo editor.Ĭreating pixel art is as simple as a few clicks. The program also allows you to save and apply your own custom presets. You can choose from an unlimited number of different pixel art backgrounds, including ones that are created with the most popular pixel art tools. This tool is very useful in a scenario where you want to create fast and original sprites that you can use in your game or graphic design projects. Pixel Art provides you with a number of built-in pixel art presets. To achieve the desired effects, you can choose from dozens of pixel art presets, so that you will not need to spend too much time getting your artwork to the desired appearance. The final result will appear as a sprite ready to be used in any game. Just load the original picture or video and then start the pixel art creation process. With Pixa you can easily create pixel art from any image-editing program. With Pixa you can create pixel art sprites in no time. Pixel Art has been created specifically for the iPhone, iPad, iPod touch and Android platforms. It’s the most efficient tool for creating instant original pixel art in the shortest time possible. If you want to create original images from any image-editing program, then Pixel Art is your best choice. You may need shrink your images first or you will have problems importing them.PixaTool 1.58 Crack+ PC/Windows The interface has an efficient layout and it is quite easy to master. It provides you with a wide range of customization controls. The software automatically turns any image into pixel art. You can apply radial or hex pixelation, change the dot size and scale and more.Ĭreating retro pixel art can't get any easier when using PixaTool. These allow you to make further tweaks and make the effect more interesting. The normal controls, on the right side of the image, can be replaced with controls for special effects. For example, you can increase or decrease the size of the pixels and apply a basic blur. PixaTool lets you make the usual image adjustments, like changing the hue, saturation and light levels, increasing or decreasing the contrast, gamma, exposure and so on, but it is also possible to tweak the pixelation effect itself. The first thing you can do is choose between several pixelation modes, like 16-bit, or others that resemble graphics from the old Nintendo or Game Boy consoles. Images are pixelated automatically once they are imported, but you can use various sliders, to the left and right of the image, to make all sorts of manual adjustments. ![]() Images can be imported instantly, through a browsing option or by dragging and dropping the file on the user interface, after which you can start working on it right away. The same package includes versions for other operating systems as well, including Linux and Mac OS X. Its components come in a ZIP archive, so you can just extract them and run the executable, without going through an installation process. The software is free to try, with some limitations. It can pixelate images at a moment's notice and it gives you full control to customize the effect according to your own needs. If you want to use certain assets in such a game or you need some pixel art for other reasons, then PixaTool is the solution you need. It's cheap to make and it gives video games a nice retro look, which goes well with nostalgic gamers. ![]() ![]() ![]() Make heads turn by amping up your glamour quotient with our extensive range of Maybelline lipsticks. Create custom looks with different shades and textures and add the perfect finishing touch to every makeup look. Heading out for dinner and need a matte liquid lipstick that will last all night? Or need a nude pink crayon lipstick for work to keep your lips feeling soft and moisturised all day? Whatever your needs and wants are, Maybelline has got you covered. From intensely creamy lipstick colours to long-lasting matte lipsticks that work just as hard as you, go and make a statement with Maybelline lipsticks!Ĭreamy matte lipsticks lie somewhere between satin and matte lipsticks, giving you the best of both worlds. These lipsticks are suitable for daily use and keep your lips feeling smooth and supple while delivering crisp and vibrant lip colour. If you love the look of matte lipstick but do not want to compromise on the soft and creamy sensation, this is the best lipstick for you! The Maybelline Color Sensational Creamy Matte Lipstick is available in a wide range of hydrating lip colours that glide smoothly while keeping your lips moisturised all day long. ![]() Take your lip game up a notch with a variety of ultra-flattering shades such as nude, pink, red, plum and more in a creamy lipstick formula. Liquid matte lipsticks are best if you want to keep your pout coloured and hydrated all day. But it is also important for you to prep your lips before applying matte lipstick. BEST RED LIPSTICK 1: SUPER STAY MATTE INK LIQUID LIPSTICK IN PIONEER.Use a lip balm to heal and soothe your lips and prevent them from over-drying and getting chapped. Need a long-lasting lipstick that will not smudge or transfer? Try the Maybelline Superstay Matte Ink Liquid Lipstick that is waterproof and lasts for up to 16 hours! These Maybelline matte lipstick shades are made of an intensely pigmented formula that does not dry out your lips and contain a unique arrow applicator that ensures a precise application every time. It’s the ultimate red for all skin tones. ![]() Bite, sip, kiss and enjoy the feeling of a liquid matte lipstick without any stickiness with the Maybelline Sensational Liquid Matte Lipstick.This super-saturated, blue-red, ultra-matte liquid lipstick gives you up to 16 hours of flawless, highly-pigmented red color, plus its kiss-proof. ![]() This Maybelline New York Lipstick is surprisingly weightless and delivers intense colour in a single swipe.Ĭrayon lipsticks are perfect for people who are always on the go and have an active and bustling lifestyle. These intense lipsticks keep you going through the day without fading or smudging, are super easy to use and glide across your lips with ease. The Maybelline Superstay Matte Ink Crayon Lipstick lasts for up to eight hours and is available in a variety of shades for you to choose from. This crayon lipstick comes with a built-in sharpener that helps keep the tip on point through every application. With so many different Maybelline new lipstick shades and formulas, it can be difficult to choose a lipstick shade that complements your skin tone and ties your whole makeup look together. Solve the dilemma by trying out all the different Maybelline lipsticks online– from Maybelline red lipstick shades to Maybelline brown lipstick shades and more with the Maybelline Lipstick Finder tool. And yes, if you need some more help to finalize your eye makeup, face makeup or lip makeup, you can try the Maybelline Virtual Try-On tool that lets you experiment with different products virtually, from the comfort of your home, without spending a single penny. To further find out your ideal foundation, concealer, and powder shade match, answer a few questions on the Maybelline Foundation Finder tool and look the best from the rest. ![]() ![]() ![]() ![]() ![]() Encourage Rooting: Maintain the soil barely moist, which will aid in stimulating root growth. Climate data used in creation of plant range maps is from PRISM Climate Group, Oregon State University, using 30 year (1981-2010) annual "normals" at an 800 meter spatial resolution. Soil Propagation Straight to Soil: Rather than using water, you may opt to insert the calloused end of your cuttings directly into a pot containing soil. Check for signs of pests or disease before beginning propagation. Other general sources of information include Calflora, CNPS Manual of Vegetation Online, Jepson Flora Project, Las Pilitas, Theodore Payne, Tree of Life, The Xerces Society, and information provided by CNPS volunteer editors, with special thanks to Don Rideout. Before beginning propagation for your Zig Zag Cactus, there are several requirements that should be met first:-A healthy parent plant: Since you’ll be taking cuttings from an existing plant in order to create new ones, it’s important that your parent specimen is healthy. Set the cuttings in a cool, dry location for at least 24 hours to allow the cut edge to callous over. Sources of plant photos include CalPhotos, Wikimedia Commons, and independent plant photographers who have agreed to share their images with Calscape. Here’s how to propagate your fishbone cactus by stem cuttings: Using a pair or sharp scissors or pruning shears, take cuttings from your plant, keeping the cuttings between 4 and 5 inches long. Fertilize once a month during growing season The best time to propagate. Propogation from seed information provided by the Santa Barbara Botanical Garden from "Seed Propagation of Native California Plants" by Dara E. The zigzag model describes four phases: phase 1 (PAMPs detected by PRRs) is followed by phase 2 (pathogens deliver effectors to interfere with PTI), which is in turn followed by phase 3 (effectors recognized by NBLRRs, ETI) then phase 4 (loss/gain of effectors over evolutionary time). PLANT MAINTENANCE Place the plant in a pot size of 10 to 12 inches in diameter, filled with the required amount of well-drained soil or potting mix organic. Grow & Care Guide for Zigzag Plant Start the guide 01. Plant observation data provided by the participants of the California Consortia of Herbaria, Sunset information provided by Jepson Flora Project. All text shown in the "About" section of these pages is available under the Creative Commons Attribution-ShareAlike License. ![]() ![]() ![]() Granted, it wasn't more powerful than the Hemi offered in the Charger or the Coronet, but these numbers were massive in the Dart's lightweight setup. The race-bred powerplant was advertised to deliver 425 horsepower and up to 490 pound-feet (664 Nm) of torque. Breathing was courtesy of 2x4-barrel Holley carburetors, a cross-ram aluminum intake manifold, and a compression ratio of 10.25:1. Power came from the 426 Hemi V8 that Chrysler had been using to terrorize the competition at the drag strip and on public roads since 1964. ![]() Finally, Hurst made modifications to the rear fenders to accommodate bigger rear wheels wrapped in slick tires. Because Dragracing involves a lot of under-the-hood meddling at the strip. It also featured four pins for full lift-off removal. On top of that, the Hemi Dart looked downright menacing thanks to the massive and impressively wide scoop on the hood. Period literature says the Hemi Dart tipped the scales at around 3,000 pounds (1,361 kg), around 500 pounds (227 kg) lighter than a 440-equipped GTS. The list included the center console, heater, sound deadening material, side mirrors, radio, carpeting, and armrests. Of course, Dodge also removed all equipment deemed unnecessary at the drag strip. Because no one needs lateral support while racing in a straight line. But the regular front seats were also replaced with simpler and lighter units sourced from the Dodge A100 van. Like most factory-built dragsters from the era, the Hemi Dart was devoid of a rear bench. The regular steel fenders and hood were replaced with fiberglass panels, while the acid-dipped doors featured thinner glass and lacked window mechanisms (they were strap-operated). While the Dart was already lighter than the Charger and the Coronet, Dodge took the opportunity and shaved even more pounds off the compact. ![]() In theory, the Hemi Dart was based on the GTS hardtop, but it went through radical modifications to become an LO23. In reality, Hurst did a lot more than that because the Darts reached the company's conversion facility as partially assembled chassis. But while Dodge's regular-production Hemi cars were put together at the company's plant, the Hemi Darts had to go to Hurst Performance in Madison Heights, Michigan, for the finishing touches. Yup, it came with a no-warranty disclaimer. received promotional materials containing Chrysler's intention to sell factory-built Dart dragsters equipped with the company's most powerful V8.It was assigned production code LO23, and it was built to meet Class B Super Stock racing specifications. It all happened in February 1968, when Dodge dealerships across the U.S. That comes with a binder full of original documents and a real vintage Hemi, This Hemi engine alone is worth a fortune! So if you ever want to have a real race car, for driving the Superstock classes in your country, or just show off on any muscle car show, this car will rock it anywhere! The car comes with its original vin, original fender tag, original title, and original engine with the correct vin stamped! Currently, the car is complete restored and looking almost new, how it came out of the factory, the original Superstock Hemi is still there and kicks ash still! A complete survivor Superstock Dodge Dart would cost around $300,000 to $400.000 Dollars these days, so for a fraction of that you can still buy a partly original Superstock car. They have once used the body of a donor car to safe this rare car, create a new car out of it. And more rare parts around the car like the plastic windows and seats, and original shifter, and more body parts and special used parts that only came on this particular Super Stock race car. This particular car has also raced back in the days, and somewhere in his life this car had a crash, and they have used a new body to save the original matching number engine. And had now history value for that moment, so almost all of these race Darts have been raced with. This Car This race Dodge Dart has had a rough life once, that is common for original drag race meant cars, there happened a lot back in the days when these cars were used for racing and abusing only. For sale: A unique 1968 Dodge Dart Super Stock LO23 Factory Race car with a story. ![]() ![]() A civil society statement was also signed by almost 100 organizations and NGOs, including Greenpeace and Friends of the Earth, rejecting the ICAO’s proposal of offsetting the aviation industry’s emissions on the basis that it would propel global warming beyond 1.5 ☌. In conjunction with these actions, a petition was signed by 50 organisations, including Attac Europe, Friends of the Earth International, Global Justice Now, Greenpeace, Indigenous Environmental Network, among several others, which are united against airport expansion projects. Aviation Growth Cancelled Due to Climate Change, in various countries, including Austria, Mexico, the United Kingdom, Canada, Turkey, France and Australia. While the conference was taking place, a group of locally-affected opposition groups and organizations coordinated complimentary global action days under the name Stay Grounded. Climate activists viewed this proposal as a greenwashing strategy. Their proposal was to have further aviation growth, incorporated with offsets that aimed to represent a way for airline passengers or 'emitters' to be encouraged to reduce emissions from other sectors as an individualized contribution towards global emission reductions. ![]() In October 2016, the ICAO held a conference on the aviation industry’s response to climate change. The network's members campaign against offsetting emissions, geo-engineering and biofuels. Stay Grounded's mission is rooted in campaigning for a reduction in aviation and airport expansion and supporting initiatives that promote alternatives to flying such as night trains and ships. The network consists of local airport opposition groups, climate justice activists, NGOs, trade unions and academics, among others. Founded in 2016, their work is rooted in fostering sustainable transport and campaigning against controversial climate strategies. Stay Grounded is a global network of more than 160 member organizations promoting alternatives to aviation to address climate change. ![]() Protest by Stay Grounded at Tegel airport in Berlin in 2019 ![]() ![]() Blackmore was a notable absence on the night, David Coverdale branding Ritchie’s no-show “an obscenity”. Also in 2016 the band were inducted into the Rock And Roll Hall Of Fame. They had another taste of mortality in 2016 when Ian Paice suffered a mini-stroke while on tour in Sweden, missing Purple gigs for the first time since 1968. They’ve reeled from the deaths of US guitarist Tommy Bolin, who some claim was badly suited (well, he did wear kaftans and geisha boots), and, more recently, Jon Lord. Over time, Purple have survived an ill-fated ‘funky period’ spearheaded by one-time bassist/vocalist Glenn Hughes. Fearsome tracks such as Mandrake Root and the cover of Hush promised much, but something was amiss in truth, they couldn’t decide whether they wanted to be Iron Butterfly or the Moody Blues, plus singer Rod Evans’ style was grounded in the hip-swinging 60s.Īll that festering resentment seems – indeed, is – a long time ago now, with the current DP line-up – Gillan, Glover, Paice, guitarist Steve Morse and keyboard player Don Airey – having enjoyed many years of stability. Briefly called Roundabout (a remnant of Curtis’ plan to form a band around a small core of players they would be joined by a revolving guest-cast who’d jump on and off a musical ‘roundabout’), Purple debuted in 1968 with their Shades Of… album. In cahoots with partner John Coletta, and along with a hot young keyboard player called Jon Lord, he began recruiting musicians to realise Curtis’ somewhat frazzled vision. (Boy, were people’s tax returns fucked up that year.) Curtis had the foresight, but he also had a penchant for LSD and unpredictable behaviour – as evinced by his decision in ’69 to quit the music business and join the Inland Revenue. (No wonder they decided to put Fairy Liquid bubbles on the cover of 1973 album Who Do We Think We Are.) The band’s roots can be traced back to 1968 (some say 1967) when Searchers drummer Chris Curtis contacted London businessman Tony Edwards to pitch the idea of creating a British rock supergroup. The story of Deep Purple is truly one of rock’s great soap operas. (Actually it’s the toaster that’s raising toast I won’t be quaffing a brandy until noon at the earliest.) And FYI, I still own that original copy of Fireball… As an increasingly decrepit 60-something-year-old, this writer is perched on a stool in the kitchen on a Sunday morning, raising a toast to Deep Purple’s epic career. Fast-forward 50 years to the present day. ![]() ![]() ![]() This strategy rescues behavioral and neurological function in a mouse model of FXS. The third and final approach involves inhibition of eIF4E phosphorylation by MNK using the antifungal phytotoxin natural product, cercosporamide. Defects in memory and spinogenesis are corrected by 4EGI-1 in Fmr1 -/- mice. A second approach involves direct inhibition of the physical interaction between eIF4E and eIF4G with the small molecule 4EGI-1. Metformin resolves behavioral deficits observed in Fmr1-deficient animals. At high doses, metformin blocks 4EBP phosphorylation by mTOR resulting in a decrease of eIF4E availability. Metformin is a translational inhibitor that affects multiple pathways including mTOR. One strategy to decrease eIF4E levels makes use of the antidiabetic drug, metformin. Multiple pharmacological approaches that modulate eIF4E activity have been applied to FXS. Furthermore, many of the phenotypes observed in Fmr1 −/− animals are rescued through introduction of a single amino acid substitution in eIF4E (S209A) that renders the protein incapable of being phosphorylated by MNK. Genetic reduction of MNK resolves behavioral deficits and restores synaptic activity in Fmr1-deficient animals. Increased levels of eIF4E phosphorylation are correlated with core phenotypes associated with FXS, both in human patients and Fmr1-deficient mice. Loss of FMRP results in elevated levels of eIF4E phosphorylation due to increased MAPK signaling upstream of MNK. The main phosphatase that regulates eIF4E is protein phosphatase 2A. eIF4E is also regulated through dephosphorylation. An additional mechanism that regulates eIF4E is post-translational modification by MNK1 and MNK2 (collectively referred to as MNK) at a single site, S209. Phosphorylation of 4EBP by mechanistic target of rapamycin (mTOR) prevents binding to eIF4E, and thus promotes formation of the eIF4F complex. eIF4E is further regulated by eIF4E binding proteins (4EBPs) that prevent eIF4E from interacting with eIF4G. eIF4E is the least abundant component of eIF4F, and its activity is meticulously controlled. eIF4E reversibly binds to the cap and fosters translation initiation through recruitment of the scaffold eIF4G and the helicase eIF4A forming the tripartite eIF4F complex. Īll mRNAs possess a 5′ cap that enables signal-dependent control of translation initiation. Restoration of translational homeostasis has emerged as a potential means to correct neuronal dysfunction and rescue behavioral deficits associated with FXS. Exaggerated protein synthesis in the brain is a hallmark of FXS and is recapitulated in animal models of Fmr1 deficiency. Multiple targets perform functions linked to synaptic plasticity. FMRP is a polysome-associated RNA-binding protein that governs translation of a large subset of mRNAs. Fmr1 encodes the fragile X mental retardation protein (FMRP). This mutation promotes epigenetic silencing and loss of the corresponding polypeptide. The most common genetic change associated with FXS is a trinucleotide (CGG) expansion in the 5′ untranslated region of the Fmr1 gene. Physiological abnormalities such as circuit hyperexcitability and abnormal spinogenesis are observed in FXS. Affected individuals display numerous behavioral deficits that include deficits in learning and memory, hyperactivity, increased anxiety, impaired social interactions, and repetitive behavioral patterns. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.įragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans and is the leading cause of autism spectrum disorder (ASD). Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. ![]() |