![]() However, in certain cases where the overall mutation load is higher – such as in cancer cells – diploidy might not be sufficient to buffer deleterious mutations 29. Diploidy, which is the presence of two copies of each gene, is certainly the most important evolutionary invention providing protection against mutation-induced gene inactivation 5, 28. This again suggests that tumors may evolve strategies to buffer for deleterious mutations. In populations of finite size, with large genomes and high mutation rates, the ratchet-like accumulation of deleterious mutations increases the likelihood of population extinction through mutational meltdown 25, 26, 27. ![]() The second explanation for the lack of detectable negative selection – though not independent from the first one – could be a consequence of the asexual nature of cancer evolution: in the absence of recombination, populations irreversibly accumulate mutations, and cells rapidly experience a fitness decrease - a process called Muller’s ratchet 24. Also, proliferation assays performed in cancer cells demonstrated that losing most genes would have a detrimental fitness effect 11. This indicates that general housekeeping functions (which should be important in somatic lineages too) are protected from mutations. E.g., globally expressed genes are under negative selection in the germline 20, 23. This is surprising given that many of the functions under negative selection in germline evolution affect general processes that should be important in every cell of the body, in particular in fast-dividing cancer cells. First, most mutations might have deleterious effects only on the development of an organism (germline evolution) but are instead tolerated in differentiated tissues or tumors (somatic evolution). Typically, two complementary answers are given to this question. These observations raise the question of how cancers can tolerate many deleterious mutations. This contrasts with negative selection during germline (organismal) evolution, where the majority of genes are under negative selection and thereby protected from mutations 20, 21, 22. While the extent of negative selection acting on cancer genomes is still under debate 3, 4, 5, 6, 15, 16, 17, 18, 19, common measures of selection – such as the ratio of non-synonymous to synonymous substitution rates (dN/dS) – indicate that most protein-coding genes lack detectable signals of negative selection in cancer genomes: as a matter of fact, 99% of coding mutations appear to be tolerated 5, 16. Specifically, among point mutations in coding regions, more than 75% are non-synonymous 12, and those mildly or strongly deleterious for cellular fitness are predicted to be within a range of about 65% 13 to >70% 14. However, in many systems – including cancer cells – the majority of coding mutations have been observed to have a deleterious role on cellular fitness: e.g., in silico evolutionary simulations 7, in vitro and in vivo proliferation assays 8, 9, 10, and whole-genome CRISPR-KO screens within different species and many tumor cell lines 11, showed a reduced in vitro proliferative fitness and a slower in vivo tumor growth, demonstrating the deleterious role of most coding passenger mutations. A small fraction of these thousands of aberrations 1, 2 is considered beneficial from the tumor perspective (driver events), while the vast majority is not undergoing detectable selection 3, 4, 5, 6 (passenger events). Ultimately, our work paves the way for the detection of novel cancer vulnerabilities by revealing genes that fall within amplifications likely selected during evolution to mitigate the effect of mutations.Ĭancer genomes evolve through the acquisition of multiple types of somatic aberrations – these include somatic single nucleotide variants (SNVs or mutations) and copy number alterations (CNAs). We show how cancer type-specific mutation landscapes drive copy number alteration patterns across cancer types. ![]() Our findings demonstrate that these potential buffering events are highly influenced by gene functions, essentiality, and mutation impact and that they occur early during tumor evolution. This could increase tolerance towards the deleterious impact of mutations by creating safe copies of wild-type regions and, hence, protecting the genes therein. Using 8,690 tumor samples from The Cancer Genome Atlas, we demonstrate that copy number amplifications frequently cover haploinsufficient genes in mutation-prone regions. This raises the question of how tumors tolerate such large amounts of deleterious mutations. ![]() While most coding mutations are deleterious, almost all protein-coding genes lack detectable signals of negative selection. Cancers evolve under the accumulation of thousands of somatic mutations and chromosomal aberrations.
0 Comments
![]() Now, select your Dot Pen again and start drawing. In this case I changed the Center X and Center Y values to 32, which is half of my total canvas size (64 pixels). Place the Symmetrical Ruler on the Canvas and, to make sure it’s on the dead-center, use the Object tool to select it and input values manually (13) Since this will be a front-facing portrait, I’ll start the drawing using the Symmetrical Ruler (12) ![]() Later in the game, you can duplicate any of your ‘common’ brushes and use it for pixel art (as long you reduce brush size to lower values and disable anti-aliasing). I suggest you follow along this tutorial using this brush only. It has a fixed 1-pixel size, anti-aliasing turned off, and no option for stabilization or color mixing. This is the simplest drawing brush available. It’s called ‘Dot Pen’ in the Marker category (11). In Clip Studio Paint you already have a pixel art pen. and during any transformation using Edit > Transform (10).In Clip Studio Paint you have to turn off anti-aliasing in: Later, we can soften the edges by adding anti-aliasing by hand (manually).Ī rule-of-thumb when using any software to create pixel art is to disable the anti-aliasing setting in brushes, tools and transformations. The aliased edge (6) is what we’re looking for when creating pixel art. This is made by adding an extra row of pixels closest to the aliased edge.Īs you can see in the example, the anti-aliased edge (7) has an automatic gradient of pixels to give the shape a smoother contour. Pixel art does not go along with automatic anti-aliasing.Īnti-aliasing is a useful algorithm that smooths edges of a shape. Set it to 100% and place in your workspace (5). To create a secondary view of your current canvas, go to Window > Canvas > New Window and open a new instance of the current canvas. ![]() (3) Ī good practice for working with pixel art is getting used to drawing zoomed while keeping an eye on the actual-size artwork (4) You can turn the grid on/off anytime using the Shift+G shortcut.
![]() While SpaceX spent its own capital to develop its previous launcher, the Falcon 1, development of the Falcon 9 was accelerated by partial NASA funding and commitments to purchase flights once specific capabilities were demonstrated. The initial launch would not occur until 2010. In October 2005, SpaceX announced plans to launch Falcon 9 in the first half of 2007. V1.0 flew from 2010–2013, V1.1 flew from 2013–2016, while V1.2 Full Thrust first launched in 2015, encompassing the Block 5 variant, is in operation since May 2018.įalcon 9 rocket family from left to right: Falcon 9 v1.0, v1.1, Full Thrust, Block 5, and Falcon Heavy Conception and funding The rocket evolved through several versions. Falcon 9 is certified for the National Security Space Launch program and NASA Launch Services Program as "Category 3", which can launch the most expensive, important, and complex NASA missions. įalcon 9 is human-rated for transporting NASA astronauts to the ISS. On 24 January 2021, Falcon 9 set a record for the most satellites launched by a single rocket, carrying 143 into orbit. The former was launched into an advantageous super-synchronous transfer orbit, while the latter went into a lower-energy GTO, with an apogee well below the geostationary altitude. The heaviest payloads flown to geostationary transfer orbit (GTO) were Intelsat 35e carrying 6,761 kg (14,905 lb), and Telstar 19V with 7,075 kg (15,598 lb). Both stages are powered by SpaceX Merlin engines, using cryogenic liquid oxygen and rocket-grade kerosene ( RP-1) as propellants. Individual boosters have flown as many as 15 flights. ![]() Since then, SpaceX has successfully landed boosters over 150 times. This feat was first achieved on flight 20 in December 2015. The booster is capable of landing vertically to facilitate reuse. ![]() The first (booster) stage carries the second stage and payload to a pre-determined altitude, after which the second stage lifts the payload to its ultimate destination. rocket with the most launches in history and with the best safety record, having suffered just one flight failure. rocket currently certified for transporting humans to the International Space Station. In 2020 it became the first commercial rocket to ever launch humans to orbit and is currently the only such vehicle capable of doing so. The first Falcon 9 ISS commercial resupply mission to the ISS launched on 8 October 2012. The first Falcon 9 launch was in June 2010. It can also be used as an expendable heavy-lift launch vehicle. Falcon 9 is a partially reusable medium-lift launch vehicle that can carry cargo and crew into Earth orbit, designed, manufactured and launched by American aerospace company SpaceX. ![]() Go with the company with servers close to your geographical location. Server location is one of the components that help raise Google page rank and other search engine rankings. The physical location of the server can influence the speed of the website where your game is hosted. It is recommended to use 5 GB RAM, 18 GB space, 8 mbit/s WAN UP and 4 mbit/s WAN Down. ![]() Minecraft can be demanding when it comes to hardware, especially if you intend to have several players with different mods.įor 5 to 7 players Intel Core-Based CPUs or AMD K8-Based CPUs at 3.4GHz or higher are required. Here are features to look for Minecraft server hosting: ![]() Understanding what makes some providers better than others before buying any Minecraft hosting is a must. What to Search for in a Minecraft Server Hosting? It also offers a support service to help you through your server setup. On top of hassle-free setup, you also get a full refund if you do not like the service. If you want to enjoy the beauty of the game without any hassle, it makes more sense to choose a Minecraft server hosting provider. And the security of resources stays at risk if you aren’t aware of the technical know-how. You’ll also have to keep your software up-to-date and server optimized. Unlike a hosted server, you need to think about your hardware setup’s power and space requirement. You also get complete access to the resources and server.īut these benefits come with a downside. With your server in place, you don’t need to pay a recurring fee to Minecraft server hosting providers. What to Search for in a Minecraft Server Hosting?īenefits of Using Own Server vs Hosted Server.Benefits of Using Own Server vs Hosted Server. ![]() ![]() When I requested more time on my trial they took WEEKS to oblige after a lot of back & forth & delays in response. The rest of the month was a total loss because the customer support took so long to respond & when they did it was nonsense & never resolved anything. I did a 30 day trial but I was only able to use Sidify for a week before I encountered the above issues. You reply immediately but then you don't hear from them for another 3+ weeks. Their responses are stupid- as though they are stalling for time. VERY Very annoying! Sidify was ZERO help on this issue.Ĭustomer support (by email only) is a JOKE. Many of the songs I converted pulled in the wrong versions of the songs- versions I didn't even know existed. No errors or informational messages are received. If I attempt to drag files or select files by clicking on the Add button simply NOTHING HAPPENS. If I attempt to select files to convert via the "+" all m4p files are grayed out & I can't select any. This functionality worked previously in Mac OS 11.6 (Big Sur) but no longer works after upgrading to Mac OS 12.6. If possible, I would give negative star! The file converter (for local files) would not let me select nor drag any files to the converter. I really believe that sidify is a life saving product to have if you are a DJ, had a great expirence. but it's a good investment if you're serious about your music. I don't have any complaints other than the price. ![]() It is the best music downloading app in the market right now! I love that it never messes up my downloads or deletes songs that I downloaded incorrectly. In addition to this, I am a DJ and I have been using Sidify to download music. Sidify lets you simply download mp3s through Spotify, then turn them back into lossless files that sound just like the originals. Forget about purchasing a cd or getting your music second-hand. It's amazing how well this app takes songs from Spotify and turns them into perfect replicas of the original files. I don't think I can say anything that has not already been said about Sidify. Some people may think that music conversion is just a gimmick but I've realized after taking a long time researching different solutions that the best converter is Sidify as it's able to convert your old and new iTunes music in the universal file format MP3 or M4A that are both supported by all devices.I am so convinced by the product Sidify that it's one of the best products ever. ![]() ![]() You can find Hickory, Maple, Oak, Pecan, Ash, and Walnut if you’re into domestic species and want to use a sustainable style of flooring in your home. There are close to 20 different types of wood available between solid and engineered styles. SpeciesĪnother area where Bellawood shines is with species selection. A few styles are matte or stained, but most feature a simple, clear finish and are of a medium tone in general. It’s a nice mix of both domestic and exotic species, including interesting choices like Pecan, Koa, and Cumaru. ![]() There are close to 20 types of engineered flooring available from Bellawood with close to a dozen species represented. These boards come in two sizes at 5/8” or ½” thick, and most are in the “Select” grade classification and wider than traditional hardwood floor boards. While not nearly as impressive as their solid flooring, the Bellawood engineered hardwood lineup has a little something for everyone. There are three widths with medium, wide and thin strip planks, but only one thickness at ¾”. You can find planks with an orange hue and boards that are a pale white along with the usual natural tones like brown and tan. Bellawood stands out from the pack compared to other manufacturers as they have focused on solid floors whereas other companies largely rely on engineered products.īellawood’s solid hardwood flooring comes in the usual shades of light, medium and dark but you’ll have 10 colors to choose from. It’s considered more sustainable in some cases but doesn’t hold up to the durability and feel of solid hardwood flooring. Most of the hardwood flooring manufacturers we’ve covered focus on engineered flooring. ![]() ![]() Within months, teenagers will stop liking it, and some major national brand will tweet “more like bae movie! lol.” So it goes. You can buy one on Redbubble if you’re the kind of person who believes that according to all known laws of aviation, there is no way a bee should be able to fly.īut be warned that this cool meme has now received significant mainstream attention, and will now begin a gradual descent into the internet’s scrapyard. Bee Movie Script - This puppy is a transcript that was painstakingly transcribed using the - StuDocu You havent viewed any documents yet. It would appear that 100,000 Tumblr notes is the threshold that makes you a local high-school celebrity.Īs for the shirt, Madison said it was a gift from a friend, created by another Tumblr user. She told BuzzFeed her casual selfie of the T-shirt blew up so quickly overnight that people she’d never met started approaching her to talk about it. Honyey begins when ouw vawiant Powwen Jocks bwing the nyectaw to the hive. We knyow that you, as a bee, have wowked youw whowe wife to get to the point whewe you can wowk fow youw whowe wife. meme, joke, text, crazy, the entire bee movie, im not even joking this is actually the whole script of the movie. Wewcome to Honyex, a division of Honyesco and a pawt of the Hexagon Gwoup. “One year, my friend Jenna signed my yearbook with as much of the script as she could fit another, Cassady, received the Bee Movie on DVD as a gift and forced all of her friends to suffer through it on principle.” Bee: (Flash forward in time and a Bee is about to jump into a pool full of honey) Bee: (The bee gets stuck in the honey and we get a short montage of Bees leaving work) (We see the Pollen Jocks flying but one of them gets a call on his antenna) Lou Lu Duva: Mission abort. Shop high-quality unique Entire Bee Movie Script T-Shirts designed and sold by independent artists. She and her friends adopted it as an inside joke years ago, before it became mainstream on Tumblr : Oh no, I accidentally read the entire bee movie script in my backyard while I drown in rain, cold temperatures, and severe wind Man, I hate it when this hap. Madison explained to BuzzFeed that her commitment to the Bee Movie bit started way before she got the shirt. The DeSanctimonious backed candidate came in a DISTANT third. “He had my Complete and Total Endorsement. “Congratulations to a ‘star’ in Kentucky, Danial Cameron, who easily won the Republican Nomination for Governor.” Trump wrote, misspelling the nominee’s first name. Trump, in a social media post Wednesday about Cameron’s victory, cited the finish by Craft, who had been an ambassador during his administration and was endorsed by a leading Trump rival, Florida Gov. His victory Tuesday will play into Trump’s efforts to solidify his status as the leader of the Republican Party heading into the 2024 presidential primary. ![]() Beshear says that his actions saved lives and that he leaned heavily on guidance from Trump’s coronavirus task force.Ī former aide to Republican Senate leader Mitch McConnell, Cameron has risen through the political ranks to become one of the most prominent Black Republicans in the country. Cameron led the successful challenge that essentially halted the governor’s COVID-era restrictions, which Cameron said amounted to executive overreach. Beshear narrowly defeated Bevin in a race that revolved around Bevin’s combative personality.Ĭameron succeeded Beshear in the attorney general’s office, and the Republican turned the tables on Beshear, mounting numerous legal challenges against state and national Democratic policies that endeared him to conservatives. During his single term as attorney general, Beshear challenged a series of executive actions by Republican Gov. In 2019, Beshear used the attorney general’s office as a springboard to the governorship. ![]() The Beshear-Cameron matchup conjures parallels from the state’s last governor’s race but with a reversal of roles for the governor. ![]() “Let me ask you: Is seeing people talk down our state and our economy, insult our people and stoke divisions going to help that next company choose Kentucky? Of course not.” “Right now somewhere in America, there is a CEO deciding where to move their business and they’re considering Kentucky,” Beshear told supporters. And he blasted the tone of the GOP gubernatorial primary after taking hits for months from the Republican candidates. Beshear, a popular Democratic governor, will face a tough reelection bid in a Republican-dominated state after a first term marked by a series of tragedies - the COVID-19 pandemic, natural disasters and a mass shooting that killed one of his closest friends.īeshear on Tuesday cited his stewardship of Kentucky’s economy - pointing to record economic development successes - in setting the stage for his fall campaign. The race now shifts to the general election, which will be one of November’s most closely watched contests and could provide clues heading into the 2024 presidential race. “Know that in this country and in Kentucky, all that matters are your values.” “To anyone who looks like me, know that you can achieve anything,” Cameron told supporters. ![]() Beshear easily dispatched two under-the-radar Democratic challengers in his own primary.Ĭameron, the state’s first Black attorney general, said in a victory speech that his campaign aims to “embody the promise of America, that if you work hard and if you stand on principle, anything is possible.” Ambassador Kelly Craft, who finished third. (AP) - Daniel Cameron won the Republican primary for Kentucky governor, becoming the first major-party Black nominee for governor in the state’s history and setting up a November showdown with Democratic incumbent Andy Beshear.Ĭameron, the state’s attorney general who was endorsed by former President Donald Trump, claimed a convincing victory Tuesday in a 12-candidate field that included state Agriculture Commissioner Ryan Quarles, who finished second, and former U.N. ![]() Maintain a presentable appearance which includes being properly dressed according to company standards, neat grooming and good hygiene.Keep vehicle clean and orderly with daily cleaning after each route operated, as well as check for lost items.Operate adaptive transportation lift to board and discharge challenged passengers using safe and responsible procedures. ![]() Operate the vehicle and stop to allow passengers to board and disembark using safe and responsible procedures. Inspect each vehicle before, during and after each trip using correct procedures and complete all necessary forms and reports.Operate the two-way communication equipment correctly and according to company policy.Properly care for the assigned vehicle and its parts as prescribed by the company to ensure safety, minimize wear and extend its useful life.Maintain good work habits through timeliness and low absenteeism for daily assignments and extra trips. Maintain, read, and understand route sheets including time changes and notify the supervisor immediately of any changes.Safely operate a vehicle on an assigned route in transporting passengers to and from designated locations, as well as related activities, in a safe, timely manner.The School Bus Driver operates a school bus and transports students safely by Company policy and local, county, state, and federal laws. Be polished, well-groomed, and maintained in personal appearance, as well as be well-mannered.Good verbal and written communication skills.Must be able to pass a criminal background check, drug test, DOT Physical, and dexterity test.Valid driver’s license for at least 5 years.Adhere to the attendance policy as dependability, punctuality, and perfect attendance is essential for your daily bus driver.Complete the school bus driver training program as prescribed by state and local policies.Attend all in-service safety meetings required by the state and local school district.Maintain routes and schedules planned by the school system personnel.Deliver bus to fleet maintenance facility as directed by a pre-arranged monthly schedule for service and inspection.Maintain orderly conduct of pupils and manage them in a positive and effective way.Provide maximum safety for passengers while on the bus and during loading and unloading.Complete legible and accurate required reports in the prescribed manner on a timely basis.Communicate effectively and professionally with school staff and the public.Conduct emergency evacuation drills as required by the local school district.Keep the assigned bus clean and sanitary at all times, mopping, wiping all seats and roof, sweeping, and washing bus.Assists students in the loading and unloading process.Exercise maximum regard for the safety and welfare of all transported students while operating a school bus.Perform light maintenance such as checking and adding fluids and fuel.Conduct thorough pre-trip and post-trip inspections of the vehicle and its special equipment and submit required documentation to the administration. He is an active member and leader in several societies including the American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, The American Society of Retina Specialists, The Macula Society, The Retina Society, The Society of Heed Fellows, The Vail Vitrectomy Society, The Pennsylvania Academy of Ophthalmology and The Greater Philadelphia Ophthalmic Society (past President). Ho is Professor of Ophthalmology at Sidney Kimmel Medical College of Thomas Jefferson University, Board Certified in Ophthalmology and a Fellow of the American College of Surgeons and the American Society of Retina Specialists. He is former Co-Director of the Wills Retina Fellowship, widely recognized as the premier retina training program in the country.ĭr. Currently, he is Attending Surgeon at Wills Eye Hospital and Director of Retina Research and Co-Director of the Retina Service at Wills Eye Hospital. He completed a Fellowship in Vitreoretinal Diseases at Manhattan Eye, Ear and Throat Hospital where he was awarded a Heed Ophthalmic Fellowship. He graduated from Columbia University College of Physicians and Surgeons and was elected Co-Chief Resident during his ophthalmology residency at Wills Eye Hospital. He is a Phi Beta Kappa graduate of Cornell University College of Arts and Sciences, receiving the highest distinction in all subjects. Ho is an internationally recognized retina specialist specializing in state of art patient care and is a leader in the development of new medical and surgical treatments including gene and cell therapies for retinal diseases such as age related macular degeneration, other macular diseases, diabetic retinopathy and surgical retinal diseases. ![]() Fellowship: Manhattan Eye, Ear, and Throat Hospitalĭr. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |