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A randomly generated, totally novel enzyme rescues mutant bacteria

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Proteins are chains of amino acids, and each link in the chain can hold any one of the 20 amino acids that life relies on. If you were to pick each link at random, the number of possible proteins ends up reaching astronomical levels pretty fast.

So how does life ever end up evolving entirely new genes? One lab has been answering that question by making its own proteins from scratch.

Way back in 2016, the same lab figured out that new, random proteins can perform essential functions. And those new proteins were really new. They were generated by scientists who made amino acid sequences at random and then kept any that folded into the stable helical structures commonly found in proteins. These proteins were then screened to see if any could rescue E. coli that were missing a gene essential to survival.

Three proteins succeeded, which indicates that they compensated for the missing gene’s essential function. But they did not do so by acting as a catalyst (meaning they weren’t enzymes).

In a recent paper in Nature Chemical Biology, however, the lab is reporting that one newer protein has acted as a catalyst.

The E. coli used in these experiments lacked the ability to use the iron provided in their medium because of the deletion of a gene that normally provides this function. So the experiments were a test to see if a randomly generated protein would be able to catalyze reactions with iron. The three proteins that had passed this test in 2016, however, simply altered gene activity so that the iron became available through other pathways.

To generate the recent enzyme, the researchers took one of the proteins that already rescued the mutant E. coli and subjected it to random mutagenesis. This ultimately produced an iron-releasing enzyme. Just like the natural enzyme, this synthetic one has a chiral preference for its substrate, meaning that it can only work with one structural form of the molecule and not its mirror image.

But its similarities to the native enzyme end there. The amino acid sequence of this synthetic enzyme bears no relation to the bacterial enzyme it replaces. This made figuring out how it works very difficult. Usually this is done by comparing the protein in question to similar ones from other species: clearly not an option here. The researchers also tried to crystallize it, which would let them figure out its structure, but no deal.

So they started mutating amino acids one by one to see which mutations rendered the enzyme inactive. This told them that the original amino acid that had been replaced must be important. This method revealed five particular amino acids that comprise the likely active site. When software that predicts protein structures was given the protein’s amino acid sequence and told that these five had to be close together, it spit out one structure that seemed the most likely.

And just like the amino acid sequence, the structure looked so totally different from the native enzyme’s that the researchers think the enzyme must work through a completely new mechanism.

The scientists made this enzyme not using any kind of rational design or strategy; they were just tooling around with random amino acid sequences and having bacteria determine if they could do what they wanted. In a completely contrived case of convergent evolution, the researchers made a protein that does not share a sequence, structure, or even mechanism with the one evolution hit upon—yet it performs the same function. A thousand-fold slower than the natural one, but it might get better if given further time to evolve.

Nature Chemical Biology, 2018. DOI: 10.1038/NCHEMBIO.2550 (About DOIs).

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satadru
1 day ago
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Wow.
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acdha
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Washington, DC
jepler
1 day ago
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RealifeCharts

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RealifeCharts

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jepler
2 days ago
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also, just think how much earlier "friday night" ends at your current age than it did at 25...
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jhamill
2 days ago
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Accurate
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#5799: Flip & ajfirecracker 's Genesis Aladdin "Game End Glitch" in 00:02.65 (new)

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This aims to reach the final credits with the least amount of input needed. This can be achieved by bugging out the demo, and then simply waiting for the game to complete itself.

Game objectives

  • Emulator used: Bizhawk 2.2.1
  • Reaches final credits
  • Ends movie early

Comments

The demo which plays is not a proper video file, it's effectively its own TAS which plays a specific input in order to produce the demonstration. However, it doesn't update the movie according to the current Input configuration, which means if we change which button does what it results in the demos no longer producing the intended effect.

Application

What does happen, will be standard deaths on most stages, which would otherwise cause you to reset on your current level. The exception here is for the bonus stage "Apu in Agrabah", which upon failing results in it advances you to the next stage instead. You will then find that the next stage the game tries to demo, is not the intended "Agrabah Rooftop", but instead the stage after the previously selected one, IE level 04. This then happens every cycle, such that next time it tries to play the demo input into level 05, then 06, all...
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jepler
2 days ago
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funny glitch
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Top Bug Hunters Make 2.7 Times More Money Than an Average Software Engineer

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An anonymous reader shares a report: A survey of 1,700 bug bounty hunters registered on the HackerOne platform reveals that top white-hat hackers make on average 2.7 times more money than the average salary of a software engineer in the same country. The reported numbers are different for each country and may depend on a bug bunter's ability to find bugs, but the survey's results highlight the rising popularity of bug hunting as a sustainable profession, especially in less developed countries, where it can help talented programmers live a financially care-free life. According to HackerOne's report, it pays to be a vulnerability researcher in India, where top bug hunters can make 16 times more compared to the average salary of a software engineer. Other countries where bug hunting can assure someone a comfortable living are Argentina (x15.6), Egypt (x8.1), Hong Kong (x7.6), the Philippines (x5.4), and Latvia (x5.2).
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jepler
2 days ago
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how much more do "top" software engineers make than average software engineers? It's a dumb comparison.
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It’s a golden age for animated film. A new Oscar rule could end it.

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The Academy just tilted the playing field in favor of The Emoji Movie — and against indie animation.

Take a look at the highest-grossing animated films of any given year and you’re guaranteed to find big-budget CGI features like Coco, The Boss Baby, and Despicable Me 3 at the top of the list. But even though the major Hollywood studios might rule the box office, each year the Oscar nominations go some ways toward balancing the scales by highlighting a diverse array of animation styles from around the world.

In 2017, for instance, alongside megahits like Zootopia and Moana, voters nominated My Life as a Zucchini, a candid and melancholic Swiss comedy set in an orphanage, which grossed all of $307,766 in the US; and The Red Turtle, a striking and silent high-concept love story directed by Michael Dudok de Wit, of the Netherlands, for Japan’s legendary Studio Ghibli.

Similarly, in 2016 the chart-topping Inside Out was joined by the wistful, nostalgic anime When Marnie Was There and Anomalisa, an artfully misanthropic oddity from indie auteur Charlie Kaufman (the writer behind Being John Malkovich and Adaptation).

Thanks to such nominations, past Oscar ceremonies have drawn attention to worthy films seen by few as well as the giant blockbusters. But that could be about to change.

Traditionally, the nominations in each Oscar category are decided on by members of the Academy’s specialist “branches”; screenplay nominations are selected by the writers branch, acting nominations by the actors branch, and so on. Then the entire membership — which can include everyone from actors to songwriters to makeup artists — votes for the eventual winner.

The sole exception is the Best Picture prize, for which the whole Academy gets to help pick the contenders. That makes sense, because all members have a stake in which films are put forth as the industry’s most exemplary. But this year, as the result of a controversial rule change, voting for the Best Animated Feature nominations will also be opened up to any member who wishes to participate.

This could mean a significant shift in focus for a category with a history of reaching outside the Hollywood studio system for its nominees, and one that plays a big part in raising the profile of foreign, independent, and stylistically diverse animation.

The Oscars have supported indie animation for 15 years

The Animated Feature Oscar was launched in 2002, as new studios like Pixar and DreamWorks emerged to challenge Disney’s virtual monopoly on mainstream US animation, allowing for a more competitive category. In the first decade after its inception, the category was ruled by big-budget Hollywood studio fare, with deserving winners like The Incredibles and Finding Nemo sitting alongside mainstream nominees that had received mediocre reviews, such as Shark Tale and Brother Bear.

Outside of a win for Hayao Miyazaki’s seminal anime Spirited Away in 2003, and a small handful foreign and independent nominees, the major studios had the category on lock. This also made for a lack of stylistic diversity, with Disney’s brand of hand-drawn realism and Pixar-esque CGI dominating the field.

As the number of animators in the Academy steadily grew — and with it, the number of animators from outside the major studio system — more diverse films began to creep into the category. Then the floodgates opened. Since 2010, 13 of 33 nominees have been either foreign, independent, or both. In that same period, only 15 nominees have been CGI. Other styles represented range from the exquisite watercolors of The Tale of the Princess Kaguya (2014) to the psychedelic stick figures of Boy and the World (2015) and the childlike puppet work of My Life as a Zucchini (2016).

This isn’t to say that indie animation has taken over the category completely. The final vote is opened up to the whole Academy, not just animators, and so the winner is almost invariably a CGI blockbuster, with Disney/Pixar alone winning nine of the past 10 awards.

“The nominations have done a tremendous job in raising the profile of indie animation,” says Dave Jesteadt, the president of GKIDS, America’s most prominent distributor of foreign and independent animation (with nine nominations to its name). “This is the idea we have been pushing for a decade now — that animated films do not need to look alike, or be similar broad family-targeting comedies.”

The Triplets of Belleville (2003), Persepolis (2007), The Illusionist (2010), The Wind Rises (2013), and others were all shown on significantly more screens following their nominations, broadening their potential audiences — and grosses — and underscoring the importance of Oscar nominations for this type of film. The Wind Rises, for example, a Miyazaki passion project recounting the life of a World War II aircraft designer, expanded from 21 screens to 496 in the week of the ceremony, and more than quadrupled the previous week’s box office take.

Such films also see big spikes in online searches for their names around the nominations and awards, further proof that a win isn’t always necessary to bring an indie film to the public’s attention.

An Oscar boost can also help indie animators fund future projects. Jesteadt points to GKIDS’ partner Cartoon Saloon, the studio behind past nominees The Secret of Kells (2009) and Song of the Sea (2014), as well as this year’s hopeful The Breadwinner, a stunning contemporary fable about a young girl in Taliban-controlled Afghanistan. Oscar nominations mean these studios “have been able to tell even more ambitious stories,” he says.

But now, the Academy’s new rule changes could spell trouble for Cartoon Saloon and other vibrant studios.

Revenge of The Lego Movie

The Red Turtle Sony Pictures Classics
A scene from The Red Turtle (2017).

The Academy announced that change in April. The reasoning behind the decision wasn’t specified, although it appears the Academy is frustrated precisely by the eclecticism that excites animation devotees. “The [nominating] committees have been under increasing criticism in recent years for shunning films like The Lego Movie and showing a marked preference for hand-drawn or stop-motion films over CG movies,” notes the Wrap.

Indeed, The Lego Movie, though a critical and commercial hit, failed to get a nomination in 2015; the selections that year were indie underdogs Song of the Sea and Princess Kaguya, alongside blockbusters like Disney’s Big Hero 6 and DreamWorks’ How to Train Your Dragon 2. Even Pixar, the category’s undisputed champion, has missed out on nods for films that dip slightly below its own high standards: Monsters University, The Good Dinosaur, and Finding Dory were all overlooked in years in which there were strong indie contenders.

If discrimination against big-budget crowd pleasers is a problem, the rule change certainly has the potential to solve it. Not only does the broader membership routinely hand the Animated Feature prize to Disney/Pixar but voters from outside of the specialist branch can be shockingly ignorant and aloof when it comes to animation.

In the Hollywood Reporter’s annual series of interviews with anonymous Oscar voters, the Animated Feature category is frequently met with either complete lack of interest or a vote for whatever the voters’ children liked (“The kids watched [Big Hero 6] three times — what does that tell you?”).

In 2015, one member of the sound branch of the Academy memorably expressed open disdain for “these two obscure freakin’ Chinese fuckin’ things that nobody ever freakin’ saw.” The reference, it turns out, was to the Japanese Princess Kaguya and the Irish Song of the Sea. Certainly, many Academy members take animation more seriously than that. But many may simply opt to nominate whichever CGI blockbuster managed to keep their kids quiet.

This year of all years, that would be a big mistake. Pixar’s Coco aside — the inevitable winner — it’s been an underwhelming year for Hollywood animation. The biggest hits include the lackluster third entries in the Cars and Despicable Me series, as well as the mystifying Boss Baby and The Emoji Movie, a genuinely loathsome feature-length smartphone commercial. And though they have their admirers, it’s hard to see The Lego Batman Movie, aimed squarely at Batfans, or Captain Underpants racking up many votes.

It would be criminal if any four of these movies were nominated alongside Coco at the expense of, say, Loving Vincent, a tender, oil-painted biopic about Vincent van Gogh; Mary and the Witch’s Flower, a fantasy adventure from alumni of Studio Ghibli; or The Breadwinner.

It may be too soon for despair. It’s possible that the non-specialist voters will take their responsibility seriously. “If opening the initial nomination process helps open more voters’ eyes to the breadth of what is truly possible in the animation medium, and makes them more excited to see these films in the future, then that would be a very positive outcome not just for us but for the entire industry,” says Jesteadt.

Looking to the nominations on Tuesday, we can only hope he’s right. The alternative would be a lamentable victory for mega budgets and commercialism, and a critical failure by the Academy to celebrate and promote great filmmaking, in all its forms.

Sam Summers is a researcher in animated film at the University of Sunderland. His latest book is Toy Story: How Pixar Reinvented the Animated Feature. Find him on Twitter at @SamSummers0.


The Big Idea is Vox’s home for smart discussion of the most important issues and ideas in politics, science, and culture — typically by outside contributors. If you have an idea for a piece, pitch us at thebigidea@vox.com.

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jepler
2 days ago
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This year, "voting for the Best Animated Feature nominations will also be opened up to any [Academy] member who wishes to participate." In case, like me, you had trouble finding amongst all the handwringing just what the problem is.
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Low Budget Bench Power Supply

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Low Budget Bench Power Supply

The idea behind this gadget surfaced while I was looking for something else and, although the front panel makes my skin crawl, it’s just an adjustable DC power supply:

Tattoo power supply - original front panel

Tattoo power supply – original front panel

This is apparently the cheapnified version of the item appearing in the eBay listing:

Tattoo Power Supply - eBay listing photo

Tattoo Power Supply – eBay listing photo

Let’s say it has the potential to be a DC power supply, although we might quibble about the “Precision” part.

As delivered, it’s a deathtrap. Of course, it’s not UL listed and I didn’t expect it to be.

How many lethal problems do you see?

Tattoo power supply - original AC wiring

Tattoo power supply – original AC wiring

For starters, it has a three-wire AC line cord with the green-and-yellow conductor chopped off flush with the outer insulation inside the heatshrink tubing just behind the transformer:

Tattoo power supply - ungrounded AC line

Tattoo power supply – ungrounded AC line

The blue wire is AC neutral, but it really shouldn’t be connected to the finger-reachable outer fuse terminal.

The brown wire is AC line, which goes directly to one power switch terminal. In the event of a hot wiring fault, an unfused conductor touching the case will test the GFI you should have on your bench wiring.

The AC line cord uses some mysterious copper-colored metallic substance that’s about as stiff as music wire:

Tattoo power supply - stiff AC wire

Tattoo power supply – stiff AC wire

The strands cannot be twisted together like ordinary copper wire, although they can be soldered. They may be copper-plated aluminum, because a magnet ignores them.

After soldering the strands together, they snap when bent:

Tattoo power supply - soldered broken AC wire

Tattoo power supply – soldered broken AC wire

Generous strain relief is not just a good idea, it’s mandatory.

After some Quality Shop Time, the ground wire now connects to the case through the transformer’s rear mounting screw, the neutral AC wire connects to the transformer, the hot AC wire goes to the tip of the line fuse, and the fuse cap terminal goes to the switch:

Tattoo power supply - AC line rewiring

Tattoo power supply – AC line rewiring

I relocated the white LED to the middle of the meter, where it looks a bit less weird:

Tattoo power supply - revised front panel

Tattoo power supply – revised front panel

I have no idea what “Porket indicate” might mean. Perhaps “Precision indicator”?

The right 1/4 inch jack, labeled “Foot”, normally goes to a foot switch you don’t need for a bench power supply, so I converted a length of drill rod into a dummy plug to short the jack contacts:

Tattoo power supply - dummy switch plug

Tattoo power supply – dummy switch plug

The tip comes from a bit of lathe and file work and the white cap comes from a bag of wire shelf hardware.

A genuine hologram sticker (!) on the back panel proclaims “1.5 – 15 VDC 2 A”, which seemed optimistic. Some fiddling with power resistors suggests tattoo liners (I learned a new word!) don’t draw much current:

  • 4 V @ 1 A
  • 8 V @ 800 mA
  • 10 V @ 600 mA

It can reach a bit over 18 V (pegging the meter) at lower current, so it’s Good Enough for small projects with un-fussy power requirements.

Caveat emptor, indeed.

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jepler
4 days ago
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"[T]he front panel makes my skin crawl"
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