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Nathan Adrian
Phelps back in international comp, advances in 100
seconds ranking him third overall in the preliminaries and second quickest among the 12 Americans. His U.S. teammate Nathan Adrian set a meet record 48.05 to lead qualifying, edging Australia's two-time world champion James Magnussen in the
Wednesday's Sports in Brief
100-meter freestyle and finished next-to-last in a star-studded field at the U.S. national championships. Nathan Adrian led all the way to win in 48.31 seconds Wednesday night, claiming his sixth title in seven years. Ryan Lochte was
Your Top Plays for Today
Phelps finishes a distant seventh in the final of the 100-meter freestyle at the U.S. National Championships, with Nathan Adrian winning. http://m.apnews.com/ap/db-268750/contentdetail.htm?contentguid=dgf9NmwJ --- VERDICT
Michael Phelps finishes next-to-last in 100-meter freestyle at U.S. nationals
Nathan Adrian led all the way to win the 100-meter freestyle at the U.S. national championships, with Michael Phelps finishing next-to
Adrian wins 100 free at US Nationals; Phelps 7th
IRVINE, Calif. (AP) Nathan Adrian led all the way to win the 100-meter freestyle at the U.S. national championships, with Michael Phelps finishing next-to
BC-AP Sports Preview Digest
IRVINE, Calif. - Olympic gold medalist Missy Franklin is joined by Michael Phelps, Ryan Lochte, Katie Ledecky, Nathan Adrian and Natalie Coughlin at the five-day U.S. nationals starting Wednesday. - NEW YORK - David Price, the 2012 AL
Kylie Palmer leads victorious Aussies at LA meet
and Palmer teamed with Mikkayla Sheridan and Carla Buchanan to win the 800 freestyle relay in 8:04.40. Olympian Nathan Adrian was the fastest qualifier for the 50 freestyle in 21.90 seconds. But he elected not to swim the evening final
Missy Franklin wins 2 events at LA Invitational
butterfly in 2:12.67, and took the 400 individual medley in 4:41.22. In the men's 100 free, Olympic champion Nathan Adrian won in 48.32. Cristian Quintero was second in 49.35 and Alexander Sukhorukov took third in 49.57. Olympian
Phelps tries sprinting in 2nd event of comeback
ll be pretty happy,'' he said. Also competing in the 50 free are former Olympic gold medalist Anthony Ervin, Nathan Adrian , and Michael Andrew, a 15-year-old from Lawrence, Kan., who has already broken over 30 national age-group
Michael Phelps shares 100 butterfly title
100-meter butterfly title Friday night in the Santa Clara Grand Prix after finishing second behind Olympic champion Nathan Adrian in the 100 freestyle. Phelps, the 18-time Olympic champion swimming in his third meet since coming out from retirement


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- 42 Comments
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am I the only one who has the video overlapping the full size images?
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i am looking forward to this, ill get it for psp, since i dont own a wii......
Brad, you're a busy muthafucker today!!! = D
Looks pretty good, but it doesn't make up for Nintendo not releasing Fatal Frame 4 outside of Japan. Bastards.
Looks awesome. It's like you said, very ambitious but if it pulls it off and finds out what scares you and what doesn't and then focuses on the things that do then this could be a damn crazy game.
dude that's messed up! and I only got a wii for mario and fire emblem! whoo-hoo!
I've followed this game for quite a while now.I am veryexcited for this "re imagining" of Silent Hill. The IGN demo was totally balls.
The morality decisions are definately the most interesting aspect of this game. Changing the appearance of the enemies? Dramatically altering the story? More games should be like that
why does this game look worse than SH 3 and 4?
Because it doesn't, considering the lighting effects with the flashlight, the no-loading/continuous world after initial load, the real-time transformation to nightmare world complete with glaciers and other effects, the open and accessible environments, the more agile character who can bash himself through doors and climb up shit rather than be 100% restricted by the environment, etc.
I do think their modeling/texturing work isn't as good as that of their Japanese co-workers though, alas what can you do. Also held back by PSP.
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I think this looks a lot better than Dead Space Extraction, I might even finally pick up a Silent Hill game! I'm really interested to see how stalking you pays off later in the game.
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Am I the only one who cares how it is for PS2? I don't have a Wii...
This game looks amazing and if it works as well as it sounds like it's going to... well then I'll be putting this up there as my Game of the Year. (I mean, at least this far. It's just really hopeful at this point, I guess?) That trailer itself is decidedly creepy.
On that note, the animations in this game are amazing. Both the facial animations and just the character movements all look really impressive. Maybe I just played a lot of Fallout 3 recently, but they're some of the best animations I've seen as of recent. And the monster's still have that classic insane movements that make them so damned terrifying. I can't wait for this game.
(Also this game isn't held back by the PSP. This is the main SKU. The PSP and PS2 (if they're still making that version?) will be the ones that get shafted if need be.)
Fatal Frame is a great series and Nintendo deciding not to release it outside Japan is a dick move.
" @Curufinwe: Nintendo doesn't see the profit in releasing a poorly reviewed, broken game. "
Some import hands-on articles stated the controls are bad but they're just of an acquired taste from what I gather, not game breaking. It's not an FPS where you need precision control, the controls hinder you similarly to the first RE games' tank style controls, to show your character isn't the most agile in the world that can just sidestep all the monstrosities. In Fatal Frame IV they did it by gimping the camera controls. Instead of aiming with the IR like in an FPS, you use tilts to move the camera view. Adventure fans would probably love the game anyway.
Okay there was a game-breaking bug under very specific conditions and possibly other issues. They could have fixed it for the US/PAL releases. Tomb Raider shipped with a game-breaking bug as well, there was a little noise about it and nothing more, no recalls or anything. In this case they already know the issue and can fix it so there's no such danger. A bug is not an excuse.
But Silent Hill: Shattered Memories is completely unrelated and looks like an awesome game. Let's hope it is :)
But yes. Let's all just watch Silent Hill which will be awesome~
You can just as easily blame Namco (it is Namco, right? I could have that wrong) for not publishing it locally. The fact is NOBODY wants to publish that thing here.
Really impressive.
Looking forward to it.
Seems like something I would not play in the dark...
Ho-ly shit.
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Looks really cool, especially if they can integrate the data in interesting ways.
Not sure I'm a fan of the trailer specifically, I think it needed much more cohesion, but the lighting works, and some of the other elements look really cool.
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I wonder if you can tell what kind of person someone is by looking at the monsters they face in this
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The game looks interesting.
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I like how they tried to hide in the closet but it didn't work. That's great because gamers have come to expect all old school game mechanics--such as nobody can see you while in a shadow or something--to work every time. It would be legitimately scary when it failed to work, and that's exactly what this game does.
"After all, how many survival horror games can you think of with no guns in them?"
Fatal Frame, Clocktower, Haunting Gorund and to a certain extent Siren.
" "After all, how many survival horror games can you think of with no guns in them?"Fatal Frame, Clocktower, Haunting Gorund and to a certain extent Siren. "
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This is now my most anticipated game for the Wii.
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Why the hell couldn't they put all this cool stuff in homecoming??? That would have been a true next gen silent hill......
I wonder if the flashlight will be able to run out of battery. That would be terrifying.
Wow, color me impressed. It looks great for a Wii game and I like that there are in-game storytelling elements.
Me and my girlfriend are very excited about this =) Assuming the PS2 release is confirmed? =S
I have to agree about the closet. Even in the trailer it made me jump a bit and I was totally expecting it.
The game sounds intense. Not having guns will make it just that much scarier.
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I want a wii for this - but not trying to troll or get hopes up
After reading that hands-on impression and watching that trailer, this game is officially on my buy list.
Ugh I've always wanted a SH1 remake and now they do it but I don't have a Wii and don't really want one and my PS2 died about a year and half ago and I replaced it with the PS3 with no BC. Really why Wii/PS2/PSP? It'd sell just as well if they just built the PS2 version with slightly next gen graphics and put it on 360/PS3. Sure the graphics and gameplay won't be great but who cares SH was never about graphics or gameplay to begin with.
Anybody notice the number of the house? "1206" 206 is the time Alex died in silent hill home coming!!!
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looks spooky

subset: commoncrawl


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"Well, bless his heart."
So the final episode of Project Runway: All Stars has arrived, and as expected, eccentric sprite Mondo has taken the crown.
Last week we asked who you thought should win, and who you thought would win. It was pretty much even, with 67% thinking Mondo would win:
Almost as many of you (62%) thought Mondo should win:
In both cases, Austin was the runner-up, while Michael finished third, which is the same order they finished in the finale, so the writing was on the wall going in to the last episode.
Below you can see Mondo's crowning moment, and he talks about what the future holds for the winner of the first Project Runway: All Stars.
Meanwhile, Austin was noticeably, and deliciously pissed when Mondo won, but he seems to be to be taking it all in stride.
Michael was a distant third, but gave the best closing interview.
On the following pages you can see each designer's complete collection. What are your final thoughts on the season? Did Mondo deserve it? What would you change if there's another All-Stars down the road?


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Wiki Headlines
23rd Oct: It's time for the second TV Tropes Halloween Avatar Contest, theme: cute monsters! Details and voting here.
main index
"...The point is I totally realized that, you know? Fate. There is fate. But it only takes you so far, because once you're there, it's up to you to make it happen.."Preston has been in love with Amanda since the first day of high school. When Amanda is dumped by her football player boyfriend Mike shortly before graduation, Preston decides to attend a big graduation party everyone's going to and declare his feelings for Amanda. Despite her reservations about Preston's plan, his best friend Denise comes to the party with him. Also in attendance at the party are Mike, and William, who has been bullied by Mike all through high school and is at the party to take final revenge on him. Denise's childhood friend Kenny is also there, hoping to lose his virginity before he goes to college.Basically a Nineties version of the classic teen comedies of The Eighties. Or a successor to American Graffiti and Dazed and Confused minus the period setting.
— Angel Stripper (Jenna Elfman).
Can't Hardly Wait provides examples of the following:


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My friend over in Sweden (@marianhackett) made me this AWESOME map of how to make my way around when I arrive in Sweden, as they'll be out of town for a few days with their partner… So I'll need to fend for myself. This won't be a problem with this trusty map to guide me along my epic journey in Viking Land Town.
I'm not sure why it's called Viking Land Town… perhaps I'm being fooled into catching a train to Denmark?


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DEReC › Publications & Documents › All
English, , 408kb
The Independent Evaluation Department of the Asian Development Bank has been tracking and reporting on the implementation of its recommendations since 1982. The objective is to increase the use of evalution findings in decision making.
English, , 679kb
This evaluation assesses the European Commission's cooperation with El Salvador over the period 1998-2008. It aims at providing an overall independent assessment of the entire EC cooperation strategy and support in the country and to provide key lessons.
English, PDF, 723kb
This is the 2009 annual report from the "Camões – Instituto da Cooperação e da Língua" (CICL)
English, , 1,782kb
The Country Program Evaluation (CPE) assessed the overall performance and results of CIDA''s interventions in Mozambique from 2004-2005 to 2008-2009, a five-year period corresponding to CIDA's latest Country Development Programming Framework (CDPF) for Mozambique.
English, , 485kb
Sida's current regional strategy for cooperation with South East Asia expires at the end of 2009. Sida required an evaluation of the current strategy as an input to the development of a new strategy for the period 2010–2014.
French, , 776kb
Edité chaque année, le bilan des évaluations présente à la fois une mise à jour des outils, activités et orientations du Pôle de l'évaluation et un bref résumé des principaux constats et enseignements des principales évaluations stratégiques réalisées au cours de l'année écoulée.
English, , 1,640kb
This evaluation of DFID's country programme in Yemen is one of a series of regular Country Programme Evaluations (CPEs) commissioned by DFID's Evaluation Department.
English, , 552kb
This report presents the findings of a Professional Peer Review of the evaluation function at the Federal Public Service of Foreign Affairs, Foreign Trade and Development Cooperation, Belgium.
Finnish, , 4,762kb
The purpose of this evaluation was to assess all aspects of the Finnish development cooperation in Ethiopia: the development needs, policies and political, economic and social situation.
English, , 907kb
The evaluation of Support to Gender Equality in Swedish Development Cooperation was designed to assess progress in the implementation of Sida's support to gender equality, and to provide input to Sida for its recommendations to the Swedish government's Gender Equality Policy.


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Last night, insurgents from the al Qaeda-affiliated Islamic State of Iraq and Syria (ISIS) seized Mosul, the largest and most important city in northern Iraq. While Ramadi and Fallujah, Sunni-dominated towns in al Anbar have long been peripheral to Iraq, Mosul is not: Saddam Hussein recruited much of his officer corps from the town. Divided between Kurds and Arabs, Mosul has been more an ethnic flashpoint in Iraq than even Kirkuk, a city two hours away which receives the lion's share of Western attention. And it has long been tense. I visited Mosul earlier this year. As I approached the city, soldiers at Iraqi checkpoints repeatedly warned me to stay away, telling me it was not safe for a Westerner. Already a tinderbox, the Syrian refugees at almost every intersection begging simply added fuel to the fire.
The Washington Post reported on a press conference given by Osama Nujaifi, brother to Mosul Governor Atheel Nujaifi, and the speaker of Iraq's parliament, easily the most important Sunni Arab politician in Iraq:
When the battle got tough in the city of Mosul, the troops dropped their weapons and abandoned their posts, making it an easy prey for the terrorists," he told a televised news conference in Baghdad. All key facilities are now controlled by the insurgents, including the airport and the prisons, said Nujaifi, who is from Mosul. "Everything is fallen. It's a crisis," he said, appealing for international and government help to retake the city. "Having these terrorist groups control a city in the heart of Iraq threatens not only Iraq but the entire region.
Mosul's fall to al Qaeda-affiliated insurgents should be a wake-up call both to the West and to the Arab world. A few lessons for the White House to learn:
- It's time to dispense with the nonsense that insurgents in Iraq exist because they dislike Prime Minister Nouri al Maliki. Al Qaeda is not on the warpath because the Iraqi army raided a protest camp in Ramadi. We shouldn't be fooled. Al Qaeda is savvy enough to feign grievance to get the West to turn on itself, but at its core it is about ideology. Despite what the State Department or Secretary of Defense Chuck Hagel may believe, not all terrorism is rooted in poverty or grievance which can be resolved by diplomacy, concessions, or incentives. Sometimes, ideology simply has to be defeated. A decade ago, Gen. David Petraeus appeased insurgents in Mosul and the result was disastrous; we shouldn't urge anyone to make the same mistake again.
- Inaction on Syria has had a cost. Prime Minister Maliki has been warning for years that the radicalization inside Syria could destabilize Iraq and he has been right. That doesn't mean the United States should arm Syrian rebels—the time for that would have been three years ago before the influx of al Qaeda. Sometimes leadership means doing the dirty work directly, and not simply leading from behind. Boots on the ground? No. But targeting high value regime and al Qaeda targets. Maybe it's time to consider that. Sanctioning Turkey if it allows its borders to be crossed with impunity for the price of a $40 bribe by radical jihadis? Certainly.
- President Obama entered office believing Iraq to be original sin. He ordered a troop withdrawal on the simple premise: If Iraq failed, he could blame Bush. And if it succeeded, he could brag about how his withdrawal enabled it. But that premature withdrawal would put security at risk was fairly obvious.
So what should the West do?
- Al Qaeda loves a vacuum, but the United States should not give it one. It's time to partner with Prime Minister Nouri al Maliki to provide him what he needs to roll back al Qaeda, no if's, and's, or but's. Iraqi Kurdistan will likely need help caring for persons displaced from Mosul, and the United States should provide that as well.
- Obama cares about his legacy. So does Secretary of State John Kerry. Neither may like it, but their legacy is more likely to be Iraq than an Iran deal or Arab-Israeli peace. Obama flubbed Syria at great expense to regional security. Iraq is now at the tipping point. Either the United States re-finds its leadership and recognizes that al Qaeda isn't on the run, or we condemn Iraq to be a replay of Syria. Let's hope Obama has the vision to realize that leadership matters.
Follow AEIdeas on Twitter at @AEIdeas.


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Correcting Four Misconceptions about my 2004 Article in JMB
In August of 2004 I received an email inquiry from plant biologist Art Hunt. He had written a draft for a blog piece aimed at reviewing a research article of mine that had just appeared in the Journal of Molecular Biology [1], and he wanted to know whether he had understood my work correctly. He clearly aimed to refute claims that were beginning to surface that my paper supported intelligent design, but he also wanted to make sure he wasn't misconstruing my work in the process. He didn't expect me to oblige—"I will understand if you decline; in fact, I would probably do the same…"—but I did.
His summary of the experiments I reported in the JMB paper was largely correct, though his understanding of my analysis was off in several respects. As a result, many of the conclusions he drew were, in my judgment, not well grounded. I gave him feedback to this effect, but since it was a blog entry rather than a peer-reviewed scientific publication, I wasn't particularly concerned to see the final version, or to respond to it.
Two things have happened since then. One is that my 2004 JMB paper has, as Hunt predicted, been cited in support of intelligent design in several prominent places, and the other is that Hunt's finished blog piece [2] has become the favored argument against using my paper in support of ID.
Here I summarize what appear to be the four most common objections to using my 2004 paper in support of ID, three of which trace back to Hunt's blog entry, the fourth perhaps originating with Steve Matheson, who joined Art Hunt last summer for critical dialog with Steve Meyer in front of an audience at Biola University. [3]
First, let's be clear what the question is. We know that living cells depend on the functions of thousands of proteins, and that these proteins have a great variety of distinct structural forms. These distinct forms are referred to as folds, and there are well over a thousand of them known today, with more being discovered all the time. The big question is: Does the Darwinian mechanism explain the origin of these folds?
One way to approach this question is to reframe it slightly by viewing the Darwinian mechanism as a simple search algorithm. If Darwin's theory is correct, then natural populations find solutions to difficult problems having to do with survival and reproduction by conducting successful searches. Of course we use the words search and find here figuratively, because nothing is intentionally looking for solutions. Rather, the solutions are thought to be the inevitable consequence of the Darwinian mechanism in operation.
If we view Darwinism in this way—as a natural search mechanism—we can restate the big question as follows: Are new protein folds discoverable by Darwinian searches? Recasting the question in this way turns out to be helpful in that it moves us from a subjective form of explanation to an objective one, where an affirmative answer needs to be backed up by a convincing probabilistic analysis.
With that background, let's look at the four objections.
Objection 1: Axe's paper doesn't claim to support intelligent design or challenge Darwinism, so it's a mistake to use it for those purposes.
Hunt seems to be reasoning this way when he repeatedly criticizes ID proponents for using my work in a misguided way, as in: "it is not appropriate to use the numbers Axe obtains to make inferences about the evolution of proteins and enzymes", and "the claims of ID proponents vis-à-vis Axe 2004 are exaggerated and wrong." [2] The idea seems to be that since I didn't make an explicit argument for ID in the paper, any such use of my work is misguided.
To Hunt's credit, he also reasons from the science, offering his opinion as to why my work doesn't support ID or undermine Darwinism (see below). Barbara Forrest and Paul Gross, on the other hand, applied Objection 1 to my earlier work without making any attempt to understand the science. Rather, their book Creationism's Trojan Horse [4] tries to make its anti-ID case with statements like, "Axe's reference list does not include any known ID proponents", and "The key words accompanying the abstract, which Axe himself supplied, do not include 'intelligent design' or anything remotely suggestive of it." I guess there's no need to use a scientific approach if you're committed to the belief that there's no connection between ID and science.
Two points need to be made in response to Objection 1. First, my paper does actually claim to be directly relevant to the origin of protein folds. The first three sentences of the abstract read [1]:
Proteins employ a wide variety of folds to perform their biological functions. How are these folds first acquired? An important step toward answering this is to obtain an estimate of the overall prevalence of sequences adopting functional folds.
As becomes clear from the rest of the abstract, the paper takes this first step by using experimental data to calculate a value for the prevalence of functional sequences. Then, under the heading Implications, the final two paragraphs of the discussion focus on what this value means for the evolution of new protein folds, concluding with this critique of the evolutionary model: "generating new folds from parts of old ones may be much less feasible than has been supposed." [1] Keep in mind that three experts in enzyme function and evolution approved of the paper in order for it to be published, so my opinion that the work is relevant to protein evolution is shared by others who know the subject very well.
Not only does the paper claim to have evolutionary implications, but it should be quite obvious that it has evolutionary implications. This, my second point in response to Objection 1, becomes clear when we frame the main question as suggested above: Are new protein folds discoverable by Darwinian searches? The first thing we need to know in order to answer this question is the size of what needs to be found relative to the whole search space, which is precisely what my JMB paper of 2004 refers to as the prevalence of functional sequences. As I've argued in detail elsewhere [5], this isn't the only thing we need to know in order to decide whether Darwin's theory is up to the task, but it certainly is a key thing to know.
And of course, if Darwin's theory turns out not to be up to the task, it would be reasonable to make use of this in making a case for ID.
Objection 2: Although Axe makes a case that functional sequences are rare in sequence space, this has no bearing on whether new protein folds can evolve. The evolution of new protein folds simply requires that functional sequences not be isolated in sequence space, which has nothing to do with how rare functional sequences are.
Hunt stated that my results "reveal little… about the 'isolation' or evolution of TEM-1 penicillinase (or any other enzyme, for that matter)." [2] Steve Matheson put the same objection this way [6]:
in order to challenge evolutionary explanation, one must demonstrate that proteins are isolated in sequence space, such that there is no stepwise trajectory that can lead from one protein to another. Isolation and rarity are not the same thing. But all Meyer claims (and all Doug Axe has tried to show) is that functional proteins are rare in sequence space.
Dennis Venema has also picked this objection up, stating it this way [7]:
The most obvious issue is that the rarity or commonality of function in protein sequence space is irrelevant to the discussion [of protein origins]. What counts is whether functional sequences in protein space are isolated from each other in a way that random mutation and natural selection cannot bridge.
It's kind of like insisting that the height from which a person has an accidental fall has nothing to do with their chance of surviving because it's the speed of impact that really matters. One could equally insist that the speed of impact is irrelevant—it's the force of rapid deceleration that really matters. In truth they all matter, and they do so for closely related reasons. The confusion comes from overlooking the causal links between them.
Yes, the Darwinian mechanism requires that the different protein folds and functions not be isolated, and yes the rarity of functional sequences has a great deal to do with whether they are isolated. I've already rebutted Objection 2 in response to Steve Matheson [3], but let's look at it again.
The above quote from Venema appears in a section titled: "No biological information by natural means?" Now, I claim that this section title is linguistically isolated. By that I do not mean that it cannot be altered and remain readable, or even that it cannot be altered and remain meaningful. What I mean is that there is virtually no freedom to generate new meaningful phrases from this one if we restrict ourselves to single-character changes and we require a meaningful phrase at every step. In other words, that title cannot undergo what is referred to as open-ended evolution.
We can get to "To biological information by natural means?", and that's about it. "To biological information by natural meats?" retains word-level meaning, but it loses all coherence as a phrase. So we appear to be stuck on an isolated island with a population of two—and not much difference between the two at that.
Why do we get stuck so quickly? If we take something much smaller, like a single three-letter word, we seem to be able to keep the transitions going: red, rod, mod, mad, mat, cat, car, tar, bar, ban, bun, sun, sin, tin, ton, won, win, gin, gun, guy, buy, boy, toy, try, pry, pay, say, shy, why … Good question. Why do three-letter words behave so differently?
Perhaps the ease of transitioning among three-letter words explains the rationale behind Objection 2. By one way of estimating, I find that about 3–4% of the possible three-letter combinations are English words. [8] This makes three-letter words rare in the sense that they are well outnumbered by nonsense three-letter combinations, and yet they do not seem to be isolated. Objection 2 seems to be motivated by the thought that proteins may behave the same way. John Maynard Smith suggested as much. [9]
On the other hand, maybe we need a more precise definition of 'rare'. Since there are twenty five ways to change a given letter into some other letter, this means there are seventy five ways to 'mutate' any three-letter word with a single letter change. Consequently, even if most of these mutants are nonsense, a success rate of 3–4% means that two or three of them are expected (on average) to be English words, and this is boosted by the fact that certain patterns of vowels and consonants are more word-rich than others.
Returning to Venema's section title, there are about a thousand ways to make a single-letter change to it: 42 positions × 26 alternatives at each position = 1092 possible mutants (including spaces but not punctuation). So, we might expect to avoid isolation if meaningful phrases among all 42-character combinations are more prevalent than about 1 in 1000. Conversely, if meaningful phrases are much less common than this, isolation is expected. Perhaps this is the relevant understanding of 'rare'.
In fact it is. And as you've probably guessed, meaningful 42-character combinations are far more rare than 1 in 1000, which explains why the islands of meaning are always isolated—mere dots in an enormously vast ocean of nonsense. Billions of sensible things can be said in 42 characters, and almost all of them can be said in many different ways, but none of that amounts to anything compared to the quadrillion quadrillion quadrillion quadrillion possible character combinations of that length (27^42 = 10^60).
That is the sense in which functional protein sequences appear to be rare, and it has everything to do with their isolation.
Objection 3: Because Axe measured mutational sensitivity from a weakly functional starting sequence rather than the fully functional natural enzyme, the mutants he generated were inappropriately disadvantaged, and this is why he arrived at such a low value for the prevalence of functional sequences.
According to Hunt, I "molded a variant that would be exquisitely sensitive to mutation." [2] Venema expressed the same concern, that the starting sequence I used was "intentionally 'hamstrung' with multiple mutations to render it far less functional than its natural counterpart." [7]
Both Hunt and Venema seem to think the outcome would have been more favorable (i.e., functional sequences would have been more prevalent) had I used the highly proficient natural enzyme as a starting point rather than the handicapped version. Actually, as a demonstration will show, the opposite is true.
Returning to Venema's subtitle, suppose we want to estimate the proportion of 42-character strings that can replace it. One way to approach this is to generate a large collection of strings that are randomized at the first seven positions, and another randomized at the second run of seven positions, and so on, for a total of six collections.
Here are a few examples of 'mutant' strings from the first collection:
npfzbifogical information by natural means
tnagyllogical information by natural means
zkjubdbogical information by natural means
sodlwdjogical information by natural means
and here are a few from the second collection:
no biolfaryewrinformation by natural means
no biolupbmjmginformation by natural means
no biolurxacryinformation by natural means
no biolfjrqgatinformation by natural means
Assuming we have an unlimited pool of readers who can examine the mutant strings, how should we proceed? If we instruct the readers to accept only those sequences that match the original, rejecting all others, then we know what the result will be. Of ten billion possible variants in each collection (27^7 = 10^10), only one will match the original. If we raise this proportion to the power six (because there are six collections) we get the expected answer: Of all possible 42-character strings, only one in 10^60 match the original.
But suppose we use a less strict approach. Suppose we simply ask the readers whether they can discern a meaningful reading, and we count all cases where the discerned reading is correct. This will increase the number of accepted mutants dramatically. If, with a bit of squinting, most mutants with two typos can be interpreted correctly—mutants like these:
ng bhological information by natural means
no biolojijal information by natural means
no biological infosmntion by natural means
then each collection will have about fifteen thousand accepted mutants instead of only one. This makes the prevalence of functional sequences in each collection about one in a million, which is much higher than the previous value of one in ten billion.
But we want to know how prevalent acceptable sequences are among all possible sequences. Let's call this fraction P. The question is, how do we calculate P now that we are using this less strict approach to accepting mutants? In answering this question we will discover two major problems with Objection 3.
It's certainly true that we will arrive at a much higher value for P if we simply raise the prevalence found for the individual collections to the power six. That calculation gives us one in (10^6)^6 , which is one in 10^36. This is a tiny fraction, but it's a whole lot larger than the one we got using the strict approach (one in 10^60).
Here's the problem, though. In calculating this higher P value, we have effectively assumed that the typo rate we found to be tolerable in the individual collections (two typos per seven positions) remains tolerable when we apply it to the full 42-character string. However, when we try this by generating full-length strings with twelve typos (maintaining the 2-in-7 ratio), we get completely unreadable gibberish:
nohbimlogicaemicrxrmation synnaludalnmeans
no giolotida binuprmazion by nktumai me ns
go hiozfgicac infeemadion zyknatural weans
Evidently we have made a mistake, because mutants that ought to be readable according to our calculation clearly aren't readable. As you may have guessed, the mistake is that the 2-in-7 typo rate was tolerable only because it was restricted to a narrow section of seven positions. The fact that the remaining 35 positions were without error compensated in large measure for the errors in the mutated section.
The remedy is to use a different starting sequence. Specifically, we need the starting sequence to be of the same quality that we intend to require of mutant sequences in order for them to be accepted. Otherwise the mismatch in quality will skew our results.
The first problem with Objection 3, then, is that it fails to recognize the importance of applying the same quality standard to the starting sequence that will be applied to the mutants derived from it. Objection 3 focuses on the fact that I used a weakly functional starting sequence without recognizing that this was called for by the fact that weakly functional variants of that sequence were accepted as 'functional'.
But there's another problem with Objection 3, having to do with the choice of a quality standard. We now know that the same standard has to be applied consistently if our results are to be meaningful, but we are still free to set that standard at any level. So, what difference does the level make?
As we've seen, if we take perfection to be the standard (i.e., no typos are tolerated) then P has a value of one in 10^60. If we lower the standard by allowing, say, four mutations per string, then mutants like these are considered acceptable:
no biologycaa ioformation by natutal means
no biologicaljinfommation by natcrll means
no biolojjcal information by natiral myans
and if we further lower the standard to accept five mutations, we allow strings like these to pass:
no ziolrgicgl informationpby natural muans
no biilogicab infjrmation by naturalnmaans
no biologilah informazion by n turalimeans
The readability deteriorates quickly, and while we might disagree by one or two mutations as to where we think the line should be drawn, we can all see that it needs to be drawn well below twelve mutations. If we draw the line at four mutations, we find P to have a value of about one in 10^50, whereas if we draw it at five mutations, the P value increases about a thousand-fold, becoming one in 10^47.
Notice two things. First, both of these P values are far more favorable than one in 10^60, and second, lowering the standard always increases the P value. This makes perfect sense—it has to become easier to meet the standard as the standard is lowered.
Having understood this, we now see that Objection 3 has things inverted. In the work described in the 2004 JMB paper, I chose to apply the lowest reasonable standard of function knowing this would produce the highest reasonable value for P, which in turn provides the most optimistic assessment of the feasibility of evolving new protein folds. Had I used the wild-type level of function as the standard, the result would have been a much lower P value which would present an even greater challenge for Darwinism. In other words, contrary to Objection 3, the method I used was deliberately generous toward Darwinism.
Objection 4: Axe's experiment doesn't reflect how evolution really works. He mutated amino acids in groups of ten, whereas evolution sifts mutations one at a time. Consequently, Axe's results tell us nothing about whether protein folds can or cannot evolve.
Combining this with the previous objection, Steve Matheson coined the phrase "whopping mutations on crippled proteins." [6] We've now seen that 'crippled' proteins are precisely what we should be looking at if we want our results to be as favorable to Darwinism as they reasonably can be. So Matheson got that one wrong. How about the whopping mutations?
Venema expressed the same objection, but seems to equivocate on its significance. In his words [7]:
…Axe did not mutate his test protein with single point mutations, but rather by adding partially randomized groups of ten amino acids at a time, something that does not resemble natural processes. While these features of Axe's work are useful standardizations for estimating the relative rarity of function[al] protein folds in his specific experimental setup, they render his work irrelevant to the issue of evolutionary isolation of functional sequences.
But if the methods I used, including mutations in groups, were useful for estimating the rarity of functional sequences, and their rarity is relevant to their isolation (see Objection 2), then it's hard to see how my methods render the results irrelevant to the evolution of new protein folds.
The first word of my paper's title is estimating, which is quite different from simulating. I had absolutely no intention of simulating the evolution of a new protein fold. Instead I set out to estimate how rare the amino acid sequences are that produce a working version of a particular fold.
Ideally the mutations would have been even more whopping. Had it been technically feasible to shuffle the mutants across their entire lengths, to generate a massive library containing all possible variants, and to test the gargantuan number of variants needed to find several functional variants, this definitely would have been the way to go. So the 'whoppingness' of the mutations really has nothing to do with how relevant the results are to protein evolution. It's merely a feasibility issue.
The estimate I got from experiments performed on a more modest scale explains why that more modest scale had to be used. I estimated that one in 10^64 of the variants that would have been produced in the whoppingly ideal experiment (where all positions are mutated simultaneously) would have had low-level function. But the library of protein variants in this ideal experiment would have had to be about a hundred billion times more massive than the sun in order for one functional variant to exist out there—somewhere. Whopping indeed. But not very practical.
So in the end Matheson's complaint about "whopping mutations on crippled proteins" is doubly wrong.
And more could be said in critique of Art Hunt's blog piece, but enough is enough. Suffice it to say that after his first section, which as I said does a reasonable job of summarizing my experimental approach, things get very confused.
[1] doi:10.1016/j.jmb.2004.06.058
[2] Axe (2004) and the evolution of enzyme function
[3] Darwinian tree-huggers—You gotta love their devotion
[4] Creationism's trojan horse
[6] Bread and circus: Signature in the cell at Biola (Part II)
[8] I used the DictionaryLookup command in Mathematica, selecting all three-letter entries and then removing ones that begin with an upper-case letter.


text:
mailing list archives
Now that doesn't mean other operators can't put in a lightning talk
about the impact or 'event' this triggered in their own NOC environments
along with what they recommend operators do to reduce the spun cycles <G>
great idea!
as i was about to send to someone else with a thinner skin than you :)
and, fwiw, i liked the haiku!
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text:
CJ Wilcox became the newest member of the Los Angeles Clippers, selected with the 28th pick in the 2014 NBA draft. The 6'5″, 195-pound small forward was named to two All Pac-12 teams at University of Washigton. The 23-year-old played all four years in Seattle and gained notoriety for a 6-9 ¾ wingspan and shooting nearly 40 percent from behind the arc.Newly promoted president of basketball operations Doc Rivers entered the draft coveting frontcourt help behind Blake Griffin and DeAndre Jordan, a player to push Matt Barnes on the wing or someone to fill Darren Collison's role, as he'll likely get a bigger paycheck elsewhere. Curiously, he went with another 2-guard despite the presence of J.J. Redick, Jamal Crawford and their previous pick.
Clippers select CJ Wilcox. Little surprising since recently drafted Reggie Bullock. — Jeff Goodman (@GoodmanESPN) June 27, 2014
Wilcox averaged 18.3 points per game as a senior and made 43% of his catch and shoot jumpers on the season, according to Draft Express. Among the prospects the Clippers were monitoring this summer was Michigan center Mitch McGary, surprisingly taken seven spots ahead by Oklahoma City. Cleanthony Early, another top collegiate player out of Wichita State, was on the board. The Clippers' night is over–barring a trade–as their second round pick was originally dealt to New Orleans for Bobby Brown in January 2010, then sent to San Antonio that October for Curtis Jerrells.
Tags: CJ Wilcox Cleanthony Early Mitch McGary NBA Draft University Of Washington


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|29 Dec 2011
Win 7 64-bit
System performance "slow" warning in any game, but running just fine
I'm very tired of seeing this message booting me to desktop just to ask me if I want to change the color scheme because it perceives my computer is running slow. Load up Batman AC? 10 minutes in focus changes from said full-screen app to this completely unnecessary 'warning'. Battlefield 3? Same thing. Assassin's Creed? Same thing. Skyrim? Oh of COURSE same thing.... I dont need Windows to tell me that my resources are being used when I KNOW they are being used...
Am I really going to have to go into Properties and Compatibility mode for EVERY game I play? Why cant such a large money gobbling corporation be intelligent enough to know that when I click on the "Keep current settings and never show me this message again" means I NEVER WANT TO SEE THAT DAMN MESSAGE EVER AGAIN, FOR ANY GAME???
Sorry, its just ridiculous that I have clicked that button so many times yet it continues to show! It specifically says "Keep the current color scheme and don't show this message again" Yet even after clicking said button it still shows... Annoying!
oh and inb4getmoarRAM.
|My System Specs
|30 Dec 2011
Microsoft Windows 8.1 Professional
I got the same pop while on BF3, just ignore it. Oh and get more ram
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