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- June 16, 2012
- 3:32 p.m.
- Suggest removal
- Reply to this post
McLovin writes:
in response to YoYo:
So tired of boomers writing about how great the boomers are and considering how many of them are out there I guess we're going to have to endure this stuff for some time. Just please shut up and thank your great-great grandkids for those SSN checks.
Spot on. Boomers have nasty habit of over-hyping their contribution to society. Now they all think they are owed something.
Boomer "Dads had no past role models to copy." Really? Were our grandparents really that bad?
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Children Who Chase Lost Voices from Deep Below Cult Movie WorshipBy Meredith Woerner PO Edit2167L The full short for Blinky™ (the bloodthirsty pet robot) has been… We've been anticipating Ruairi Robinson's evil robot short Blinky™ for years! Wait no more, the full short's out for public consumption! Watch it now, and don't worry — your kids are perfectly safe! Plus a musical short with Doug Jones! Read… 3/20/11 6:30pm 3/20/11 6:30pmBehind Abe's Big Fish Eyes: io9 Talks To Hellboy II's Doug Jones
MoviesBy Meredith Woerner PO Edit125L Gooey bio-slime breasts and one vengeful GPS Snot fetishists, your day has come! This week in cult check out the very naked (and very slimy) trailer for Contagion, a glimpse at the Makoto Shinkai's new anime movie, and Tom Holland's (Fright Night, Thinner) latest project. Read… 11/14/10 9:16pm 11/14/10 9:16pmIndulge Your Taste For Cheese And Goo With "Bio-Slime"Snowy Apocalyptic Biker Cowboys Race Flying Cars

subset: commoncrawl


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Club Beat #53 Interview – Stefano Noferini: Toolroom, Techno & Talent
If Stefano Noferini is spinning anywhere in or around London, Planet Notion will be there. Never shy of expressing our appreciation of this maestro's mixing and production skills, we couldn't resist having a quick chat with him after his set in the Toolroom Knights arena at Global Gathering.
Read our interview below as Stefano Noferini talks Toolroom, techno and talent on his record label, as well as giving us a heads up on some hot new releases.
How did you get involved with Toolroom?
I have been working with Toolroom since three years ago when I released my first track. It was very good; it was number one on all the charts on beatport. It was Burujava. I will probably remix Burujava 2012 for the Toolroom Knights compilation.
What feedback have you received about your latest release on Toolroom, your Sometimes/You Make Me Feel EP?
Sometimes is a really underground style; it is one of the best tracks for me for 2012. You Make Me Feel is a little bit mainstream; it's good because it's like the old-school style house. And also the video is very nice. I've had a lot of very nice feedback about this, especially for the video. It's like the story of me. In a couple of clips I'm a bit drunk but who cares!
How has your sound changed throughout your career?
I have been a DJ and producer since 1994. I played and produced a lot of techno music at that time and in 1997 I collaborated with producers like Sven Väth and I played a lot of techno festivals like Energy in Switzerland in front of one million people; it was great! And then my career changed in 2001 when I changed the sound engineer, the sound of the collaborators and changed the manager. This was really important; this was a big change.
Now I come back into techno because I love the techno music sound and style, especially the techno of the 1990s; I love it, absolutely. The newest track I've made is totally different from them all; it's a really techno style. It'll be released probably at the end of this year.
Where do your labels fit in with this?
I have two labels; one is a little bit mainstream, but Deeperfect is underground, so they are different. I have lots of DJs that produce on Deeperfect and I have a lot of collaborations with artists. Now I am very happy because the label is absolutely doing well.
What new releases have you got coming out on Deeperfect?
I have a new collaboration with Mar-T, the Spanish DJ, resident at Amnesia. He is a good producer also. We also have another release by the famous Zoo Brazil. I love Zoo Brazil; super, super good producer and funny guy.
Also, Mr.Bizz. For me, he is one of the best new producers for techno music. The guy comes from Sardinia in Italy. He has a techno touch and I like it because it's a tribal sound mixed with old-school techno. I love it! We have a collaboration between Stefano Noferini and Mr.Bizz for September or maybe November. I played the track this afternoon [at Global Gathering].
Who else would you like to collaborate with?
For 2013 I want to collaborate with a pop artist, but I won't say the name until it's done. They are a big influence in the history of house music in the 1990s. They are the best artist for me. I cross my fingers. Also, I want to collaborate more with some DJs like Umek, Mr.Bizz and Mark Knight, of course. We have a track together, me and Mark Knight. It's probably out at the end of this year.
What is your next release?
My next release, out this Monday [30th July] on beatport, is part 1 of Remix Me. It's an album concept with a lot of DJs remixing my tracks: part 1 with 6 tracks and part 2 with 6 tracks. And I have a release on the Toolroom album, Toolroom Knights, out at the end of September. I have a lot of things going on!
Part 1 of 'Remix Me' is available now.
Follow Stefano Noferini and Radius Agency on twitter.
Check out Toolroom Records and Global Gathering.
-Ann Bartholomew


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text: The Toyota A-BAT (Advanced Breakthrough Aero Truck) interests us because it injects some much-needed new thinking into the pickup sector. The A-BAT offers substantial versatility, and yet it fights the gigantism that has become pervasive in the truck market--as evidenced by Toyota's own Tundra. The trapezoidal styling and high beltline give the A-BAT a big-truck look, but the concept is considerably smaller than the once-compact Tacoma and is about the size of a RAV4. "We wanted to reinvestigate the compact truck and bring it into modern times," says Kevin Hunter, president of Toyota's West Coast design studio. And this at a time when conventional wisdom had given up compact trucks for dead. The A-BAT is not only RAV4-sized, it also mirrors the popular crossover in its seating position and its unibody construction. Although it features four-wheel drive, the ground clearance is modest (about the same as a Highlander), as it's optimized for on-road use and urban environments, where today's pickups are unwieldy. Toyota is getting more and more mileage out of its hybrid technology, so it is perhaps not surprising to see it here. Paired with a transverse-mounted, four-cylinder engine, the hybrid system has the potential to produce a real breakthrough in pickup fuel economy, which, with a few exceptions, seldom exceeds 20 mpg. The A-BAT's other major innovations center around its cargo-carrying abilities. The truck features a midgate that extends the four-foot cargo box two feet into the passenger compartment. Dropping the tailgate adds another two feet of length, allowing the A-BAT to carry four-by-eight-foot building materials. Underbed storage is accessed via a drawer (an idea seen previously on the Dodge Rampage show truck). The four-seat cab features a large opening over the rear-seat area that allows tall items to poke through; and the rear seat-bottom cushions disappear backward, under the bed, rather than simply folding up. "The truck market is ripe for a change," claims A-BAT chief designer Ian Cartabiano. He might hear some arguments from Honda dealers, whose lots are full of unsold Ridgelines, but perhaps a less expensive, more economical, and more compact offering would find a new audience. Here's hoping Toyota is brave enough to try. Cool Details (pictured below) 1. The A-BAT's rear seatback can fold down, allowing the cargo bed to expand, Chevy Avalanche-style. 2. The cargo hold features pull-out storage bins in the side walls and a first-aid kit in the tailgate. Underbed storage is accessed via a rear drawer. 3. On top of the dashboard, the A-BAT has a solar panel that charges a portable battery pack. Toyota is studying this idea as a way to keep a car's battery charged when it is parked for long periods.


text:
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Ike Turner
Ike Turner
Ike Turner is certainly one of the most dehumanized figures in rock history. Mention his name and the first association that comes to most anyone's mind is "abusive husband," not "soul star" or "rock & roll pioneer." According to legend, Turner was a tyrannical ogre who used physical violence and psychological intimidation to control his infinitely more talented wife Tina, while indulging his own appetites for cocaine and women at every turn. That's not entirely accurate, although by most accounts Turner did quite a bit to earn that reputation; he spent time in prison due to his drug problems, and his own refutations of Tina's allegations of abuse have been inconsistent at best over the years. Still, this view of Turner as villain does a disservice to his very real musical legacy as an instrumentalist and bandleader. As a pianist in the early '50s, Turner helped lay the groundwork for rock & roll; he was also a distinctive guitarist with a biting, nasty tone, and was one of the first to make the whammy bar an integral part of his sound. It's true that he was nowhere near the singer Tina was, and it's probably also true that she was his ticket to stardom; moreover, his songwriting, while sometimes inspired, often possessed a generic quality that made consistent chart appearances difficult. But as a bandleader, his disciplinarian approach -- when it wasn't manifesting itself in darker fashion, that is -- resulted in undeniably tight, well-drilled ensembles and some of the most exhilarating live shows the R&B world ever saw -- centered around Tina, yes, but spectacles nonetheless. If Turner isn't exactly the most defensible character around, in the end his musical strengths and weaknesses deserve the same objective appraisal as anyone.
Similar Artists
Bobby "Blue" Bland
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Tina Turner
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Howlin' Wolf
Count Basie
Big Joe Turner
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Wynonie Harris
Pinetop Perkins


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text:
indriyaṁ tv indriyāṇāṁ tvaṁ
devāś ca tad-anugrahaḥ
avabodho bhavān buddher
jīvasyānusmṛtiḥ satī
devāś ca tad-anugrahaḥ
avabodho bhavān buddher
jīvasyānusmṛtiḥ satī
Word for word:
indriyam — the power to illuminate their objects; tu — and; indriyāṇām — of the senses; tvam — You; devāḥ — the demigods (who regulate the various senses); ca — and; tat — of them (the demigods); anugrahaḥ — the mercy (by which one's senses can act); avabodhaḥ — the power of decision; bhavān — You; buddheḥ — of intelligence; jīvasya — of the living entity; anusmṛtiḥ — the power of recollection; satī — correct.
You are the power of the senses to reveal their objects, the senses' presiding demigods, and the sanction these demigods give for sensory activity. You are the capacity of the intelligence for decision-making, and the living being's ability to remember things accurately.
Śrīla Viśvanātha Cakravartī points out that whenever one of the material senses is involved with its object, the presiding demigod of that particular sense organ must give his sanction. Ācārya Viśvanātha Cakravartī explains the word anusmṛti in this verse in its higher sense, as one's recognition of himself as an eternal spirit soul.


text: Gennady Bystritsky wrote: > SWIG is especially good for a small task as you can get it done in no > time to the extent you would spend tons of time doing manually. If you > care about rubyish API it is also doable, by using SWIG directives like > '%rename' in your interface description file. And the type mapping is > just fabulous. SWIG is good for a small task if you know SWIG. I use %rename and typemaps in my own applications, but I found the learning curve somewhat steep--not worth climbing, in my experience, for a simple task like Martin's. If Martin expects to do more work along those lines, the learning time may be a good investment. Steve


text:
With their successful Clockwork Angels tour well underway, Alex Lifeson of Rush recently told Guitar World magazine that things were not always so upbeat.
When recalling the band's Caress of Steel tour he said, "We were already extremely in debt, and it was just getting worse and worse. The crowds were getting smaller and there didn't seem to be much interest in the album at the time. Everybody around was concerned about what the future was going to be. So there was a lot of reflection. I thought, Well, you know, I guess I could be a plumber again if I had to…"
The band persevered despite the dwindling support. Eventually, they struck a production deal with Mercury label and the band itself became "responsible for delivering the record, the artwork — everything — in its completed form. It was really up to us. But they [Mercury] did lament the fact that we seemed to no longer have the same interests as we had initially. And they were concerned about that. Of course they were concerned about that—they had invested a lot of money and time and effort in us. And they wanted only what was best for the band, which was for us to make them a lot of money! And that's fine. They're a business and that's what they do. I get it. That's okay. Truthfully, I think it lit a fire under us."
Read more at Gibson.com


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Originally published December 15, 2011 at 10:01 PM | Page modified December 16, 2011 at 6:26 AM
FedEx orders 27 Boeing 767s, delays 11 777s
The 767s will be about 30 percent more fuel-efficient than the MD-10 jets they're replacing, some of which are more than 40 years old, FedEx said.
Bloomberg News
FedEx said Thursday it has signed a deal to buy 27 new Boeing 767-300 aircraft.
The jets have a list price of $4.7 billion but, after standard discounts, they have an estimated value of $2.1 billion, according to data from aircraft-valuation firm Avitas.
The 767s will be about 30 percent more fuel-efficient than the MD-10 jets they're replacing, some of which are more than 40 years old, FedEx said.
Three of the new jets will be delivered in fiscal 2014 and six a year from 2015 through 2018.
FedEx will delay receipt of 11 Boeing 777s now on order. Two will be deferred from fiscal 2013, five from 2014 and one a year from 2015 through 2018, FedEx said.
The company is also exercising two options for 777 jets, which will be shipped at the end of its delivery schedule.
Boeing worked with FedEx "for months" on the schedule adjustment, said Boeing Commercial Airplanes CEO Albaugh.
"They did slide some airplanes out, and we were able to slide other good customers into those positions," Albaugh said in an interview in New York.
"In fact, this really solidifies our skyline in the out years, so this worked well for them and worked well for us," he said.
FedEx originally planned to use the 777s on international markets where it now uses MD-11s, sliding the older jets into domestic slots filled by MD-10s, said Chief Executive Fred Smith.
When Boeing continued production of its 767 model, FedEx decided to use that aircraft to replace MD-10s domestically and continue using the MD-11 internationally, he said.
Also Thursday, FedEx posted a quarterly profit that beat analysts' estimates as U.S. consumers, bolstered by a better labor market, increased holiday orders from online retailers.
Profit for the three months through November rose 76 percent to $497 million, or $1.57 a share — topping the $1.53 average estimate of analysts.
Sales climbed 10 percent to $10.6 billion, in line with estimates.


text: Re: remotely add text to a file2001-08-14 06:17:55Matt suggested to Luka, | # add the first line from the body to spam word list | :0b:$PMDIR/lock | * ^From: Me <me(_at_)some\(_dot_)address> | * ^Subject: add to spam list | | sed -n 1p >>$PMDIR/crap-b.lst | | Just an idea, untested.. Looks good; I'd modify it, though, to allow more than one new address per message and to let sed exit when the lines to be added end. # add lines from top of body to spam word list :0bi: # let procmail name the local lockfile; `i' to let sed exit early * ^From: Me <me(_at_)some\(_dot_)address> * ^Subject: add to spam list | sed -ne/^$/q -ep >> $PMDIR/crap-b.lst There is a risk that someone else will fake a message from you to mess with your word list, but you are just marking such messages and not discarding them, so no damage could result from that. Even so, you might want to consider adding a password to the conditions. _______________________________________________ procmail mailing list procmail(_at_)lists(_dot_)RWTH-Aachen(_dot_)DE http://MailMan.RWTH-Aachen.DE/mailman/listinfo/procmail


text:
Matthew 24:35 Heaven and earth will pass away, but My words will never pass away. The final analysis is this: If the United States does not continue to spiral into the pit of oblivion and appears to be on the rise, Yahweh has set an hourglass that will run out for not just Satan and his followers, but everyone and everything within this reality. Everything will be completely obliterated out of existence. Is that what our Creator wants? Of course not - no more than She wanted sin to enter Her body in the beginning of mankind's start.
However, Yahweh is dead serious about every statement She has ever made, and if Satan should get the upper hand, this creation / generation living will have witnessed the final chapter in this reality. Father will end from creations beginning, just as She is doing now on this planet. We all have much at stake. Never feel that Father will not give Satan Dawn Lucifer a real chance to win. If Father did that, then the scales of justice would be tilted. If that were so, Father would not be fair and just.
We must understand Father's wisdom, in that She expects results from Her own side. If all things went exactly as Father ordained, then Adam and Eve would not have sinned, nor would Dawn Lucifer. But this is not the case. The inside chance that sin could manifest itself happened. The loss of this war is possible, but the ramification of that loss is even worse than sin existing for six-thousand years. Yet, it must come to an end one way or the other.
Father has always held the power to win out over Dawn Lucifer. But Father cannot simply destroy him and say we've won this war. To do so would not prove anything except Her ability to crush Her enemies with the wave of Her mighty hand. She told us we all have a stake in our future existence. This includes all of you. Everything each of us do in our stewardships is to further Father's plan.
The final denominator is that this creation is a test of whether or not it should exist at all. Each of us wants to win this war, so pray to Father that She gives all of the wisdom to carry out Her plan to fulfillment. We have received the warning from Her, and we, the Lions of Zion (LOZ), are diligently continuing to try and bring to bear Her prophecies before the hourglass runs dry. Pray that Dawn Lucifer does not overtake us in spirit or combat with his cunning mind. Much is at stake.
Psalm 54:2 God, hear my prayer; listen to the words of my mouth.
Psalm 84:8 LORD God of Hosts, hear my prayer; listen, God of Jacob. Selah


text:
No one is more prolific than Posner. I briefly considered writing a thesis on his jurisprudence generally, but it became an impossibly large project. (Reading his works alone would've taken years — and that was back in '91; he's done a lot more writing since then.) I had to settle for a sliver (an economic analysis of free speech law), and that discrete subject yielded 90-some pages of analysis on my part.
Not to be a killjoy, but.. ugh. Posner. Cf "I just think that almost all Americans would consider that turning back the civil liberties clock to, say, 1960 would be worthwhile if as a result some horrendous terrorist attack was prevented." http://leiterreports.typepad.com/blog/2005/01/response_to_com.html
The other day I was at a cocktail party arguing with economists about utility functions. Like Posner, they had their opinions, and I had mine. Eventually, they asked, if you think you know other people's utility functions better than they, why don't you trade on them?
I do, of course. I have a nice alpha, if not yet significant at .05.
Man, 1960! What a schmuck.
A real public service would be making the record in Judge Posner's cases available. It would be interesting to see how closely his opinions match up to the reality of the cases.
When you are the most cited judge in U.S. history, you make your own reality.
I bought his recent book, "Not a suicide Pact" and recommend it strongly, particularly on the merits of the recent Hamdan-Detainee legislation. I share Mr. Wu's view that Posner is worth paying attention to. I don't know where he finds the time to do all that he does.
The Law Blog covers the legal arena's hot cases, emerging trends and big personalities. It's brought to you by lead writer Jacob Gershman with contributions from across The Wall Street Journal's staff. Jacob comes here after more than half a decade covering the bare-knuckle politics of New York State. His inside-the-room reporting left him steeped in legal and regulatory issues that continue to grab headlines.
Comment or tip? Write to firstname.lastname@example.com or email@example.com


text:
Favstar gets even better if you sign in.
Some people are like Slinky's. Pretty much useless but make you smile when you push them down the stairs.
Sarcasm isn't an option, it comes with the package. If you can't handle it, don't come near me
Would like to say sorry! To all the people that I haven't offended or pissed off today! Look at the bright side there's always tomorrow!
After twelve years of therapy my psychiatrist said something that brought tears to my eyes. He said, "No hablo ingles."
I quit smoking today. So far, I dont want a smoke, but I do want to choke the shit out of everyone that's whistling and happy!
Anytime my boss asks me to takes notes, I think this better be under 140 characters, fucker!
Sittin on couch & hubs shakes his weiner at me, winks & goes to the room. I knew what was up...fml I haven't had any sleep!
I hate stupid people that you have to tell the same information to over and over again!
The only reason people get lost in thought is because it's unfamiliar territory.
Hubs wants to know if he flies to another timezone, fucks and flies back, is it still cheating bc of the time difference. I said YES dumbass
Quit DMing me you fucking perv! I will NOT send you "hot shots" as you keep requesting. I am not yours to look at! Fucking perv
Rude and can be nasty. I retweet what I find funny. If you don't like my attitude or the retweets, get off of my page, I am not trying to impress you!


text:
The outlook for students in the petroleum industry is excellent.
That's right. Due to the average age of both AAPG and SEG members and the prospects of this group retiring in the next 10-15 years, opportunities should be good for students.
At many of the AAPG Section meetings I have had an opportunity to talk to student groups about their future. I generally give them some ideas l have compiled that might help them in their future careers.
(Some of my comments are derived from Robert E. Megill's book, How To Be a More Productive Employee.)
The following is a "top ten" list of suggestions for students. Remember, we are all still students, so these pieces of advice are intended for all of us.
Life-Long Learning. School is never out, and life-long learning is important in our profession. The geoscientist who doesn't stay up with the latest ideas or technology is soon left far behind.
The adage "learn something new every day" is important. It only has to be one thing each day!
An important part of learning is to "read the books." A great one to start with is the AAPG/DPA book Guiding Your Career as a Professional Geologist. Also read the top selling business and professional development books.
Goal Setting. If you don't know where you are going, where do you think you will end up? Develop a road map for the future. Be your own boss and control your career (regardless of where you are working). Establish long-term and short-term goals and write them down. Review your goals at least weekly and stay focused on the action steps (or tasks) needed to accomplish the goals.
Attitude. Have you ever heard the saying "your attitude makes your attitude?" There are several attitudes that will help make you a productive employee. Have a service attitude. What can you do to make your boss' job easier? Get all your assignments done on time and done well. Go the "extra mile." Do more than is expected from your superiors! Do what needs to be done. Even if something is not in your job description, help out in other areas if it improves the efficiencies of the group. If you are ever a consultant you will find out that everything is in your job description.
Pride In Your Work. Take pride in the work you do. Do the best job you are capable of every time. If you tell your boss or colleagues you will do something, then follow through. This is the essence of integrity. Have the satisfaction of doing a good job. Do the tasks without expecting any rewards (bonuses, accolades, etc.).
Believe in Yourself. Your education and work experience are important factors to give you confidence. This confidence enables you to take on tasks others will not. You will also inspire confidence in others about your abilities. Be careful not to go beyond confidence into the arrogance category.
High Ethics. The Golden Rule is the foundation of ethical behavior. Treat others as you want to be treated. AAPG has one of the best code of ethics amongst professional organizations. Read it, frame it and practice it. The general principles of the code are printed at the end of this column. If a situation doesn't have the right feel to it, don't do it. Don't be tempted by riches or greed.
Learn Teamwork Skills. Just about every company has teams that accomplish the goals and objectives of the company. It is critical that you learn how to work well within a team. You don't have to like everyone but you do need to get along. Show respect and patience for everyone.
Build Your Net. Networking is critical for your successful career. Building a network of contacts (both business and social) is an important part of your development. Your business network will help you in future employment needs, information trades, etc. When you go to a luncheon or conference, make sure you meet new people. Sitting with your friends may not be the best way to build your net. A simple way to get to know new people is to take them to lunch.
Learn Leadership Skills. Leaders basically direct, train, inspire, motivate and evaluate. These skills are not natural to everyone, so take the time to study them and practice them. Learning how to train, inspire and motivate people is critical. You don't have to be the boss to be a good leader.
Enjoy What You Do! You will spend the majority of your waking hours on the job. Make sure you enjoy what you do. If you don't enjoy it, perhaps a change is necessary. Enjoying what you do at work will carry over into your home life.
An easy way to learn and practice these ideals is to get involved in AAPG. AAPG can assist you in staying up with technology and science. By joining committees you can build your network, develop leadership skills and develop teamwork skills. AAPG offers many forums on ethics, etc.
Make sure AAPG is a part of your professional career.
The general principles of the AAPG Code of Ethics (AAPG Constitution) are as follows:
It is important that every member review the entire Code of Ethics on a regular basis. Remember that your reputation is your most important asset.


text:
How sad that we need the nanny state to tell us we've had enough because we can't do it on our own"
there is no price on the life of a child. We must take action on dangerous dogs"
So many storylines. So much action. Absorbing sport from start to finish"
it doesn't matter if it's in front of 50,000 fans or two men and a dug - there needs to be a universal punishment across all levels of football"
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"It was a great weekend and I'm delighted with the commitment and effort each member of the team put into this competition" - Director of Sport Judith Ramsay
St Bernadette's from Tullibody won the event held at Tullibody Civic Centre and Dollar school Strathdevon scored the most points at the Ochil Leisure Centre.
A fine display by Gartcosh keeper Wilson denied Doune Castle the chance to pick up three points in their latest Caledonian League match
Strathendrick rose to the challenge and played with a confidence which made nonsense of their results to date.
The competition, which involved a run followed by a bike ride and a second run, was open to youngsters aged eight to 16 from schools across Stirling and proved popular despite the chilly weather
Eve, the current world champion and Olympic team skip, trains regularly at the Peak - both on the ice and in the gym where she builds up on her strength technique.
Andy Murray looks set to be crowned BBC Sports Personality of the Year after being named among the 10-strong shortlist for the prize.
He may be the first British man to win Wimbledon for 77 years and the hottest of favourites for BBC Sports Personality of the Year.
Central District coach Adam Brown is helping to ensure that up to 1800 primary school children in the Stirling, Bridge of Allan and Bannockburn areas can get the chance to give tennis a try.
Central Athletic Club runners turned out in numbers at Alloa for the second match of the East of Scotland Cross Country League on Saturday.
Glenbrae Riding Club, which has members from the Stirling area, picked up the club of the year honour at the annual horsescotland awards in Cumbernauld.
Teams from the Clackmannanshire Primary Schools Sports Association P6 Basketball Tournaments were given the chance to meet the Glasgow Rocks and play at the Emirates Stadium in front of 2000 people.
Stirling Swimming's younger members put in great performances at the West District Short Course Championships in Cumbernauld earlier this month.
Stirling-based curler Eve Muirhead starts out on her bid for European glory in Norway tomorrow in Norway as Stirling Sports Award's Sports Person of the Year Award.
Stirling County youngster Duncan Arthur is the latest player to benefit from the Alan Armstrong Rugby Scholarship.
Doune Castle bounced back to form after their disappointing Scottish Amateur Cup exit with a confident performance against the Glasgow students.
Bridge of Allan's Florie McLeish will do anything to reach the peak of triathlon – but even she admits she has pushed herself to the limit this year.
Young athletes are being invited to come and try out Beaconhurst School's first ever Duathlon which takes place at Stirling University next week.
Balfron High School's girls took the honours at the recent Stirling Schools Secondary Badminton Championships held at the Peak.
Duncan is a member of County's successful Under-18 squad which won the National Youth Championship in 2013. As well as playing rugby, Duncan is a full-time student studying Chemical Engineering at Strathclyde University.
Birth, deaths, marriages, church notices, in memoriam.
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text:
US D450593 S1 Claims(1)
Description FIG. 1 is a perspective view of the top front and one side of a bottle and closure primarily for detergent or personal care composition; FIG. 2 is a front view thereof; FIG. 3 is a rear view thereof; FIG. 4 is a side view thereof; FIG. 5 is a top plan view thereof; and, FIG. 6 is a bottom plan view thereof. Rotate |


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Part of the strength of Ottawa's economy is the diversity of its industries. Ottawa's knowledge-based sectors continue to grow employing over 75,000 employees within 1,922 companies. The Knowledge Based Support Services sector is the largest with 570 companies established in the community followed by the software sector with a total of 362 companies in the region. The Aerospace and Defence, eBusiness, Telecommunications and Cleantech industries also have a significant impact in Ottawa's high tech sector with a total of 609 companies between them. Although the Knowledge-Based Support Services industry employs the largest number of people, the Telecommunications sector follows closely and has the second largest employer. The Software and Aerospace and Defence sectors also play a hefty role in the community, employing 23,155 people between them.
Supported by a strong professional services cluster, Ottawa's economy is complemented by a vibrant tourism sector and the presence of more than 110,000 government employees. With the highest level of R&D spending per capita in the country, the Ottawa region has become the home of leading economic clusters. An economic powerhouse with a quality of life second to none, Ottawa is one of North America's fastest growing economies, and one of the world's most progressive centres of innovation.
Key Industries with Greatest Potential
In partnership with the City of Ottawa, Invest Ottawa has identified key sectors that demonstrate the greatest potential for growth:
Aerospace, Security & Defense
Ottawa has become a leader in the development of innovative aerospace and defence-related applications.
Canada's largest concentration of clean energy researchers & companies, whose breakout technologies are providing competitive & environmentally responsible solutions.
Digital Media
Ottawa's digital media sector exudes creativity and innovation and is supported by an impressive advanced education and research infrastructure.
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Ottawa boasts skilled crews and top-flight production companies, plus federal and provincial incentives can offer significant savings for productions.
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Ottawa: The Complete Wireless Telecommunications Ecosystem. Firms that own 74% of the global optical telecom market have a presence in Ottawa.
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Sophie Chen
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Senior Business Development Manager, Life Sciences
(613) 828-6274 ext. 212
twitter: @ioLifeScience
Kelly Daize
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Senior Business Development Manager, Europe
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Walter Noble
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Bernadette Terry
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Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX
Bell, Jeffrey A.
Ho, Kenneth L.
Farid, Ramy
Acta Crystallographica Section D: Biological Crystallography
2012;68(Pt 8):935-952.
All-atom models derived from moderate-resolution protein crystal structures contain a high frequency of close nonbonded contacts, independent of the major refinement program used for structure determination. All-atom refinement with PrimeX corrects many of these problematic interactions, producing models that are better suited for use in computational chemistry and related applications.
All-atom models are essential for many applications in molecular modeling and computational chemistry. Nonbonded atomic contacts much closer than the sum of the van der Waals radii of the two atoms (clashes) are commonly observed in such models derived from protein crystal structures. A set of 94 recently deposited protein structures in the resolution range 1.5–2.8 Å were analyzed for clashes by the addition of all H atoms to the models followed by optimization and energy minimization of the positions of just these H atoms. The results were compared with the same set of structures after automated all-atom refinement with PrimeX and with nonbonded contacts in protein crystal structures at a resolution equal to or better than 0.9 Å. The additional PrimeX refinement produced structures with reasonable summary geometric statistics and similar R free values to the original structures. The frequency of clashes at less than 0.8 times the sum of van der Waals radii was reduced over fourfold compared with that found in the original structures, to a level approaching that found in the ultrahigh-resolution structures. Moreover, severe clashes at less than or equal to 0.7 times the sum of atomic radii were reduced 15-fold. All-atom refinement with PrimeX produced improved crystal structure models with respect to nonbonded contacts and yielded changes in structural details that dramatically impacted on the interpretation of some protein–ligand interactions.
H atoms; van der Waals radii; restraints; nonbonded contacts; clashes; molecular geometry; model quality; force fields; refinement; riding H atoms; electrostatics; hydrogen bonds
Related Articles
Automated protein structure modeling in CASP9 by I-TASSER pipeline combined with QUARK-based ab initio folding and FG-MD-based structure refinement
Xu, Dong
Zhang, Jian
Roy, Ambrish
Zhang, Yang
2011;79(Suppl 10):147-160.
I-TASSER is an automated pipeline for protein tertiary structure prediction using multiple threading alignments and iterative structure assembly simulations. In CASP9 experiments, two new algorithms, QUARK and FG-MD, were added to the I-TASSER pipeline for improving the structural modeling accuracy. QUARK is a de novo structure prediction algorithm used for structure modeling of proteins that lack detectable template structures. For distantly homologous targets, QUARK models are found useful as a reference structure for selecting good threading alignments and guiding the I-TASSER structure assembly simulations. FG-MD is an atomic-level structural refinement program that uses structural fragments collected from the PDB structures to guide molecular dynamics simulation and improve the local structure of predicted model, including hydrogen-bonding networks, torsion angles and steric clashes. Despite considerable progress in both the template-based and template-free structure modeling, significant improvements on protein target classification, domain parsing, model selection, and ab initio folding of beta-proteins are still needed to further improve the I-TASSER pipeline.
protein structure prediction; threading; contact prediction; ab initio folding; CASP
Related Articles
Efficient Algorithms to Explore Conformation Spaces of Flexible Protein Loops
Yao, Peggy
Dhanik, Ankur
Marz, Nathan
Propper, Ryan
Kou, Charles
Liu, Guanfeng
van den Bedem, Henry
Latombe, Jean-Claude
Halperin-Landsberg, Inbal
Altman, Russ Biagio
Ieee/Acm Transactions on Computational Biology and Bioinformatics
Several applications in biology—e.g., incorporation of protein flexibility in ligand docking algorithms, interpretation of fuzzy X-ray crystallographic data, and homology modeling—require computing the internal parameters of a flexible fragment (usually, a loop) of a protein in order to connect its termini to the rest of the protein without causing any steric clash inside the loop and with the rest of the protein. One must often sample many such conformations in order to explore and adequately represent the conformational range of the studied loop. While sampling must be fast, it is made difficult by the fact that two conflicting constraints—kinematic closure and clash avoidance—must be satisfied concurrently. This paper describes two efficient and complementary sampling algorithms to explore the space of closed clash-free conformations of a flexible protein loop. The "seed sampling" algorithm samples broadly from this space, while the "deformation sampling" algorithm uses seed conformations as starting points to explore the conformation space around them at a finer grain. Computational results are presented for various loops ranging from 5 to 25 residues. More specific results also show that the combination of the sampling algorithms with a functional site prediction software (FEATURE) makes it possible to compute and recognize calcium-binding loop conformations. The sampling algorithms are implemented in a toolkit, called LoopTK, which is available at https://simtk.org/home/looptk.
Protein kinematics; protein loop structure; conformation sampling; deformation sampling; inverse kinematics; calcium-binding proteins
Related Articles
NCIPLOT: a program for plotting non-covalent interaction regions
Contreras-García, Julia
Johnson, Erin R.
Keinan, Shahar
Chaudret, Robin
Piquemal, Jean-Philip
Beratan, David N.
Yang, Weitao
Journal of chemical theory and computation
Non-covalent interactions hold the key to understanding many chemical, biological, and technological problems. Describing these non-covalent interactions accurately, including their positions in real space, constitutes a first step in the process of decoupling the complex balance of forces that define non-covalent interactions. Because of the size of macromolecules, the most common approach has been to assign van der Waals interactions (vdW), steric clashes (SC), and hydrogen bonds (HBs) based on pairwise distances between atoms according to their van der Waals radii. We recently developed an alternative perspective, derived from the electronic density: the Non-Covalent Interactions (NCI) index [J. Am. Chem. Soc. 2010, 132, 6498]. This index has the dual advantages of being generally transferable to diverse chemical applications and being very fast to compute, since it can be calculated from promolecular densities. Thus, NCI analysis is applicable to large systems, including proteins and DNA, where analysis of non-covalent interactions is of great potential value. Here, we describe the NCI computational algorithms and their implementation for the analysis and visualization of weak interactions, using both self-consistent fully quantum-mechanical, as well as promolecular, densities. A wide range of options for tuning the range of interactions to be plotted is also presented. To demonstrate the capabilities of our approach, several examples are given from organic, inorganic, solid state, and macromolecular chemistry, including cases where NCI analysis gives insight into unconventional chemical bonding. The NCI code and its manual are available for download at http://www.chem.duke.edu/~yang/software.htm
Related Articles
REMO: A New Protocol to Refine Full Atomic Protein Models from C-alpha Traces by Optimizing Hydrogen-Bonding Networks
Li, Yunqi
Zhang, Yang
Protein structure prediction approaches usually perform modeling simulations based on reduced representation of protein structures. For biological utilizations, it is an important step to construct full atomic models from the reduced structure decoys. Most of the current full-atomic model reconstruction procedures have defects which either could not completely remove the steric clashes among backbone atoms or generate final atomic models with worse topology similarity relative to the native structures than the reduced models. In this work, we develop a new protocol, called REMO, to generate full atomic protein models by optimizing the hydrogen-bonding network with basic fragments matched from a newly constructed backbone isomer library of solved protein structures. The algorithm is benchmarked on 230 non-homologous proteins with reduced structure decoys generated by I-TASSER simulations. The results show that REMO has a significant ability to remove steric clashes, and meanwhile retains good topology of the reduced model. The hydrogen-bonding network of the final models is dramatically improved during the procedure. The REMO algorithm has been exploited in the recent CASP8 experiment which demonstrated significant improvements of the I-TASSER models in both atomic-level structural refinement and hydrogen-bonding network construction.
Protein structure prediction; reduced modeling; protein structure refinement; hydrogen-bonding network; structure clustering; steric clash
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The other 90% of the protein: Assessment beyond the Cαs for CASP8 template-based and high-accuracy models
Keedy, Daniel A.
Williams, Christopher J.
Headd, Jeffrey J.
Arendall, W. Bryan
Chen, Vincent B.
Kapral, Gary J.
Gillespie, Robert A.
Block, Jeremy N.
Zemla, Adam
Richardson, David C.
Richardson, Jane S.
2009;77(Suppl 9):29-49.
For template-based modeling in the CASP8 Critical Assessment of Techniques for Protein Structure Prediction, this work develops and applies six new full-model metrics. They are designed to complement and add value to the traditional template-based assessment by GDT (Global Distance Test) and related scores (based on multiple superpositions of Cα atoms between target structure and predictions labeled "model 1"). The new metrics evaluate each predictor group on each target, using all atoms of their best model with above-average GDT. Two metrics evaluate how "protein-like" the predicted model is: the MolProbity score used for validating experimental structures, and a mainchain reality score using all-atom steric clashes, bond length and angle outliers, and backbone dihedrals. Four other new metrics evaluate match of model to target for mainchain and sidechain hydrogen bonds, sidechain end positioning, and sidechain rotamers. Group-average Z-score across the six full-model measures is averaged with group-average GDT Z-score to produce the overall ranking for full-model, high-accuracy performance.
Separate assessments are reported for specific aspects of predictor-group performance, such as robustness of approximately correct template or fold identification, and self-scoring ability at identifying the best of their models. Fold identification is distinct from but correlated with group-average GDT Z-score if target difficulty is taken into account, while self-scoring is done best by servers and is uncorrelated with GDT performance. Outstanding individual models on specific targets are identified and discussed. Predictor groups excelled at different aspects, highlighting the diversity of current methodologies. However, good full-model scores correlate robustly with high Cα accuracy.
homology modeling; protein structure prediction; all-atom contacts; full-model assessment
Related Articles
Correcting pervasive errors in RNA crystallography through enumerative structure prediction
Chou, Fang-Chieh
Sripakdeevong, Parin
Dibrov, Sergey M.
Hermann, Thomas
Das, Rhiju
Nature methods
Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors, and steric clashes. To address these problems, we present Enumerative Real-space Refinement ASsisted by Electron density under Rosetta (ERRASER), coupled to PHENIX (Python-based Hierarchical Environment for Integrated Xtallography) diffraction-based refinement. On 24 datasets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves average Rfree factor, resolves functionally important discrepancies in non-canonical structure, and refines low-resolution models to better match higher resolution models.
Related Articles
RNABC: Forward Kinematics to Reduce All-Atom Steric Clashes in RNA Backbone
Wang, Xueyi
Kapral, Gary
Murray, Laura
Richardson, David
Richardson, Jane
Snoeyink, Jack
Journal of mathematical biology
Although accurate details in RNA structure are of great importance for understanding RNA function, the backbone conformation is difficult to determine, and most existing RNA structures show serious steric clashes (≥ 0.4Å overlap) when hydrogen atoms are taken into account. We have developed a program called RNABC (RNA Backbone Correction) that performs local perturbations to search for alternative conformations that avoid those steric clashes or other local geometry problems. Its input is an all-atom coordinate file for an RNA crystal structure (usually from the MolProbity web service), with problem areas specified. RNABC rebuilds a suite (the unit from sugar to sugar) by anchoring the phosphorus and base positions, which are clearest in crystallographic electron density, and reconstructing the other atoms using forward kinematics. Geometric parameters are constrained within user-specified tolerance of canonical or original values, and torsion angles are constrained to ranges defined through empirical database analyses. Several optimizations reduce the time required to search the many possible conformations. The output results are clustered and presented to the user, who can choose whether to accept one of the alternative conformations.
Two test evaluations show the effectiveness of RNABC, first on the S-motifs from 42 RNA structures, and second on the worst problem suites (clusters of bad clashes, or serious sugar pucker outliers) in 25 unrelated RNA structures. Among the 101 S-motifs, 88 had diagnosed problems, and RNABC produced clash-free conformations with acceptable geometry for 71 of those (about 80%). For the 154 worst problem suites, RNABC proposed alternative conformations for 72. All but 8 of those were judged acceptable after examining electron density (where available) and local conformation. Thus, even for these worst cases, nearly half the time RNABC suggested corrections suitable to initiate further crystallographic refinement. The program is available from http://kinemage.biochem.duke.edu.
kinematic chain; RNA backbone conformation; RNA backbone adjustment; RNA crystallography; automated rebuilding; steric clash; S-motifs; all-atom contacts; structure validation
Related Articles
Molecular modeling of the heterodimer of human CFTR's nucleotide-binding domains using a protein–protein docking approach
Huang, Sheng-You
Bolser, Diana
Liu, Hao-Yang
Hwang, Tzyh-Chang
Zou, Xiaoqin
Journal of molecular graphics & modelling
We have presented a new protein–protein docking approach to model heterodimeric structures based on the conformations of the monomeric units. The conventional modeling method relies on superimposing two monomeric structures onto the crystal structure of a homologous protein dimer. The resulting structure may exhibit severe backbone clashes at the dimeric interface depending on the backbone dissimilarity between the target and template proteins. Our method overcomes the backbone clashing problem and requires no a priori knowledge of the dimeric structure of a homologous protein. Here we used human Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel whose dysfunction causes cystic fibrosis, for illustration. The two intracellular nucleotide-binding domains (NBDs) of CFTR control the opening and closing of the channel. Yet, the structure of the CFTR's NBD1–NBD2 complex has not been experimentally determined. Thus, correct modeling of this heterodimeric structure is valuable for understanding CFTR functions and would have potential applications for drug design for cystic fibrosis treatment. Based on the crystal structure of human CFTR's NBD1, we constructed a model of the NBD1–NBD2 complex. The constructed model is consistent with the dimeric mode observed in the crystal structures of other ABC transporters. To verify our structural model, an ATP substrate was docked into the nucleotide-binding site. The predicted binding mode shows consistency with related crystallographic findings and CFTR functional studies. Finally, genistein, an agent that enhances CFTR activity, though the mechanism for such enhancement is unclear, was docked to the model. Our predictions agreed with genistein's bell-shaped dose-response relationship. Potential mutagenesis experiments were proposed for understanding the potentiation mechanism of genistein and for providing insightful information for drug design targeting at CFTR. The method used in this study can be applied to modeling studies of other dimeric protein structures.
Molecular modeling; Molecular docking; CFTR
Related Articles
Gaia: automated quality assessment of protein structure models
Kota, Pradeep
Ding, Feng
Ramachandran, Srinivas
Dokholyan, Nikolay V.
Motivation: Increasing use of structural modeling for understanding structure–function relationships in proteins has led to the need to ensure that the protein models being used are of acceptable quality. Quality of a given protein structure can be assessed by comparing various intrinsic structural properties of the protein to those observed in high-resolution protein structures.
Results: In this study, we present tools to compare a given structure to high-resolution crystal structures. We assess packing by calculating the total void volume, the percentage of unsatisfied hydrogen bonds, the number of steric clashes and the scaling of the accessible surface area. We assess covalent geometry by determining bond lengths, angles, dihedrals and rotamers. The statistical parameters for the above measures, obtained from high-resolution crystal structures enable us to provide a quality-score that points to specific areas where a given protein structural model needs improvement.
Availability and Implementation: We provide these tools that appraise protein structures in the form of a web server Gaia (http://chiron.dokhlab.org). Gaia evaluates the packing and covalent geometry of a given protein structure and provides quantitative comparison of the given structure to high-resolution crystal structures.
Contact: email@example.com
Supplementary information: Supplementary data are available at Bioinformatics online.
Related Articles
A sequence analysis system encompassing rules for DNA helical distortion.
Shapiro, B A
Nussinov, R
Lipkin, L E
Maizel, J V
Nucleic Acids Research
Recently, it has been shown by Calladine (1982) and Dickerson (1983) that DNA distortions due to steric clashes between opposing purines and pyrimidines can be quantitated based upon four sum functions. The distortions involve helical twist, roll, torsion angle variations and propeller twist. It is the contention of the authors that these perturbations in structure act as information carriers for various external DNA interactions. This paper describes a system that incorporates these four rules and various other functions that permit the systematic interactive exploration for significant patterns as a consequence of these steric clashes.
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RosettaAntibody: antibody variable region homology modeling server
Sircar, Aroop
Kim, Eric T.
Gray, Jeffrey J.
Nucleic Acids Research
2009;37(Web Server issue):W474-W479.
The RosettaAntibody server (http://antibody.graylab.jhu.edu) predicts the structure of an antibody variable region given the amino-acid sequences of the respective light and heavy chains. In an initial stage, the server identifies and displays the most sequence homologous template structures for the light and heavy framework regions and each of the complementarity determining region (CDR) loops. Subsequently, the most homologous templates are assembled into a side-chain optimized crude model, and the server returns a picture and coordinate file. For users requesting a high-resolution model, the server executes the full RosettaAntibody protocol which additionally models the hyper-variable CDR H3 loop. The high-resolution protocol also relieves steric clashes by optimizing the CDR backbone torsion angles and by simultaneously perturbing the relative orientation of the light and heavy chains. RosettaAntibody generates 2000 independent structures, and the server returns pictures, coordinate files, and detailed scoring information for the 10 top-scoring models. The 10 models enable users to use rational judgment in choosing the best model or to use the set as an ensemble for further studies such as docking. The high-resolution models generated by RosettaAntibody have been used for the successful prediction of antibody–antigen complex structures.
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Structure-based Protocol for Identifying Mutations that Enhance Protein-Protein Binding Affinities
Sammond, Deanne W.
Eletr, Ziad M.
Purbeck, Carrie
Kimple, Randall J.
Siderovski, David P.
Kuhlman, Brian
Journal of molecular biology
The ability to manipulate protein binding affinities is important for the development of proteins as biosensors, industrial reagents, and therapeutics. We have developed a structure-based method to rationally predict single mutations at protein-protein interfaces that enhance binding affinities. The protocol is based on the premise that increasing buried hydrophobic surface area and/or reducing buried hydrophilic surface area will generally lead to enhanced affinity if large steric clashes are not introduced and buried polar groups are not left without a hydrogen bond partner. The procedure selects affinity enhancing point mutations at the protein-protein interface using three criteria: 1) the mutation must be from a polar amino acid to a non-polar amino acid or from a non-polar amino acid to a larger non-polar amino acid, 2) the free energy of binding as calculated with the Rosetta protein modeling program should be more favorable than the free energy of binding calculated for the wild type complex and 3) the mutation should not be predicted to significantly destabilize the monomers. The Rosetta energy function emphasizes short-range interactions: steric repulsion, Van der Waals forces, hydrogen bonding, and an implicit solvation model that penalizes placing atoms adjacent to polar groups. The performance of the computational protocol was experimentally tested on two separate protein complexes; Gαi1 from the heterotrimeric G-protein system bound to the RGS14 GoLoco motif, and the E2, UbcH7, bound to the E3, E6AP from the ubiquitin pathway. 12 single-site mutations that were predicted to be stabilizing were synthesized and characterized in the laboratory. 9 of the 12 mutations successfully increased binding affinity with 5 of these increasing binding by over 1.0 kcal/mol. To further assess our approach we searched the literature for point mutations that pass our criteria and have experimentally determined binding affinities. Of the 8 mutations identified, 5 were accurately predicted to increase binding affinity, further validating the method as a useful tool to increase protein-protein binding affinities.
Computational Protein Design; Protein-Protein Interactions; Protein Binding Hotspots; Rosetta Molecular Modeling Software; Hydrophobic Effect
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KOSMOS: a universal morph server for nucleic acids, proteins and their complexes
Seo, Sangjae
Kim, Moon Ki
Nucleic Acids Research
2012;40(Web Server issue):W531-W536.
KOSMOS is the first online morph server to be able to address the structural dynamics of DNA/RNA, proteins and even their complexes, such as ribosomes. The key functions of KOSMOS are the harmonic and anharmonic analyses of macromolecules. In the harmonic analysis, normal mode analysis (NMA) based on an elastic network model (ENM) is performed, yielding vibrational modes and B-factor calculations, which provide insight into the potential biological functions of macromolecules based on their structural features. Anharmonic analysis involving elastic network interpolation (ENI) is used to generate plausible transition pathways between two given conformations by optimizing a topology-oriented cost function that guarantees a smooth transition without steric clashes. The quality of the computed pathways is evaluated based on their various facets, including topology, energy cost and compatibility with the NMA results. There are also two unique features of KOSMOS that distinguish it from other morph servers: (i) the versatility in the coarse-graining methods and (ii) the various connection rules in the ENM. The models enable us to analyze macromolecular dynamics with the maximum degrees of freedom by combining a variety of ENMs from full-atom to coarse-grained, backbone and hybrid models with one connection rule, such as distance-cutoff, number-cutoff or chemical-cutoff. KOSMOS is available at http://bioengineering.skku.ac.kr/kosmos.
Related Articles
Conformation Dependence of Backbone Geometry in Proteins
Berkholz, Donald S.
Shapovalov, Maxim V.
Dunbrack, Roland L.
Karplus, P. Andrew
Structure (London, England : 1993)
Protein structure determination and predictive modeling have long been guided by the paradigm that the peptide backbone has a single, context-independent ideal geometry. Both quantum-mechanics calculations and empirical analyses have shown this is an incorrect simplification in that backbone covalent geometry actually varies systematically as a function of the Φ and Ψ backbone dihedral angles. Here, we use a nonredundant set of ultrahigh-resolution protein structures to define these conformation-dependent variations. The trends have a rational, structural basis that can be explained by avoidance of atomic clashes or optimization of favorable electrostatic interactions. To facilitate adoption of this new paradigm, we have created a conformation-dependent library of covalent bond lengths and bond angles and shown that it has improved accuracy over existing methods without any additional variables to optimize. Protein structures derived both from crystallographic refinement and predictive modeling both stand to benefit from incorporation of the new paradigm.
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A simple reference state makes a significant improvement in near-native selections from structurally refined docking decoys
Liang, Shide
Liu, Song
Zhang, Chi
Zhou, Yaoqi
Near-native selections from docking decoys have proved challenging especially when unbound proteins are used in the molecular docking. One reason is that significant atomic clashes in docking decoys lead to poor predictions of binding affinities of near native decoys. Atomic clashes can be removed by structural refinement through energy minimization. Such an energy minimization, however, will lead to an unrealistic bias toward docked structures with large interfaces. Here, we extend an empirical energy function developed for protein design to protein–protein docking selection by introducing a simple reference state that removes the unrealistic dependence of binding affinity of docking decoys on the buried solvent accessible surface area of interface. The energy function called EMPIRE (EMpirical Protein-InteRaction Energy), when coupled with a refinement strategy, is found to provide a significantly improved success rate in near native selections when applied to RosettaDock and refined ZDOCK docking decoys. Our work underlines the importance of removing nonspecific interactions from specific ones in near native selections from docking decoys.
knowledge-based potential; energy score functions; reference state; binding affinity; docking decoys
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Phosphorylation Regulates Assembly of the Caspase-6 Substrate-Binding Groove
Velázquez-Delgado, Elih M.
Hardy, Jeanne A.
Structure (London, England : 1993)
Caspases, a family of apoptotic proteases, are increasingly recognized as being extensively phosphorylated, usually leading to inactivation. To date, no structural mechanism for phosphorylation-based caspase inactivation is available, although this information may be key to achieving caspase-specific inhibition. Caspase-6 has recently been implicated in neurodegenerative conditions including Huntington's and Alzheimer's diseases. A full understanding of caspase-6 regulation is crucial to caspase-6-specific inhibition. Caspase-6 is phosphorylated by ARK5 kinase at serine 257 leading to suppression of cell death via caspase-6 inhibition. Our structure of the fully inactive phosphomimetic S257D reveals that phosphorylation results in a steric clash with P201 in the L2′ loop. Removal of the proline side chain alleviates the clash resulting in nearly wild-type activity levels. This phosphomimetic-mediated steric clash causes misalignment of the substrate-binding groove, preventing substrate binding. Substrate-binding loop misalignment appears to be a widely used regulatory strategy among caspases and may present a new paradigm for caspase-specific control.
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A possible degree of motional freedom in bacterial chemoreceptor cytoplasmic domains and its potential role in signal transduction
Hu, Weiguo
International Journal of Biochemistry and Molecular Biology
We describe an array of gaps in an antiparallel four-helix bundle structure, the cytoplasmic domains of bacterial chemoreceptors. For a given helix, the side chain interactions that define a helix's position are analyzed in terms of residue interfaces, the most important of which are a-a, g-g, d-d, g-d, and a-d. It was found that the interdigitation of the side groups does not entirely fill the space along the long axis of the structure, which results in a rather regular array of gaps. A simulated piston motion of helix CD1 along the helical axis direction by 1.2Å shows that 85% of the side chain interactions still satisfy Van der Waals criteria, while the remaining clashes could be avoided by small rotations of side chains. Therefore, two states could exist in the structure, related by a piston motion. Analysis of the crystal structure of a small four-helix bundle, the P1short domain of CheA in Thermotoga Maritima, reveals that the two coexisting states related by a 1.3-1.7Å piston motion are defined by the same mechanism. This two-state model is a plausible candidate mechanism for the long distance signal transduction in bacterial chemoreceptors and is qualitatively consistent with literature chemoreceptor mutagenesis results. Such a mechanism could exist in many other structures with interdigitating α-helices.
Four-helix bundle; chemoreceptors; dynamics; signal transduction
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kinDOCK: a tool for comparative docking of protein kinase ligands
Martin, Laetitia
Catherinot, Vincent
Labesse, Gilles
Nucleic Acids Research
2006;34(Web Server issue):W325-W329.
KinDOCK is a new web server for the analysis of ATP-binding sites of protein kinases. This characterization is based on the docking of ligands already co-crystallized with other protein kinases. A structural library of protein kinase–ligand complexes has been extracted from the Protein Data Bank (PDB). This library can provide both potential ligands and their putative binding orientation for a given protein kinase. After protein–protein structural superposition, the ligands are transferred from the template complexes to the target protein kinase. The resulting complexes are evaluated using the program SCORE to compute a theoretical affinity. They can be dynamically visualized to allow a rapid mapping of important steric clashes and potential substitutions relevant for specificity and affinity. These characteristics allow a quick characterization of protein kinase active sites including conformation changes potentially required to accommodate particular ligands. Additionally, promising pharmacophores can be identified in the focussed library. These features will help to rationalize or optimize virtual screening (VS) on larger chemical compound libraries. The server and its documentation are freely available at .
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NMSim Web Server: integrated approach for normal mode-based geometric simulations of biologically relevant conformational transitions in proteins
Krüger, Dennis M.
Ahmed, Aqeel
Gohlke, Holger
Nucleic Acids Research
2012;40(Web Server issue):W310-W316.
The NMSim web server implements a three-step approach for multiscale modeling of protein conformational changes. First, the protein structure is coarse-grained using the FIRST software. Second, a rigid cluster normal-mode analysis provides low-frequency normal modes. Third, these modes are used to extend the recently introduced idea of constrained geometric simulations by biasing backbone motions of the protein, whereas side chain motions are biased toward favorable rotamer states (NMSim). The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. On a data set of proteins with experimentally observed conformational changes, the NMSim approach has been shown to be a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or more sophisticated sampling techniques. The web server output is a trajectory of generated conformations, Jmol representations of the coarse-graining and a subset of the trajectory and data plots of structural analyses. The NMSim webserver, accessible at http://www.nmsim.de, is free and open to all users with no login requirement.
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Computational Screening of the Human TF-Glycome Provides a Structural Definition for the Specificity of Anti-Tumor Antibody JAA-F11
Tessier, Matthew B.
Grant, Oliver C.
Heimburg-Molinaro, Jamie
Smith, David
Jadey, Snehal
Gulick, Andrew M.
Glushka, John
Deutscher, Susan L.
Rittenhouse-Olson, Kate
Woods, Robert J.
Sem, Daniel S.
PLoS ONE
Recombinant antibodies are of profound clinical significance; yet, anti-carbohydrate antibodies are prone to undesirable cross-reactivity with structurally related-glycans. Here we introduce a new technology called Computational Carbohydrate Grafting (CCG), which enables a virtual library of glycans to be assessed for protein binding specificity, and employ it to define the scope and structural origin of the binding specificity of antibody JAA-F11 for glycans containing the Thomsen-Friedenreich (TF) human tumor antigen. A virtual library of the entire human glycome (GLibrary-3D) was constructed, from which 1,182 TF-containing human glycans were identified and assessed for their ability to fit into the antibody combining site. The glycans were categorized into putative binders, or non-binders, on the basis of steric clashes with the antibody surface. The analysis employed a structure of the immune complex, generated by docking the TF-disaccharide (Galβ1-3GalNAcα) into a crystal structure of the JAA-F11 antigen binding fragment, which was shown to be consistent with saturation transfer difference (STD) NMR data. The specificities predicted by CCG were fully consistent with data from experimental glycan array screening, and confirmed that the antibody is selective for the TF-antigen and certain extended core-2 type mucins. Additionally, the CCG analysis identified a limited number of related putative binding motifs, and provided a structural basis for interpreting the specificity. CCG can be utilized to facilitate clinical applications through the determination of the three-dimensional interaction of glycans with proteins, thus augmenting drug and vaccine development techniques that seek to optimize the specificity and affinity of neutralizing proteins, which target glycans associated with diseases including cancer and HIV.
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2-Methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl 4-bromobenzene-1-sulfonate
El-Azab, Adel S.
Abdel-Aziz, Alaa A.-M.
Ng, Seik Weng
Tiekink, Edward R. T.
Acta Crystallographica Section E: Structure Reports Online
2012;68(Pt 3):o759-o760.
The title molecule, C22H17BrN2O4S, has a twisted U shape, the dihedral angle between the quinazolin-4-one and bromobenzene ring systems being 46.25 (8)°. In order to avoid steric clashes with adjacent substituents on the quinazolin-4-one ring, the N-bound tolyl group occupies an orthogonal position [dihedral angle = 89.59 (8)°]. In the crystal, molecules are connected into a three-dimensional architecture by C—H⋯O interactions, with the ketone O atom accepting two such bonds and a sulfonate O atom one.
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Iterative Assembly of Helical Proteins by Optimal Hydrophobic Packing
Wu, G. Albert
Coutsias, Evangelos A.
Dill, Ken A.
Structure (London, England : 1993)
We present a method for the computer-based iterative assembly of native-like tertiary structures of helical proteins from alpha-helical fragments. For any pair of helices, our method, called MATCHSTIX, first generates an ensemble of possible relative orientations of the helices with various ways to form hydrophobic contacts between them. Those conformations having steric clashes, or a large radius of gyration of hydrophobic residues, or with helices too far separated to be connected by the intervening linking region, are discarded. Then, we attempt to connect the two helical fragments by using a robotics-based loop-closure algorithm. When loop closure is feasible, the algorithm generates an ensemble of viable interconnecting loops. After energy minimization and clustering, we use a representative set of conformations for further assembly with the remaining helices, adding one helix at a time. To efficiently sample the conformational space, the order of assembly generally proceeds from the pair of helices connected by the shortest loop, followed by joining one of its adjacent helices, always proceeding with the shorter connecting loop. We tested MATCHSTIX on 28 helical proteins each containing up to 5 helices and found it to heavily sample native-like conformations. The average RMSD of the best conformations for the 17 helix-bundle proteins that have 2 or 3 helices is less than 2 Å; errors increase somewhat for proteins containing more helices. Native-like states are even more densely sampled when disulfide bonds are known and imposed as restraints. We conclude that, at least for helical proteins, if the secondary structures are known, this rapid rigid-body maximization of hydrophobic interactions can lead to small ensembles of highly native-like structures. It may be useful for protein structure prediction.
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Comparison of Segger and Other Methods for Segmentation and Rigid-Body Docking of Molecular Components in Cryo-EM Density Maps
Pintilie, Grigore
Chiu, Wah
Segmentation and docking are useful methods for discovery of molecular components in cryo-EM (Electron Cryo-Microscopy) density maps of macromolecular complexes. In this paper, we describe the segmentation and docking methods implemented in Segger. For 12 targets included in the 2010 Cryo-EM Modeling Challenge, we segmented the regions corresponding to individual molecular components using Segger. We then used the segmented regions to guide rigid-body docking of individual components. An assessment in the accuracy of the component segmentation of the targets based on Segger and other methods was made by comparing the docking results of individual components to the segmented regions. The docking results were evaluated by comparison to published structures and by calculation of several scores including atom inclusion, density occupancy, and geometry clash.
cryo-EM; segmentation; map based modeling
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The Role of Electrostatics in Siderophore Recognition by the Immunoprotein Siderocalin1
Hoette, Trisha M.
Abergel, Rebecca J.
Xu, Jide
Strong, Roland K.
Raymond, Kenneth N.
Journal of the American Chemical Society
Iron is required for virulence of most bacterial pathogens, many of which rely on siderophores, small-molecule chelators, to scavenge iron in mammalian hosts. As an immune response, the human protein Siderocalin binds both apo and ferric siderophores in order to intercept delivery of iron to the bacterium, impeding virulence. The introduction of steric clashes into the siderophore structure is an important mechanism of evading sequestration. However, in the absence of steric incompatibilities, electrostatic interactions determine siderophore strength of binding by Siderocalin. By using a series of isosteric enterobactin analogs, the contribution of electrostatic interactions, including both charge-charge and cation-π, to the recognition of 2,3-catecholate siderophores has been deconvoluted. The analogs used in the study incorporate a systematic combination of 2,3-catecholamide (CAM) and N-hydroxypyridinonate (1,2-HOPO) binding units on a tris(2-aminoethyl)amine backbone, [tren(CAM)m(1,2-HOPO)n where m = 0, 1, 2, or 3 and n = 3 – m]. The shape complementarity of the synthetic analog series was determined through small molecule crystallography and the binding interactions investigated through a fluorescence-based binding assay. These results were modeled and correlated through ab initio calculations of the electrostatic properties of the binding units. Although all the analogs are accommodated in the binding pocket of Siderocalin, the ferric complexes incorporating decreasing numbers of CAM units are bound with decreasing affinities (Kd = >600, 43, 0.8 and 0.3 nM for m = 0-3). These results elucidate the role of electrostatics in the mechanism of siderophore recognition by Siderocalin.
Siderocalin; siderophore; iron; virulence; innate immunity; cation-π
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text:
I found my garland for $1 at Goodwill and immediately knew it had the potential to be something cuter.
First decide how many bows you will need and what size you want them to be. I cut strips that were 9" by 3.25" for the bows, and the smaller strips that make up the middle of the bow and attach the bow to the garland were 4" by .875". Stitch the long edges of the bigger pieces. You can use a machine; I did mine by hand since I wasn't going for a perfect look. Sew all the way around the smaller parts. These stitches are purely decorative because felt won't ravel, which is one of the reasons I chose felt for this project. Not having to hem things saves SO much time.
Take the bigger pieces and fold each of the shorter sides towards the middle so they overlap. sew through all three layers using large stitches, then pull the thread tight so that the bow gathers. Sew through the gathers several times to hold them in place.
Now attach your velcro (mine is the adhesive backed kind, another time-saver) to the short pieces so that you can wrap them around both the bow and the garland. Attaching them to the garland this way allows you to move them around until you get the placement right. I used paperclips to hang my garland, bent as shown.
Hang and enjoy!


text:
Latest Headlines
Camden police are asking for the public to help them find a missing woman.
IKEA is recalling millions of children's lamps following the death of a child ...
The Air Force unveiled today a sweeping list of voluntary and involuntary force ...
The late Dale Earnhardt's famed No. 3 will be back on track in the elite Sprint ...
For the next two weeks, high school football's all-star games will take center ...
Scores From Tuesday, Dec. 10
Doug Stanglin, USA TODAY
Russia has urged Syria to put its chemical weapons under international control, Foreign Minister Sergey Lavrov told reporters Monday.
"We have passed our offer to (Syrian Foreign Minister Walid) Al-Muallem and hope to receive [a] fast and positive answer," Sergey Lavrov said, according to RT.com, the Russian news agency, and the Associated Press.
Lavrov said Monday that if such a move would help avert a possible U.S. strike on Syria, Russia will start work "immediately" to persuade Syria to give up the control of its chemical arsenals.
Lavrov told reporters that Russia would urge Syria to concentrate its chemical weapons in certain areas under international oversight and then dismantle them.
The Obama administration has accused the Assad regime of an attack with chemical weapons near Damascus Aug. 21 that killed more than 1,400 people. President Obama has called on Congress to back a limited strike against Syria in response.
Lavrov, who spoke after talks Monday with al-Moallem, said that U.N. chemical weapons experts should complete their probe of the attack and present their findings to the U.N. Security Council.
"We have agreed to push for the soonest return of inspectors," Lavrov said.
Al-Moallem said his government was ready to host the U.N. team, and insisted that Syria is ready to use all channels to convince the Americans that it wasn't behind the attack.
He added that Syria was ready for "full cooperation with Russia to remove any pretext for aggression."
Syria is one of five countries -- including Angola, North Korea, Egypt, and South Sudan -- that have not signed the Chemical Weapons Convention drawn up in 1992.
The arms control treaty, signed by 189 country, bans the use and production of chemical weapons and calls for their destruction. Myanmar, also known as Burma, and Israel have signed the agreement, but have not ratified it.
Earlier in London, Secretary of State John Kerry was asked if Assad could do anything to avoid a military strike.
"Sure. He could turn over every single bit of his chemical weapons to the international community in the next week," he said. "Turn it over. All of it, without delay. And allow the full and total accounting for that. But he isn't about to do it."
Later, State Department spokesperson Jen Psaki was asked of Kerry's remarks amounted to an ultimatum.'
"Secretary Kerry was making a rhetorical argument about the impossibility and unlikelihood of Assad turning over chemical weapons he has denied he used," she said in a statement. "His point was that this brutal dictator with a history of playing fast and loose with the facts can not be trusted to turn over chemical weapons otherwise he would have done so long ago. That's why the world faces this moment."
In an interview with Charlie Rose for CBS This Morning, Syrian President Bashar Assad denied using chemical weapons to attack his own people, but would neither confirm nor deny that his government kept such weapons. But, he said, if they existed, they were "in centralized control."
Syria has denied launching the Aug. 21 attack, insisting along with its ally Russia that the attack was launched by the rebels to drag the U.S. into war. Assad told CBS that his troops were attacked by chemical weapons and were not the aggressors.
"Our soldiers in another area were attacked chemically," he told Rose. "Our soldiers. They went to the hospital -- as casualties because of chemical weapons."
In his call for a negotiated settlement, Lavrov said that Russia will continue to promote a peaceful settlement and may try to convene a gathering of all Syrian opposition figures to join in negotiations. He added that a U.S. attack on Syria would deal a fatal blow to peace efforts.
Lavrov wouldn't say how Russia could respond to a possible U.S. attack on Syria, saying that "we wouldn't like to proceed from a negative scenario and would primarily take efforts to prevent a military intervention."
President Vladimir Putin said that Moscow would keep providing assistance to Syria in case of U.S. attack, but he and other Russian officials have made clear that Russia has no intention to engage in hostilities.
Assad, in his interview with CBS, said the U.S. would face "repercussions" in the event of an attack
Contributing: Associated Press


text:
Bell Alibi$40.00
Bell's Alibi is a durable, stylish and comfortable helmet they'll love. It has the same tough Fusion In-Mold Microshell used in Bell's adult helmets, plus their easy, one-handed ErgoDial fit system and Cam-lock strap levers for a great fit and feel. This fun helmet has 23 vents and a snap-on visor… [more] |


text:
Help Me Hank: Disappearing Dry Cleaners
Going to the dry cleaners is about as predictable as it comes, you're gonna see bags of clothes spinning around and the person in back pressing the shirts and the people taking clean stuff home.
But here is what Gladys Jones saw when she went to her dry cleaners -- not machines, not bags, not people and most distressingly, not her boyfriend's clothes.
- Gladys Jones
"It was a pair of dress slacks, men's dress slacks, and a mans dress shirt."
Gone. It all started when Gladys put the shirt and pants in the cleaners, got this receipt and then headed off on vacation.
- Gladys Jones
"So we decided to get them when we got back from vacation, which when we came back from vacation, they weren't there to get."
There was a message on her answering machine:
- Message on Machine
"We will be going out of business and our last day is June 30..."
Problem! Gladys had been thousands of miles away. Got the message weeks later!
- Hank
"Could you have picked up your clothes in time?"
- Gladys Jones
"No way that was possible."
So what good is a cleaning ticket with no cleaners?
- Gladys Jones
"I was upset, I was like you know, I put my clothes in the cleaners, where are my clothes at?"
Good question, the disappearing dry cleaners had left no forwarding phone number and no new address.
- Gladys Jones
"It left me nowhere to go."
That's when she called "Help Me Hank." We found business records at town hall, found that the owners had moved to the Cape and then found their new number. But could we find the clothes?
The owners told us they had lost their lease and tried to get everyone's clothes returned, but how about Ms. Jones? They checked that ticket number and good news... soon after a big package from the Cape arrived at Gladys's door
- Hank
"And inside?"
- Gladys Jones
"The missing clothes, everything is back."
What battle are you fighting? Maybe I can help, send it to email@example.com