A picture is worth 1,000 words when it comes to understanding how things work, but 3D moving pictures are even better. That's especially true for scientists trying to stop cancer by better understanding the proteins that make some chemotherapies unsuccessful. Researchers for decades have had to rely at best on static images of the key proteins related to recurring cancers. Now SMU biochemist John G. Wise at Southern Methodist University, Dallas, has brought to life in a moving 3D computer model the structure of human P glycoprotein, which is thought to contribute to the failure of chemotherapy in many recurring cancers. "This is a very different approach than has been used historically in the field of protein structure biochemistry," Wise said. "Historically, proteins are very often viewed as static images, even though we know that in reality these proteins move and are dynamic." The model is a powerful new discovery tool, says Wise, particularly when combined with high performance supercomputing. The dynamic 3D model already has made it possible for Wise to virtually screen more than 8 million potential drug compounds in the quest to find one that will help stop chemotherapy failure. "This has been a good proof of principle," said Wise, a research associate professor in the SMU Department of Biological Sciences. The research is funded by the National Institute of General Medical Sciences, National Institutes of Health. Seeking new drugs that would allow chemotherapeutic compounds to enter and destroy cancer cells Since the 1970s it has been known that the so called multidrug resistance protein, P gp, is most likely responsible for the failure of many chemotherapy drugs. P gp is nature's way of pumping toxins from a cell, but if cancer cells express more P gp than cells normally would, the chemotherapy is no longer effective because the protein considers it a toxin and pumps it out before it can destroy the cancer. "We are currently screening about 40,000 compounds per day on SMU's High Performance Computer," Wise said. "We found a couple hundred compounds that were interesting, and so far we chose about 30 of those to screen in the lab," Vogel said. "From those, we found a handful of compounds that do inhibit the protein. We were thrilled. Now we're going back into the models and looking for other compounds that might be able to throw a stick in the pump's mechanism." Massive increases in computational power in recent years have made the screening research possible, Wise said. "Ten years ago you couldn't have docked 8 million compounds there just wasn't enough computational power." Human P gp: "We don't know what it looks like exactly." Every organism has a version of P gp. Its structure has been previously determined for some organisms mostly bacteria, but also in mice by studying the arrangement of atoms within protein crystals. However, the exact structure of the human enzyme remains unclear. Wise deduced the structure of human P gp by relying on evolutionary relationships and scientific understanding of how proteins are put together. He then used computer programs to model the protein in a way that brings the static picture of the human pump to life in the computer. To develop the model, Wise used freely available simulation software developed by researchers at the University of Illinois, the National Institutes of Health and the Scripps Research Institute. Wise and Vogel use compounds from ZINC, a free database of more than 21 million commercially available compounds for virtual screening. ZINC is provided by the Department of Pharmaceutical Chemistry at the University of California, San Francisco. "We can physically build these molecules in the computer, in silico, and computationally we can model a variety of conditions: We can raise the temperature to 37 degrees Centigrade, we can have the right salts and all the right conditions, just like in a wet lab experiment. We can watch them thermally move and we can watch them relax," Wise said. "The software is good enough that the model will move according to the laws of physics and the principles of biochemistry. In this way we can see how these compounds interact with the protein in a dynamic way, not just in a snapshot way." Even with the 3D dynamic model and a supercomputer, the odds are stiff Theoretically, if a drug can be found that can temporarily knock out the sump pump proteins, then all those cancer chemotherapies that don't work for a patient will work again. "The ultimate goal of our research would be to find a compound that is safe and effective," Wise said. Even with a supercomputer, however, the odds are steep. "Out of a hundred good inhibitors that we might find, 99 of them might be extremely toxic and can't be used. In the pharmaceutical industry there are many, many candidates that fall by the wayside for one reason or another," he said. "They metabolize too quickly, or they're too toxic, or they're not soluble enough in the acceptable solvents for humans. There are many different reasons why a drug can fail. Finding a handful has been a great confirmation that we're on the right track, but I would be totally amazed if one of the first we've tested was the one we're looking for." Vogel is an associate professor and director of SMU's Center for Drug Discovery, Design and Delivery. CD4 was launched by SMU's Biological Sciences and Chemistry departments and has as its mission the search for new drug therapies and delivery methods that can be developed into clinical applications. SMU has an uplink facility located on campus for live TV, radio, or online interviews. To speak with an SMU expert or book an SMU guest in the studio, call SMU News Communications at 214 768 7650. Nike Roshe Run Woven Men Black ,Men Nike Free Run 3 Deep Royal Blue Silver Volt Quilted Nike Roshe Run Army Green Meihei Women Nike Free Run 4.0 Night Blue Volt Pure Platinum White Men Nike Free Run 2 Black Gym Red Quilted Men Nike Free Run 5.0+ Black Metallic Silver Dark Grey Quilted Men Nike Free Run 3 Pure Platinum Reflect Silver Volt Women Nike Free Run 3 Hot Punch Pink Grey Women Nike Free Run 3 Total Orange Silver Platinum Volt Nike Roshe Run Men Royal Volt Out on the wing a 69 years old footballer gathers the ball and sets off on a solo run down the field with not an opponent in sight. Suddenly, from the terrace springs a sprightly octogenarian heading toward the player and, like a bolt from the blue, bringing him crashing to the ground. Stretched on the grass, the footballer shakes his head, unable to recognise the source of the tackle. Only when he rolls over does he find the fully clothed old man extricating himself from a tangle of legs . . . and scurrying back to the terrace, like a bat from hell. When the player's pretence of anger has subsided and the cameras are switched off, the two men smile and shake hands. They have just re enacted an incident from a county intermediate final that took place on that very spot in McHale Park forty eight years earlier. But no one was smiling that day in 1965 when the unprecedented scuffle broke out between Billy Fitzpatrick, the victim of the attack, and Liam O'Toole his assailant. In the fervent flux of the game between Ballintubber and Garrymore lay the genesis of the incident, the first intermediate competition to be held in the county in almost thirty years. It was a thrill a minute tussle with the outcome in doubt up to the end. Garrymore were a point ahead two minutes from the end when their 21 years old star, Billy Fitzpatrick, won possession out on the left flank. With a clear path ahead he commenced another of his distinguished solos. On the terrace, Ballintubber supporter Liam O'Toole yelled for someone to take up the challenge as Fitzpatrick wended menacingly down the wing. Gripped in an irresistible urge to intervene, O'Toole impulsively barged onto the field and wrestled the Garrymore man to the ground. Fans stared in disbelief. "We had been level and I was after scoring a point, "said Billy. "Ballintubber attacked, and our goalie saved a shot. There was a free out for us. Matt Grier the full back took the free. "I was standing all on my own. The short free came out to me. I looked down along the sideline and it was clear. Time was nearly up and I decided to waste time by carrying the ball down the wing. "I had sixty yards to cover and I went off like a bullet. The next thing I was grounded. It was as if something fell from heaven down on top of me. I didn't know what had happened and then I saw this man lying on top of me with his Sunday suit on him." The incident won him a free and served only to run down the clock, as Garrymore held on to win by that single point. What the consequences might have been if they lost is imponderable? Only in the following week did the two men discover that they were related. "My mother and Liam were first cousins. Liam was first cousin of the father of Dublin footballer Anton O'Toole, and I was a first cousin of Anton," said Billy. Liam, who was 37 at the time, said what he did was wrong. John O'Shea of Ballintubber was having problems with his eyes and wanted to be replaced. "I was shouting for a sub to be put on, but the selectors were on the other side of the pitch. And here was this fellow (Billy) going like a hare. He was going for a goal and I got too excited. I couldn't resist it when Billy came up the field." The match was regarded as a classic, with fortunes swaying from end to end and players on both sides reaching singular depths of courage and commitment that obscured the impact the incident might otherwise have had. This reporter saw the funny side of it. "You smiled as you watched a Ballintubber supporter run onto the field to tackle a Garrymore defender in the dying seconds of the game," I wrote. "But you did not blame him. For it was that type of intoxicating game when the scrape of a finger or the bat of an eyelid could mean the difference between victory and defeat." The re enactment of the tackle was the brainchild of Liam O'Toole's granddaughter Niamh Morley who is studying through Media through Irish in Carraroe for her Masters. "We have to do a 10 minute short film for one of our classes. I had a few ideas and then I thought of Granddad. I had heard the story before. I knew he had run onto the pitch and shouldered Billy," said Niamh. She mentioned it to her lecturer and he thought it was hilarious and urged her to run with it. Some of her friends doing the same course came along to McHale Park to help out. Niamh said she had been to matches with her granddad and knew how passionate he was about football. "And being mam's cousin, I knew Billy. "I have to go back to edit it and will use it as a ten minute film for class. Youd never know we might enter it in a competition." The years rest lightly on 84 years old Liam. Lithe and nimble, you would mistake him for a man twenty years younger. The sight of his sprint from the terrace to vigorously tackle Billy in a trial run sent his granddaughter into a paroxysm of laughter. He was a member of the Ballintubber team that beat Swinford in the county junior final of 1954 but which they lost which they on an objection. He went to England for a few years after that and played a lot of football in Birmingham. Highly regarded for his reliability in whatever position he held, Liam returned to marry and settle in his native Ballintubber where he became a leading member of the community and of the local GAA club. He is well known in Irish dancing circles for set dancing. "I can still run. I go dancing every week, and I go out in every set. We have a calendar and we go to where ever they are held. It can be anywhere," he said. "I think the dancing keeps you fit." Nike Roshe Run Woven Men Black,There was no escaping my parents' constant reminders of how blessed we were growing up. I wouldn't say we were well off, but we had enough, and we were taught to be gracious. It's a practice I've continued to exercise as I've grown into an adult. There's always something more to want: A bigger house, a nicer car, a better job, a fancy vacation, or more money. It's easy to look around and see what everyone else has and wish you had it too. It's great to have goals to reach for, but it's just as important to recognize how much you already possess, and be thankful for that. "Gratitude" is kind of a big work for my 3 year old, but there's no better time of year to bring up words like gracious and thankful, so I set out to talk to her about what these words mean. After making a simple and fun gratitude game involving a discussion jar, I made this video of how our first Thanksgiving time discussion of gratitude went. I'm hoping to update it each year with their new and (hopefully) more mature answers. There are lots of other ways to get the discussion going, including some fun crafts you can make together. Here are a handful of ideas to get you going, include a link to the story behind our gratitude jar game. Click theimagesto be taken to the tutorials. This Internet site provides information of a general nature and is designed for educational purposes only. If you have any concerns about your own health or the health of your child, you should always consult with a physician or other healthcare professional.
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