Drugs important in the battle against cancer behaved according to predictions when tested in a computer-generated model of P-glycoprotein, one of the cell’s key molecular pumps.
The new model allows researchers to dock nearly any drug in the P-gp protein and see how it will actually behave in P-gp’s pump, said Associate Professor John G. Wise, lead author on the journal article announcing the advancement and a faculty member in SMU’s Department of Biological Sciences, Dedman College of Humanities and Sciences.
SMU biologists developed the computer generated model to overcome the problem of relying on only static images for the structure of P-gp. The protein is the cellular pump that protects cells by pumping out toxins.
But that’s a problem when P-gp targets chemotherapy drugs as toxic, preventing chemo from killing cancer cells. Scientists are searching for ways to inhibit P-gp’s pumping action.
“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”
The SMU researchers tested Tariquidar, a new P-gp inhibitor still in clinical trials. Inhibitors offer hope for stopping P-gp’s rejection of chemotherapeutics by stalling the protein’s pumping action. Pharmacology researchers disagree, however, on where exactly Tariquidar binds in P-gp.
When run through the SMU model, Tariquidar behaved as expected: It wasn’t effectively pumped from the cell and the researchers observed that it prefers to bind high in the protein.
“Now we have more details on how Tariquidar inhibits P-gp, where it inhibits and what it’s actually binding to,” Wise said.
The new findings indicate that the secret to elite sprinting speeds lies in the distinct limb dynamics sprinters use to elevate ground forces upon foot-ground impact.
“Our new studies show that these elite sprinters don’t use their legs to just bounce off the ground as most other runners do,” said human biomechanics expert Ken Clark, a researcher in the SMU Locomotor Performance Laboratory and lead author on the studies. “The top sprinters have developed a wind-up and delivery mechanism to augment impact forces. Other runners do not do so.”
The new findings address a major performance question that has remained unanswered for more than a decade. Previous studies had established that faster runners attain faster speeds by hitting the ground more forcefully than other runners do in relation to their body weight. However, how faster runners are able to do this was fully unknown. That sparked considerable debate and uncertainty about the best strategies for athletes to enhance ground-force application and speed.
“Elite speed athletes have a running pattern that is distinct,” Clark said. “Our data indicate the fastest sprinters each have identified the same solution for maximizing speed, which strongly implies that when you put the physics and the biology together, there’s only one way to sprint really fast.”
The critical and distinctive gait features identified by the study’s authors occur as the lower limb approaches and impacts the ground, said study co-author and running mechanics expert Peter Weyand, director of the Locomotor Performance Lab.
“We found that the fastest athletes all do the same thing to apply the greater forces needed to attain faster speeds,” Weyand said. “They cock the knee high before driving the foot into the ground, while maintaining a stiff ankle. These actions elevate ground forces by stopping the lower leg abruptly upon impact.”
The new research indicates that the fastest runners decelerate their foot and ankle in just over two-hundredths of a second after initial contact with the ground.
The findings are reported in the Journal of Applied Physiology in the article, “Are running speeds maximized with simple-spring stance mechanics?” It appears online at Physiology.org in advance of appearing in the print journal.
“It is a rare event that geology is a catalyst of public cooperation and celebration,” says geologist and volcano expert Jim Quick, SMU’s associate vice president for research and dean of graduate studies.
The new Sesia-Val Grande Geopark is an example of just that, says Quick, whose international team in 2009 discovered a fossil supervolcano that now sits at the heart of the new geopark. The discovery sparked worldwide scientific interest and a regional geotourism industry.
The communities joined forces more than two years ago to promote the park’s creation, which UNESCO made official in September. The geopark spans tens of thousands of acres and has at its center the massive, 282 million-year-old fossil supervolcano.
“Sesia Valley is unique,” said Quick. “The base of the Earth’s crust is turned up on edge, exposing the volcano’s plumbing — which normally extends deep into the Earth and out of sight. The uplift was created when Africa and Europe began colliding about 30 million years ago and the crust of Italy was turned on end. We call this fossil the ‘Rosetta Stone’ for supervolcanoes because the depth to which rocks are exposed will aid scientific understanding of one of nature’s most massive and violent events and help us to link the geologic and geophysical data.”
The fossil supervolcano was discovered by Quick’s scientific team, which included scientists from Italy’s University of Trieste. The supervolcano has an unprecedented 15 miles of volcano plumbing exposed from the surface to the source of the magma deep within the Earth. Previously, the discovery record for exposed plumbing was about three miles, said Quick.
Only a handful of locations worldwide are chosen annually for UNESCO’s coveted geopark designation, which supports national geological heritage initiatives.
Some adolescents who suffer with symptoms of depression also may be at risk for developing anxiety, according to a new study of children’s mental health.
The study found that among youth who have symptoms of depression, the risk is most severe for those who have one or more of three risk factors, said SMU psychologist Chrystyna Kouros, who led the study.
Specifically, those who are most vulnerable are those who have a pessimistic outlook toward events and circumstances in their lives; those who have mothers with a history of an anxiety disorder; or those who report that the quality of their family relationships is poor, Kouros said.
A depressed adolescent with any one of those circumstances is more at risk for developing anxiety, the researchers found. The findings suggest that mental health professionals could target adolescents with those risk factors. Early intervention might prevent anxiety from developing, Kouros said.
“Depression or anxiety can be debilitating in itself,” said Kouros, an assistant professor of psychology in SMU’s Dedman College of Humanities and Sciences. “Combined, however, they are an even bigger threat to a child’s well-being. That’s particularly the case during adolescence, when pre-teens and teens are concerned about fitting in with their peers. Anxiety can manifest as social phobia, in which kids are afraid to interact with friends and teachers, or in school refusal, in which children try to avoid going to school.”
Kouros co-authored the research with psychiatrist Susanna Quasem and psychologist Judy Garber, both of Vanderbilt University. Data for the study were collected by Garber, a Vanderbilt professor of psychology and human development.
The finding was based on data from 240 children from metropolitan public schools and their mothers, all of whom were assessed annually for six years. The children were followed during the important developmental period from sixth grade through 12th grade. The study was evenly divided between boys and girls.
Consistent with previous research, the authors found also that “symptoms of anxiety were a robust predictor of subsequent elevations in depressive symptoms over time in adolescents.” That link has been known for some time, Kouros said, and the current study confirmed it.
Less well understood by researchers, however, has been the link between depressive symptoms developing further into elevated anxiety, she said.
“The current study showed that depressive symptoms were followed by elevations in anxious symptoms for a subset of youth who had mothers with a history of anxiety, reported low family relationship quality, or had a more negative attributional style,” the authors reported.
SMU graduate student researchers have discovered two new supernovae, and their observations of these massive exploding stars will help improve the astronomical “tape measure” that scientists use to calculate the acceleration of the expansion of the universe.
A supernova discovered Wednesday, Feb. 6, 2013 exploded about 450 million years ago, said Farley Ferrante, a graduate student in the Department of Physics who made the initial observation.
The exploding star is in a relatively empty portion of the sky labeled “anonymous” in the faint constellation Canes Venatici. Home to a handful of galaxies, Canes Venatici is near the constellation Ursa Major, best known for the Big Dipper.
A second supernova discovered Tuesday, Nov. 20, 2012 exploded about 230 million years ago, said Ferrante, who made the initial observation. That exploding star is in one of the many galaxies of the Virgo constellation.
The supernova that exploded about 450 million years ago is officially designated Supernova 2013X. It occurred when life on Earth consisted of creatures in the seas and oceans and along coastlines. Following naming conventions for supernovae, Supernova 2013X was nicknamed “Everest” by Govinda Dhungana, an SMU graduate student who participated in the discovery.
The supernova that exploded about 230 million years ago is officially designated Supernova 2012ha. The light from that explosion has been en route to Earth since the Triassic geologic period, when dinosaurs roamed the planet. “That’s fairly recent as these explosions go,” Ferrante said. Dhungana gave the nickname “Sherpa” to Supernova 2012ha.
Everest and Sherpa are two of about 200 supernovae discovered worldwide in a given year. Before telescopes, supernovae observations were rare — sometimes only several every few centuries, according to the scientists.
“Everest and Sherpa aren’t noteworthy for being the youngest, oldest, closest, furthest or biggest supernovae ever observed,” Ferrante said. “But both, like other supernovae of their kind, are important because they provide us with information for further science.”
Everest and Sherpa are Type 1a supernovae, the result of white dwarf explosions, said Robert Kehoe, physics professor and leader of the astronomy team in the Department of Physics.
The scientists explain that a white dwarf is a dying star that has burned up all its energy. It is about as massive as the Earth’s sun. Its core is about the size of the Earth. The core is dense, however, and one teaspoon of it weighs as much as Mount Everest, Kehoe said.
A white dwarf explodes if fusion restarts by tugging material from a nearby star, according to the scientists. The white dwarf grows to about one and a half times the size of the sun. Unable to support its weight, Kehoe said, collapse is rapid, fusion reignites and the white dwarf explodes. The result is a Type 1a supernova.
“We call these Type 1a supernovae standard candles,” Ferrante said. “Since Type 1a supernovae begin from this standard process, their intrinsic brightness is very similar. So they become a device by which scientists can measure cosmic distance. From Earth, we measure the light intensity of the exploded star. As star distances from Earth increase, their brilliance diminishes.”
While Sherpa is a standard Type 1a, Everest is peculiar. It exhibits the characteristics of a Type 1a called a 1991T, Ferrante said.
“Everest is the result of two white dwarfs that collide, then merge,” he said.
Like other Type 1a supernovae, Everest and Sherpa provide scientists with a tiny piece to the puzzle of one of the greatest mysteries of the universe: What is dark energy?
Every Type 1a supernova provides astronomers with indirect information about dark energy, which makes up 73 percent of the mass-energy in the universe. It’s theorized that dark energy explains the accelerating expansion of our universe at various epochs after the Big Bang.
“Every exploding star observed allows astronomers to more precisely calibrate the increasing speed at which our universe is expanding,” Ferrante said. “The older the explosion, the farther away, the closer it was to the Big Bang and the better it helps us understand dark energy.”