Initiative to increase global health research

Updated 3:00 PM December 7, 2005

Scholarship & Creativity

Building a better hydrogen trap
Using building blocks that make up ordinary plastics, but putting them together in a new way, U-M researchers have created a class of lightweight, rigid polymers they predict will be useful for storing hydrogen fuel.

Crystalline sheets produced in covalent organic frameworks. Researchers say the new class of lightweight, rigid polymers will be useful in storing hydrogen fuel. (Image courtesy Adrien Côté)

The work is described in the Nov. 17 issue of the journal Science.

The trick to making the new materials, called covalent organic frameworks (COFs), was coaxing them to assume predictable crystal structures—something that never had been done with rigid plastics.

“Normally, rigid plastics are synthesized by rapid reactions that randomly cross-link polymers,” says postdoctoral fellow Adrien Côté, first author on the Science paper. “Just as in anything you might do, if you do it really fast, it can get disorganized.”

For that reason, the exact internal structures of such materials are poorly understood, making it difficult to predict their properties. But Côté and colleagues tweaked reaction conditions to slow down the process, allowing the materials to crystallize in an organized fashion instead of assembling helter skelter.

As a result, the researchers can use X-ray crystallography to determine the structure of each type of COF they create and, using that information, quickly assess its properties.

“Once we know the structure and properties, our methodology allows us to go back and modify the COF, making it perform better or tailoring it for different applications,” Côté says. “This is the first step to what we think is going to be a very large and useful class of materials,” Côté says.

Côté and Omar Yaghi, the Robert W. Parry Collegiate Professor of Chemistry, collaborated on the research with Assistant Professor of Chemistry Adam Matzger, graduate students Annabelle Benin and Nathan Ockwig, and Arizona State University Professor Michael O’Keeffe.

The work was funded by the National Science Foundation, the U.S. Department of Energy and the Natural Sciences and Engineering Research Council of Canada.
—Nancy Ross-Flanigan, News Service

Are women tougher when it comes to heart disease?
Women with heart problems may be tougher about their disease than their male counterparts, a U-M study suggests. And that difference may help explain why they’re less likely to get aggressive care for the No. 1 killer of both women and men.

In a study published in the November issue of the American Journal of Medicine, researchers from the College of Pharmacy and the Cardiovascular Center (CVC) report the results of an exhaustive survey of 490 heart patients treated at U-M for a heart attack or severe chest pain who were enrolled in a research registry.

In all, the 142 women and 348 men rated the severity of their heart disease about the same. But in fact, the women had much worse disease, took many more medicines, and experienced more serious symptoms and limitations on their daily lives, according to their medical records and answers on standardized questionnaires.

The women who had major problems related to their heart disease were just as likely to rate their disease as mild to moderate as men with much less severe problems. And when the researchers took into account the differences between patients, the men were significantly more likely than women with similar disease levels to perceive their disease as severe.

“It’s important to understand women’s perceptions, beliefs and attitudes about cardiac disease and its treatment,” says senior author Steven Erickson, an associate professor of clinical sciences in the College of Pharmacy and a clinical pharmacist at the U-M Health System (UMHS). “If women do not perceive their cardiac disease as severe, they may not pursue medical evaluation, treatment or rehabilitation.”

The root cause of these gender differences has puzzled researchers for years, says co-author Dr. Kim A. Eagle, CVC clinical director and the Hewlett Professor of Internal Medicine in the Medical School.

In addition to Erickson and Eagle, study authors are first author David Nau, an associate professor in the College of Pharmacy; Jeffrey Ellis, a former Pharmacy Services fellow at UMHS; Eva Kline-Rogers, a member of the Michigan Cardiovascular Outcomes Research and Reporting Program; and Usha Mallya, a former doctoral student in the College of Pharmacy.
—Kara Gavin, UMHS Public Relations

Mice could help make sense of one of the senses
Christopher Nosrat believes his lab has bred mice with an amplified sense of taste.
That could mean more than mice distinguishing cheddar from Swiss. So-called supertaster mice could provide insights into the nerve systems that send signals from the tongue to the brain and how taste buds develop.

Nosrat, an assistant professor of dentistry, recently received a $1.7 million, five-year grant from the National Institutes of Health to study sense of taste.

As part of the NIH grant, Nosrat’s lab bred a transgenic mouse with high levels of brain-derived neurotrophic factor. Nosrat’s earlier work had shown that mice without the protein known as BDNF lost taste buds and nerve connections to the brain, so he wanted to see if extra BDNF had the opposite effect.

Pictures of the mice tongues give strong indications that indeed is the case, as they have about 20 percent more taste buds, and their papillae—the tiny bulb-like structures on the tongue that house taste buds—are much larger. They also have more clusters of taste pores, the opening in a papilla where taste receptor cells come in contact with whatever is being tasted in the mouth.

Nosrat presented his early results at the Society for Neuroscience’s annual meeting in Washington, D.C. He traveled to the conference with Robert Bradley and Charlotte Mistretta, dentistry professors who have studied taste for decades.

One of Nosrat’s next tasks is a series of behavioral tests to find out if his mice really are supertasters.

For example, if you put two water bottles in a mouse’s cage—one with plain water and one with sugar water—watching for their preferences will give an indication of whether they taste a difference.

Proof positive would give confirmation that more BDNF boosts the development of the tasting system, which could lead to treatment for people who’ve lost sense of taste.
—Colleen Newvine, News Service

Unobserved actions of mutual funds can predict performance
Mutual fund investors should consider more than a fund’s past returns or expenses. They also should account for the unobserved actions of mutual fund managers, say business school researchers.

“Despite extensive disclosure requirements, mutual fund investors do not observe all actions of fund managers,” says Lu Zheng, assistant professor of finance at the Stephen M. Ross School of Business. “They do not observe the exact timing of the purchases and the sales of securities and the corresponding transaction costs.

“On the one hand, fund investors bear hidden costs, such as trading costs, agency costs and negative investor externalities. On the other hand, they can benefit from unobserved interim trades by skilled fund managers who can use their informational advantage to time the purchases and the sales of the individual stocks optimally.”

In a new study, Zheng and colleagues Clemens Sialm of the Ross School and Marcin Kacperczyk of the University of British Columbia estimate the impact of unobserved actions on mutual fund returns by using the return gap—the difference between the actual fund return and the buy-and-hold return of a portfolio that invests in the previously disclosed holdings.

Funds with favorable past return gaps tend to perform consistently better before and after adjusting for differences in their risks and styles, they say. The top 10 percent of funds with the highest lagged return gap yields an average excess return of 1.2 percent per year relative to the market return, whereas the bottom 10 percent of funds with the lowest return gap yields an average excess return of -2.2 percent per year.

“Since funds with low correlations are more opaque, unobserved actions are more important for these funds,” says Sialm, assistant professor of finance. “Our results indicate that such opaque funds tend to exhibit particularly low return gaps, which suggests that these funds are subject to more agency problems, which induce them to camouflage their effective portfolio strategies.”
—Bernie DeGroat, News Service

Radiation treatment prolongs liver cancer patients’ lives
Surgery is the most effective way to treat tumors that grow in the liver, but for most patients, the tumor is growing in a way that it can’t be removed. When that happens, few options remain.

Researchers at the Comprehensive Cancer Center are reporting success with a new method of attacking cancerous tumors. Radiation is aimed precisely at the tumor—not the entire liver—and 400 times the normal amount of chemotherapy is fed directly to the liver. The combination delivers an intensive punch to the tumors while limiting exposure to normal tissue.

In results of a study reported in the Dec. 1 issue of the Journal of Clinical Oncology, patients received radiation twice daily for two weeks, along with a continuous infusion of the chemotherapy drug floxuridine. The patients then had a two-week break before repeating the radiation and chemotherapy regimen for another two weeks.

The treatment was developed by Dr. Theodore Lawrence, the Isadore Lampe Professor and Chair of Radiation Oncology, and Dr. William Ensminger, professor of internal medicine.

“The patients with metastatic colorectal cancer who were entered in this trial, for example, were for the most part out of chemotherapy options at the time of referral. These are patients that we estimate would have had a life expectancy of nine, maybe 12 months. They also did not have any surgical or other local treatment options,” says lead study author Dr. Edgar Ben-Josef, associate professor of radiation oncology in the Medical School.

Additional study authors are Daniel Normolle, research assistant professor of radiation oncology; Suzette Walker, nurse practitioner; Daniel Tatro, radiation therapy dosimetrist; Randall K. Ten Haken, professor of radiation oncology; Dr. James Knol, associate professor of surgery; Dr. Laura Dawson, clinical assistant professor of radiation oncology; and Dr. Charlie Pan, a lecturer in radiation oncology.

Funding for the study was from the National Institutes of Health.
—Nicole Fawcett, Comprehensive Cancer Center

Titan gives clues to Earth’s early history
Readings from the Huygens probe of the surface and atmosphere around Saturn’s largest moon, Titan, give researchers a peek back through time to when and how Earth’s atmosphere formed, and how our primitive planet looked before life took a foothold.

This stereographic projection of Descent Imager/Spectral Radiometer images from the European Space Agency’s Huygens probe combines 60 images in 31 triplets, projected from a height of 3,000 meters (9,843 feet) above the black ‘lakebed’ surface. The bright area to the north (top of the image) and west is higher than the rest of the terrain, and covered in dark lines that appear to be drainage channels.

The images were then stitched together using one of several projection algorithms (in this case ‘stereographic’) to produce a full mosaic. The images used to construct this mosaic were taken on Jan. 14, 2005.

The Cassini-Huygens mission is a cooperative project of NASA, the European Space Agency and the Italian Space Agency. The Jet Propulsion Laboratory, a division of the California Institute of Technology in Pasadena, manages the Cassini-Huygens mission for NASA’s Science Mission Directorate, Washington, D.C. The Cassini orbiter was designed, developed and assembled at JPL. The Descent Imager/Spectral team is based at the University of Arizona, Tucson, Ariz. (Photo by ESA/NASA/JPL/University of Arizona)

The Huygens space probe, launched from the Cassini spacecraft Dec. 25, 2004, took the first direct measurements of Titan’s atmosphere and surface as it parachuted onto the moon Jan.14. The instrument that made the measurements, called Gas Chromatograph Mass Spectrometer (GCMS), was built by the Goddard Space Flight Center and U-M.

The new findings are outlined in the paper, “The Abundances of Constituents of Titan’s Atmosphere From the GCMS Instrument on the Huygens Probe,” available in the on-line edition of the journal Nature.

The spectrometer recorded several new and important findings, says Sushil Atreya, professor of atmospheric, oceanic, and space sciences (AOSS) and a member of the team. Atreya and George Carignan, AOSS research scientist emeritus, helped design the spectrometer and interpret the readings.

The first and perhaps most significant discovery, Atreya says, is the spectrometer did not detect the primordial noble gases. Their detection would have signaled that the atmosphere on Titan today is the same as acquired at the time of Titan’s formation.

Instead, nitrogen on Titan formed from ammonia, which is believed to be the same way nitrogen formed on Earth.

“Titan and Earth have a lot of similarities from the very beginning,” Atreya says. “The most important aspect of Titan is that it has an Earth-like atmosphere. No other body in the solar system outside Earth has a massive nitrogen atmosphere. It’s like a window into the past of the Earth.”

The spectrometer also discovered that methane is the second most abundant gas on Titan, comprising 5 percent of the atmospheric volume. Surprisingly, methane was found to play a similar role on Titan as does water in the hydrological cycle on Earth.
—Laura Bailey, News Service

New tool makes cell membranes faster, cheaper
A laboratory testing chip developed at U-M should make it quicker and cheaper to test drug interactions with cell membranes, and could prove invaluable to an emerging field called lipidomics.

The device, called a lipid membrane chip, enables researchers to make many different types of artificial cell membranes with various lipid compositions simultaneously and on the same chip, which in turn makes it possible to run multiple drug interaction tests at once, says Michael Mayer, assistant professor of biomedical engineering and chemical engineering in the College of Engineering.

The lipid membrane is a sort of film around the cell that holds the cell together—much like a balloon filled with water—with permeability regulated by the cell. Once viewed as passive elements, scientists now realize that the lipid layer can play a role in serious diseases, including cancer and diabetes, Mayer says.

The emerging field of lipidomics examines how different lipids affect the function of the cell membrane. Mayer and doctoral student Sheereen Majd co-wrote a paper on the new testing method that is available online in the journal Angewandte Chemie International Edition.

The most common current technology for membrane test chips puts individual droplets of lipid one-by-one onto a surface for testing. This method takes time and consumes precious laboratory chemicals. The U-M method stamps artificial membranes with various lipid composition onto a glass surface, much like a common office stamp. A hydrogel stamp with the consistency of hard jelly absorbs the lipids like a sponge so the stamp can be used to “print” more than 100 times without re-inking. The raised portions of the stamp, or posts, can be inked with different lipid compounds. A two-by-two inch stamp could hold more than 150 posts per square inch, Mayer says.

While testing the new hydrogel stamp, Mayer and Majd showed that the prescription anti-inflammatory nimesulide’s interaction with the lipid membrane varied, depending on the membrane’s cholesterol content.
—Laura Bailey, News Service

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