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April 28, 2005


Researchers confirm Einstein’s prediction of cosmic magnification

Applying cutting-edge computer science to a wealth of new astronomical data, University researchers and their colleagues in the Sloan Digital Sky Survey (SDSS) reported this week the first robust detection of cosmic magnification on large scales, confirming a prediction of Einstein’s General Theory of Relativity applied to the distribution of galaxies, dark matter and distant quasars.

These findings, accepted for publication in the Astrophysical Journal, detail the subtle distortions that light undergoes as it travels from distant quasars through the web of dark matter and galaxies before reaching the Earth.

The SDSS discovery ends a two-decade-old disagreement between earlier magnification measurements and other cosmological tests of the relationship between galaxies, dark matter and the overall geometry of the universe.

“The distortion of the shapes of background galaxies due to gravitational lensing was first observed more than a decade ago, but no one had been able to reliably detect the magnification part of the lensing signal,” said lead researcher Ryan Scranton, a postdoctoral fellow in Pitt’s Department of Physics and Astronomy.

As light makes its 10-billion- year journey from a distant quasar, it is deflected and focused by the gravitational pull of dark matter and galaxies, an effect known as gravitational lensing. The SDSS researchers definitively measured the slight brightening, or “magnification,” of quasars and connected the effect to the density of galaxies and dark matter along the path of the quasar light. The SDSS team has detected this magnification in the brightness of 200,000 quasars.

Astronomers have been trying to measure this aspect of gravitational lensing for two decades. However, the magnification signal is a very small effect — as small as a few percent increases in the light coming from each quasar.

Detecting such a small change required a very large sample of quasars with precise measurements of their brightness.

The breakthrough came earlier this year, using a precisely calibrated sample of 13 million galaxies and 200,000 quasars from the SDSS catalog. The data available from the SDSS solved many of the technical problems that had plagued earlier attempts to measure the magnification. However, the key to the new measurement was the development of a novel way to find quasars in the SDSS data. By using new statistical techniques, SDSS scientists were able to extract a sample of quasars 10 times larger than conventional methods, allowing for the extraordinary precision required to find the magnification signal.


Researcher sheds light on alternative gene splicing

Human cells produce more varieties of proteins than can be accounted for by the relatively modest number of genes in the human genome. The key to this protein-coding bounty is alternative splicing, in which one or more transcribed exons — nucleotide sequences that code for a specific segment of the protein — are excluded from the final messenger RNA before it is translated into protein. While the majority of human genes are spliced alternatively, little is known about specific RNA sequences that dictate exclusion of these exons.

In a study published in the May issue of PLoS Biology, Paula Grabowski, a Pitt professor of biology, and colleagues show that three short sequences, two within the excluded exon and one in an adjacent intron, or non-coding nucleotide sequence, trigger exclusion in at least one gene, and probably a large handful of others as well.

Grabowski and colleagues studied this process in a class of proteins essential for brain function called glutamate receptors. As the name implies, the glutamate receptors bind to glutamate, the principal excitatory neurotransmitter in the brain. NMDA glutamate receptors, which play a role in memory formation and neuronal development, are composed of multiple subunits. Within the NR1 subunit, exclusion or inclusion of the CI cassette exon has dramatic functional consequences. The CI exon appears in the forebrain but is virtually absent in the hindbrain. How this differential splicing is regulated is poorly understood.

The authors noted an atypical but highly conserved GGGG motif in the intron just downstream from the splice site that ends the CI exon. When they introduced point mutations in this motif, the exon was included up to four times as often. The rate of exclusion, or silencing, could be increased dramatically by the addition of another GGGG tetrad farther inside the intron.

Systematic mutation within the exon identified a pair of UAGG motifs that also promoted exon silencing, an effect that could be enhanced even further by introducing a third, artificial UAGG. The pair of UAGG tetrads appears to work in combination with the GGGG tetrad, since without the former sequences, the latter had little power to silence CI expression. Silencing is mediated by binding of UAGG to the ribonucleoprotein hnRNP A1, which also apparently interacts with the GGGG within the intron.

The authors next examined a series of genomic database searches to identify these motifs in other genes. They reasoned that if the triad was a common means of exon silencing, it should be overrepresented among genes known to undergo alternative splicing. In more than 90,000 exons in human and mouse genomes, they found 16 with the motif pattern, of which three (19 percent) were known skipped exons. In contrast, among those without the pattern, the proportion of skipped exons was only 5 percent. They also found that the GGGG motif by itself was overrepresented among skipped exons, indicating it probably plays a significant role in exon exclusion even without its UAGG partners.

These results alone cannot explain why one cell type includes an exon while another excludes it, since the primary transcript in different cell types is the same. Instead, these differences likely are explained by tissue-specific differences in levels of splicing factors or binding proteins. With such small absolute gene numbers, it is clear that the specific trio identified by Grabowski and colleagues is only one of many likely to regulate exon inclusion. In the search for others, this study indicates the value of bioinformatics strategies that employ not only specific sequences, but also spatial configurations, the researchers said.


Chili peppers, some veggies may inhibit cancer

Two new studies suggest that vegetables such as broccoli and spices like red chili pepper may provide a cancer-fighting benefit by slowing or preventing the growth of cancerous tumor cells. The finding, presented at the annual meeting of the American Association for Cancer Research, looked at the effect of these dietary agents on cancers that have extremely poor prognoses despite advances in surgery and other therapies.

Sanjay K. Srivastava, lead investigator and assistant professor of pharmacology in the School of Medicine, said: “In our studies, we decided to look at two particular cancers — ovarian and pancreatic — with low survival rates, to ascertain the contribution of diet and nutrition to the development of these cancers. We discovered that red chili pepper and broccoli appear to be effective inhibitors of the cancer process. The contribution of diet and nutrition to cancer risk, prevention and treatment has been a major focus of research in recent years because certain nutrients in vegetables and dietary agents appear to protect the body against diseases such as cancer.”

The first study looked at the chemotherapeutic potential of capsaicin, the “hot” ingredient in red chili pepper that often is associated with antioxidative and anti-inflammatory activities, and found that it exhibited anti-cancer activity against pancreatic cancer cells. Pancreatic cancer is one of the most aggressive cancers with an extremely poor prognosis.

Srivastava and colleagues treated human pancreatic cells with capsaicin and found that it disrupted the mitochondrial function, resulting in the release of cytochrome c, which induced apoptosis, or programmed cell death, in the cancerous cells without affecting normal pancreatic cells.

In the second study, the researchers examined the therapeutic benefits on ovarian cancer of phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables such as broccoli. Ovarian cancer, one of the leading causes of gynecologic cancer-related deaths among women in the United States, often is detected at an advanced stage, making it difficult to treat successfully.

In the study, ovarian cancer cells were exposed to PEITC for 24 hours, which resulted in significant inhibition of the protein expression of epidermal growth factor receptor (EGFR). EGFR plays a crucial role in the growth of ovarian cancer cells. PEITC treatment also inhibited the activation of Akt, which is responsible for protecting cancer cells against apoptosis. The concentrations of PEITC used in the study were at levels that may be achieved through dietary intake.

These studies were supported by a grant from the National Cancer Institute. Co-investigators include Sivakumar Loganathan and Ian Humphreys, both in the Department of Pharmacology, School of Medicine.


Genetic studies rate perfect X

Every week on the CBS network’s new series “Numb3rs,” an FBI agent relies on his math genius brother to find patterns and equations that help to solve crimes. With its new Apple Xserve G5 computing cluster, the Graduate School of Public Health (GSPH) is solving double-helix puzzles in human genetics every day — and faster than a speeding FBI-issue bullet.

Using the school’s newly installed 125-node Xserve cluster, more than 30 investigators and scientific teams engaged in more than 120 complex research projects have all the computing power they could ask for, according to M. Michael Barmada, associate professor of human genetics at GSPH. Paid for with a shared resource grant from the National Institutes of Health, the human genetics computing cluster is among the fastest at an academic medical center in the United States.

“Our division of statistical genetics is looking for genes that influence diseases,” explained Barmada, whose research focuses on the genetic epidemiology of common yet complex disorders such as diabetes and inflammatory bowel disease. “In a sense, we’re gene hunters.”

Barmada and his colleagues are using their new computing power — dubbed locally as the Gattaca Cluster for a 1997 film — to analyze data involving the many genes that lead to variations in human traits, from those that regulate differences in height and bone density to those that influence susceptibility to disease. The Gattaca Cluster supports dozens of highly specialized statistical genetics applications used in ongoing research projects. Using genetic analysis algorithms, the computer can evaluate unique markers that characterize a segment of an individual’s genetic material and attempt to correlate the markers with patterns of transmission through a family or population.

“Our studies — even those that analyze just 400 markers in a population of, say, 20 families with 25 people each — can be extremely intensive,” Barmada said.

David Whitcomb, professor of medicine, cell biology and physiology and human genetics at the School of Medicine, has done extensive studies on the genetic basis of pancreatic cancer, the fifth leading cause of cancer death in the United States. He is excited about the human genetics Xserve cluster’s capacity to increase productivity on these studies, as well as others he is pursuing on pancreatitis, which can lead to pancreatic cancer.

“Most disease is caused by a combination of genetic mutations and environmental stress,” said Whitcomb, who also is chief of the Division of Gastroenterology, Hepatology and Nutrition and director of the Center for Genomic Studies. “Such a combination might give an individual 500 times the average risk of a given disease in the general population or more.”

Trying to sort out genuine risk from arbitrary observation stretches the limits of old statistical methods, Whitcomb added.

“We are looking at the possible interactions of multiple genes and environmental factors in our group of patients,” he said. “There are thousands of possible genetic and environmental factors that might combine to result in disease. The computer can help to predict which factors are disease-causing and which are innocent bystanders.”

This is done by simulating an entire population of people and “testing” a group of imaginary patients with laboratory results from actual patients tens of thousands of times, explained Whitcomb. Eventually, the computer is able to sort out the genetic and environmental factors that may cause complex diseases.


Grant sets up Claude D. Pepper Center of Excellence

Roughly one-third of older adults are burdened with a multitude of health problems related to mobility and balance disorders that pose a risk of falling, a risk that increases with age.

“When older adults are unsure of their physical balance and stability, they become afraid to do things, their independence is lost, they become less active — their whole life changes,” said Stephanie A. Studenski, professor of geriatric medicine at the School of Medicine.

Studenski and her colleagues have received a $7.5 million, five-year research grant from the National Institute on Aging (NIA) to study causes, consequences and effective interventions surrounding mobility and balance disorders in older adults.

The grant enables the creation of a Claude D. Pepper Older Americans Independence Center at Pitt, one of just nine such NIA Centers of Excellence in the country, each with its own specific focus. The mission of the Pittsburgh center is to promote independence among older Americans by reducing the frequency, severity and consequences of mobility and balance disorders.

“Instability may be like senility was 40 years ago — common and considered a normal part of aging — but actually due to definable processes that could lead to specific interventions,” said Studenski, who is principal investigator on the grant and staff geriatrician at the University of Pittsburgh Medical Center (UPMC) and the Pittsburgh VA Health System.

“In both clinical and research settings, assessment of balance and falls and therapeutic exercise are not standardized and may not be targeted toward specific impairments. That is why a team of specialists is needed to look at all physiological, psychological and environmental factors,” she said.

Studenski’s research team includes more than 50 investigators who are specialists from five different schools — School of Medicine, Graduate School of Public Health (GSPH), School of Nursing, School of Health and Rehabilitation Sciences and School of Engineering.

Neil M. Resnick, professor of medicine and chief of the Division of Geriatric Medicine, the School of Medicine, and director of Pitt’s Institute on Aging, said: “This is the very first time that such a comprehensive research team has worked together on this level to understand the causes and consequences of balance disorders in older adults and develop innovative strategies needed to address this very common and disabling condition facing our increasingly older population.”

The Pepper centers, established in 1989, are sponsored by the National Institute on Aging and are named after the late Claude D. Pepper, a U.S. senator who became known as the “spokesman for the elderly” when he was chair of the House Select Committee on Aging from 1977 through 1983.

The Pittsburgh center is the only new Pepper center awarded this year. The other centers are at Harvard, Johns Hopkins, Wake Forest, Yale, UCLA, the University of Maryland, the University of Michigan and the University of Texas at Galveston.

The short-term goals of the Pittsburgh center are to foster the translation of basic research findings into clinical intervention research, develop and evaluate new interventions for balance disorders based on specific causes as well as multi-factor approaches, and serve as a resource to the nation about balance disorders and aging. The long-term goals are to incorporate effective interventions into usual care in diverse health care and community settings, and define evidence-based differential diagnoses of balance disorders for use in clinical practice.

The Pittsburgh center integrates 11 ongoing projects at Pitt and is sponsoring six new projects in the first year. Additional new projects will be funded each year.

The Pittsburgh center has five research resource cores: participants, measurement, technology, data management and analysis, and adherence and retention. The participant core, led by Jane A. Cauley, of the GSPH’s epidemiology department, ensures and optimizes the recruitment and retention of study participants.

The measurement core, led by Debra K. Weiner, School of Medicine departments of medicine, psychiatry and anesthesiology, promotes and facilitates high-quality research with a web-based library of interdisciplinary measures for use by investigators at all levels of training, and consultation on how to use these measures.

The technology core, led by Mark Redfern of the School of Engineering and School of Medicine, provides innovative assessment techniques in the numerous bioengineering and neuro-imaging facilities throughout the campus to promote an understanding of biomechanical, anatomical and physiological influences on balance problems of aging.

The data management and analysis core, led by Susan Sereika of the School of Nursing and GSPH, provides expertise and technical assistance for data management, and quantitative and qualitative analysis.

The adherence and retention core, led by Jacqueline Dunbar-Jacob, School of Nursing dean, provides consultation to investigators regarding the design and development of adherence and retention components of new projects.

In addition to the research cores, there is a research career development core, led by Susan Greenspan of the School of Medicine, that promotes the development of independent researchers in age-related mobility and balance research who can lead and participate in collaborative multidisciplinary projects.

Also, a pilot and exploratory projects core, led by Anne Newman of GSPH and the School of Medicine, supports preliminary studies by senior and junior researchers and promotes innovative research.

A leadership and administration core, led by Studenski, supports conferences, seminars, reporting, budgets, communications and an external advisory committee.

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