Biology & Biochemistry

BC and BU Awarded Program Project Grant to Study White Blood Cells Involved in Leukemia

2011-10-24T12:00:00.000-07:00

Professor Thomas Chiles of the Biology Department, and colleagues at Boston University Medical Center, have been awarded a five-year, multimillion-dollar program project grant from the National Institutes of Allergy and Infectious Disease of the National Institutes of Health (NIH).

Their research will focus on understanding the growth and differentiation of a small subset of white blood cells called B-1a lymphocytes (B-1a cells). B-1a cells, which are found in the peritoneal cavity, and B-2 cells, which are located in the spleen and lymph nodes, help destroy pathogens that enter the body, and then help the body acquire immunity against those particular pathogens, protecting the body from future invasion. However, an over-production of B-1a cells can lead to autoimmune diseases and leukemias.

Thomas Chiles's group at Boston College, working with Dr. Thomas Rothstein of Boston University's Department of Medicine, previously demonstrated that the rules that govern cell cycle control and differentiation to immunoglobulin-secreting plasma cells are different in B-1a cells than in B-2 cells.

As part of the new NIH-funded program project, research carried out at Boston College will seek to better understand the molecular mechanisms that control when B-1a cells enter the cell cycle and proliferate. Insights from these studies will help us understand the molecular basis of several human lymphoproliferative disorders associated with B-1a cells, including a form of cancer called chronic lymphocytic leukemia.

Chronic lymphocytic leukemia, which involves overproduction of white blood cells by the bone marrow, is the most common type of leukemia in adults.

To learn more about research going on in the Chiles Laboratory, please visit:
bc/schools/cas/biology/facadmin/chiles/

BY JOHN P. ROCHE

Maintained: Biology Department

URL: bc/schools/cas/biology/news/chiles/

© 2004 The Trustees of Boston College

New Book Uses ABCs To Teach Children Microbiology

2011-10-21T12:00:00.000-07:00

A new children's book from ASM Press uses the familiar genre of the ABC book to introduce readers to the not-so-familiar world of microbes. The Invisible ABCs will delight readers of all ages with its colorful presentation and spectacular selection of illustrations. Intended for school-age children and younger, this unique new book will stimulate parents, teachers, librarians, and even older students to discover the fascinating world of microorganisms.

"We are immersed in microbes. They live in our bodies, in our food, and in everything that surrounds us; we cannot live without them. The Invisible ABCs presents answers to questions that we all have an interest in, such as 'Why can cows use grass for food but humans can't?' and 'Why do we get gas after we eat beans?'" says author Rodney Anderson, a microbiologist and professor at Ohio Northern University, who presents photos he has collected of microorganisms shaped like letters of the alphabet to illustrate the significant role microbes play in our daily lives.

This intriguing book contains a glossary of important terms, as well as endpapers illustrating the relative size of organisms from viruses to whales. Age-appropriate vocabulary and examples are used to communicate important scientific principles and concepts throughout the vibrant pages of The Invisible ABCs. A companion website provides deeper understanding for those who seek to learn more about microorganisms.

The Invisible ABCs can be purchased through ASM Press online at estore.asm/ or through other online retailers.

ASM Press is the book publishing arm of the American Society for Microbiology (ASM), the oldest and largest single life science membership organization in the world. The ASM's mission is to promote research in the microbiological sciences and to assist communication between scientists, policy makers, and the public to improve health and foster economic well-being.

Contact: Jim Sliwa

American Society for Microbiology

Worldwide Research Archive Doubles In Size Since 2004

2011-10-18T12:00:00.000-07:00

The Protein Data Bank this month reached a significant milestone in its 37-year history as the 50,000th molecule structure was released into its archive, joining other structures vital to pharmacology, bioinformatics, and education.

With its origins in a handwritten petition circulated at a scientific meeting, the PDB is the single worldwide repository for the three-dimensional structures of large molecules and nucleic acids. This freely available online library allows biological researchers and students to study, store and share molecular information on a global scale. Officially founded in 1971 with seven structures at Brookhaven National Laboratory, the archive is currently managed by a consortium called the worldwide Protein Data Bank (wwPDB).

Today, the PDB archive receives approximately 25 new experimentally-determined structures from scientists each day - and more than 5 million files are downloaded from the PDB archive every month. Users include structural biologists, computational biologists, biochemists, and molecular biologists in academia, government, and industry as well as educators and students.

Notable examples include recent structures of the adrenergic receptor, which will revolutionize the discovery of drugs to fight heart disease, allergies, and numerous other diseases, and the many structures of enzymes from HIV, which have been pivotal in the design of new therapies to fight AIDS.

"Advances in science and technology have helped the archive grow by leaps and bounds in the last 10 years," said Dr. Helen M. Berman, director of the RCSB PDB and Board of Governors professor of chemistry and chemical biology, noting that the size of the PDB has doubled in just the last three-and-a-half years.

"We are estimating that the PDB will not only double, but triple to 150,000 structures by 2014," said Dr. Philip E. Bourne, Associate Director of the RCSB PDB and professor of pharmacology at the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.

The RCSB PDB is based at Rutgers University in New Jersey, and the San Diego Supercomputer Center (SDSC) and Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California at San Diego. Bourne, a distinguished scientist with SDSC, has been leveraging the resources of the supercomputer center to create a highly uniform and robust process for archiving and providing access to the molecular structures.

The RCSB PDB is responsible for releasing PDB entries into the archive after they have been reviewed and annotated. At Rutgers, RCSB PDB members annotate structures and develop the sophisticated infrastructure needed to handle these complex data. The primary PDB FTP site is based at SDSC, which serves as the distribution point for PDB users. In addition to the SDSC site, there are failover sites at both the UCSD Skaggs School and Rutgers University to ensure constant access.

In addition to a comprehensive website and database that lets users search, analyze, and visualize the structures of biological macromolecules and their relationships to sequence, function, and disease, the RCSB PDB features a Molecule of the Month series, which recently published its 100th installment. Proteins, one of the main building blocks for living organisms, come in a variety of shapes, with the form of a protein corresponding to its function. The structures housed in the PDB demonstrate great diversity in size, complexity, and function, including:
Insulin, the protein deficient in diabetic patients

p53 tumor suppressor, a protein often implicated in cancer

Anthrax toxin, the disease-causing protein made by anthrax

Amyloid peptide, a protein implicated in Alzheimer's disease

The RCSB PDB is supported by funds from the National Science Foundation, the National Institute of General Medical Sciences, the Office of Science, the Department of Energy, the National Library of Medicine, the National Cancer Institute, the National Center for Research Resources, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes & Digestive & Kidney Diseases.

Source: Jan Zverina

University of California - San Diego

Study Identifies New Mechanism Linking Activation Of Key Heart Enzyme And Oxidative Stress

2011-10-15T12:00:00.000-07:00

A study, led by University of Iowa researchers, reveals a new dimension for a key heart enzyme and sheds light on an important biological pathway involved in cell death in heart disease. The study, published in the May 2 issue of Cell, has implications for understanding, and potentially for diagnosing and treating, heart failure and arrhythmias.

The UI researchers and colleagues from Vanderbilt University in Nashville, Tenn., focused on calmodulin kinase II, or CaM kinase II, a well-studied enzyme critical to many fundamental processes including heartbeat and thought.

Scientists know that CaM kinase's activity is sustained by adding a phosphate group -- a process known as phosphorylation. The new study proves that oxidation -- adding oxygen -- also can sustain the enzyme's activity, and like phosphorylation, the mechanism can be reversed to inactivate the kinase.

"Our results suggest that oxidation of CaM kinase is a dynamic and reversible process that may direct cell signaling in health and disease," said Mark Anderson, M.D., Ph.D., UI professor of internal medicine and molecular physiology and biophysics and senior study author. "Because CaM kinase activity is involved in arrhythmias, hypertrophy and heart cell death, this work also provides new insights into a disease pathway in heart that may lead to development of new drugs to treat heart disease."

In patients with heart failure, the level of angiotensin II -- a signaling molecule that promotes oxidation and cell death -- is elevated. Using a specially created antibody, the researchers found that angiotensin II also increases the amount of oxidized CaM kinase.

In addition, by replacing the cell's normal CaM kinase with a CaM kinase unable to be oxidized, the scientists were able to block angiotensin-induced cell death. Scientists hope this discovery might lead to therapies that prevent cell death by blocking CaM kinase oxidation.

Currently, "angiotensin-blockers" are a mainstay for treating patients with sick hearts, but they work indirectly by targeting receptors on the cell surface. Anderson, who also is the Potter-Lambert Chair in Cardiology and director of the UI Division of Cardiovascular Medicine, suggested that by understanding the signaling mechanisms that occur inside the cell, it might be possible to inhibit the angiotensin pathway more directly. This approach may also preserve some of the good effects mediated by the cell surface receptor.

Using a wide range of scientific techniques and experimental methods, the team, led by Anderson and Jeffrey Erickson, Ph.D., a UI postdoctoral fellow, pinned down the details of the internal signaling mechanism.

Specifically, they showed that oxidation of two neighboring methionines -- sulfur-containing amino acids -- can sustain CaM kinase activity. Loss of these two methionines prevents activation by oxidation. They also found that they could return CaM kinase to its inactive state and inhibit heart cell death and dysfunction by using an enzyme called methionine sulfoxide reductase A (msrA), which reverses the methionine oxidation. Studies in worms, fruit flies and mice have shown that msrA increases lifespan, but, until now, the enzyme's targets in heart were unknown.

The UI team compared mice without the msrA enzyme to normal mice when the animals underwent disease stresses, including excess angiotensin or induced heart attacks. The mice without msrA were more likely to die than normal mice under these circumstances, and the levels of oxidized CaM kinase were much higher in mice that lacked the enzyme.

Anderson speculated that the findings could implicate msrA as a susceptibility gene for patients - potentially, variations in the gene might help explain why some people do so badly after a heart attack where others do well.

The study demonstrates a direct link between CaM kinase activation and oxidative stress, two processes that are implicated in a wide variety of physiological and disease states. These findings will likely have broad implications and applications in basic research, diagnostics and new therapeutic approaches and represent an example of translation science of the type supported and encouraged by the new Institute for Clinical and Translational Science at the UI.

"This study also is a great example of collaborative science," added Anderson. "We had to apply expertise from several different labs to tackle this problem. So, the ease with which we can collaborate across disciplines at the UI and between institutions was enormously beneficial."

The work involved researchers from the UI Roy J. and Lucille A. Carver College of Medicine's Departments of Internal Medicine, Radiation Oncology and Biochemistry; and Vanderbilt University.

In addition to Anderson and Erickson, the UI researchers included Peter Mohler, Ph.D., assistant professor of internal medicine; Douglas Spitz, Ph.D., professor of radiation oncology in the Free Radical and Radiation Biology Graduate Program; Robert Weiss, M.D., professor of internal medicine; Madeline Shea, Ph.D., professor of biochemistry; Mei-ling Joiner, Xiaoqun Guan, Ph.D.; William Kutschke; Jinying Yang; John Lowe; Susan O'Donnell; Nukhet Aykin-Burns, Ph.D.; Matthew Zimmerman, Ph.D.; and Kathy Zimmerman.

The researchers from Vanderbilt University included, Carmine Oddis, M.D.; Ryan Bartlett, Ph.D.; Amy-Joan Ham, Ph.D.; and Roger Colbran, Ph.D.

The study was funded in part by the National Institutes of Health, the Pew Charitable Trust and the UI Research Foundation.

Source:

University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

Jennifer Brown

University of Iowa

Identification Of Stem Cells That Repair Injured Muscles Has Important Implications For Muscular Dystrophy

2011-10-12T12:00:00.000-07:00

A University of Colorado at Boulder research team has identified a type of skeletal muscle stem cell that contributes to the repair of damaged muscles in mice, which could have important implications in the treatment of injured, diseased or aging muscle tissue in humans, including the ravages of muscular dystrophy.

The newly identified stem cells are found within populations of satellite cells located between muscle fibers and the surrounding connective tissue that are responsible for the repair and maintenance of skeletal muscles, said Professor Bradley Olwin of CU-Boulder's molecular, cellular and developmental biology department.

When muscle fibers are stressed or traumatized, satellite cells divide to make more specialized muscle cells and repair the muscle, said Olwin. The stem cell population identified by the CU team within the satellite cells -- dubbed "satellite-SP" cells -- were shown to renew the satellite cell population after injection into injured muscle cells, contributing to recovery of muscle tissue in the laboratory mice.

"This research shows how satellite cells can maintain their populations within injured tissues," said Olwin. "The hope is this new method will allow us to repair damaged or diseased skeletal muscle tissue."

A paper on the subject was published in the March 5 issue of the journal Cell Stem Cell. Co-authors on the study included the MCD biology department's Kathleen Tanaka, John Hall and Andrew Troy, as well as Dawn Cornelison from the University of Missouri and Susan Majka from the University of Colorado Denver.

Stem cells are distinguished by their ability to renew themselves through cell division and differentiate into specialized cell types. In healthy skeletal muscle tissue, the population of satellite cells is constantly maintained, leading the CU-Boulder team to believe that at least some of the satellite cell population in the mouse study included stem cells.

For the study, the researchers injected 2,500 satellite-SP cells into a population of satellite cells within injured mouse muscle tissue. They found that 75 percent of the satellite cells that reproduced were derived from the previous satellite-SP cells injected into the tissue. The results demonstrated the injected satellite-SP cells were renewing the satellite cell pool, Olwin said.

"The key point here is we are not just repairing the tissue," said Olwin. "We injected a permanent, self-renewing population of stem cells. One advantage of using this technology is that we can use a relatively small number of stem cells and do the job with a small number of injections -- in this case, only one."

The research has implications for a number of human diseases, he said. In muscular dystrophy, the loss of a protein called dystrophin causes the muscle to literally tear itself apart, a process that cannot be repaired without cell-based intervention. Although injected cells will repair the muscle fibers, maintaining the muscle fibers requires additional cell injections.

The research was funded in part by the National Institutes of Health and the Muscular Dystrophy Association. Olwin is now collaborating with a group at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle to extend the research.

Source: Bradley Olwin

University of Colorado at Boulder

Deadly Fungus Decimating Bat Populations Cannot Be Controlled By Culling

2011-10-09T12:00:00.000-07:00

Culling will not stop the spread of a deadly fungus that is threatening to wipe out hibernating bats in North America, according to a new mathematical model.

White-nose syndrome, which is estimated to have killed over a million bats in a three year period, is probably caused by a newly discovered cold-adapted fungus, Geomyces destructans. The new model examines how WNS is passed from bat to bat and concludes that culling would not work because of the complexity of bat life history and because the fungal pathogen occurs in the caves and mines where the bats live.

"Because the disease is highly virulent, our model results support the hypothesis that transmission occurs in all contact areas," write the paper's authors, Tom Hallam and Gary McCracken, both of the University of Tennessee. "Our simulations indicated culling will not control WNS in bats primarily because contact rates are high among colonial bats, contact occurs in multiple arenas, and periodic movement between arenas occurs."

Ground work on the model was initiated in a 2009 modeling workshop on white-nose syndrome held at the National Institute for Mathematical and Biological Synthesis (NIMBioS) in Knoxville, Tennessee. At the interdisciplinary workshop, experts in the fields of bat physiology, fungal ecology, ecotoxicology, and epidemiology discussed ways in which mathematical modeling could be applied to predict and control the spread of WNS.

"NIMBioS' support for the workshop that initiated this project was crucial in helping formulate models that could be useful in looking at white-nose syndrome," Hallam said.

Culling of bats in areas where the disease is present is one of several options that have been considered by state and federal agencies as a way to control the disease. However, a review of management options for controlling WNS in the paper indicates that culling is ineffective for disease control in wild animals and in some cases, can exacerbate the spread.

White-nose syndrome first appeared in a cave in upstate New York in 2006, and has since spread to 14 states and as far north as Canada. Regional extinctions of the most common bat species, the little brown bat, are predicted within two decades due to WNS.

Eating up to two-thirds of their body weight in insects every night, bats help suppress insect populations ultimately reducing crop damage and the quantities of insecticides used on crops. Bats also play an important ecological role in plant pollination and seed dissemination.

Citations: Hallam TG, McCracken GF. 2011. Management of the panzootic white-nose syndrome through culling of bats. Conservation Biology 25(1): 189-194.

Source:

Catherine Crawley

National Institute for Mathematical and Biological Synthesis (NIMBioS)

New $1.16 Million Study Investigates How Dietary Iron Is Used By Cells

2011-10-06T12:00:00.000-07:00

A four-year study on iron metabolism within cells, an essential process that impacts both iron deficiency and iron toxicity, conditions responsible for a multitude of human diseases, is underway at the University at Buffalo funded by a $1.16 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Daniel Kosman, Ph.D., professor of biochemistry in the UB School of Medicine and Biomedical Sciences, is lead researcher on the study.

"The concern about how iron is managed in our cells has never been more acute," said Kosman. "The reasons for this are three-fold. First is the endemic problem of iron deficiency that the World Health Organization estimates afflicts 80 percent of the world's population, or more than 5 billion people.

"Iron deficiency is not confined to developing nations. In the U.S., 5 percent of newborns and 7 percent of new mothers have clinical symptoms of iron deficiency. Reducing the incidence of this nutritional deficit is one of the objectives of the U.S. Department of Health and Human Services' Healthy People 2010 program.

"Second is the broad recognition that the 'corrosive chemistry' associated with iron and oxygen interactions is a major factor in a multitude of human diseases."

Too much iron in tissues, called iron-loading, is thought to increase the risk of tumor development, infection, cardiomyopathy, joint disorders and several endocrine and neurodegenerative disorders.

"And third, we now have an increasingly sophisticated knowledge and understanding of iron metabolic pathways, the proteins involved in these pathways and how these pathways are regulated in all organisms, making this issue ripe for investigation," he said.

Kosman proposes that a general mechanism of cellular iron metabolism requires that iron-handling proteins involved in sequential steps in the pathway must be "architecturally arranged" contiguously in the cell's membranes, at the interfaces between membranes and soluble compartments or within soluble compartments.

The researchers will test this form-function model of ionic iron metabolism by focusing on three steps critical to maintaining the proper balance of iron in cells: 1) the reduction of ferric to ferrous iron and the subsequent transport of ferrous iron into a cell; 2) the "hand-off" of this ferrous iron from a membrane protein to iron chaperones in the cell's cytoplasm; and 3) the utilization of this ionic iron for the activation of essential iron-containing enzymes.

"These three components of cellular iron metabolism are relatively under-investigated," said Kosman, "yet they represent the essence of cell iron metabolism in all organisms."

Understanding the intermediary metabolism of iron is one of the primary objectives of a program announcement from NIH titled "Metals In Medicine," he noted. This announcement encourages studies that lead to the "identification and characterization of the macromolecular players and vesicular compartments involved in metal ion homeostasis and metal trafficking."

Arvinder Singh, Ph.D., a post-doctoral research associate in Kosman's lab; and William E. Wiltsie, a doctoral candidate in biochemistry, also will be involved in the research.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs.

Contact: Lois Baker

University at Buffalo

Minor Genetic Differences Between Individuals Change The Effect Of A Common Medication, Study Shows

2011-10-03T12:00:00.000-07:00

Medicine has moved a little bit closer to the era of tailor-made treatments, based on the unique genetic profiles of individual patients, according to recent research conducted by Dr Rima Rozen of the Research Institute of the McGill University Health Centre (RI MUHC) at the Montreal Children's Hospital and McGill University. Her study, published June 18 in the journal Pharmacogenetics and Genomics, shows how minor genetic differences between individuals alter the way a common drug affects the body.

Rozen has measured the impact of Methotrexate -- a drug that inhibits the metabolism of folate -- on mice with an altered MTHFR gene, which is a gene crucial for folate metabolism. The results were striking: after treatment with Methotrexate, mice with the altered gene had approximately 20 per cent less hemoglobin and red blood cells than their counterparts with non-altered genes. The altered mice also showed increased susceptibility to liver and kidney damage following treatment.

"We know that these results are applicable to humans because a parallel mutation in the human MTHFR gene affects human folate metabolism similarly. The results demonstrate that medication affects subjects differently according to individual genetic traits," Dr. Rozen explained. "And tests exist to detect this mutation." Genetic testing would allow physicians the modify treatment based on each patient's personal genetic makeup, limiting potential side effects.

In earlier studies, Rozen's laboratory cloned the MTHFR gene and identified the common variant which interferes in folate metabolism in human populations. Between 10 and 15 per cent of the total caucasian population have two copies of the variant in MTHFR. Folate, a form of water-soluble Vitamin B2, is essential to the production of red blood cells and provides protection against spina bifida, other birth defects, and heart disease. Patients with cancer or auto-immune diseases are often treated with medications that affect folate metabolism, but physicians are not trained to verify how patients naturally metabolize folate, even though this could be an important factor in effective treatment.

"This is a first step towards personalized medicine that is based not only on symptoms but also on the patient's own genetic 'baggage,'" Rozen said. "This trend definitely represents the medicine of the future."

This release is available in French.

Dr. Rima Rozen is a Scientist in the Medical Genetics and Genomics Axis of the RI MUHC at the Montreal Children's Hospital. At McGill University, she holds the positions of Associate Vice-Principal (Research and International Relations) and Professor in the Human Genetics, Pediatrics and Biology Departments.

This study was funded by the Canadian Institutes of Health Research (CIHR) and the U.S. National Institutes of Health (NIH). Students working on Dr. Rozen's study also received scholarships, such as a Turkish Higher Education Council-Hacettepe University Hospital scholarship, a Cole Foundation Award, and a Studentship Award from the Montreal Children's Hospital Research Institute.

The Montreal Children's Hospital (MCH) is the pediatric teaching hospital of the McGill University Health Centre (MUHC) and is affiliated with McGill University. The MCH is a leader in providing a broad spectrum of highly specialized care to newborns, children, and adolescents from across Quebec. Our areas of medical expertise include programs in brain development/behaviour, cardiovascular sciences, critical care, medical genetics and oncology, tertiary medical and surgical services, and trauma care. Fully bilingual, the hospital also promotes multiculturalism and serves an increasingly diverse community in more than 50 languages. The Montreal Children's Hospital sets itself apart with its team approach to innovative patient care. Our health professionals and staff are dedicated to ensuring children and their families receive exceptional health care in a friendly and supportive environment.

The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.

The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santГ© du QuГ©bec.

For further details visit: muhc.ca/research.

Source: Isabelle Kling

McGill University Health Centre

First Compound That Specifically Kills Cancer Stem Cells Found

2011-09-30T12:00:00.000-07:00

The cancer stem cells that drive tumor growth and resist chemotherapies and radiation treatments that kill other cancer cells aren't invincible after all. Researchers reporting online on August 13th in the journal Cell, a Cell Press publication, have discovered the first compound that targets those cancer stem cells directly.

"It wasn't clear it would be possible to find compounds that selectively kill cancer stem cells," said Piyush Gupta of the Massachusetts Institute of Technology (MIT) and the Broad Institute. "We've shown it can be done."

The team including MIT's Robert Weinberg and the Broad Institute's Eric Lander developed a new high-throughput screening method that makes it possible for the first time to systematically look for agents that kill cancer stem cells. That ability had previously eluded researchers due to the rarity of those cells within tumor cell populations and their relative instability in laboratory culture.

In the new study, the researchers manipulated cultured breast cancer cells to greatly enrich for those with the stem-like properties, including increased resistance to standard cancer drugs. They then screened a library of 16,000 natural and commercial chemical compounds for their ability to kill those stem-like cells and not other cancer cells. That screen turned up 32 contenders.

The researchers narrowed that list down to a handful of chemicals that they could readily get in sufficient quantities for further testing on normal cancer stem cells. Of those, one called salinomycin was the clear winner.

Salinomycin reduced the proportion of breast cancer stem cells by more than 100-fold compared to a commonly used chemotherapeutic drug for breast cancer called paclitaxel (aka Taxol™). Salinomycin-treated cells were less able than paclitaxel-treated ones to seed tumors when injected into mice, they report. Salinomycin treatment also slowed the growth of the animals' tumors.

Studies of salinomycin-treated human breast tumors also showed a loss in the activity of genes associated with cancer stem cells.

Exactly how salinomycin's works against cancer stem cells, the researchers don't yet know. As its name suggests, the chemical has antibiotic properties that likely aren't relevant to its newfound cancer stem cell-killing ability. It also disturbs cells' potassium balance.

It remains unclear whether salinomycin itself might find its way to the clinic, Gupta said, since many pharmaceutical steps are involved in the drug discovery process. Nevertheless, the chemical does serve as an immediate tool for manipulating cancer stem cell numbers and observing the effects on cancer's spread and progression.

The findings also highlight a new avenue for the development of cancer therapies, the researchers say.

" To date, rational cancer therapies have been designed to target specific genetic alterations present within tumors," they wrote. "The findings here indicate that a second approach may also prove useful - namely, searching for agents that target specific states of cancer cell differentiation. Accordingly, future therapies could offer greater possibilities for individualized treatment by considering both the genetic alterations and differentiation states present within the cancer cells of a tumor at the time of diagnosis."

They envision a future in which combination therapies might couple more traditional cancer drugs with those designed to hit the cancer stem cells that would otherwise get left behind.

The researchers include Piyush B. Gupta, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Tamer T. Onder, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA; Guozhi Jiang, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Kai Tao, Tufts Medical Center, Boston, MA; Charlotte Kuperwasser, Tufts Medical Center, Boston, MA; Robert A. Weinberg, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, MIT Ludwig Center for Molecular Oncology, Cambridge, MA; and Eric S. Lander, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Harvard Medical School, Boston, MA.

Source:
Cathleen Genova

Cell Press

View drug information on Taxol.

Paradoxical Protein Might Prevent Cancer

2011-09-27T12:00:00.000-07:00

One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.

Molecular signal pathways that stimulate the division of stem cells are generally the same as those active in tumour growth. This limits the possibility of treating cancer as the drugs that kill cancer cells also often adversely affect the body's healthy cells, particularly stem cells. A new study from Karolinska Institutet, conducted in collaboration with an international team of scientists led by Professor Jonas FrisГ©n, is now focusing on an exception that can make it possible to treat a form of colon cancer.

The results concern a group of signal proteins called EphB receptors. These proteins stimulate the division of stem cells in the intestine and can contribute to the formation of adenoma (polyps), which are known to carry a risk of cancer. Paradoxically, these same proteins also prevent the adenoma from growing unchecked and becoming cancerous.

The new results show that EphB controls two separate signal pathways, one of which stimulates cell division and the other that curbs the cells' ability to become cancerous. Using this knowledge, the scientists have identified a drug substance called imatinib, which can inhibit the first signal pathway without affecting the other, protective, pathway.

"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," says Maria Genander, one of the researchers involved in the study.

Imatinib has so far proved to inhibit cell division in intestinal tumour cells in vitro and in mice. The substance is a component of the drug Glivec, which is used, amongst other things, in the treatment of certain forms of leukaemia. Whether it can also be used against adenoma and colon cancer in humans remains to be seen. The company that manufactures the drug did not fund the study.

Publication:

Maria Genander, Michael M. Halford, Nan-Jie Xu, Malin Eriksson, Zuoren Yu, Zhaozhu Qiu, Anna Martling, Gedas Greicius, Sonal Thakar, Timothy Catchpole, Michael J. Chumley, Sofia Zdunek, Chenguang Wang, TorbjГ¶rn Holm, Stephen P. Goff, Sven Pettersson, Richard G. Pestell, Mark Henkemeyer & Jonas FrisГ©n
Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression

Cell, print issue, 13 Nov 2009

Source: Press Officer Katarina Sternudd

Karolinska Institutet

Anti-inflammatory Effects Of Pomegranate In Rabbits: A Potential Treatment In Humans?

2011-09-24T12:00:00.000-07:00

Oral ingestion of pomegranate extract reduces the production of chemicals that cause inflammation suggests a study published in BioMed Central's open access Journal of Inflammation. The findings indicate that pomegranate extract may provide humans with relief of chronic inflammatory conditions.

The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.

Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.

Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.

Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.

The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi "the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients". He adds that, "Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood."

Notes:

1. Bioavailable Metabolites of Pomegranate (Punica granatum L) Fruit Extract Preferentially Inhibit COX2 Activity ex vivo and IL-1b-induced PGE2 Production in Articular Cartilage Chondrocytes in vitro.

Meenakshi Shukla, Kalpana Gupta, Zafar Rasheed, Khursheed A Khan and Tariq M Haqqi

Journal of Inflammation (in press)

Article available at the journal website: journal-inflammation/

All articles are available free of charge, according to BioMed Central's open access policy.

2. Tariq Haqqi is now with the Department of Pathology, Microbiology & Immunology, School of Medicine, at the University of South Carolina, Columbia.

3. Journal of Inflammation is an Open Access, peer-reviewed online journal on all aspects of research into inflammation.

4. BioMed Central (biomedcentral/) is an independent online publishing house committed to providing immediate access without charge to the peer-reviewed biological and medical research it publishes. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.

Source: Charlotte Webber

BioMed Central

Study Finds That Blood Test Can Gauge Prostate Cancer Risk

2011-09-21T12:00:00.000-07:00

New genomics research has found that a simple blood test can determine which men are likely to develop prostate cancer. Researchers at Wake Forest University School of Medicine and colleagues found that five genetic variants previously associated with prostate cancer risk have a strong cumulative effect.

Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.

The article was published "Online First" today and will be included in the Feb. 28 print issue.

The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages all participants of a prostate cancer study in Sweden.

"This is significant and could affect clinical care," said senior researcher Jianfeng Xu, M.D., Dr. PH., professor of epidemiology and cancer biology. "The information could substantially improve physicians' ability to assess risk and determine the need for more aggressive screening or even a biopsy."

For example, the test may be especially useful in men with a family history of prostate cancer or those who have a marginally elevated PSA (prostate specific antigen), he said.

The study is also important because it is one of the first to illustrate how a combination of several genes can affect risk of disease. Genomics teams nationwide are currently searching for combinations of genes that may underlie common diseases such as cancer, diabetes and asthma.

Currently, age, race and family history are the three factors associated with increased risk of prostate cancer. Family history is believed to account for about 10 percent of prostate cancer cases. Strikingly, researchers estimated that the five variants combined could account for about 40 percent of cases.

"Our finding provides an opportunity to supplement the well-established risk factors by looking at how many of these variants a man has inherited," said Xu. "It may provide a much better weapon to guide clinicians."

Until last year, no specific genetic variants had been consistently identified as markers for prostate cancer risk. Then, advances in technology allowed researchers to take a more systematic approach to looking at the entire genome. Instead of solely studying genes that they suspected were related to disease susceptibility, they could study the entire genome and look for associations.

Through these searches, several research teams identified five genetic locations associated with risk of developing prostate cancer: three on chromosome 8q24, one on chromosome 17q12 and one on 17q24.3.

Each variant alone was associated with moderate risk, but the effect wasn't considered significant enough to justify testing individuals. The current study was the first to evaluate whether there is a cumulative effect from having multiple variants.

"When we considered the variants together we discovered their potential for predicting individual risk," said Xu. "Because of the cumulative effects of these risk variants and family history, for the first time associations found through genome-wide screening appear to be useful in clinical practice."

The researchers said further study is needed to determine how their findings of genetic testing may complement PSA (prostate-specific antigen) testing. The researchers found that the risk associated with the genetic variants is independent of PSA results.

"This suggests that a subset of men deemed to have a low risk of prostate cancer based on their PSA levels may in fact be at significantly elevated risk due to inheriting one or more of the genetic variants," said S. Lilly Zheng, M.D., associate professor of internal medicine and the first author of the paper.

Genetic testing of these five variants will soon be offered at a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory at Wake Forest University School of Medicine.

Co-researchers include senior author Henrik Gronberg, M.D., Ph.D. professor at the Karolinska Institutet in Stockholm, Sweden, and William B. Isaacs, Ph.D, professor at Johns Hopkins Medical Institutions in Baltimore, Md.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

Wake Forest University Baptist Medical Center

Medical Center Blvd.

Winston-Salem, NC 27157-1015

United States

www1.wfubmc

Strategic Approach To Early-Detection Of Pancreatic Cancer Biomarkers

2011-09-18T12:00:00.000-07:00

A cancer scientist from Johns Hopkins has convinced an international group of colleagues to delay their race to find new cancer biomarkers and instead begin a 7,000-hour slog through a compendium of 50,000 scientific articles already published to assemble, decode and analyze the molecules that might herald the furtive presence of pancreatic cancer.

With limited resources available for the exhaustive and expensive testing that needs to be done before any candidate can be considered a bona fide biomarker of clinical value, it's important to take stock of the big picture and strategize, says Akhilesh Pandey, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and founder and director of the Institute of Bioinformatics in Bangalore, India.

Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team published their compendium on April 6 in PLoS Medicine. They systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.

More than 200 genes are shortlisted because they were reported in four or more published studies to be overexpressed - meaning that the proteins they make are in higher abundance in people with pancreatic cancer than in people without the disease. This qualifies them as "excellent candidates" for the further studies that are needed to validate them as sensitive and specific biomarkers, note the authors.

Pandey says he was motivated by the fact that even leading cancer investigators had no real idea about how many candidate biomarkers for pancreatic cancer had already been identified, much less how they stacked up against each other in terms of clinical value in detecting early stages of the disease. Such biomarkers are highly valued because they gallop Paul Revere-like through the bloodstream and can signal early warnings of clinically invisible cancers and other diseases.

"Curation and databases are not very sexy concepts," says Pandey. "But we can't keep doing the exciting new discovery stuff and never take the time to catalog our results and share them."

Taking pancreatic cancer biomarkers to prove the value of such a strategic "big picture" approach, Pandey says it could serve as a basis for other disease-marker research.

"For the first time with pancreatic cancer - and potentially with any cancer - we have a handle on the number of candidates already identified and a real sense of how big an army we should send on the mission of further testing them," says Pandey.

Pandey's ultimate goal is to ferret out the best protein biomarker for pancreatic cancer - a molecule that reveals itself in an accessible bodily fluid and therefore can be detected with ease and accuracy - just like the protein biomarker that's made early on by a developing fetus and is exploited by at-home pregnancy tests.

The "gold standard" pancreatic cancer biomarker would possess both high sensitivity and specificity for early diagnosis. Cancer, at its most basic, is an abnormal population of cells that produce specific molecules - biomarkers - which healthy, cancer-free bodies do not. Cancer also tends to be incipient, Pandey says.

The ideal biomarker would allow for easy diagnosis when a cancer is still young, before it spreads to other organs. It could also help clinicians make informed decisions about treatments and better predict of outcomes, Pandey says: "Biomarkers could tell us who should undergo surgery, who should get chemotherapy, and in which people a cancer is likely to recur."

Biomarker discovery is an exploding area of research, Pandey says, yielding ever-increasing amounts of data - more than any one person can hope to keep track of, unless it's all strategically collected for widespread study.

"We want to initiate a trend by proving the importance of collection and cataloging," Pandey says, "which are exercises that many might view as tedious."

The team's next step is to create a searchable Web database that is universally available and free.

Notes:

The research was supported in part by the Lustgarten Foundation for Pancreatic Cancer Research.

Authors of the paper, in addition to Pandey, are H.C. Harsha and Arivusudar Marimuthu of the Institute of Bioinformatics, Bangalore, India; Manipal University, Karnataka, India; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Also, Kumaran Kandasamy, Suresh Mathivanan, and Manoj Kashyap of the Institute of Bioinformatics, Bangalore, India, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Prathibha Ranganathan, Sandhya Rani, Subhashri Ramabadran, Sashikanth Gollapudi, Lavanya Balakrishman, Sutopa B. Dwivedi, Deepthi Telikicherla, Lakshmi Dhevi N. Selvan, and Renu Goel, of the Institute of Bioinformatics, Bangalore, India; Robert Vizza of The Lustgarten Foundation for Pancreatic Cancer Research, New York; Robert J. Mayer and James A. DeCaprio of the Dana-Farber Cancer Institute, Boston; Sudhir Srivastava of the Cancer Biomarkers Research Group, NIH; Samir M. Hanash of the Fred Hutchinson Cancer Research Center, Seattle; and Ralph H. Hruban of the Departments of Pathology and Oncology at the Sol Goldman Pancreatic Cancer Institute, Johns Hopkins.

Source:
Maryalice Yakutchik

Johns Hopkins Medical Institutions

Canada's New Government Invests $583 Million In The Next Generation Of Canadian Researchers

2011-09-15T12:00:00.000-07:00

Dr. Colin Carrie, Parliamentary Secretary to the Honourable Maxime Bernier, Minister of Industry and Minister responsible for the Natural Sciences and Engineering Research Council of Canada (NSERC), and Dr. Suzanne Fortier, President of NSERC, have announced the results of the 2007 Grants and Scholarships awards, which will see $583 million disbursed to 10,000 professors and students across Canada.

As a result of the current competition, some 3,300 professors from across Canada will receive $458.8 million in Discovery Grants to support their research in the natural sciences and engineering. (These awards are normally paid out over five years.)

In addition, 2,402 young university researchers - 2,148 at the graduate level and 254 at the postdoctoral level - will receive $99.2 million to pursue their studies in these fields, while 4,296 undergraduate students will receive Undergraduate Student Research Awards worth a total of $19.3 million to give them hands-on research experience in a laboratory.

"Our newly released science and technology strategy - Mobilizing Science and Technology to Canada's Advantage - recognizes the importance of doing more to turn ideas into innovations that provide solutions to our environmental, health and other important challenges, and to improve Canada's economic competitiveness," said Parliamentary Secretary Carrie. "These awards will help ensure that this country's best and brightest professors and students can continue their work and their contribution to the prosperity and well-being of all Canadians."

This year also sees the introduction of the Discovery Accelerator Supplements, a new NSERC initiative to foster research excellence. With a total of $6 million in new funding, this initiative will provide significant supplements to a select group of researchers in order to boost their productivity at a critical juncture in their careers.

"These new grants target 50 outstanding researchers. Based on their success and accomplishments so far, we believe they are poised to make real breakthroughs in their fields, and we believe it is critically important to support them financially at this time," observed Dr. Fortier.

NSERC is a federal agency whose role is to make investments in people, discovery and innovation for the benefit of all Canadians. The agency invests in people by supporting some 23,000 university students and postdoctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,000 university professors every year and helps make innovation happen by encouraging about 1,300 Canadian companies to invest in university research and training. Over the past 10 years, NSERC has invested $6 billion in basic research, university-industry projects, and the training of Canada's next generation of scientists and engineers.

For more information, contact:

Isabelle Fontaine

Office of the Honourable Maxime Bernier

Minister of Industry

Background Information

The 15 universities receiving the largest allocation of NSERC grants and scholarships this year are:

University of Toronto: $65.8 million

University of British Columbia: $46.4 million

McGill University: $38.6 million

University of Alberta: $31.9 million

University of Waterloo: $29.9 million

The University of Western Ontario: $21.2 million

Universite de Montreal: $19.7 million

University of Calgary: $18.5 million

Dalhousie University: $18.0 million

Universite de Sherbrooke: $17.8 million

Universite Laval: $17.6 million

McMaster University: $17.3 million

Queen's University: $16.0 million

University of Ottawa: $15.7 million

University of Manitoba: $14.0 million

Contact: Michael Dwyer

Natural Sciences and Engineering Research Council

Only Two Genes Make The Difference Between Herbaceous Plants And Trees

2011-09-12T12:00:00.000-07:00

Scientists from VIB at Ghent University have succeeded in converting annual plants into perennials. They discovered that the deactivation of two genes in annuals led to the formation of structures that converted the plant into a perennial. This was most likely an important mechanism in plant evolution, initiating the formation of trees.

Annuals and perennials

Annual crops grow, blossom and die within one year. Perennials overwinter and grow again the following year. The life strategy of many annuals consists of rapid growth following germination and rapid transition to flower and seed formation, thus preventing the loss of energy needed to create permanent structures. They germinate quickly after the winter so that they come out before other plants, thus eliminating the need to compete for food and light. The trick is basically to make as many seeds as possible in as short a time as possible.

Perennials have more evolved life strategies for surviving in poor conditions. They compose perennial structures such as overwintering buds, bulbs or tubers. These structures contain groups with cells that are not yet specialised, but which can later be converted when required into new organs such as stalks and leaves.

The flowering of annuals

Annual crops consume all the non-specialised cells in developing their flowers. Thus the appearance of the flower signals means the end of the plant. But fortunately they have left seeds that sense - after winter - that the moment has come to start up. Plants are able to register the lengthening of the days. With the advent of longer days in the spring, a signal is sent from the leaves to the growth tops to activate a limited number of blooming-induction genes.

Deactivating two genes

VIB researchers, such as Siegbert Melzer in Tom Beeckman's group, have studied two such flower-inducing genes. They have deactivated them in thale cress (Arabidopsis thaliana), a typical annual. The VIB researchers found that mutant plants can no longer induce flowering, but they can continue to grow vegetatively or come into flower much later. Melzer had found that modified crops did not use up their store of non-specialised cells, enabling perennial growth. They can therefore continue to grow for a very long time.

As with real perennials these plants show secondary growth with wood formation creating shrub-like Arabidopsis plants.

Raising the veil of evolution

Researchers have been fascinated for a long time by the evolution of herbaceous to woody structures. This research clearly shows only two genes are in fact necessary in this process. This has probably been going on throughout the evolution of plants. Furthermore it is not inconceivable this happened independently on multiple occasions.

Relevant scientific publication

The research appears in the leading journal Nature Genetics (Siegbert Melzer et al., Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana).

Funding

This research was financed by VIB, UGent, IWT, FWO.

Tom Beeckman is in charge of the Root Development research group in the VIB Plant Systems Biology department, UGent - under the management of Dirk InzГ©. Click here for more information.

VIB is a non-profit research institute in life sciences. Approximately 1100 scientists and technicians perform basic research into the molecular mechanisms that are responsible for the functioning of the human body, plants and micro-organisms. By means of a strong partnership with four Flemish universities - UGent, K.U.Leuven, Universiteit Antwerpen and Vrije Universiteit Brussel - and a robust investment programme, VIB bundles the strengths of 65 research groups into one institute. Their research aims at fundamentally pushing out the boundaries of our knowledge. With its technology transfer activities VIB aims to convert research results into products for the consumer and the patient. VIB develops and disseminates a broad range of scientifically based information on all aspects of biotechnology. More information on vib.be.

The Universiteit Gent (UGent) is one of the largest Dutch-speaking universities, with more than 30,000 students. The course options include almost all academic courses that are offered in Flanders.
The UGent prides itself on being an open, socially engaged and pluralistic university with an international perspective. More information on ugent.be.

Universiteit Gent

New Protocol Quickly And Efficiently Differentiates Human Embryonic Stem Cells Into Committed Neural Precursor Cells

2011-09-09T12:00:00.000-07:00

Investigators at the Burnham Institute for Medical Research (Burnham) have developed a protocol to rapidly differentiate human embryonic stem cells (hESCs) into neural progenitor cells that may be ideal for transplantation. The research, conducted by Alexei Terskikh, Ph.D., and colleagues, outlines a method to create these committed neural precursor cells (C-NPCs) that is replicable, does not produce mutations in the cells and could be useful for clinical applications. The research was published on March 13 in the journal Cell Death and Differentiation.

When the C-NPCs created using the Terskikh protocol were transplanted into mice, they became active neurons and integrated into the cortex and olfactory bulb. The transplanted cells did not generate tumor outgrowth.

"The uniform conversion of embryonic stem cells into neural progenitors is the first step in the development of cell-based therapies for neurodegenerative disorders or spinal injuries," said Dr. Terskikh. "Many of the methods used to generate neural precursor cells for research in the lab would never work in therapeutic applications. This protocol is very well suited for clinical application because it is robust, controllable and reproducible."

Dr. Terskikh notes that the extensive passaging (moving cells from plate to plate) required by some protocols to expand the numbers of neural precursor cells limits the plasticity of the cells, can introduce mutations and may lead to the expression of oncogenes. The Terskikh protocol avoids this by using efficient conversion of hESCs into primary neuroepithelial cells without the extensive passaging.

The scientists were able to rapidly neuralize the hESCs by culturing them in small clusters in a liquid suspension. The cells developed the characteristic "rosettes" seen in neuroepithelial cells. The C-NPCs were then cultured in monolayers. Immunochemical and RT-PCR analysis of the cells demonstrated that they were uniformly C-NPCs. Whole-genome analysis confirmed this finding. Immunostaining and imaging showed that the cells could be differentiated into three distinct types of neural cells. The team then demonstrated that the C-NPCs differentiated into neurons after transplantation into the brains of neonatal mice.

Notes:

This research received funding from the National Institutes of Health and the California Institute for Regenerative Medicine.

About Burnham Institute for Medical Research

Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.

Source:
Josh Baxt

Burnham Institute

Brain Protein Reduces Alzheimer's Plaques In Mice

2011-09-06T12:00:00.000-07:00

Increasing levels of a protein that helps the brain use cholesterol may slow the development of Alzheimer's disease changes in the brain, according to researchers studying a mouse model of the disease at Washington University School of Medicine in St. Louis.

Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer's disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.

The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer's treatment: altering the brain's use of lipids, a class of fat-soluble compounds that includes cholesterol.

"It's becoming clear that ABCA1 may be a good drug target for Alzheimer's therapies," Holtzman says. "There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer's treatment."

Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren't soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.

In the circulatory system, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the "good" cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis.

Holtzman was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer's disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual's risk of developing late-onset Alzheimer's disease.

In earlier research, Holtzman's lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they utilized mice lacking the gene for ABCA1 and bred them to mouse model of Alzheimer's disease, the animals developed a much great number of the brain plaques that are characteristic of the disease.

For the new experiment, Holtzman laboratory members Suzanne Wahrle, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer's disease mouse model, they found mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.

The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman theorizes that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. But further research is needed to prove this theory.

A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. However, Holtzman notes, these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.

Holtzman is conducting additional studies to clarify the details of the relationship between ABCA1, apoE and amyloid beta.

Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. Journal of Clinical Investigation, February 2008 (online January 17)

Funding from the National Institutes of Health, the O'Brien Center for Kidney Disease Research, Eli Lilly and Co, the Canadian Institutes of Health Research and the American Health Assistance Foundation supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University in St. Louis

One Brookings Dr., Campus Box 1070

St. Louis, MO 63130

United States

wustl

Using Probes To Control Chemistry - Molecule By Molecule

2011-09-03T12:00:00.000-07:00

Using probes originally designed to detect and image topographical features on surfaces, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have demonstrated the ability to initiate and spatially localize chemical reactions on the submicron scale. They have been able to reliably manipulate chemistry on a very, very small scale in contrast to normal beaker-type reactions carried out in bulk. Such "site-selective" chemistry, taken down to the molecule-by-molecule level, could lead to new ways to etch small-scale electronic circuits, the development of extremely sensitive chemical sensors, as well as a better understanding and control of chemical reactions such as those used to convert sunlight into electricity in solar cells.

"Atomic force microscopy (AFM) uses probes that are analogous to the stylus on an old-style record player," says Brookhaven Lab materials scientist Stanislaus S. Wong. However, as opposed to "feeling" the nature of slight variations of pits within record grooves, AFM probes normally detect intermolecular interactions, related to changes in surface chemistry. "What we've demonstrated in our work is the ability to alter the AFM probe so it can be used not just passively, to sense chemistry, but actively, to initiate or control chemical reactions on a surface," Wong said.

In their proof-of-principle experiment, Wong's group attached titanium dioxide nanoparticles to the end of a conventional AFM probe and used it to photocatalytically oxidize selected sites on a thin film of photoreactive dye -- a model for understanding photocatalysis in solar cells. Mandakini Kanungo, a postdoctoral researcher in Wong's lab, will describe this work in a talk at the 231st national meeting of the American Chemical Society (ACS) in Atlanta, Georgia, on Thursday, March 30, 2006.

In the experiment, oxidized and unaffected areas of the dye were often separated by a mere 0.1 microns (millionths of a meter). The hope is to increase the spatial resolution of the technique to affect changes molecule by molecule, or at the one-nanometer (billionths of a meter) scale, Wong says.

Being able to control chemistry at this level has many potential applications. First, it gives the scientists deeper insight into the kinetics of reactions at the molecular level when, for example, a catalyst triggers the in situ oxidation of a chemical in the presence of light. This reaction is important toward understanding how to convert sunlight into useable forms of energy such as electricity. A "close-up" view of the chemistry will allow scientists to experiment with different types of catalyst particles, sizes and shapes of particles, and other characteristics to see precisely how these changes affect the kinetics and other dynamic properties associated with the photocatalytic process. This work could ultimately lead to the design of more efficient catalysts and more efficient solar cells.

In another application, Wong says, "You can use the AFM tip almost like an ultrafine pencil to draw out areas that you would like to react. This creates nanometer-scale 'lines' that are different from the chemistry of surrounding areas on the substrate." In essence, he says, you can etch out such "lines of reactivity," using chemistry to "draw," for example, nanoscale circuits. Such small-scale circuits could further shrink the scale of electronic devices, as well as increase the efficiency and/or speed of data storage and retrieval.

One important benefit of this technique is that it is environmentally friendly, Wong says, using no electric current or potentially harmful reaction conditions. Furthermore, the technique has such high specificity that it offers the potential for single-molecule detection and analysis -- a benefit with possible applications in refined chemical sensor technology. Such sensors might be able to detect as little as a single molecule of a potentially hazardous material released, for example, in a terror attack.

To learn more about the technique, recent results, and potential applications, attend Kanungo's ACS talk on Thursday, March 30, 2006 at 2:30 p.m. in Room B213 of the Georgia World Congress Center.

This research was funded by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.

One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization. Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: bnl/newsroom

Contact: Karen McNulty Walsh

kmcnultybnl

DOE/Brookhaven National Laboratory

Protein Identified That Regulates Effectiveness Of Taxol Chemotherapy In Breast Cancer

2011-08-31T12:00:00.000-07:00

Cancer researchers at Georgetown University Medical Center have taken a step towards understanding how and why a widely used chemotherapy drug works in patients with breast cancer.

In laboratory studies, the researchers isolated a protein, caveolin-1, showing that in breast cancer cells this protein can enhance cell death in response to the use of Taxol, one of two taxane chemotherapy drugs used to treat advanced breast and ovarian cancer. But in order to work, they found the protein needs to be "switched on," or phosphorylated. The results were reported in the Journal of Biological Chemistry.

Their finding suggests it may eventually be possible to test individual breast cancer patients for the status of such molecular markers as caveolin-1 in their tumors to determine the efficacy-to-toxicity ratio for Taxol, said the study's first author, postdoctoral fellow Ayesha Shajahan, Ph.D., of Lombardi Comprehensive Cancer Center at Georgetown.

"Because breast tumors are not all the same, it is important to know the cancer's molecular makeup in order to increase the efficiency, and lower the toxicity, of chemotherapy drugs, and this work takes us some steps forward in this goal," she said. "It also offers insights into why some breast cancer cells can become resistant to therapeutic drugs."

Additionally, the study identifies caveolin-1 as a new molecular target for increasing the efficacy of taxanes, according to the study's lead investigator, Robert Clarke, Ph.D., D.Sc., a Professor of Oncology and Physiology & Biophysics. "This is important because the taxanes are active drugs in breast cancer, so now that we know caveolin-1 is a new mechanism to explain how these drugs kill breast cancer cells, we can potentially take advantage of that fact to improve these agents."

The taxanes are Taxol (also known as paclitaxel) and Taxotere (docetaxel). Taxol was originally derived from the Pacific yew tree, and Taxotere is a semi-synthetic version of Taxol with slight chemical changes. These drugs stabilize a cell's "microtubules," the road-like protein structures that send chemical signals to all parts of the cell, and which must be flexible if a cell is to divide. Taxanes lock these structures into place, not allowing them to change when the cell begins to divide - which is necessary for tumor growth. Research has also indicated that the drugs induce programmed cell death (apoptosis) in cancer cells by inactivating an "apoptosis stopping protein" called BCL2, thus stopping it from inhibiting cell death.

Caveolin-1 is a protein that is found in most cells under normal conditions and it is involved in an array of cellular events that ranges from vesicle trafficking to cell migration. It is, therefore, as a key regulator of multiple events within the cell.

In cancer, the expression level of caveolin-1 can vary depending on cell type. However, the precise role of caveolin-1 in cancer has been controversial: whether it acts as a suppressor or facilitator of tumor formation depends on the cell type. In human breast cancer, caveolin-1 has been known to act as a tumor suppressor since caveolin-1 expression is down-regulated during the primary stages of breast cancer. More recent studies indicate that that caveolin-1 expression is increased in more aggressive types of breast cancer.

Under the mentorship of Clarke, Shajahan sought to determine factors that regulate expression and function of caveolin-1 in the breast. In this study, the researchers show that in their breast cancer cell model that phosphorylated caveolin-1 increased cell death by activating other key regulators vital to both breast cancer progression and cell death, including BCL2, the same protein that Taxol works on; p21, which controls cell cycle progression; and the tumor suppressor p53.

If caveolin-1 isn't phosphorylated, breast cancer cells appear to be resistant to Taxol treatment, the researchers conclude. "Thus, this study opens an area of investigation in our lab that will concentrate on understanding how this multi-tasking protein can serve as a marker for chemotherapeutic drug efficacy," Shajahan said.

The study was supported by grants from the National Institute of Health, and the Department of Defense to Clarke and a postdoctoral fellowship award from Susan G. Komen Breast Cancer Foundation to Shajahan. The other co-authors for this study were Aifen Wang, M.Sc., Markus Decker, B.Sc., and . Minetta C. Liu, M.D. from Georgetown University Medical Center, and Richard D. Minshall, Ph.D. from the University of Illinois at Chicago.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO).

Contact: Laura Cavender

Georgetown University Medical Center

View drug information on Taxol; Taxotere.

Easily Blocked Protein May Help Stop Parasites

2011-08-28T12:00:00.000-07:00

Researchers at Washington University School of Medicine in St. Louis have identified a parasite protein that has all the makings of a microbial glass jaw: it's essential, it's vulnerable and humans have nothing like it, meaning scientists can take pharmacological swings at it with minimal fear of collateral damage.

The protein, calcium dependent protein kinase 1 (CDPK1), is made by Toxoplasma gondii, the toxoplasmosis parasite; cryptosporidium, which causes diarrhea; plasmodium, which causes malaria; and other similar parasites known as apicomplexans.

In the May 20 issue of Nature, researchers report that genetically suppressing CDPK1 blocks the signals that toxoplasma parasites use to control their movement, preventing them from moving in and out of host cells. They also found that toxoplasma's version of CDPK1 is easier to disable than expected and identified a compound that effectively blocks its signaling ability.

"Kinases are proteins that are common throughout biology, but the structures of CDPKs in apicomplexans much more closely resemble those found in plants than they do those of animals," says senior author L. David Sibley, PhD, professor of molecular microbiology. "We showed that these differences can be exploited to identify potent and specific inhibitors that may provide new interventions against disease."

Infection with toxoplasma is most familiar to the general public from the recommendation that pregnant women avoid changing cat litter. Cats are commonly infected with the parasite, as are many livestock and wildlife. Humans also can become infected by eating undercooked meat or by drinking water contaminated with spores shed by cats.

Epidemiologists estimate that as many as one in every four humans worldwide is infected with toxoplasma. Infections are typically asymptomatic, only causing serious disease in patients with weakened immune systems. In some rare cases, though, infection in patients with healthy immune systems leads to serious eye or central nervous system disease, or congenital defects in the fetuses of pregnant women.

Sibley studies toxoplasma both to find ways to reduce human infection rates and as a model for learning about other apicomplexans, such as plasmodium, that are more significant sources of disease and death.

The new study, led by graduate student Sebastian Lourido, began as an effort to determine what CDPK1 does for toxoplasma. Researchers genetically modified the parasite, eliminating its normal copy of CDPK1 and replacing it with a version of the gene that they could turn on and off. When they turned the new gene off, they found that they had paralyzed the parasite, preventing it from moving and from breaking into and out of host cells. Turning the gene back on restored these abilities.

Further tests revealed that CDPK1 controls toxoplasma's ability to secrete microneme proteins, sticky proteins that act as handholds and allow the parasites to move about their environment and pass through host cell membranes.

In a separate collaborative paper published earlier this month in Nature Structural and Molecular Biology, scientists in the laboratory of co-author Raymond Hui, PhD, principal investigator of parasitology at the Structural Genomics Consortium of the University of Toronto, determined the three dimensional structure of the CDPK1 protein. Researchers found that the area drugs would normally bind in order to disable the protein was more accessible than in virtually all other kinases, including those that control signaling in humans.

"To our surprise, CDPK1 just has a naturally large keyhole for inhibitors to slide into," Lourido says. "This good fortune allowed us to exploit bulky kinase inhibitors that had been previously pioneered by the laboratory of Kevan Shokat, PhD, professor of cellular and molecular pharmacology at the University of California, San Francisco, and a Howard Hughes Medical Institute investigator."

When tested on parasites, the bulky inhibitors successfully blocked CDPK1 function and parasite infectivity without affecting human cells.

Lourido suspects CDPK1 may play a similar role in plasmodium, but its version of the protein is predicted to be harder to selectively target with inhibitors. Little is known about what CDPK1 does in cryptosporidium, but since it shares close similarity to toxoplasma, it may also be essential and susceptible to inhibition by similar compounds.

Sibley and Lourido plan to learn more of the details of how CDPK1 controls microneme secretion, using toxoplasma as a model to study the functions of parasites and how they differ from human cells. The successful toxoplasma inhibitor is now undergoing further testing in animals to see if it can eventually be adapted for clinical use to prevent infection in humans.

Lourido S, Shuman J, Zhang C, Shokat KM, Hui R, Sibley LD. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature, May 20, 2010.

Funding from the American Heart Association and the National Institutes of Health supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Source: Washington University in St. Louis

Medical Evacuation Procedures Targeted By US Air Force Grant

2011-08-25T12:00:00.000-07:00

University of Cincinnati (UC) researchers have received a grant in excess of $2 million from the U.S. Air Force School of Aerospace Medicine to determine the ideal time to fly that minimizes health complications to injured soldiers due to the rush to move them from the battlefield into a safe zone.

"There is a sense of urgency about getting these wounded soldiers to a cleaner, safer environment," explains Col. Warren Dorlac, MD, co-principal investigator on the UC study. "Our overriding goal is to protect patients from anything that could potentially lead to a cascade of medical complications that will jeopardize survival. But the reality is that evacuation is happening at a time when they are most prone to a secondary hit."

According to U.S. military reports, about 30 to 50 soldiers are critically wounded each month and require medical evacuation out of a war zone. Most are in transit to a full-service hospital within 48 hours.

Avoiding this "second hit" - such as a serious infection or pneumonia - improves survival dramatically. Doing so is challenging, however, in the middle of a war zone where medical troops are being cared for in maze of canvas and plywood hospital tents.

Dorlac and his colleagues believe there may be a direct link between inflammatory changes in the body and the timing of strategic medical evacuation movements.

For this study, UC researchers will investigate how early evacuation of combat casualties affects the body's inflammatory response, possibly predisposing already critically wounded people to death from related complications.

"We need to understand the biological effects of the hypobaric environment so we can minimize the risk for additional injuries," says Dorlac, associate professor of surgery at UC and director of the Cincinnati Center for Sustainment and Readiness Skills (C-STARS) program housed in University Hospital.

Currently, no data exists on the impact of the hypobaric environment - characterized by reduced oxygen levels - and altitude on patients recovering from traumatic injuries.

"Determining the ideal time to fly could reduce infection, minimize hospital stays and result in fewer amputations and deaths for the soldiers defending our country," adds Dorlac.

Because of the nature of a combat zone, the average medical evaluation plane quickly ascends 8,000 feet within 10 minutes. The plane is very different than a hospital intensive care unit - 90 decibels of noise, lots of vibration and a pressurized environment that results in less oxygen to revive tissues and relieve stress on the body's systems.

This, says Dorlac, is far from the ideal setting for a traumatic brain-injured or other severely injured patient.

"When we send a patient up in an airplane, we're essentially putting them into an environment we know can't be good for them in an effort to move them to safety," he adds. "A dark, quiet intensive care unit with very little stimulation or distraction is preferable. Even minor movements can cause a change in intracranial pressure."

For this two-phase study, the UC team will create three animal models representative of traumatic military combat injuries: controlled hemorrhage, hepatic ischemia reperfusion and scald/burn.

The controlled hemorrhage model, characterized by a low but sustainable level of blood pressure, is meant to reflect a soldier who has experienced a heavy-bleeding wound but doesn't reach a field hospital to receive fluids for several hours.

Hepatic ischemia reperfusion model represents a patient who needs serious abdominal surgery that requires re-establishing blood flow to a major organ.

The scald/burn model corresponds to a blast burn wound from weapon fire.

"Each model has a different inflammatory response, all of them severe and relevant to injuries our soldiers are experiences during war," explains Alex Lentsch, PhD, co-principal investigator of the study and director of UC's surgical research unit.

"By understanding how the inflammatory response evolves over the course of different injuries, flight times and altitudes," he adds, "we will be able to better target care for patients who have been severely injured and need to be moved across country."

After taking baseline biological measurements, researchers will test whether moving to an altitude of 8,000 feet increases the body's inflammatory response. This information is necessary to determine an ideal to time to fly that minimizes the risk for additional medical complications.

Cellular inflammation markers in the blood will be measured before and after flight to determine how different altitudes affect the body's inflammatory response after injury.

"When a person experiences trauma and loses a lot of blood, the body sends warning signals and stimulates certain cells that will try to fix or repair the problem, causing inflammation," explains Lentsch. "But this storm of cellular response is unselective. This all eventually leads to multiple organ dysfunction."

The study's second phase will focus on a more complex brain injury model using concepts learned in the initial research. Researchers will continue to look at the effect of flight timing and altitude on the patient's inflammatory response but also monitor blood oxygenation levels and intracranial pressure.

Three areas have been shown to increase brain tissue loss and increase mortality in head injured patients: lack of oxygen (hypoxia); low blood pressure (hypotension); and increased intracranial pressure, which can be brought on by a low oxygen environment characteristic of a medical evacuation plane.

"There is nothing known beyond anecdotal evidence about inflammation's affects on the survival of patients with traumatic injuries, so we have a great opportunity to learn more about this problem and make an impact on the real world."

Timothy Pritts, MD, PhD, and Lt. Col. Gina Dorlac, MD, are co-investigators in this study. Maj Stephen Barnes, MD, previously of CSTARS Cincinnati will also stay involved. Testing will take place both at UC and Brooks Air Force Base in San Antonio, Texas.

Source: Amanda Harper

University of Cincinnati

Flies Show Link Between Sleep And Immune System

2011-08-22T12:00:00.000-07:00

Go a few nights without enough sleep and you're more likely to get sick, but scientists have no real explanation for how sleep is related to the immune system. Now, researchers at the Stanford University School of Medicine are finding that fruit flies can point to the answers.

What they have learned thus far is that illness and sleep disruption may be a two-way street: sick flies can't sleep, and losing sleep makes them more susceptible to infection.

"When flies get sick, they stop sleeping," said David Schneider, PhD, assistant professor of microbiology and immunology. "Disrupting sleep in turn disrupts the immune system, which makes them even more infected and it's downhill from there in a 'spiral of death." Schneider is the senior author of a study on the sleep patterns of flies, published in Current Biology.

Schneider worked with postdoctoral scholar Mimi Shirasu-Hiza, PhD, who is the study's first author, to examine the connection between illness and sleep patterns by infecting fruit flies with one of two bacteria - Streptococcus pneumoniae or Listeria monocytogenes.

The infected flies lost their "day" and "night" patterns of activity, which are part of the regular changes that occur in the course of a day, called circadian rhythm. Uninfected flies alternate between 12 hours of high activity and 12 hours of low activity. The researchers found the sick flies had fewer sleep sessions and shorter periods of continuous sleep than did healthy flies. They basically just didn't sleep well, concluded the researchers.

The researchers can't say for sure whether a disruption of the brain's central clock, which is the area of the fly brain that exhibits circadian gene activity, was responsible for the changes seen in the sick flies; but the behavior of the ill flies looked a lot like that of flies known to have disruptions in their genes controlling circadian rhythm.

So the next step, after confirming that flies lost sleep when infected, was to ask the converse: when sleep is disrupted, does that affect immunity"

The challenge was how to disrupt the flies' sleep. Schneider tried building a machine that jostled the flies randomly. "All it was really good at doing was throwing the tubes around the room," said Schneider. "Also it was too regular, the flies got used to it so they could nap."

Another option was to keep the flies in continuous light. But Schneider and Shirasu-Hiza decided that an even better way would be to turn to established fly strains isolated decades ago that possess disruptions in their genes controlling circadian rhythm. In this case, these mutant flies could be kept under exactly the same light and temperature conditions as the normal flies.

They looked at flies that were defective in one of two genes, called "timeless" and "period". They found that the loss of either gene's function made the flies more sensitive to bacterial infections and these sick flies died significantly faster than control flies, which lived two to four times as long as the sick ones.

"We want to know how the internal clock knows the animal is infected, and how does the immune system know that you are not sleeping properly" said Schneider. "How do those messages get sent back and forth"

Their findings also raise the question of why the flies have a change in their sleep pattern when infected. The researchers speculate that from an evolutionary standpoint, there may be some microbes that are fought better when sleep is disrupted, although clearly not the two microbes they tested in the current study. "We think that is the reason flies do this," said Schneider, "but sometimes it's a good thing, sometimes it's a bad thing."

Building on their findings, they can begin to answer these questions. Shirasu-Hiza will be testing mutant flies with other circadian rhythm genes missing.

They hope their work inspires researchers who work on vertebrates to explore the molecular underpinnings of the interaction between sleep and immunity.

"The cool thing is that many of the clock genes are conserved between flies and vertebrates; we have 'period' and we have 'timeless'," said Schneider. "As usual, it doesn't work in exactly the same way, but what the fly does is let us find genes that are involved in the process, and then go figure out exactly how they are rewired to work in the human. The fly is really good for prospecting."

This work was funded by the National Institutes of Health, the Irvington Institution and the National Science Foundation. Other Stanford researchers who contributed to this study are: postdoctoral scholar Marc Dionne, PhD, graduate student Linh Pham, and graduate student Janelle Ayres.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.

Contact: Mitzi Baker

Stanford University Medical Center

Researchers Determine How Mosquitoes Survive Dengue Virus Infection

2011-08-19T12:00:00.000-07:00

Colorado State University researchers have discovered that mosquitoes that transmit deadly viruses such as dengue avoid becoming ill by mounting an
immediate, potent immune response. Because their immune system does not eliminate the virus, however, they are able to pass it on to a new victim. In
a study published February 13 in the open-access journal PLoS Pathogens, the researchers show that RNA interference - the mosquito immune response
-- is initiated immediately after they ingest blood containing dengue virus, but the virus multiplies in the mosquitoes nevertheless.

Dengue fever and dengue hemorrhagic fever are major global public health burdens, with up to 100 million cases occurring annually, yet no vaccines or
specific preventative medicines are currently available. The Aedes aegypti mosquito transmits dengue virus. Determining how the virus evades the
mosquito's defense is an important next step in research that aims to fight disease by interrupting the growth of dengue virus within the mosquito
before it can be transmitted.

RNA interference is an evolutionarily ancient antiviral defense used by mosquitoes and other invertebrates to destroy the RNA of many invading
arthropod-borne viruses. This team of researchers previously showed that ramping up the RNA interference response in mosquitoes prevented dengue
infection, and now they show that temporarily impairing this immune response increased virus transmission.

The investigators analyzed RNA from adult mosquitoes, finding that both the trigger and initiator molecules for RNA interference were formed after
infection, yet viral RNA could readily be detected in the same mosquitoes. They also measured infectious virus rates in the mosquitoes' saliva,
which revealed levels whereby the mosquitoes could transmit the disease to humans.

These findings indicate that genetic manipulation of RNA interference could be a significant weapon in stopping dengue virus transmission by Aedes
aegypti.

CITATION:

"Dengue Virus Type 2 Infections of Aedes aegypti
Are Modulated by the Mosquito's RNA Interference Pathway."
PLoS Pathog 5(2): e1000299. doi:10.1371/journal.ppat.1000299

dx.plos/10.1371/journal.ppat.1000299

About PLoS Pathogens

PLoS Pathogens publishes outstanding original articles that significantly advance the understanding of pathogens and how they
interact with their host organisms. All works published in PLoS Pathogens are open access. Everything is immediately available subject only to the
condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses
the Creative Commons Attribution License.

plospathogens

About the Public Library of Science

The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.

Public Library of Science

Brain Research Poised To Dramatically Advance Global Society

2011-08-16T12:00:00.000-07:00

World-renowned scientists convened at George Mason University on May 21 and 22 to call for a 10-year intellectual revolution - the "decade of the mind." The proceedings that will be published after this historic gathering will make the case for a $4 billion public research initiative dedicated to reaching the next level of understanding the human brain--the yet-to-be-discovered inner workings of the mind. The symposium also outlined the dramatic implications the decade will have on the global economy and health care.

"We are at the 'tipping point' of making enormous advances in public health, particularly in managing diseases that affect the mind, such as Alzheimer's disease, Parkinson's disease, autism and schizophrenia," said Jim Olds, director of Mason's Krasnow Institute for Advanced Study. "We at Mason are honored to be hosting this gathering of the world's leading researchers in brain study who together will outline the vision for the 'Decade of the Mind' that we will present to federal policymakers."

The two-day symposium included nine sessions, each featuring one aspect of brain research, and was moderated by scientists from the Krasnow Institute for Advanced Study. The symposium was anchored by a plenary session including the nine panelists. Moderated by New York Times science writer George Johnson, the session provided an open forum for the scientists to discuss their groundbreaking research in areas such as neuroscience, neurobiology, computer science, psychology, robotics and economics. The panel also explained the urgency to continue the study of the human mind and the benefits this research could bring to society.

"It is our intention to cover a lot of ground in two days because we need to capture the magnitude of the impact of what we are proposing to Congress," said Olds. "A 10-year focus to bring the enormous promise of brain research will launch an intellectual revolution here and throughout the world, with lasting impacts on society."

In the United States today, more than five million people are living with Alzheimer's disease according to the Alzheimer's Association. The number of people affected by this ultimately fatal disease will only increase over the next decade as early onset Alzheimer's begins to affect the baby boomer generation.

Today, one in 17 Americans suffer from a serious mental illness, the leading cause of disability in the U.S. for people 15 to 44 years old, according to the National Institute on Mental Health. New brain research during the initiative, coupled with advances in MRI technology and other non-invasive research tools, will allow scientists to better understand what causes these illnesses and how to manage or cure them.

This initiative also could help thousands of soldiers, sailors and airmen who have served in Afghanistan and Iraq more quickly and easily recover from brain injuries caused during combat, especially by improvised explosive devices.

Further research could allow advances in robotics and artificial intelligence that would make most future military vehicles - and aircraft - operate unmanned and autonomously, thereby saving thousands of lives during combat operations.

"The economic impact of the 'Decade of the Mind' will be felt in all levels of society," said Olds. "By translating our knowledge of the human mind to building more intelligent machines and computer applications, we can improve the welfare of millions of people worldwide."

The groundwork for this initiative was laid during the "Decade of the Brain," declared by President George H.W. Bush in 1990. It produced immense advances in brain research, including the development of MRI scanners and progress in the understanding of Alzheimer's disease and mental illness. Using these advances as a basis for further exploration into the human mind, this new decade would provide the nation's scientific community the opportunity to understand more about the mind than ever before and tackle some of society's most pressing challenges.

Decade of the Mind symposium presenters included: Marcus Raichle, MD, Washington University (St. Louis) School of Medicine; Nancy Kanwisher, PhD, Massachusetts Institute of Technology; John Holland, PhD, University of Michigan; Dharmendra Modha, PhD, IBM; Giulio Tononi, MD, PhD, University of Wisconsin; George A. Bekey, PhD, University of Southern California; Gordon Shepherd, PhD, Yale University; Vernon Smith, PhD, George Mason University, Nobel Laureate; and George Johnson, New York Times science writer, plenary session moderator.

For more information about the Decade of the Mind symposium, visit krasnow.gmu/decade.

About the Krasnow Institute for Advanced Study

The Krasnow Institute for Advanced Study seeks to expand understanding of mind, brain and intelligence by conducting research at the intersection of the separate fields of cognitive psychology, neurobiology and the computer-driven study of artificial intelligence and complex adaptive systems. These separate disciplines increasingly overlap and promise progressively deeper insight into human thought processes. The institute also examines how new insights from cognitive science research can be applied for human benefit in the areas of mental health, neurological disease, education and computer design.

About George Mason University

George Mason University, located in the heart of Northern Virginia's technology corridor near Washington, D.C., is an innovative, entrepreneurial institution with national distinction in a range of academic fields. With strong undergraduate and graduate degree programs in engineering, information technology, biotechnology and health care, Mason prepares its alumni to succeed in the workforce and meet the needs of the region and the world. Mason professors conduct groundbreaking research in areas such as cancer, climate change, information technology and the biosciences, and Mason's Center for the Arts brings world-renowned artists, musicians and actors to its stage. Its School of Law is recognized by U.S. News and World Report as one of the top 50 law schools in the United States.

Contact: Jim Greif

George Mason University

Autophagy Is The Key To Survival And Virulence For A Fungal Pathogen

2011-08-13T12:00:00.000-07:00

Autophagy is a process whereby cells recycle material during stress situations, such as when nutrients are scarce. Some cells also use this process as an immune defense mechanism to eliminate pathogens. However, new data, generated in mice by Peter Williamson and colleagues, at the University of Illinois at Chicago, has identified autophagy as a new virulence-associated trait and survival mechanism for Cryptococcus neoformans - a fungal pathogen that commonly infects immunocompromised individuals, such as those with HIV.

In the study, a mutant form of C. neoformans that lacked the protein Vps34 PI3K (known as the vps34D mutant) was found to be less able to form autophagy-related 8-labeled (Atg8-labeled) vesicles than normal C. neoformans. Furthermore, the vps34D mutant was less virulent in mice than normal C. neoformans. Consistent with a crucial role for autophagy in determining the extent of the disease caused by infection with C. neoformans, a strain of C. neoformans in which Atg8 expression was knocked down showed reduced virulence in mice. The authors therefore suggested that more detailed understanding of this virulence pathway might lead to new drugs for treating individuals who become infected with C. neoformans.

TITLE: PI3K signaling of autophagy is required for starvation tolerance and virulence of Cryptococcal neoformans

AUTHOR CONTACT:

Peter R. Williamson

University of Illinois at Chicago, Chicago, Illinois, USA.

Source: Karen Honey

Journal of Clinical Investigation

Discovery Explains How Cold Sore Virus Hides During Inactive Phase

2011-08-10T12:00:00.000-07:00

Now that Duke University Medical Center scientists have figured out how the virus that causes cold sores hides out, they may have a way to wake it up and kill it.

Cold sores, painful, unsightly blemishes around the mouth, have so far evaded a cure or even prevention. They're known to be caused by the herpes simplex virus 1 (HSV1), which lies dormant in the trigeminal nerve of the face until triggered to reawaken by excessive sunlight, fever, or other stresses.

"We have provided a molecular understanding of how HSV1 hides and then switches back and forth between the latent (hidden) and active phases," said Bryan Cullen, Duke professor of molecular genetics and microbiology.

His group's findings, published in Nature, also provide a framework for studying other latent viruses, such as the chicken pox virus, which can return later in life as a case of shingles, and herpes simplex 2 virus, a genitally transmitted virus that also causes painful sores, Cullen said.

Most of the time, HSV1 lives quietly for years, out of reach of any therapy we have against it. It does not replicate itself during this time and only produces one molecular product, called latency associated transcript RNA or LAT RNA.

"It has always been a mystery what this product, LAT RNA, does," Cullen said. "Usually viral RNAs exist to make proteins that are of use to the virus, but this LAT RNA is extremely unstable and does not make any proteins."

In studies of mice, the team showed that the LAT RNA is processed into smaller strands, called microRNAs, that block production of the proteins that make the virus turn on active replication. As long as the supply of microRNAs is sufficient, the virus stays dormant.

After a larger stress, however, the virus starts making more messenger RNA than the supply of microRNAs can block, and protein manufacturing begins again. This tips the balance, and the virus ultimately makes proteins that begin active viral replication.

The new supply of viruses then travels back down the trigeminal nerve, to the site of the initial infection at the mouth. A cold sore always erupts in the same place and is the source of viruses that might infect another person, either from direct contact, or sharing eating utensils or towels, Cullen said.

The approach to curing this nuisance would be a combination therapy, Cullen said. "Inactive virus is completely untouchable by any treatment we have. Unless you activate the virus, you can't kill it," he said.

Cullen and his team are testing a new drug designed to very precisely bind to the microRNAs that keep the virus dormant. If it works, the virus would become activated and start replicating.

Once the virus is active, a patient would then take acyclovir, a drug that effectively kills replicating HSV1.

"In principle, you could activate and then kill all of the virus in a patient," Cullen said. "This would completely cure a person, and you would never get another cold sore."

He and the team are working with drug development companies in animal trials to begin to answer questions about how to deliver this drug most effectively.

Co-authors included Jennifer Lin Umbach, Ph.D., and Heather W. Karnowski, B.S., of the Duke Department of Molecular Genetics and Microbiology and Center for Virology, and Martha F. Kramer, Igor Jurak, and Prof. Donald M. Coen of the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. This work was supported by two NIH grants.

Source: Mary Jane Gore

Duke University Medical Center

View drug information on Acyclovir Capsules.

'LEGO-Like' Building Blocks To Halt Cell Growth Wins Hebrew University Prize

2011-08-07T12:00:00.000-07:00

A method for delivery of drugs to targeted cells through the design of specific molecular structures called SIB (Small Integrated Building Blocks) has won a prestigious scientific prize for a Ph.D. student in organic chemistry at the Hebrew University of Jerusalem

Jerusalemite Nir Qvit, 34, will be one of those receiving the Kaye Innovation Award on June 13, during the 69th meeting of the Hebrew university Board of Governors.

Qvit has shown through his research that it is possible to greatly increase drug delivery efficiency by designing specific molecular structures made up of known pharmaceutically effective peptides (small protein molecules) that are attached to tailor-made, geometric-like structures called "scaffolding."

Each scaffold is specifically designed to combine the peptides in such a way that they will form an effective medicinal combination and so that they will bind to the receptors of specific targeted cells. Qvit refers to his process as somewhat analogous to building different kinds of structures through the use of LEGO.

Qvit, a student of Prof. Chaim Gilon of the Department of Organic Chemistry, has shown, for example, that with a particular combination of peptides and scaffold design, it is possible to create a synthetic molecule that will bind to the IGF-1 (insulin-like growth factor-1) receptor. IGF-1 is a protein that plays a critical role in the proliferation of many cancers, including prostate, lung, breast, colon and brain cancers. The binding action of the molecule to the receptor inhibits the activation of the IGF-1 protein in the cells, thus halting the cancerous growth.

Through this process of "combinational chemistry," involving peptides and scaffold design, Qvit says that many different types of molecules can be built that will reach specifically targeted cells, offering hope for treatment of not only cancer, but other diseases as well, without harming healthy cells.

The Kaye Innovation Awards have been given annually since 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff, and students of the Hebrew University to develop innovative methods and inventions with good commercial potential which will benefit the university and society.

Contact: Jerry Barach

The Hebrew University of Jerusalem

Assembly Of Molecules Critical To Protein Function Witnessed By Researchers

2011-08-04T12:00:00.000-07:00

A Virginia Tech research group lead by two biochemistry graduate students has isolated proteins responsible for the iron-sulfur cluster assembly process and witnessed the necessary protein interactions in vivo - within a cell. They have captured pathway intermediates and observed protein interactions between the two major players in iron-sulfur cluster assembly.

Iron-sulfur clusters are critical to life on earth. They are necessary for protein function in cellular processes, such as respiration in humans and other organisms and photosynthesis by plants. "But we do not understand how Fe-S molecules are made or the specifics of how they bond," said Callie Raulfs of Christiansburg, Va. "It does not happen spontaneously. It has to be regulated."

Diseases such as Friedrich's ataxia and several types of anemia are a result of iron-sulfur cluster (ISC) assembly malfunctions.

Using genetic and biochemical techniques, Ph.D. students Raulfs and Ina P. O'Carroll, of Tirana, Albania, have isolated components of the ISC machinery in the process of making iron-sulfur clusters. "This work provides insight into the sequential steps of the iron-sulfur cluster assembly process, helping to explain how molecules of iron and sulfur are synthesized and distributed in cells," said O'Carroll.

The work, "In vivo iron-sulfur cluster formation," by Raulfs, O'Carroll, Virginia Tech post-doctoral associates Patricia C. Dos Santos of Brazil and Mihaela-Carmen Unciuleac of Romania, and Dennis R. Dean of Blacksburg, professor of biochemistry and director of the Fralin Biotechnology Center at Virginia Tech, has been published in the Proceedings of the National Academy of Science (PNAS) Online Early Edition the week of June 16-20, 2008.

Previous studies by Dean and others have demonstrated that proteins can assemble clusters from components in vitro systems - that is, outside of an organism. Ten years ago, working with nitrogen-fixation systems, Dean's lab was the first to discover ISC proteins. Now Dean's students, Raulfs and O'Carroll, are the first to witness the assembly process in vivo - within a cell.

"The cool thing is we've come up with a way to observe ISC proteins from their native host with a cluster attached," said O'Carroll. "The system also allows us to capture different phases of the process."

The students have isolated three different intermediates of the ISC proteins involved in intercellular biosynthesis - or the cluster assembly process.

Rather than multiplying the proteins by placing them in E. coli, the Virginia Tech team used Azotobacter vinelandii, an aerobic, soil microbe that fixes nitrogen from the atmosphere, to obtain natural levels of the ISC proteins. "A vinelandii grows quickly and keeps the interior of the cell free of oxygen, which is important, since oxygen can destroy Fe-S clusters," said Raulfs, who first isolated a protein complex with a cluster attached, providing in vivo evidence that the two proteins get together and form a cluster.

"Because we are isolating proteins from the cell, we are also able to observe interactions between different Fe-S cluster asembly proteins," said O'Carroll. "We have been able to isolate a complex between the two major players in iron-sulfur assembly, the cluster assembly scaffold (IscU) and the sulfur-delivery protein (IscS)."

The methodology is to add a histidine amino acid tag to the ISC proteins "so we can fish the proteins out of the cell," said O'Carroll.

"Because we are fishing the cluster-containing protein out of the cell that has all of the other assembly proteins present at physiological levels, we are able to observe what else comes with the protein. What was really exciting in this case was that we saw large amounts of one of the other iron sulfur cluster assembly protein, IscS." said O'Carroll.

The work marks the first time researchers have been able to observe ISC proteins from the balanced environment of the native cell.

Next, they plan to determine the role of the individual genes in the set that produces ISC proteins in order to determine the effect of each gene on the assembly process. "The goal is to determine the events and the order in the ISC assembly process so we can figure out how cells make clusters and deliver them to specific target proteins," said O'Carroll.

The researchers are now developing a system that others can use to study proteins.

Raulfs received her undergraduate degree from the College of William and Mary. She has been a fellow in the Exploring Interfaces through Graduate Education and Research (EIGER) project, a National Science Foundation Integrative Graduate Education and Research Traineeship (IGERT) program at Virginia Tech.

O'Carroll received her undergraduate degree from McDaniel College. Dos Santos is the senior postdoc in the Dean lab. Unciuleac is now a post-doctoral fellow with the Molecular Biology Program at the Sloan-Kettering Institute.

The research is supported by the National Science Foundation.

Source: Susan Trulove

Virginia Tech

Evolution's Steps Revealed By Structure Of 450 Million Year Old Protein

2011-08-01T12:00:00.000-07:00

A detailed map that pinpoints the location of every atom in a 450-million-yeard-old resurrected protein reveals the precise evolutionary steps needed to create the molecule's modern version, according to researchers from the University of North Carolina at Chapel Hill and the University of Oregon.

Until now, scientists trying to unravel the evolution of the proteins and other molecules necessary for life have worked backwards, making educated guesses based on modern human body chemistry. By moving forward from an ancient protein, the team laid out the step-by-step progression required to reach its current form and function.

The study appears in the journal Science.

"We were able to see exactly how mutations in the ancient structure led to the modern receptor," said lead author Eric Ortlund, who carried out the research as a UNC-Chapel Hill postdoctoral fellow. Ortlund is now an assistant professor of biochemistry in the Emory University School of Medicine.

In the current study, Ortlund and Matt Redinbo, a professor of chemistry, biochemistry and biophysics at UNC-Chapel Hill, generated a three-dimensional picture of the ancient receptor with an imaging technique called X-ray crystallography. The nanoscale image revealed the receptor's structure, down to the placement of every atom. With the structure in place, Ortlund and his colleagues retraced evolution's path.

The researchers examined the precursor to a modern protein known as a glucocorticoid receptor. In humans, the receptor plays a crucial role, responding to the hormone cortisol and regulating the body's stress response. The two -- receptor and hormone -- fit together as precisely as a lock and key. The precursor preferred a different hormone, so several mutations were necessary before the lock could fit the cortisol key.

The University of Oregon team, which included postdoctoral scientist Jamie Bridgham, resurrected the ancient protein via a large database of modern receptor genes. This earlier work, which compared the genetic similarities and differences among two of these modern genes, found the receptor descended from a single common genetic ancestor 450 million years ago. The researchers then recreated the ancient receptor in the laboratory.

Only seven mutations were needed to bridge the 450-million-year gulf, the researchers found. However, not every mutation changed the protein's function. These "permissive" mutations appear to pave the way for future, more significant changes. "It's like they prepared for opportunity to knock in the form of a new hormone," Ortlund said.

The permissive mutations bolstered the receptor's structure, like contractors reinforce a historic home's foundation before making renovations. After these changes took place, a more extreme mutation repositioned an entire group of atoms, bringing them closer to fitting the cortisol hormone. Another created the tight new fit with cortisol.

"These permissive mutations are chance events. If they hadn't happened first, then the path to the new function could have become an evolutionary road not taken," said co-author Joe Thornton, a professor of evolutionary biology at the University of Oregon.

The researchers worked out which mutations came first by synthesizing different versions of the mutated protein in the laboratory. Had the radical mutations come first, the receptor protein would have lost its function entirely, they found.

The research was funded by the National Institutes of Health, the National Science Foundation, a UNC Lineberger Comprehensive Cancer Center fellowship to Ortlund and an Alfred P. Sloan research fellowship to Thornton.

Source: Becky Oskin

University of North Carolina at Chapel Hill

Genomics researchers discover protein deficit that causes drug toxicity

2011-07-29T12:00:00.000-07:00

Mayo Clinic researchers have discovered an inherited structural mechanism that can make drugs for some diseases toxic for some patients. The mechanism decreases a protein and in turn causes certain individuals to metabolize thiopurine drugs differently. Thiopurine therapies are used to treat patients with childhood leukemia, autoimmune diseases and organ transplants. The Mayo researchers say their finding advances the field of pharmacogenomics, which tailors medicine to a patient's personal genetic makeup.

In the current issue of the Proceedings of the National Academy of Sciences, (pnas/cgi/content/abstract/102/26/9394) Mayo researchers report that under certain genetic conditions, key proteins are not formed properly -- they are "misfolded." When misfolding happens, the quality-control process in the cell detects the misfolded proteins and tags them for immediate destruction or quarantines them in a "cellular trash can" known as an aggresome (last syllable rhymes with "foam"). Whether destroyed or aggregated into the aggresome, the effect is the same: the patient's body suffers a protein deficit that disrupts the enzyme that metabolizes thiopurine.

"Our finding is surprising because the aggresome is a new kind of mechanism to study to explain this. It's quite different from what we were thinking even a few years ago," says Liewei Wang, M.D., Ph.D., lead Mayo researcher in the study. "People are still debating what its function really is, but it appears to play a role here by receiving misfolded proteins."

Significance of the Research

"Nobody has shown before that the aggresome plays a role in thiopurine metabolism, and it's a significant contribution," says Richard Weinshilboum, M.D., the Mayo Clinic researcher who first described the genetically variable response to thiopurine drugs over 20 years ago. "From a clinical point of view, the genetic test we developed at Mayo to predict response to thiopurine drugs has been invaluable to pharmacogenomic medicine -- and now this finding is taking us in promising new directions because we believe our findings can be generalized to apply to many instances in the field."

The finding helps explain what goes wrong under certain genetic conditions -- and suggests mechanisms which might help predict which genetic changes could alter the effect of drugs. Prior efforts to explain the mystery of thiopurine metabolism had focused on biochemical mechanisms -- not changes in protein levels.

Background

Researchers have known for decades that 1 in 300 patients of Caucasian European genetic background has two copies of the variant gene -- specifically, a switch in 2 out of 245 amino acids -- that results in the absence of the protein needed to properly metabolize thiopurine drugs. In patients with the genetic defect, instead of helping heal, a standard dose of thiopurine drugs can cause fatal bone marrow destruction. Though Mayo Clinic researchers described this genetically variable response and the danger it presents over 20 years ago, no one had been able to explain the cellular mechanism behind it.

Mayo Clinic

mayo

Secrets Of A Life-Giving Amino Acid Revealed By Yale Researchers

2011-07-26T12:00:00.000-07:00

Selenium is a trace element crucial to life - too little or too much of it is fatal. In the July 17 issue of the journal Science, researchers at Yale University and University of Illinois at Chicago detail the molecular mechanisms that govern its metabolism in the human body.

"It must require an intricately regulated uptake system," said Dieter SГ¶ll, co-senior author of the paper, Sterling Professor of Molecular Biophysics and Biochemistry at Yale. "There are 25 human selenoproteins, and most of them are probably essential for life."

Selenium is thought to offer protection from diverse human ailments including adverse mood states, cardiovascular disease, viral infections and cancer.

Selenocysteine is the most active metabolite of selenium in humans. It is unique among amino acids because it is the only one synthesized directly on a transfer RNA (tRNA) molecule, which shuttles the amino acids to the protein-making machinery within cells. Proteins that contain selenocysteine are responsible for recycling protective antioxidants such as vitamin C and coenzyme Q10.

SГ¶ll's team for the first time captured images of how selenocysteine is created on a super-sized tRNA molecule, which seems to have a highly specialized role in nature. The 20 other amino acids and their associated tRNAs use the same protein vehicle, called an elongation factor, for transport to the ribosome. However, nature has provided this large tRNA molecule with a specialized elongation factor that chauffeurs only selenocysteine to the ribosome.

"This structure reveals most aspects of the mechanism for the formation of selenocysteine and provides an answer to 20 years of biochemical work in the field," said Sotiria Palioura, lead author of the study and an M.D./Ph.D. candidate at Yale.

The findings may lead to greater understanding of autoimmune liver disease. The tRNA complex described in the Science paper is the target of antibodies in patients with Type 1 autoimmune hepatitis. "The region that the antibody is supposed to recognize is at the business end of this molecule, where we see the reaction happening," Palioura said.

"Selenocysteine has been found to be a critical component of enzymes involved in a number of normal and disease processes," said Michael Bender of the National Institutes of Health's National Institute of General Medical Sciences. "This basic study, which has shed light on selenocysteine's unique biosynthetic pathway, could ultimately have an impact on many aspects of human health, including the immune response, neurodegeneration, cardiovascular disease, and cancer."

Other Yale authors on the paper were R. Lynn Sherrer and Thomas A. Steitz. Senior co-author on the paper was Miljan Simonovic of the University of Illinois at Chicago.

Funding for the research was provided by the National Institute for General Medical Sciences, the Department of Energy, and the Howard Hughes Medical Institute at Yale University.

Citation: Science, July 17

Source
Yale University

Jet-Propelled Imaging For An Ultrafast Light Source

2011-07-23T12:00:00.000-07:00

John Spence, a physicist at Arizona State University, is a longtime user of the Advanced Light Source at Lawrence Berkeley National Laboratory, where he has contributed to major advances in lensless imaging. It's a particularly apt propensity for someone who works with x-rays, since they can't be focused with ordinary lenses.

As new light sources evolve to produce brighter x-rays in faster pulses, lensless imaging becomes ever more critical for science. Among the promises of superbright, ultrafast x-ray pulses is the ability to solve the structure of the complicated molecules from which our bodies are made. All living things are made of proteins and nucleic acids, but relatively few of the atomic structures of the thousands, perhaps millions, of varieties of proteins are known.

The Linac Coherent Light Source (LCLS) will soon begin operation at the SLAC National Accelerator Laboratory in Palo Alto, California, using energetic electrons from a linear accelerator to produce coherent x-rays with an instrument called a free electron laser (FEL). The x-rays will be delivered 120 times a second in pulses only a tenth of a trillionth of a second long - about the time it takes light to travel the width of a human hair. These brief, bright pulses offer a novel approach to the problem of protein structure.

Unfolding the origami

Proteins begin as strings of amino acids that fold themselves into an amazing variety of origami-like structures, whose bumps and crannies and distribution of electrical charges determine how they act individually or fit together to form complex molecular machines. Simple organisms like viruses often consist of a few proteins fitted together to enclose a thread of DNA or RNA.

Proteins are usually large molecules containing many thousands of atoms. Drug molecules are much smaller, and do their work by attaching themselves to the larger protein molecules. A knowledge of the arrangement of a protein's atoms is therefore a great help to drug designers, who like to understand how a drug molecule will dock with a protein to promote or inhibit its activity, or cripple the organism of which it is a part.

Until now, the best way to solve the structure of a protein or virus has been with x ray crystallography. The crystal consists of many copies of the protein or virus arranged in regular order. As the crystal rotates in the x-ray beam, x-rays scatter off the atoms and reveal - once these complex diffraction patterns have been converted into a 3-D image by computers - how the electrons, and thus the atoms, are arranged.

But many proteins can't be crystallized at all, and others are so difficult to crystallize it's virtually impossible to obtain crystals large enough to use in today's light sources.

Ultrafast, ultrabright x-rays offer a way past this dilemma. The idea is that a quick pulse of tightly focused x-rays can be diffracted from a microcrystal or even a single protein or virus in solution. The pulse is so brief that it comes and goes before any of the atoms can move, freezing their orientation like a strobe light. Just as important, a sufficiently brief pulse may terminate before radiation damage effects can start. In this way it can outrun radiation damage, always one of the fundamental limitations to imaging in biology.

Another quick pulse could be diffracted from another copy of the protein in a different orientation. As the process is repeated, diffractions from different angles give the overlapping views needed for the computer to construct a 3-D image of the structure.

It's a great idea, but as Spence notes, there are a few problems. "So as not to scatter, the x-ray beam has to be in a high vacuum, but a protein or virus in its natural state is usually wet. As in T. S. Eliot's Wasteland, water is life. How do we maintain the protein or virus in an aqueous environment inside the vacuum?"

Shot from a microcannon

The answer was what Spence calls a "particle gun, like an ink-jet printer," designed to inject a beam of water droplets across the tightly focused x-ray beam in single file, each droplet so small it contains only a single protein or virus. He and colleagues Bruce Doak and Uwe Weierstall of ASU designed a nozzle that can fire liquid droplets, each less than a millionth of a meter in diameter (one micrometer), faster than hundreds of thousands of times a second. The sample jet is designed to shoot droplets right through a pulsed beam of x-rays a billion times brighter than any ever created in a light source before.

It wasn't easy. Nozzles made of solid material like glass invariably clog up, limiting droplets to at best 20 micrometers across. What Spence and his colleagues wanted was a jet of particles less than a micrometer in size. ASU postdoc Dan DePonte has done most of the recent hard work needed to make it all function.

Back in 1878 Lord Rayleigh, a professor of experimental physics at Cambridge University, discovered that a smooth, cylindrical jet of liquid emerging from an orifice spontaneously breaks up to form a train of spherical droplets. In the late 1990s, physicist Alfonso GaГ±ГЎn-Calvo of the University of Seville found a way to surround the streaming liquid with pressurized gas to make a co-flowing liquid sheath. By adjusting gas and liquid pressure and other parameters, he was able to create a "virtual nozzle" that could shrink the diameter of the liquid jet to a thread so small it would not clog the physical aperture of the tube. In effect, the gas sheath acts to focus the liquid stream.

Spence and his colleagues needed a true microthread of liquid, however, one that produced droplets sized a millionth of a meter or less. In their nozzle, liquid flows through a narrow capillary inside the tube through which the gas flows; the liquid issues from the capillary some distance from the opening in the outer tube, so the gas surrounds it, then increases speed and pressure as it approaches the opening, squeezing and accelerating the thin stream of liquid until it is so small that the proteins or viruses dissolved in the liquid can only fit into the droplets one at a time.

And the nozzle won't clog, because even a particle bigger than the sample protein or virus - bigger than the stream of liquid itself - can still fly through the glass nozzle without hitting the walls and getting stuck.

The frequency at which the droplets emerge can be controlled by an oscillator the researchers call an "acoustic trigger." Tuning the acoustic trigger adjusts the frequency so that each droplet containing a protein or virus meets an incoming pulse of x-rays.

The entire device - which the researchers call a gas dynamic virtual nozzle (GDVN) - is only about a millimeter in diameter (not counting feed lines and cables) and fits to the side of the beamline's vacuum chamber. After passing through the beam, the liquid droplets and the gas (typically carbon dioxide) freeze in a trap opposite the injection point, without significantly reducing the vacuum.

In 2008 Spence and his colleagues, including Berkeley Lab's David Shapiro, successfully tested the GDVN on the Advanced Light Source beamline 9.0.1, managed by Berkeley Lab's Stefano Marchesini. The test was done with protein microcrystals extracted from the fluid in which researchers were attempting to grow larger crystals. These are the smallest protein nanocrystals from which diffraction patterns have ever been obtained, and the first from membrane protein nanocrystals - among the most resistant to crystallization.

Although the microcrystals weren't individual protein specimens, and while the 9.0.1's x-ray beams aren't as bright or as rapidly pulsed as SLAC's LCLS will be, the experiment demonstrated the jet technique's high potential for speeds and exposures that won't subject the samples to radiation damage. Some of the patterns the researchers obtained come from nanocrystals just a few molecules on a side, with a width of about 100 billionths of a meter (100 nanometers). At SLAC, the researchers plan to steadily reduce the nanocrystal size down to single molecules.

The corresponding reduction in scattered intensity will hasten and improve lensless imaging. The first step in lensless imaging is scattering the beam from the sample; the second step is constructing the image by interpreting and combining the data from the diffracted x-rays.

In order to merge the different views (projections) of an object, which is subsequently vaporized in this "diffract-and-destroy" mode, it is important that they all be identical. In biology, that leaves only molecules like proteins and viruses. DNA or RNA inside a virus is often packed differently in each virus, and cells are not identical at the molecular level, so cannot be studied in 3-D by this method.

Besides identical particles, successful data-merging also depends partly on knowing how the sample was oriented in the beam - easy to do with a large crystal, not so easy to do with a sample inside a drop of liquid whizzing across the beam. It may be possible to orient flying droplets by optical methods such as polarized laser beams or with specially shaped nozzles.

Perhaps simpler is to use the ever-increasing power of the computer - which for a lensless imaging system is where most of the functions of a lens reside. Computer systems have been developed that infer the orientation of the sample from the diffraction pattern itself, even when as few as four percent of the pixels in the detector light up. It does take a lot of diffraction patterns to derive an image this way - as many as 10 million - which will take the LCLS a few hours until better ways of orienting the droplets can be devised.

Nevertheless, Spence's group recently obtained excellent diffraction patterns of MS2 virus capsids at the ALS by subtracting the diffraction "noise" of the liquid jet itself. These capsids, made in Mat Francis's lab at the University of California at Berkeley, are the shells of the virus lacking its RNA genome and have the regular shape of buckyballs. Eventually the LCLS will be able to get a good diffraction pattern from a target like this with a single ultrabright pulse. In this case, however, computer processing was able to derive an excellent pattern by averaging diffraction from a series of samples.

DePonte will soon install Spence and Doak's ultrafine, ultrafast "inkjet printer," tested at the ALS, on the powerful new SLAC machine. It will be the first step into a bold new future for investigating the biological universe, one big molecule at a time.

Additional information

"X-ray imaging beyond the limits," by Henry N. Chapman, appeared in Nature Materials, April, 2009.

"Powder diffraction from a continuous microjet of submicrometer protein crystals," by D. A. Shapiro, H. N. Chapman, D. DePonte, R. B. Doak, P. Fromme, G. Hembree, M. Hunter, S. Marchesini, K. Schmidt, J. Spence, D. Starodub, and U. Weierstall, appeared in the Journal of Synchrotron Radiation, November, 2008.

"Gas dynamic virtual nozzle for generation of microscopic droplet streams," by D. P. DePonte, U. Weierstall, K. Schmidt, J. Warner, D. Starodub, J. C. H. Spence, and R. B. Doak, appeared in the Journal of Physics D: Applied Physics, 19 September, 2008.

Source:
Paul Preuss

DOE/Lawrence Berkeley National Laboratory

Genetic Compatibility And Hatching Success In The Sea Lamprey (Petromyzon Marinus). Is There A Better Half?

2011-07-20T12:00:00.000-07:00

It often assumed that the quality of a potential mate in terms of how their genes affect their offspring quality is a fixed feature of each individual.

However, it is becoming increasingly apparent that this is not always the case, and that mates may vary in compatibility more than in quality. We fertilised separate batches of eggs from female sea lampreys (a parasitic fish) with sperm from several different males.

This revealed that the viability of offspring was mainly dependent on how compatible partners were. For female lampreys, there are no good or bad males, but there are better halves.

Royal Society Journal Biology Letters

Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.

Biology Letters

Controlling Nitric Oxide Levels Could Further Improve Effectivness Of Anticancer Therapies

2011-07-17T12:00:00.000-07:00

Manipulating levels of nitric oxide (NO), a gas involved in many biological processes, may improve the disorganized network of blood vessels supplying tumors, potentially improving the effectiveness of radiation and chemotherapy. In an upcoming issue of the journal Nature Medicine, researchers from the Steele Laboratory of Radiation Oncology at Massachusetts General Hospital (MGH) report an experiment in which NO production was selectively suppressed in tumor cells while being maintained in blood vessels. The result was a significant improvement in the appearance and function of the tumor's blood supply.

"Our finding suggest that the creation of perivascular NO gradients - differences between the levels produced in blood vessels and those found in tumor tissue - may be able to normalize tumor vasculature," says Dai Fukumura, MD, PhD, of the Steele Laboratory, who led the study. "Combining the use of angiogenesis inhibitors, which normalize vasculature through a different mechanism, with the blockade of nonvascular NO production may produce even greater improvement in therapeutic outcomes."

The blood vessels that develop around and within tumors are leaky and disorganized, interfering with delivery of chemotherapy drugs and with radiation treatment, which requires an adequate oxygen supply. Combining angiogenesis inhibitors, drugs that suppress the growth of blood vessels, with traditional anticancer therapies has improved patient survival in some tumors. That success supports a theory developed by Rakesh K. Jain, PhD, director of the Steele Laboratory, that the agents temporarily 'normalize' blood vessels, creating a period during which other treatments can be more effective.

Since angiogenesis is one of many physiologic activities mediated by NO, the MGH research team hypothesized that restricting NO production to blood vessels also could improve tumor vasculature. Using cancer cells from human brain tumors, they suppressed the enzyme that controls NO production in nonvascular tissue. When the modified tumor cells were implanted into mice, analysis of the resulting tumors showed that NO was present primarily in blood vessels, with significant reductions in tumor cells. Vessels in the growing tumors were more evenly distributed and less distorted than those in tumors grown from untreated tissue.

"Angiogenesis inhibitors block formation of new vessels by directly or indirectly inhibiting the proliferation and survival of vascular endothelial cells. But since their overall effect is to reduce the density of blood vessels, the ability of those agents to normalize tumor vasculature may not last long," says Fukumura. "Blocking nonvascular NO production and maintaining NO levels around the vessels appears to keep endothelial cell function at the proper level." An associate professor of Radiation Oncology at Harvard Medical School, Fukumura notes that the strategy now should be investigated in other types of tumors.

The Nature Medicine report has been released online and was supported by grants from the National Cancer Institute. In addition to Fukumura and Jain, co-authors of the article are first author Satoshi Kashiwagi, MD, PhD, Kosuke Tsukada, PhD, Lei Xu, MD, PhD, Junichi Miyazaki, MD, PhD, Sergey Kozin, DSc, PhD, James Tyrrell, PhD, and Leo Gerweck, PhD, all of the Steele Lab; and William Sessa, PhD, Yale University School of Medicine.

Massachusetts General Hospital (massgeneral/), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Source: Sue McGreevey

Massachusetts General Hospital

Special Laser "Tweezers" For Medicine, Communications And Harvesting Energy

2011-07-14T12:00:00.000-07:00

Star Trek fans will remember "tractor beams," lasers that allowed the Starship Enterprise to trap and move objects. Tel Aviv University is now turning this science fiction into science fact - on a nano scale.

A new tool developed by Tel Aviv University, Holographic Optical Tweezers (HOTs) use holographic technology to manipulate up to 300 nanoparticles at a time, such as beads of glass or polymer, that are too small and delicate to be handled with traditional laboratory instruments. The technology, also known as "optical tweezers," could form the basis for tomorrow's ultra-fast, light-powered communication devices and quantum computers, says Dr. Yael Roichman of Tel Aviv University's School of Chemistry.

She's using these tweezers to build nano structures that control beams of light, aiding in the development of anything from optical microscopes to light-fuelled computer technology, she reports.

Holding onto the light

HOTS are a new family of optical tools that use a strongly-focused light beam to trap, manipulate and transform small amounts of matter. First proposed as a scientific theory in 1986 and prototyped by a University of Chicago team in 1997, holographic optical tweezers have been lauded as indispensible for researching cutting-edge ideas in physics, chemistry, and biology.

Dr. Roichman and her team of researchers are currently pioneering the use of optical tweezers to create the next generation of photonic devices. Made out of carefully arranged particles of materials such as silicon oxide and titanium oxide, these devices have the ability to insulate light, allowing less energy to be lost in transmission.

"Our invention could increase transmission speed and save energy, important for long-life batteries in computers, for instance," says Dr. Roichman.

Photons are already used in optical fibers that bring us everyday luxuries like cable TV. But Dr. Roichman says this technology can be taken much further. In her lab at Tel Aviv University, she is advancing the previous study of photonic crystals, which control and harness light, by manipulating a variety of particles to create 3D heterogeneous structures. The ability to insulate light in a novel way, preserving its potential energy, is central to this goal.

No known material today can resist the flow of light - its energy is either absorbed by, reflected off, or passed through materials. But Dr. Roichman has devised a new layering technique using special crystals central to the creation of photonic devices. These photonic crystals are arranged to create a path along which light can travel. If they're arranged correctly, she says, the light is trapped along the path.

In Dr. Roichman's approach, different materials are added to absorb or amplify light as required. She is hopeful that the ability to build these devices will transform communications, telescopic instruments, and even medical technology, making them more efficient and powerful.

Shining a light into a bacterium's belly

One project Dr. Roichman is working on tracks the effectiveness of antibiotics. Her improvements to optical microscopy will, for the first time, allow researchers to look at the internal processes within bacteria and see how different types of antibiotics attack them. More than that, her optical tweezers can isolate the bacteria to be studied, handling them without killing them.

Dr. Roichman, whose previous research was published in the journals Applied Optics and Physics Review Letters, notes that HOTs give researchers a platform with infinite possibilities. They give science a valuable tool to reach into the microscopic world - and their building potential is endless.

Source:

George Hunka

American Friends of Tel Aviv University

Ingredient Found In Green Tea Significantly Inhibits BreastCancer Growth In Female Mice

2011-07-11T12:00:00.000-07:00

Green tea is high in the antioxidant EGCG (epigallocatechin-3- gallate) which helps prevent the body's cells from becoming damaged and prematurely aged. Studies have suggested that the combination of green tea and EGCG may also be beneficial by providing protection against certain types of cancers, including breast cancer. A new study conducted by researchers at the University of Mississippi researchers now finds that consuming EGCG significantly inhibits breast tumor growth in female mice. These results bring us one step closer to better understanding the disease and potentially new and naturally occurring therapies.

The study was conducted by Jian-Wei Gu, Emily Young, Jordan Covington, James Wes Johnson, and Wei Tan, all of the Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS. Dr. Gu will present his team's findings, entitled, Oral Administration of EGCG, an Antioxidant Found in Green Tea, Inhibits Tumor Angiogenesis and Growth of Breast Cancer in Female Mice, at the 121st Annual Meeting of the American Physiological Society, part of the Experimental Biology 2008 scientific conference.

The Study

Epidemiological studies suggest that green tea and its major constituent, EGCG, can provide some protection against cancer. Because these studies were very limited, the anti-cancer mechanism of green tea and EGCG was not clear. As a result, the researchers examined whether drinking EGCG (just the antioxidant infused in water) inhibited the following: expression of VEGF (vascular endothelial growth factor, which is found in a variety of breast cancer types); tumor angiogenesis (thought to help tumors expand by supplying them with nutrients); and the growth of breast cancer in female mice.

Seven week old female mice were given EGCG (25 mg/50 ml) in drinking water for five weeks (approximately 50-100 mg/kg/day.) The control mice received regular drinking water. In the second week of the study mouse breast cancer cells were injected in the left fourth mammary glands of the mice. Tumor size was monitored by measuring the tumor cross section area (TCSA). Tumors were eventually isolated and measured for tumor weight, intratumoral microvessel (IM) density (using staining), and VEGF protein levels (using ELISA).

At the end of the five week period the researchers found that oral consumption of EGCG caused significant decreases in TCSA (66%), tumor weight (68%), IM density 155В±6 vs.111В±20 IM#mm^2) and VEGF protein levels (59.0В±3.7 vs. 45.7В±1.4 pg/mg) in the breast tumors vs. the control mice, respectively (N=8; P

Timing Precision In Population Coding Of Natural Scenes In The Early Visual System

2011-07-08T12:00:00.000-07:00

The timing of spiking activity across neurons is a fundamental aspect of the neural population code. Individual neurons in the retina, thalamus, and
cortex can have very precise and repeatable responses but exhibit degraded temporal precision in response to suboptimal stimuli.

To investigate the
functional implications for neural populations in natural conditions, the authors recorded in vivo the simultaneous responses, to movies of natural
scenes, of multiple thalamic neurons likely converging to a common neuronal target in primary visual cortex. They show that the response of individual
neurons is less precise at lower contrast, but that spike timing precision across neurons is relatively insensitive to global changes in visual
contrast.

Overall, spike timing precision within and across cells is on the order of 10 ms. Since closely timed spikes are more efficient in inducing
a spike in downstream cortical neurons, and since fine temporal precision is necessary to represent the more slowly varying natural environment, we
argue that preserving relative spike timing at a;10-ms resolution is a crucial property of the neural code entering cortex.

Citation:

"Timing precision in population coding of natural scenes in the early visual system."
Desbordes G, Jin J, Weng C, Lesica NA, Stanley GB, et al. (2008)

PLoS Biol 6(12): e324. doi:10.1371/journal.pbio.0060324

Click here to view article online.

JOURNAL PLoS BIOLOGY

plosbiology

Mirus Bio Announces Efficient New Genetic Immunization Method To Produce Antibodies

2011-07-05T12:00:00.000-07:00

Scientists at Mirus Bio
Corporation have developed a genetic immunization technique for making
high-quality antibodies faster and more cheaply than by conventional methods.
This proprietary process is described in the February issue of the journal
BioTechniques. It involves an innovative new method of intravenously
injecting DNA into animals, whose immune systems respond by producing
antibodies that can be harvested for subsequent use.

Antibodies are part of the body's immune system. Because they can bind to
and neutralize specific antigens, such as proteins, viruses, and cancer cells,
they have become useful tools in medical diagnosis and scientific research.
Antibodies are also used for the targeted treatment of diseases, such as
cancer.

Conventional methods of generating antibodies require the slow process of
identifying, isolating, and purifying the protein which serves as the target
antigen. The resulting protein is then injected into animals to elicit an
antibody response, after which the antibodies are harvested and used for their
intended purpose. However, due to the processes employed, such purified
proteins may not be identical to the natural antigenic protein, and therefore
may not be as potent at eliciting an immune response. They can also be very
difficult to manufacture. The cost and uncertainty of this process, both in
dollars and time, represent significant hurdles. The new technique developed
at Mirus Bio bypasses these hurdles and enables research animals to naturally
produce antigenic proteins that elicit a potent antibody response. This
offers a higher quality antibody in less time at reduced cost.

"This represents yet another breakthrough application of our nucleic acid
delivery portfolio," notes Jon A. Wolff, M.D., Mirus Bio's Chief Scientific
Officer. This research was conducted by Mary Kay Bates, Hans Herweijer,
Ph.D., and their colleagues at Mirus Bio and the University of
Wisconsin-Madison.

This research tool is available for licensing for those who wish to use it
within the biotechnology and pharmaceutical industry, either for internal
research or as part of a commercial antibody production service.

About Mirus Bio Corporation

Mirus Bio Corporation is a leader in the emerging fields of gene therapy
and RNA interference, based upon its expertise in nucleic acid chemistry and
delivery. The company currently markets state-of-the-art DNA and siRNA
transfection and labeling products to researchers worldwide. In addition, the
company is developing novel human therapeutics enabled by its proprietary
Pathway IV(TM) delivery platform. The company's lead therapeutic is a
treatment for Muscular Dystrophy, which is being developed collaboratively
with Transgene S.A. of Strasbourg, France.

Mirus Bio Corporation

mirusbio

In Schizophrenia And Bipolar Disorder, Life Is Not Black And White

2011-07-02T12:00:00.000-07:00

Schizophrenia and bipolar disorder affect tens of millions of individuals around the world. These disorders have a typical onset in the early twenties and in most cases have a chronic or recurring course. Neither disorder has an objective biological marker than can be used to make diagnoses or to guide treatment.

Findings in Biological Psychiatry, published by Elsevier suggest that electroretinography (ERG), a specialized measure of retinal function might be a useful biomarker of risk for these disorders, and retinal deficits may contribute to the perceptual problems associated with schizophrenia and bipolar disorder.

Over the past several years, research has suggested that cognitive impairments in schizophrenia might be linked to early stages of visual perception. This work is now drawing attention to the function of the retina, the component of the eye that detects light. Within the retina, rods are light sensors that respond to black and white, but not to color. Rods are particularly important for maintaining vision under conditions of low light and for detecting stimuli at the periphery of vision. Cones are light sensors that detect color and perceive stimuli at the center of vision.

Using ERG, Canadian researchers Marc HГ©bert, Michel Maziade and their colleagues observed that the ability of light to activate rods was significantly reduced in currently healthy individuals who descended from multigenerational families that had members diagnosed with either schizophrenia or bipolar disorder. In contrast, the response of their cones to light was normal.

"We take for granted that other people experience the world in the same way that we do. It is important to appreciate that for schizophrenia and bipolar disorder, as for colorblindness or selective hearing loss, people who appear to perceive the world normally may actually have subtle but important problems with perception, which may contribute to other adaptive impairments," comments Dr. John Krystal, Editor of Biological Psychiatry.

Scientists are still searching for a valid biomarker for the heritable risk for schizophrenia and bipolar disorder. Although the current data are interesting, extensive testing is still needed before the utility of this measure as a risk biomarker can be evaluated.

Source: Elsevier

Technique Traces Origins Of Disease Genes In Mixed Races

2011-06-29T12:00:00.000-07:00

A team of researchers from Washington University in St. Louis and the Israeli Institute of Technology (Technion) in Haifa has developed a technique to detect the ancestry of disease genes in hybrid, or mixed, human populations.

The technique, called expected mutual information (EMI), determines how a set of DNA markers is likely to show the ancestral origin of locations on each chromosome. The team constructed an algorithm for the technique that selects panels of DNA markers in order to render the best picture of ancestral origin of disease genes. They then tested the algorithm to show that it is more powerful and accurate than standard algorithms that are currently used.

The result is easier identification of inherited genes that cause diseases in people of mixed races, which researchers call "population admixture." Nephrologists, for instance, have noted that African-Americans are far more likely than Europeans to die rapidly of end-stage, progressive renal failure due to kidney disease. Many African-Americans, though, have genes that originated in Europe due to ethnic mixing. The technique helps researchers isolate the genetic causes of disease by detecting from which continent the recurrent disease genes originated.

A current research goal is to treat or even prevent kidney disease with gene or drug therapies.

"This technique will allow researchers to analyze which regions of the genome are associated with end-stage, progressive renal failure," said Alan R. Templeton, Ph.D., the Charles Rebstock Professor of Biology. "Once the regions are identified, then you look at the individual genes and ask: Are there genetic factors involved with this, and if so, what are the candidates?"

It's a good bet, Templeton said, that the disease genes are highly likely to have emerged from Africa, as African-Americans have shown the tendency to die more quickly of the disease.

The technique and algorithm apply beyond this particular disease, Templeton added.

"We can look at many different hybrid human populations with this algorithm and use it on a diversity of diseases," he said.

"Our novel approach extends previous methods by incorporating knowledge on population admixture, drawing a more precise picture of the mosaic of ancestries along an individual's genome," said Sivan Bercovici, Templeton's colleague at Technion and primary author of a research paper published in Genome Research.

The researchers analyzed DNA from 575 cases of African-Americans with end-stage progressive renal failure and compared it to controls that did not have the disease. They came up with a panel of approximately 2,000 genetic markers. Enough, Templeton said, "to cover the whole genome."

To tease out the origins of disease-causing genes, researchers use a technique called mapping by admixture linkage disequilibrium (MALD), a powerful approach to identify regions of the genome that have genes associated with disease. It takes advantage of differences in disease prevalence between populations to look for variation patterns that are over-represented in groups with high susceptibility to a certain disorder.

Both EMI and the algorithm make MALD more accurate and efficient.

A paper discussing the technique and algorithm is published in the current issue of Genome Research 18, 661-667.

Written by Tony Fitzpatrick

Washington University in St. Louis

The Identification And Functional Evaluation Of Small, Non Coding RNAs In The Regulation Of Complex Biological Processes

2011-06-26T12:00:00.000-07:00

ORLANDO, FL () - In a joint meeting of the SBUR and SUO, Dr. Victoria Robinson discussed that small non-coding RNAs are important in the regulation of complex biological processes. She stated that RNA was probably the first biological molecule, have lots of secondary structure and catalyze reactions and serve critical functions. Only 2% of our DNA codes for protein and the other 85% was felt to be "junk". Yet, now it is felt that half of that is unique DNA and the majority of the human genome is transcribed into RNA. Non-coding RNAs (ncRNAs) are a large family of molecules and very diverse. The ncRNAs are powerful sequence specific post-transcriptional regulators for gene expression. One siRNA targets one miRNA. miRNA are endogenously encoded genes with diverse physiological functions. They bind target mRNAs and suppress translation. In contrast to siRNA, miRNA targets many mRNAs. While siRNA forms intracellular complexes, miRNA are transcribed into hairpin loops that is then unwound and each piece can target different genes.

The first miRNA was described in 1933 and the second one in 2000. In 2001, 3 papers showed that miRNA was conserved in many organisms, including humans. In situ hybridization of miRNA was described in 2007 and now it is a blooming field of research. The name given to miRNA reflects the species and sequence and order of discovery. miRNA is now recognized to be endogenous genes and are an ancient mechanism of gene regulation. There are >700 human miRNAs presently described. Target algorithms predict hundreds of targets for each miRNA. In one study, algorithms to predict the number of targets is variable, thus target validation is required.

miRNAs are tumor suppressor genes and can undergo mutation. For example, p53 undergoes transcriptional activation and miR-34 is expressed and involved in regulation of this pathway. Challenges in the field include better target prediction and databases. Cancer cells in general may use an alternative splicing mechanism to avoid miR regulation. Also, mammalian protein translation is not fully understood and understanding other ncRNA mechanisms such as heterochromatin silencing is under investigation. She concluded that every tumor type has mRNAs and will be developed as tumor targets.

Presented by Victoria Robinson, MD, at the Annual Meeting of the American Urological Association (AUA) - May 17 - 22, 2008. Orange County Convention Center - Orlando, Florida, USA.

Reported by Contributing Editor Christopher P. Evans, MD, FACS

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Proteomics Technology To Focus On Neurological Complications Of HIV

2011-06-23T12:00:00.000-07:00

The National Institute on Drug Abuse of the National Institutes of Health has awarded a three-year, $3-million grant to Albert Einstein College of Medicine of Yeshiva University to establish a research center to study the neurological complications that afflict people infected with HIV, the virus that causes AIDS.

Despite the effectiveness of antiretroviral therapy for HIV, neurological complications associated with HIV infection - including cognitive, behavioral, and motor abnormalities - have become more common as infected individuals live longer.

"More than a quarter of those infected with HIV exhibit some form of cognitive impairment," says Ruth Hogue Angeletti, Ph.D., professor of developmental & molecular biology and of biochemistry at Einstein, who will direct the Einstein Proteomics Research Center for HIV-Associated Neurological Disorders and Substance Abuse. "By the time HIV-infected people have progressed to AIDS, more than half display significant neurological deficits."

This new proteomics center will use powerful mass spectrometers to identify the brain proteins responsible for neurological complications in people infected with HIV - particularly those who are also addicted to drugs. Proteomics is the branch of molecular biology that studies the set of proteins expressed by the genes of an organism.

HIV's neurological complications (commonly referred to as neuro-AIDS) primarily stem from toxic proteins produced by immune cells called monocytes, which recruit HIV into the central nervous system. Neuro-AIDS can lead to AIDS dementia complex, HIV-related encephalitis, and fungal and parasitic infections.

The Einstein Proteomics Research Center will investigate the mechanism by which HIV infection causes neurological deficits and identify biomarkers that signal when these deficits begin and how they progress over time.

"The biomarkers identified by this new center should permit the early detection of neurological disease in HIV-infected individuals," says co-principal investigator Harris Goldstein, M.D., director of the Einstein-Montefiore Center for AIDS Research and professor of pediatrics and of microbiology & immunology at Einstein.

"We have developed a unique transgenic HIV mouse model that displays some features of neuro-AIDS," Dr. Goldstein notes. "By studying this mouse model in the proteomics center, we'll be able to determine how HIV infection influences the proteins expressed in the brain. These results may help us to pinpoint new therapeutic targets for preventing the progression of this devastating consequence of HIV infection."

Several studies of autopsy tissue show that the destructive neuro-AIDS process is worsened by drug abuse, particularly the use of opioids such as heroin. Unfortunately, the combination of HIV infection and drug addiction is all too common. In New York City, for example, more than half of all AIDS cases result directly or indirectly from injection drug use.

"Therefore, the intersection between HIV infection and opioid use represents an especially important area of neuro-AIDS research on which our proteomics center will focus," says Dr. Angeletti.

Each of the center's projects will evaluate the neurological effects of buprenorphine - a new, less-addictive alternative to methadone. Compared with methadone, buprenorphine can be given at higher doses with fewer adverse effects. But it could conceivably contribute to neurological problems when used by drugs addicts who are infected with HIV.

"The blood-brain barrier protects the brain from HIV-infected monocytes and other neuroinflammatory mediators, and we don't yet know how buprenorphine affects this barrier," says co-principal investigator Joan W. Berman, Ph.D., professor in the departments of pathology and microbiology & immunology at Einstein. "We need to understand buprenorphine's neurological impact before use of the drug becomes widespread in this patient population."

On the other hand, the center's research may show that buprenorphine is a better alternative than methadone for people infected with HIV. "Because of its unique pharmacological properties, buprenorphine may provide neuropsychological benefits for HIV-infected people who are addicted to opioids," says Julia H. Arnsten, M.D., M.P.H., the center's other co-principal investigator and professor of medicine, of epidemiology & population health, and of psychiatry and behavioral sciences at Einstein.

As part of the study, Dr. Arnsten will recruit a cohort of HIV-infected patients who are undergoing treatment for drug addiction. These people will be monitored to see whether buprenorphine influences the development of neurological deficits.

Other key investigators for this center are Dr. Louis Weiss in the departments of pathology and of medicine, Dr. Andras Fiser in the departments of systems & computational biology and of biochemistry, Dr. Abdissa Negassa in the department of epidemiology & population health, and Dr. Monica Rivera-Mindt in the department of psychology at Fordham University.

Source:
Deirdre Branley

Albert Einstein College of Medicine

Molecules In Plants May Have Beneficial Effect On Alzheimer's Disease

2011-06-20T12:00:00.000-07:00

A set of molecules found in certain plants appears to have a beneficial effect in brain tissue associated with Alzheimer's disease, according to a new study conducted in mice. The study was led by researchers at the University of South Florida and Cedars-Sinai Medical Center. An article in the Journal of Cellular and Molecular Medicine is available online.

Terrence Town, Ph.D., one of the senior authors of the study, is available to provide more information about this study. He is a research scientist with the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai Medical Center, and with the hospital's neurosurgical research center, the Maxine Dunitz Neurosurgical Institute.

Researchers administered molecules called flavonoids, which are found in certain fruits and vegetables, to a mouse model genetically programmed to develop Alzheimer's disease. Using two of these molecules, luteolin and diosmin, they were able to reduce the levels of a protein called amyloid-beta, which forms the sticky deposits that build up in the brains of patients with Alzheimer's. The researchers also determined that these molecules work by targeting a protein called presenilin-1, which has long been linked to Alzheimer's as a genetic cause of this devastating and untreatable illness.

The results may offer a new approach to therapy for patients suffering from this neurodegenerative illness, which is the most common cause of dementia and is estimated to affect more than five million people in the United States.

"These flavonoids are widely available in natural foods and it appears that they may be used in purified form as therapeutic agents. The compounds have few if any side effects and are naturally occurring in citrus fruits. They also can be found as dietary supplements in health food stores," Town said.

Jun Tan, M.D., Ph.D., with the University of South Florida Department of Psychiatry, headed the study. Other authors are: Kavon Rezai-Zadeh (first author), R. Douglas Shytle, Ph.D., Yun Bai, M.D., Ph.D., Jun Tian, M.D., Ph.D., Huayan Hou, M.D., Ph.D., Takashi Mori, D.V.M., Ph.D., Jin Zeng, M.D., and Demian Obregon.

The study was supported by the National Institutes of Health and the Johnnie B. Byrd Sr. Alzheimer's Center & Research Institute.

Citation: Journal of Cellular and Molecular Medicine, "Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease ОІ-amyloid production," published online April 17, 2008

Cedars-Sinai Medical Center

8700 Beverly Blvd., Rm 2429A

Los Angeles, CA 90048

United States

cedars-sinai

NRC, UOttawa Scientists First To Watch A Chemical Bond Break Using Molecule's Electrons

2011-06-17T12:00:00.000-07:00

Scientists at the National Research Council of Canada (NRC) and the University of Ottawa (uOttawa) enjoyed a bird's eye view of a chemical bond as it breaks.

The making and breaking of chemical bonds underlie the biochemical processes of life itself. A greater understanding of the quantum processes that lead to chemical reactions may lead to new strategies in the design and control of molecules - ultimately leading to scientific breakthroughs in health care and diagnostic medicine, quantum computing, nanotechnology, environmental science and energy.

The NRC-uOttawa team, led by Dr. David Villeneuve, achieved their feat using a technique developed several years ago at NRC in which an image was obtained of a single electron orbiting a molecule. In the current experiment, which is reported in the July 29th edition of Nature, scientists injected bromine gas into a vacuum chamber. There, an ultra brief ultraviolet light pulse caused the bromine molecules to separate into their individual atoms (a bromine molecule is composed of two bromine atoms). A few femtoseconds later, an intense infrared laser pulse caused the molecule to emit an attosecond-duration X-ray burst that contained a snapshot of the atom's position as the molecule fell apart and revealed how the electrons rearranged themselves.

"Due to the strange laws of quantum physics," Dr. Villeneuve explains, "a molecule that is broken apart by an ultraviolet laser pulse is at the same time unaffected by the pulse, a paradox, much like SchrГ¶dinger's Cat is both dead and alive."

The interference of the x-rays emitted by the two quantum states of the molecule was used to find the location of the atoms and to watch over a period of only 200 femtoseconds as it progressed from being a molecule to being two separate atoms. The experiment reached a precision below 500 zeptoseconds in clocking the emitted x-ray bursts. "It is exciting to see the quantum transformation as it goes from being a molecule, in which electrons are shared, to individual atoms, says Villeneuve.

According to Professor Paul Corkum, co-author and a pioneer in attosecond physics, "In real life we are most sensitive to motion if there is a fixed background for reference. We have shown that it is the same in the molecular world. Unreacting molecules - usually a nuisance in an experiment - can also form a reference. Against this fixed background we become so sensitive to motion that we can see just few dissociating molecules. The experiment is another important step towards the dream of filming chemical reactions."

The research was conducted at JASLab, the Joint Attosecond Science Laboratory, a shared laser facility between the National Research Council of Canada and the University of Ottawa, with the participation of the Technical University of Vienna. JASLab is one of the top laboratories in the world conducting research on the attosecond timescale.

How Fast is Really Fast?

Femtosecond = A femtosecond is an incredibly short period of time. One femtosecond is one millionth of one billionth of a second or 1 / 1,000,000,000,000,000 seconds

Attosecond = An attosecond is even shorter! One attosecond is to one second as one second is to the age of the universe. One attosecond is one billionth of one billionth of a second or 1 / 1,000,000,000,000,000,000 seconds.

Zeptosecond = A zeptosecond is still a shorter period of time. A spaceship traveling at the speed of light will travel from one side of a hydrogen atom to the other in 500 zeptoseconds. A zeptosecond is 1 / 1,000,000,000,000,000,000,000 seconds.

Source:

Helene Letourneau

National Research Council of Canada

'Surprising Link' Points Toward A New Antibiotic

2011-06-14T12:00:00.000-07:00

As the best drugs become increasingly resistant to superbugs, McMaster University researchers have discovered a completely different way of looking for a new antibiotic.

In a paper published May 29 in the journal Chemistry and Biology, with colleagues in Germany and Wilfrid Laurier University, they report on work with the bacteria Staphylococcus aureus bacteria, the leading cause of infections in hospitals and the second most common community-acquired infection. Fewer and fewer antibiotics are effective against this bacteria.

Cell wall-active antibiotics, such as penicillin, kill bacteria by blocking production of the cell wall.

The researchers provide new evidence for genetic connections among three processes in the cell wall - teichoic acid, peptidoglycan and poly-isoprenoid synthesis. "Never before has such a profound link been drawn between these biosynthetic pathways supported by genetic, computational and biochemical evidence," they said in their paper.

"We found a connection that perhaps no one expected in the way the cell wall synthesis is wired," said lead author Eric Brown, professor and chair of the department of biochemistry and biomedical sciences in the Michael G. DeGroote School of Medicine.

"We found they are inextricably linked in their genetics and biochemistry," he said. "Along the way in this study, we have built a system that is ripe for being exploited as a way to search for small molecule drugs that would target these processes."

Potentially, he said, this may lead to the development of a new antibiotic.

Brown said the current arsenal of antibiotics was developed during the golden age of antibiotic drug discovery from 1930 to 1960, and then development stopped.

Research began again in earnest, he said, when troublesome strains of hospital and community-acquired infections began to emerge, such as MRSA (methicillin-resistant Staphylococcus aureus). "Since the 1960s, drug companies have for, the most part, been tweaking existing molecules, such as building better penicillin with minor changes to the original scaffold. But, you are not very far away from resistance when all you do is a little tweak."

The discovery of a "surprising link" between the three processes involved in cell wall synthesis lets researchers build a method of looking for molecules that will disturb the balance between them. "It offers a completely different way of looking for a new antibiotic that would be active against the cell wall," Brown said.

Source:
Veronica McGuire

McMaster University

Important Advance In Imaging Of Cell Death

2011-06-11T12:00:00.000-07:00

For quite some time, the "Holy Grail" in medical imaging has been the development of an effective method to image cell death as a means to intervene early in diseases and rapidly determine the effectiveness of treatments. A new paper by researchers at the University of Notre Dame and the Washington University School of Medicine describes important progress in using a synthetic probe to target dead and dying cells in mammary and prostate tumors in living animals.

Bradley D. Smith, Emil T. Hofman Professor of Chemistry and Biochemistry at Notre Dame, points out that the group of researchers had previously discovered that synthetic zinc (II)-dipicolylamine (Zn-DPA) coordination complexes can selectively target the outer surfaces of anionic (negatively charged) cell membranes. Furthermore, fluorescent versions of these Zn-DPA complexes act as imaging probes that can distinguish dead and dying mammalian cells from healthy cells in a cell culture and also selectively target bacteria in contaminated samples.

The researchers also recently demonstrated that a fluorescent near-infrared probe referred to as PSS-794 can be used to image bacterial infections in mice, indicating that PSS-794 has a notable ability to selectively target anionic cells in living animals.

In the new paper, the researchers describe a significant expansion of the animal imaging capability of PSS-794 by showing that it can target the anionic dead and dying cells within tumors in rat and mouse models. The research is an important step toward the development of optical imaging probes that could determine, noninvasively, the amount and type of cell death in tumors. Such imaging techniques could help clinicians accurately determine the grade of tumors and the stage of cancers, as well as to measure the effectiveness of treatments.

The researchers also believe that analogous probes can be developed that would allow for deep tissue imaging of cancers in humans.

Smith points out that although the study focused on mammary and prostate tumors, imaging of cell death is broadly useful for treatment of numerous conditions, including cardiovascular disease, neurology, renal disease and even transplant rejection.

The research, described in the Journal of the American Chemical Society, was supported by the National Institutes of Health, Notre Dame's Walther Cancer Center and the Notre Dame Integrated Imaging Facility.

Source:
Bradley Smith

University of Notre Dame

The Association For Molecular Pathology Releases Position Statement On Oversight Of Laboratory Tests

2011-06-08T12:00:00.000-07:00

The Association for Molecular Pathology (AMP) has released its new position statement on the oversight of laboratory developed tests (LDTs), a recent focus of debate among policy makers, the laboratory community and other stakeholders. AMP's statement outlines the organization's commitment to providing high quality tests and its recognition of the need for implementation of appropriate oversight mechanisms. The association also met with officials from the United States Food and Drug Administration tasked with reviewing applications for diagnostic devices to inform them of the new position statement and discuss FDA's approach to regulating tests.

In recent years, there has been increased attention on the oversight of LDTs among policy makers, manufacturers, regulators and the laboratory community. While AMP believes that current mechanisms are sufficient in ensuring patient safety and broad access to high quality tests, AMP is taking this opportunity to elucidate its position on the issue.

"We believe that laboratory developed tests are an essential and central component of clinical care," said AMP President Dr. Karen Mann. She continued, "There is no evidence that the current oversight system has been inadequate or that there have been systemic problems."

In its position statement, AMP highlights that laboratories performing molecular tests are subject to the Clinical Laboratory Improvement Amendments and all laboratory directors are extensively trained professionals who adhere to all training requirements, certifications, licensure, and other regulations. Dr. Mann stressed the need to foster innovation, "As policymakers, regulators, and other stakeholders consider modifying the current oversight process, AMP urges them to ensure continued patient access to testing." AMP calls for stakeholders to avoid proposals that would hinder innovation in diagnostics, slow the rapid development and modification of necessary tests and impede the practice of medicine as all specialties rely on diagnostic tests.

AMP's specific recommendations include:
Laboratory directors or medical directors should review and reaffirm their policies and procedures for reviewing and documenting that appropriate validation studies have been performed for all tests developed in their laboratories with due consideration of clinical utility and clinical utilization.

CLIA should reassess utilization of resources and enforcement capabilities in order to meet its current mandate. CLIA should strengthen its enforcement capabilities by hiring more inspectors and improve the training of its inspectors.

To increase transparency, CMS should make information collected from laboratories in the CLIA program available and easily accessible to the public and other regulators.

Proficiency testing is a requirement of certification. When a formal proficiency testing program is not available, laboratories must perform and document alternative assessments as directed by CLIA.

Some tests may require greater scrutiny, such as those with hidden or nontransparent algorithms, and should be subject to additional review by regulators.

All LDTs should be subject to the same oversight mechanisms, and molecular tests should not be unduly scrutinized.

Any changes to the current oversight system should occur after a formal rule making process or statutory change.

Source:
Mary Steele Williams

Association for Molecular Pathology

Nerves Under Control

2011-06-05T12:00:00.000-07:00

The proper transmission of nerve signals along body nerves requires an insulation layer, named myelin sheath. To be efficient this sheath is designed to have a certain thickness and researchers from the ETH ZГјrich have now discovered that proteins Dlg1 and PTEN interact to control the myelin sheath thickness. Recently published in Science their discovery improves our understanding of Charcot-Marie-Tooth neurodegenerative diseases and open a new avenue in the potential treatment of these incurable and debilitating diseases.

A crucial factor in the transmission of nerve signals is the myelin layer - also known as the myelin sheath - which surrounds the axons. Axons are nerve cell projections through which the signals are relayed; the myelin sheath is formed by the Schwann cells in the peripheral nervous system, i.e. in the nervous system outside the brain and spinal chord. If it is too thick or too thin, the signal transmission slows down; if the myelin sheath becomes too badly damaged, it can cause diseases like Charcot-Marie-Tooth diseases. Patients suffer from an increasing weakness of the hands and feet, which gradually spreads to the arms and legs, sometimes even making them wheelchair-bound for the rest of their lives.

But which molecules regulate the thickness of the myelin sheath? Scientists at ETH Zurich from the research groups around biologists Ueli Suter and Nicolas Tricaud set about finding out. They have now published their findings in an online article in the journal "Science".

The scientists didn't have to start their search entirely from scratch, however, having already developed a mouse model for a sub-type of Charcot-Marie-Tooth disease; the model is based upon a mutation in the gene for the protein MTMR2 and leads to hypermyelination by the Schwann cells. What's more, the researchers already knew from other studies that MTMR2 interacts with Dlg1.

In experiments conducted on cell cultures and the sciatic nerve in mice, the researchers were now able to demonstrate that Dlg1 inhibits myelin growth. For this to work, however, it needs to enlist the help of another signal protein: PTEN. Together, they ensure that the growth of the myelin sheath does not go to excess in the mouse's development. If the brake is "released" by suppressing Dlg1 or PTEN, it results in myelin excess that not only leads to an extra-thick myelin sheath, but also to its degeneration. This process is characteristic of various diseases of the peripheral nervous system and , as it was revealed in the mouse model of Charcot-Marie-Tooth disease the Dlg-PTEN brake no longer works in these diseases. Nicolas Tricaud is convinced that the project helps to understand the basic molecular mechanisms of myelination, as well as offering new opportunities to define how the misdirection of these processes can cause neurodegenerative diseases and how this might be remedied.

Source: ETH ZГјrich

Fighting Hunger: Norman Borlaug, Rob Horsch To Keynote International Lecture

2011-06-02T12:00:00.000-07:00

Nobel Peace Prize recipient Norman Borlaug and Rob Horsch of the Gates Foundation will discuss the challenges of developing agricultural technologies to feed the world to kick off the International Annual Meetings of the American Society of Agronomy (ASA), Crop Science Society of America (CSSA), and Soil Science Society of America (SSSA) in New Orleans. They will speak on Sunday, Nov. 4 from 7 to 8 pm in the Grand Ballroom of the Hilton Riverside.

Horsch will present "New Investments in Crops, Soils, and Small Holder Farmers -- Why the Bill & Melinda Gates Foundation is Supporting Agricultural Development," followed by Borlaug on "Challenges for the Crop Scientist in the 21st Century." Both leaders in agriculture, they have utilized technology to fight hunger issues around the world.

Known as the father of the "Green Revolution," Borlaug has been commended for his contributions to science and his ability to influence political policy for the good of humanity. He is one of only five people in history to be awarded the Nobel Peace Prize (1970), Presidential Medal of Freedom (1977), and Congressional Gold Medal (2007). He also received the National Medal of Science (2005) and countless awards throughout his career.

Borlaug worked for 16 years to solve a series of wheat production problems in Mexico and to help train Mexican scientists for the Cooperative Wheat Research and Production Program, a joint undertaking by the Mexican government and Rockefeller Foundation. His new wheat varieties and improved crop management practices transformed agricultural production in Mexico during the 1940s and 1950s and later in Asia and Latin America, sparking what today is known as the "Green Revolution." Because of his achievements to prevent hunger and famine around the world, it is said that Borlaug has saved more lives than anyone.

Previously employed by Monsanto Company, Horsch worked to develop technologies for low-income countries and farmers to improve crop yields and incomes. He launched programs to transfer and apply technology to developing countries, train and educate scientists around the world, and communicate the benefits and risks of agricultural biotechnology.

Horsch joined the Bill & Melinda Foundation as a senior program officer in the agricultural development program in November 2006. He has served on the editorial boards of several leading plant science journals and as an advisor to the National Science Foundation and U.S. Department of Energy. In 1999, he was awarded the 1998 National Medal of Technology by President Bill Clinton for contributions to agricultural biotechnology.

The ASA-CSSA-SSSA Annual Meetings will be Nov. 4-8 at the Morial Convention Center. More than 4,000 scientists and professionals from around the world will attend research presentations on climate change, urban planning, crop production, hazardous waste, human health, bioenergy and more. For information about the meetings, including the abstracts online, go to acsmeetings/.

The ASA (agronomy/), CSSA (crops/) and SSSA (soils/) are educational organizations helping their 11,000+ members advance the disciplines and practices of agronomy, crop and soil sciences by supporting professional growth and science policy initiatives, and by providing quality, research-based publications and a variety of member services.

Source: Sara Uttech

American Society of Agronomy

'Gatekeepers' Of Breast Cancer Transition To Invasive Disease Identified By Scientists

2011-05-30T12:00:00.000-07:00

Scientists have made a significant discovery that clarifies a previously poorly understood key event in the progression of breast cancer. The research, published by Cell Press in the May issue of the journal Cancer Cell, highlights the importance of the microenvironment in regulating breast tumor progression and suggests that it may be highly beneficial to consider therapies that do not focus solely on the tumor cells but are also targeted to the surrounding tissues.

Progression of breast cancer begins with abnormal epithelial proliferation that progresses into localized carcinoma, called ductal carcinoma in situ (DCIS); invasive carcinoma; and eventually, metastatic disease. DCIS is believed to be a precursor to invasive ductal carcinoma, but comprehensive molecular profiling studies comparing DCIS and invasive ductal carcinomas have not yielded tumor-stage-specific genetic signatures. "These studies have focused mainly on the tumor epithelial cells and have not explored the role of the microenvironment in tumor expression," says lead study author Dr. Kornelia Polyak from the Dana-Farber Cancer Institute in Boston.

Dr. Polyak and colleagues explored the involvement of the microenvironment in tumor progression by examining myoepithelial cells, which are known to play a critical role in mammary gland development and to have negative effects on tumor cell growth and invasion. To study the interactions between breast cancer cells and myoepithelial cells, the researchers used a human model of breast tumor progression called MCFDCIS, which forms DCIS-like lesions that spontaneously progress to invasive tumors, a pathology that closely resembles human disease.

Using this model, the researchers observed that normal myoepithelial cells suppress tumor growth and invasion in the absence of detectable genetic changes in the tumor epithelial cells. They went on to identify an intricate network involving TGFb, Hedgehog, cell adhesion, and p63 that appears to play a critical role in myoepithelial cell differentiation. Perturbation of key mediators of these signaling pathways led to a loss of myoepithelial cells and a progression to invasion.

"Here, we show that a key event of tumor progression is the disappearance of the myoepithelial cell layer due to defective myoepithelial cell differentiation regulated by intrinsic and microenvironment signals. Thus, myoepithelial cells can be considered gatekeepers of the in situ to invasive carcinoma transition; understanding the pathways that regulate their differentiation may open new venues for cancer therapy and prevention," offers Dr. Polyak.

The researchers include Min Hu and Jun Yao of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Danielle K. Carroll of Harvard Medical School in Boston, MA; Stanislawa Weremowicz of Brigham and Women's Hospital and Harvard Medical School in Boston, MA; Haiyan Chen of Dana-Farber Cancer Institute and Harvard School of Public Health in Boston, MA; Daniel Carrasco of Dana-Farber Cancer Institute in Boston, MA; Andrea Richardson of Brigham and Women's Hospital and Harvard Medical School in Boston, MA; Shelia Violette of Biogen-Idec in Cambridge, MA; Tatiana Nikolskaya and Yuri Nikolsky of GeneGo, Inc. in St. Joseph, MI; Erica L. Bauerlein and William C. Hahn of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Rebecca S. Gelman of Dana-Farber Cancer Institute and Harvard School of Public Health in Boston, MA; Craig Allred of Washington University School of Medicine in St. Louis, MO; Mina J. Bissell of Lawrence Berkeley National Laboratory in Berkeley, CA; Stuart Schnitt of Harvard Medical School and Beth-Israel Deaconess Medical Center in Boston, MA; and Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.

This work was supported in part by NIH, DOD, and ACS grants, a Susan G. Komen Foundation fellowship, Biogen-Idec., and Novartis Pharmaceuticals, Inc.

Hu et al.: "Regulation of In Situ to Invasive Breast Carcinoma Transition." Publishing in Cancer Cell 13, 394-406, May 2008. DOI 10.1016/j.ccr.2008.03.007 cancercell/

Source: Cathleen Genova

Cell Press

Muscle May Be Protected From Atrophy By A Natural Hormone

2011-05-27T04:57:00.000-07:00

Researchers have found a potential new treatment for the common problem of muscle atrophy. Results of the animal study were presented at The Endocrine Society's 91st Annual Meeting in Washington, D.C.

Muscular atrophy is a debilitating process that results in an extensive loss of muscle mass and function, which greatly worsens quality of life. It occurs in diseases such as cancer, diabetes, AIDS and heart failure, negatively affecting the patients' prognosis. Also, muscular atrophy can occur with aging, inadequate food intake such as in anorexia nervosa, or disuse (in those who are bedridden or who must keep a limb immobile) or as a side effect of glucocorticoid steroid therapy. Nerve injury also triggers severe muscular atrophy.

Currently, there are few options to treat the problem. Some of the treatments, such as anabolic steroids (testosterone) and insulin-like growth factor 1 (IFG-1), raise concerns about safety and effectiveness, said study co-author Andrea Graziani, PhD. He is a molecular biologist with the Department of Clinical and Experimental Medicine and the Biotechnology Center for Applied Medical Research, University of Piemonte Orientale, Novara, Italy.

"Because of the wide impact of muscular atrophy on public health, it is of pivotal importance to find new and better drug strategies to treat it," Graziani said.

Graziani and his co-workers are studying des-acyl ghrelin, a form of ghrelin, the appetite-stimulating hormone found in the body. Until recently, researchers thought that des-acyl ghrelin was inactive because it does not share the main activities of ghrelin-stimulating appetite, fat and the release of growth hormone.

However, Graziani's group recently found that des-acyl ghrelin shares some biological activities with ghrelin, such as stimulating differentiation of other cells, including - important to this study - cells that are precursors to skeletal muscle cells.

In this new study, the researchers discovered that des-acyl ghrelin has a direct anti-atrophic activity on the skeletal muscle of mice with muscular atrophy caused by either denervation (nerve injury) or fasting. Mice that were genetically altered to have increased levels of des-acyl ghrelin had less skeletal muscle loss than the untreated control mice. This held true for both causes of muscular atrophy.

The mechanism by which des-acyl ghrelin protects muscle against atrophy is not yet known, the authors reported. However, it is distinct from the action of anabolic steroids and IGF-1.

Notes:

The following Italian agencies supported this work: Telethon, Regione Piemonte, and Italian Ministry for University and Research. Nicoletta Filigheddu, a researcher at the University of Piemonte Orientale's Biotechnology Center, will present the study's findings.

Source:
Aaron Lohr

The Endocrine Society

Using A Pest's Chemical Signals To Control It

2011-05-26T04:48:00.000-07:00

Agricultural Research Service (ARS) scientists are tapping into the biochemistry of one of the world's most damaging insect pests to develop a biocontrol agent that may keep the pest away from gardens and farms.

Aphids spread diseases that cost gardeners and farmers hundreds of millions of dollars each year. Some of the insecticides available are not environmentally friendly, and because aphids are developing insecticide resistance, some growers are being forced to use more of the chemicals.

Ronald J. Nachman, a chemist with the ARS Southern Plains Agricultural Research Center at College Station, Texas, is working with chemical signals known as neuropeptides that aphids and other organisms use to control and regulate a wide range of body functions, such as digestion, respiration, water intake and excretions. The effect triggered by the chemical signal is normally turned off when the neuropeptide is broken down by enzymes in the body. Nachman is developing neuropeptide mimics, or analogues, with slightly altered molecular structures that will not break down. His goal is to kill the pest by disrupting its digestion, water intake or some other biological function.

Nachman, along with Guy Smagghe of Ghent University in Belgium and other colleagues, mixed five candidate analogues into dietary solutions and fed each one to 20 caged pea aphid (Acyrthosiphon pisum) nymphs. The scientists found that one of the formulations killed 90 to 100 percent of the aphids within three days, at a rate and potency comparable to insecticides now on the market. The study was recently published in the journal Peptides.

Any biocontrol agent would have to be thoroughly tested before being released for commercial use. Nachman is continuing to test and evaluate the neuropeptide mimics. But he said the molecular structures of the class of neuropeptide he is studying, known as insect kinins, are so unique that such a biocontrol agent is unlikely to have any effect on humans, plants or other types of organisms.

ARS is the principal intramural scientific research agency of the U.S. Department of Agriculture (USDA). The research supports the USDA priority of promoting international food security.

Source:

Dennis O'Brien

United States Department of Agriculture-Research, Education, and Economics

The Lives Of Stroke Patients Could Be Saved By Leukemia Drug

2011-05-25T04:39:00.000-07:00

The drug tPA is the most effective treatment currently available for stroke patients, but its safety is limited to use within the first three hours following the onset of symptoms. After that, tPA may cause dangerous bleeding in the brain. However, in a study published in Nature Medicine, investigators from the Stockholm Branch of the Ludwig Institute for Cancer Research (LICR) and the University of Michigan Medical School show that these problems might be overcome if tPA is combined with the leukemia drug, imatinib (Gleevec®). The results demonstrate that imatinib greatly reduces the risk of tPA-associated bleeding in mice, even when tPA was given as late as five hours after the stroke had begun. The LICR team, in collaboration with the Karolinska University Hospital in Stockholm, is now planning a clinical trial with imatinib in stroke patients.

According to the World Health Organization (WHO), 80 percent of the 15 million strokes that occur each year are caused by the type of blood clots in the brain that tPA can dissolve. Today, less than 3% of patients with this type of stroke receive tPA because the narrow safety window has often passed by the time a stroke patient reaches a hospital and is diagnosed. If the planned clinical trial with stroke patients in Sweden confirms the findings of the present study, there is great promise that imatinib or similar drugs could be administered to stoke patients to increase the therapeutic window of tPA.

The basis for this novel proposal is the key growth factor PDGF-CC, which has now been discovered to control the blood brain barrier (a structure that normally shields the brain from the blood). When tPA acts on PDGF-CC, the blood-brain barrier becomes porous and can start to leak. Imatinib inhibits the detrimental effect of PDGF-CC by binding to its receptor PDGFR alpha, seemingly without hindering tPA's therapeutic effect, which is to break down clots that have lodged in the brain's blood vessels.

"Ten years ago our research group identified the growth factor PDGF-CC, and we are now very excited having unraveled a mechanism in the brain involving this factor", says Professor Ulf Eriksson, who leads the LICR team. "This finding has indeed the potential to revolutionize the treatment of stroke."

This study was conducted by investigators from: Ludwig Institute for Cancer Research, Stockholm Branch, Sweden; University of Michigan Medical School, Ann Arbor, USA; Karolinska Institute, Stockholm, Sweden; University of Maryland, Baltimore, USA; and Emory University, Atlanta, USA. Funding was provided by the Ludwig Institute for Cancer Research, the National Institutes of Health, the Novo Nordisk Foundation, the Swedish Research Council, the Swedish Cancer Foundation, the LeDucq Foundation and the Inga-Britt and Arne Lundberg Foundation.

About LICR

The Ludwig Institute for Cancer Research (LICR) is the largest international non-profit institute dedicated to understanding and controlling cancer. With operations at 73 sites in 17 countries, LICR's research network quite literally spans the globe. LICR has developed an impressive portfolio of reagents, knowledge, expertise, and intellectual property, and has also assembled the personnel, facilities, and practices necessary to patent, clinically evaluate, license, and thus translate, the most promising aspects of its own laboratory research into cancer therapies.

Source: Sarah White

Ludwig Institute for Cancer Research

View drug information on Gleevec.

Cockroach-like robot leads new research effort

2011-05-24T04:30:00.000-07:00

BERKELEY - A cockroach-like robot named RHex is the starting point for a major project to understand animals' most distinguishing trait - how they move without falling over.

The National Science Foundation (NSF) announced today (Thursday, Sept. 16) a $5 million, five-year grant to the University of California, Berkeley, that will fund an all-star team of biologists, engineers and mathematicians from universities across the country to try to understand the mechanical and neurological basis of locomotion. The grant is one of six totaling nearly $30 million through NSF's Frontiers in Integrative Biological Research (FIBR) program, which supports integrative research that addresses major questions in the biological sciences.

"The hallmark of life is movement," said Robert Full, professor of integrative biology at UC Berkeley and leader of the team. "Yet, no single systems-level model, reaching from neurons to muscles to the skeleton to the whole body, can explain the control that makes movement possible. You have so many nerves and so many muscles, how in the world do you actually move forward?"

Researchers from UC Berkeley, the University of Michigan, Princeton University, Cornell University and Montana State University will focus on RHex, a short, six-legged robot that scampers like a cockroach, as a working model of the principles they're seeking to uncover. By tweaking the robot and using it as a physical model, they hope to tease apart the complex neural and muscular networks in insects.

At the same time, they will conduct biomechanical and neurological experiments on insects and develop mathematical models to improve the robot. This multi-pronged approach will allow them to uncover the neural and muscular control and feedback loops that lead to the remarkably similar patterns of whole-body motion in animals as diverse as crabs, cockroaches, lizards, dogs and humans.

"The robot has to operate in the real world, like the animal does, so we can use it for testing hypotheses," Full said. "We know, for example, that the body's center of mass bounces along like a pogo stick, which is embodied in the robot, but we don't know how its parts - its legs, feet, actuators or muscles - sum up to give that remarkably general pattern of movement.

"Now we can ask questions like, 'What if you had a more compliant leg? What if you had two joints in that leg, what does that give you versus one joint?' We can start putting artificial muscles in. Of course, that will make a better robot, but that is not the goal of this program."

Full has studied animal locomotion for 30 years, providing important insight not only to biologists, but also to engineers who have designed robots like RHex that mimic the movements of animals. RHex was built by Full's collaborators at the University of Michigan, led by Daniel Koditschek, professor of electrical engineering and computer science. But Full has contributed to other robots too: Ariel, which walks like a crab and was designed to operate in the surf zone and right itself if upended; Mecho-Gecko, which climbs up walls; and the Stanford-built Sprawlita, which bounces five body lengths at a time thanks to six piston-driven legs.

But, he admits, a biologist and an engineer can go only so far in understanding locomotion without the help of mathematicians and specialists in dynamics who can create models that can be tested on animals and robots. Full has coined the phrase "neuromechanical systems biology" for this multidisciplinary approach, which integrates data across mathematical models, numerical simulations, robot models and biological experiments.

The team he has assembled represents the best in these areas. While Full has run cockroaches, crabs, geckos and other animals on treadmills, across gelatin and over complex terrains to understand their stability, he is eager to team up with an experimental neurophysiologist who is able to interpret insects' neural code. John Miller, a professor of cell biology and neuroscience and director of the Center for Computational Biology at Montana State University, Bozeman, hopes to be able to rewrite that code while measuring motion, forces and neuromuscular signals. They will work closely with two mathematicians - Philip Holmes, professor of mechanical and aerospace engineering at Princeton University, and John Guckenheimer, professor of mathematics and theoretical and applied mechanics at Cornell University - who will analyze animal data to produce the mathematical models. The models will, in turn, provide feedback to Koditschek's robotic cockroach, which will serve as a controlled experiment that's easier to manipulate than real animals but able to tackle real-world challenges.

"This robot, the most mobile one built and created from the fundamental principles of what we know about animals, is going to help us address the grand challenge in biology - how they move," Full said.

NSF's FIBR program encourages investigators to identify major understudied or unanswered questions in biology and to use innovative approaches to address them by integrating the scientific concepts and research tools from across disciplines, including biology, mathematics and the physical sciences, engineering, social sciences and the information sciences. Among the other projects funded by NSF this year are BeeSpace, an interactive environment for studying social behavior in honey bees; a project that will examine how species that live together, evolve together; and a project examining how climate affects genetic variation and evolution.

"FIBR is one of the premier, crosscutting programs in biology at NSF," said Mary Clutter, head of NSF's Biological Sciences directorate. "By undertaking highly innovative and broadly integrative approaches to research in biology, FIBR projects tackle grand challenges and promote the training of a new and fearless generation of scientists willing and able to bridge conventional disciplinary boundaries."

Contact: Robert Sanders

rlspa.urel.berkeley

510-643-6998

University of California - Berkeley

Ecological Consequences Of Late Quaternary Extinctions Of Megafauna

2011-05-23T04:21:00.000-07:00

As humans spread over the globe from about 50 000 years ago, megafauna such as mammoths, giant kangaroos and many others vanished. How did this sudden loss of large herbivores affect ecosystems?

This review finds evidence that in many places vegetation types changed dramatically, becoming less open and less diverse. Many plant species that evolved in environments with megafauna may be in long-term decline, for example because they now lack effective seed dispersers.

To properly understand and conserve living vegetation, we need to consider how it was once shaped by giant animals, and if possible re-create those interactions.

Proceedings of the Royal Society B: Biological Sciences

Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of the journal is diverse and is especially strong in organismal biology.

rspb.royalsocietypublishing

BD Biosciences Announces First Winners Of Expanded Research Grant Program

2011-05-22T04:12:00.000-07:00

BD Biosciences, a segment of BD (Becton, Dickinson and Company), announced the first seven winners of its expanded BD Biosciences Research Grant Program who will receive research reagents valued at a total of $70,000 to conduct innovative cellular analysis research.

"Even in tough economic times, life science research must go on because it's important to the health of our economy, and more importantly, the health of our society," said Robert Balderas, Vice President of Biological Sciences, BD Biosciences. "BD Biosciences expanded the grant program for that very reason and hopes the winners' research will increase our understanding of disease and lead to important biomedical breakthroughs."

An independent panel of distinguished scientists selected the winners. Each grant recipient will receive a $10,000 grant of research reagents to help carry out their research.The winners of the BD Biosciences Research Grant Program for this cycle are:

Jeffrey A. Gold, M.D., is Associate Professor of Medicine at the Oregon Health and Sciences University. Dr. Gold's research focuses on sepsis, a system-wide bacterial infection that is the tenth leading cause of death in the United States.In septic patients, eosinophils, immune system cells that fight infection, are depleted while neutrophils are weakened. Dr. Gold will explore the hypothesis that interleukin-5 can rescue immune system components that are crucial for fighting sepsis. Dr. Gold's abstract is titled, "Novel Role for IL-5 in Sepsis."

Mary Cloud B. Ammons, Ph.D., is a research scientist in the Center for Biofilm Engineering at Montana State University. Dr. Ammons studies biofilm, a specialized state in which bacteria exist as a colony instead of free-standing organisms. Dr. Ammons will study the interactions between biofilms and the innate immune system, which consists of macrophages and neutrophils. The hope is that inducing macrophages to enter an anti-inflammatory vs. a pro-inflammatory phenotype will result in new treatments for biofilm-associated illness such as chronic infections and non-healing sores. Dr. Ammons' abstract is titled, "Immunity to Bacterial Biofilm."

Peter Antinozzi, Ph.D., is Assistant Professor in the Departments of Biochemistry and Internal Medicine, Wake Forest University School of Medicine. One of the challenges to analyzing biopsy samples is conducting "high content" screens from a small amount of very valuable tissue. Dr. Antinozzi, who is studying changes occurring in kidney cells in patients in diabetic nephropathy, uses automated confocal fluorescence microscopy to image all kidney cell types with a minimum of sample preparation. His work will directly benefit scientists who analyze human cells implicated in chronic diseases, and specifically could lead to diagnostic or prognostic tests for diabetic nephropathy. Dr. Antinozzi's abstract is titled, "A Novel High-Content Assay for Renal Cell Biology."

Melanie Dart, Ph.D., is an Assistant Scientist at the University of Wisconsin, Madison. Her work centers on immune system T-cell interactions with collagen V, a protein involved in the development and progression of atherosclerotic plaque. Dr. Dart will analyze blood and plaque samples from patients who have undergone vascular surgery to determine the correlation between plaque pathology and populations of two important classes of T-cells: regulatory T-cells, which suppress the inflammatory immune response, and effector T-cells, which induce it. The ultimate goal is therapies that suppress undesirable immune responses to atherosclerotic plaque. Dr. Dart's abstract is titled, "Atherosclerosis and Collagen V."

Nilufer Esen-Bilgin, M.D., is a Research Fellow at the University of Michigan. Her research interests lie in sindbis virus, an alphavirus that causes neuronal death in mice and serves as a model for human neurologic disease. Dr. Esen-Bilqin will attempt to unravel the immune response to sindbis infection, which is believed to result in neural damage. Knowing which specific macrophages and T-cells are infiltrating the nervous systems of infected animals will shed light on the pathology of sindbis-associated nerve damage, and it is hoped, analogous human diseases. Dr. Esen-Bilqin's abstract is titled, "Infiltrating Myeloid Cells."

Celine S. Lages, Ph.D. is a Postdoctoral Research Fellow at the Cincinnati Children's Hospital Medical Center. One consequence of aging is an attenuated immune response and the subsequent emergence of immune-associated disorders. Dr. Lages will study the impact of regulatory T-cells (Treg) on this process. Treg cells are super-regulators of the immune response: too high and immune competence decreases, while too little can result in autoimmunity. Understanding the conversion of "ordinary" T-cells to Treg in aging could lead to therapies that prevent that transformation, and thereby reduce the consequences of waning immunity. Dr. Lages' abstract is titled, "Role of Peripheral Conversion in Regulatory T-Cell Accumulation in Aging."

H. Scott Rapoport, Ph.D. is a Senior Scientist at Tengion, Inc., which researches the re-growth of organs and tissues using a combination of a patient's own cells and a biocompatible material. The success of such implants, known as "constructs," can depend on the activation states of macrophages. Initial work will focus on the point at which activation is initiated, and the contribution of the construct towards activation states leading to construct acceptance and rejection. This understanding should lead to rational design of constructs that induce favorable macrophage responses.Dr. Rapoport's abstract is titled, "Macrophage Diversity."

The expanded BD Biosciences Research Grant Program will award another seven scientists a total of $70,000 worth of research reagents in May 2010 to help cover year-round research needs. Grant applications should focus on research in one of seven core areas: stem cell, multicolor flow cytometry, cell signaling, cancer, immune function, infectious diseases and neurosciences.

Additional information about the grant program, including the application process and deadlines, is available here.

About the BD Biosciences Research Grant Program

BD Biosciences' Research Grant Program aims to reward and enable important research by providing vital funding for scientists pursuing innovative experiments to advance the scientific understanding of disease. The grant submissions are judged by a distinguished research panel of non-affiliated scientists. Through its grant program, BD Biosciences supports innovation in research and development as well as help enable the next generation of scientific breakthroughs.

Source

BD

Researchers Unveil Near Complete Protein Catalog For Mitochondria

2011-05-21T04:03:00.000-07:00

Imagine trying to figure out how your car's power train works from just a few of its myriad components: It would be nearly impossible. Scientists have long faced a similar challenge in understanding cells' tiny powerhouses called "mitochondria" from scant knowledge of their molecular parts.

Now, an international team of researchers has created the most comprehensive "parts list" to date for mitochondria, a compendium that includes nearly 1,100 proteins. By mining this critical resource, the researchers have already gained deep insights into the biological roles and evolutionary histories of several key proteins. In addition, this careful cataloging has identified a mutation in a novel protein-coding gene as the cause behind one devastating mitochondrial disease. A full description of the work appears in the July 11 print edition of the journal Cell.

"For years, a fundamental question in cell biology has gone largely unanswered what proteins function in mitochondria?" said Vamsi Mootha, an associate member at the Broad Institute of Harvard and MIT and a Harvard Medical School assistant professor at Massachusetts General Hospital, who led the study. "By creating a comprehensive list, we now have a valuable resource that has already helped enhance our understanding of mitochondrial biology and disease."

Mitochondria are linchpins of cellular life, found within the cells of all eukaryotes from yeast to humans. These miniaturized organs ("organelles") are well known for their role in providing cellular energy. They have also been implicated in a wide range of normal and disease processes, including diabetes, neurodegeneration, cancer, drug toxicity and aging.

Although mitochondria have their own genome a vestige from their days as free-living bacteria the vast majority of the critical mitochondrial proteins are derived not from their genome, but rather from the nuclear genome. However, even with the wealth of genome sequence data now available, scientists have struggled to identify which genes encode the roughly 1,200 proteins that make up a functional mitochondrion.

Researchers from the Broad Institute, Harvard Medical School, and Massachusetts General Hospital worked together to address this problem, drawing on the power of a multi-faceted approach that includes large-scale, mass spectrometry-based proteomics to measure proteins in mitochondria from a variety of tissues; computational methods to help identify those proteins that cannot be reliably detected; and microscopy to confirm within human cells the localization of presumptive mitochondrial proteins.

"The technologies and analytical methods for measuring proteins on a large scale are really transforming what we can learn about human biology," said Steve Carr, director of the Proteomics Platform at the Broad Institute and a co-author of the Cell paper. "By applying them to mitochondria isolated from fourteen different mouse tissues, we've completed one of the most comprehensive proteomic analyses of any organelle to date."

As a result of their analyses, the researchers identified a total of 1,098 mitochondrial proteins to form a compendium they have named "MitoCarta," and which is available to the entire scientific community. Notably, about one-third of this inventory has not been previously linked to the organelle.

To shed light on the functions of the newly uncovered mitochondrial proteins, the researchers compared the proteins' corresponding gene sequences across hundreds of species, from humans and fish to fungi and bacteria. "Proteins with similar roles often share similar histories, meaning they're gained or lost together during evolution," said Mootha. "We decided to use this tendency to our advantage to decipher how some mitochondrial proteins work."

By examining the organelle's proteins through this evolutionary lens, the researchers uncovered a striking pattern. A group of key mitochondrial proteins, known to be absent in yeast but otherwise present among eukaryotes, are actually missing from several other single-celled species. In organisms that have them, including humans and other mammals, these proteins contribute to a boot-shaped, multi-protein structure, which forms the gateway to a critical step in the energy-generation process. By virtue of these proteins' shared and unusual past, Mootha and his colleagues were able to identify several additional proteins that are also associated with this crucial mitochondrial structure, known as complex 1.

In addition to offering insights into mitochondrial biology, these discoveries also paved the way for a breakthrough in understanding mitochondrial disease. For decades, doctors have diagnosed patients with deficiencies in complex I function. These disorders affect about 1 in 5,000 newborns, are genetic in origin, and are lethal in the first few years of life. Yet for many cases a culprit gene cannot be found. However, thanks to MitoCarta and its corresponding evolutionary analyses, the researchers and their collaborators at the University of Melbourne and Royal Children's Hospital in Australia identified a mutation in a novel gene, called C8orf38, as one cause of complex I disease.

"Our finding underscores the power of this protein catalogue to open new vistas on disease," said Mootha. "It promises to shed light not only on rare metabolic diseases, but common diseases as well."

This work was supported by a grant from the National Institute of General Medical Sciences, one of the National Institutes of Health.

Paper cited:

Pagliarini DJ et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell July 11, 2008.

About the Broad Institute of MIT and Harvard

The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.

The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities.

Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.

For further information about the Broad Institute, go to broad.mit.

Media Backgrounder: A Primer on Mitochondria

1. What are mitochondria and where are they found?

Mitochondria are bean-shaped compartments within cells that supply energy. These compartments, a type of membrane-bound organelle, are found in eukaryotes organisms whose cells have nuclei, the home of the genome. Multicellular organisms (humans, mice, fish, etc.) as well as some unicellular ones, like yeast, are counted as eukaryotes. Bacteria, though, are not: They are considered prokaryotes for their lack of organelles, including mitochondria and nuclei.

Intriguingly, mitochondria vary widely across organisms and even within an organism. Drastic differences can exist in the number of mitochondria per cell, their size and morphology, and even their biochemical capabilities. For example, fatty acids readily broken down by mitochondria in muscle, but not brain tissue. Because of a lack of molecular knowledge about mitochondria and their resident proteins, the basis for such differences is largely unclear.

2. What do mitochondria do?

Although mitochondria are perhaps best known for their roles in energy metabolism, they also participate in a plethora of other key biological processes. These include critical functions such as programmed cell death (or "apoptosis"), a normal mechanism through which old or damaged cells can be eliminated.

Defects in mitochondria are associated with more than 50 human diseases, ranging from in-born errors of metabolism in infants to neurodegeneration in adults. Moreover, several common diseases, such as cancer and type 2 diabetes, have been associated with mitochondrial dysfunction. Prescription drugs can also disrupt mitochondria. Such drug-induced toxicity is a reason why some drugs are pulled from the market and why some potential drugs fail the clinical trial process.

3. Where do mitochondria come from?

Mitochondria, it turns out, have their own tiny genome. And in humans, this mitochondrial DNA is inherited solely from the mother. Such maternal inheritance arises because mitochondria from sperm are lost following fertilization, while those contributed by the egg persist. Because it is maternally inherited, mitochondrial DNA can provide clues about human history, including the most recent common matrilineal ancestor of living humans (so-called "Mitochondrial Eve".)

But there are, in fact, paternal contributions to mitochondria. The parts of the mitochondria that are derived from nuclear genes actually come from both parents (see below). This follows a core principle of human genetics: of the 23 pairs of chromosomes that make up your nuclear genome, roughly half come from Mom and the other half from Dad.

Evolutionarily speaking, mitochondria have a very interesting history. They are descendants of an ancient bacterium a relative of the modern bacterial species, Rickettsia prowazekii that some 2 billion years ago was enveloped by another cell. That moment marked the beginning of a long and mutually beneficial relationship with eukaryotic cells, known as endosymbiosis. As a result of such "co-habitation", eukaryotic cells and mitochondria have evolved and adapted to life together, such that now, neither can survive alone.

4. Where do the proteins in mitochondria come from?

Because of the organelle's unusual past, the molecular pieces that make up mitochondria have undergone some shuffling of their own. Mitochondria carry a small circular genome, a vestige of their days as free-living bacteria that has been winnowed during evolution to just a few protein-coding genes.

The human mitochondrial genome was decoded in 1981, a full 20 years before the human genome itself was decoded. The organelle's genome consists of roughly 16,000 chemical units called base pairs, much smaller than the nuclear genome's 3 billion base pairs. The mitochondrial genome includes just 37 genes: 13 genes that encode proteins and 24 additional non-protein coding genes.

The rest of the genes required for a functioning mitochondrion, roughly 1,200 to 1,500 in total, now reside in the nucleus. Identifying these genes from DNA sequence data alone has proven immensely difficult, which is why other large-scale approaches namely proteomics and computational methods are required to pinpoint them.

Broad Institute

7 Cambridge Center

Cambridge, MA 02142

United States

broad.mit

Using Lyme Disease As A Model, MU Researchers Find Inflammatory Disease Treatments Will Improve Through The Use Of Lipidomics

2011-05-20T03:54:00.000-07:00

According to the National Center for Chronic Disease Prevention and Health Promotion, 46 million Americans have arthritis. Many of these people take over-the-counter anti-inflammatory medications that block production of certain molecules, known as bioactive lipids, to reduce pain and swelling. Yet, the role of these lipids is not yet understood completely, and medications may have adverse side effects. Recently, University of Missouri researchers completed the first comprehensive analysis of bioactive lipids in an inflammatory response triggered by the Lyme disease agent, Borrelia burgdorferi. This analysis could shed light on the role bioactive lipids play in inflammatory diseases.

"Many diseases, such as arthritis, cardiovascular disease and diabetes are associated with chronic inflammation," said Charles Brown, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. "The first step in finding an effective treatment is to understand the basics of an inflammatory response, including the role of bioactive lipids. Understanding how bioactive lipids regulate the disease processes will lead to the development of drugs that have more specific targets and less adverse side effects."

In the study, researchers investigated the role of certain bioactive lipids in mice infected with Borrelia burgdorferi, the bacteria responsible for Lyme disease. Eicosanoids, which are bioactive lipids that play an important role in inflammatory disease, were extracted from mice that displayed symptoms of Lyme arthritis and from mice who showed no symptoms. The researchers found differences in the amounts of specific eicosanoids in the samples, which correlated with the severity of arthritis in the mice.

"The process of inflammation is not a passive event, but instead is a coordinated, orderly process actively signaled by specific protein and lipid molecules," Brown said. "Previous studies investigating eicosanoids have focused on singular pathways or phases of the inflammatory response. These studies provided an incomplete picture and gave the impression that some bioactive lipids function in isolation. In our study, we were able to measure virtually all of the known eicosanoids at the same time and examine a more complete picture of the inflammatory response."

The findings from this study also could translate into a diagnostic tool for assessing individual patients, assist with the development of more disease-specific therapies, and facilitate the progress of individualized medicine, resulting in more effective treatments for inflammatory diseases with fewer side effects.

Lyme arthritis occurs in 60 to 80 percent of individuals not treated with antibiotics at the time of their infection, and patients are typically given anti-inflammatory drugs to treat their pain and swelling. Arthritis in mice caused by Lyme disease is a good model for how bioactive lipids regulate the process of inflammation, because researchers can observe the process from start to finish, Brown said.

The study, "Lipidomic Analysis of Dynamic Eicosaniod Responses During the Induction and Resolution of Lyme Arthritis," was published in the June issue of The Journal of Biological Chemistry. It was co-authored by Brown; Victoria Blaho, post doctoral researcher in the MU College of Veterinary Medicine; Matthew Buczynski, researcher at the University of California; and Edward Dennis, researcher at the University of California.

Source:
Kelsey Jackson

University of Missouri-Columbia

VIB And UZ-KU Leuven Join Forces And Bring State-of-the-art Technology To Flanders

2011-05-19T03:45:00.000-07:00

Genome research can now be done 100 times faster

Belgium-Flemish biotechnologists have a world-wide reputation for deciphering genetic code. In order to further strengthen this leading position, two Flemish research institutes are joining forces and bringing new technology to Flanders which will record DNA 100 times faster than current methods. This is an essential asset as these DNA analyses hold the key to the decipherment and treatment of genetic disorders.

Why decipher DNA?

The full DNA of an organism -- the genome -- determines what that organism looks like and how it functions. The better we understand this, the more we can learn about the intricacies of living beings. We know the broad outline of human DNA, and scientists are now determining the DNA differences between people. These differences characterise the diversity of people but they also hold the key to a higher risk for genetic disorders such as dementia, psychosis, diseases of the heart and blood vessels, and cancer. If we know and understand the differences, we can also use them as the foundation for new treatments.

However, to record these differences efficiently, it is essential that everything moves much faster than the current technology allows. This has now become possible. So-called 'new generation' sequence technology has recently been developed, but it is still very expensive.

Nevertheless, VIB and UZ.-K.U. Leuven have joined forces to give Flemish scientists access to this state-of-the-art technology. Via a co-ordinated investment program, they are bringing Roche's DNA sequence technology platform, the so-called 454 sequencing, to Flanders.

What is 454 sequencing?

This technique provides an ingenious manner to super-efficiently decipher DNA code. DNA fragments are isolated in drops of water, which function as micro-reactors. Using these pieces of DNA, 10 million identical copies are made and they are simultaneously (but individually) sequenced. This is all done on a tablet the size of a credit card which contains 1.6 million little holes in which sequence reactions are generated. Seven hours later, the DNA sequences are produced by the computer, thereby rendering a wealth of data. This technology has the advantage of producing large parts of sequences from the genomes that are to be recorded, which benefits not only the speed but also the accuracy of the information. In short, the larger the pieces of the puzzle, the quicker and more precise the image of the entire picture.

Determining sequences can now be done 100 times faster than the technologies which are currently being used. With the next version of the new technology, which should be available within a year, one experiment will yield yet another 10 times more sequence, so 1000 times more than now. Therefore, with the new technology, Flemish scientists will in one day be able to gather DNA data that would today take 3 years to compile. This is truly revolutionary!

Applications for VIB and UZ-K.U. Leuven

In order to make optimal use of these substantial investments, VIB and UZ-K.U.Leuven are mutually coordinating activities on both units. Both parties will exchange expertise and will make capacity available to one another. In addition, VIB and UZ-K.U.Leuven will be able to grant Flemish researchers from other centers access to this revolutionary technology via this platform.

The 454 sequencer will be embedded in the Genetic Service Facility of the VIB Department of Molecular Genetics, University of Antwerp under the direction of Christine Van Broeckhoven . New technology will be developed under the supervision of Jurgen Del-Favero, supporting basic research such as sequencing new, full genomes of interesting organisms (e.g. pathogenic organisms) and tracing DNA differences that cause illnesses. On top of that, there will be a large investment in translational research focusing on the development of more efficient and cheaper genetic diagnostic tests. The University of Antwerp guarantees a structural contribution towards the cost of this new investment.

Quote from VIB: "This technology will allow us to more quickly identify the molecular mechanisms of illness."

With this investment, UZ-K.U.Leuven wishes to stimulate translational research which will, through interaction between researchers and clinicians, generate genuine innovations in the field of patient care. A powerful DNA diagnostic platform to find mutations in genes which cause, among other things, breast and bowel cancer, or are involved in illnesses such as heart, vascular illnesses and diabetes, can contribute to significant diagnostic and therapeutic possibilities.

Quote from UZ-K.U.Leuven: "This technology brings fundamental research closer to patient applications."

Source: Ann Van Gysel

VIB, Flanders Institute for Biotechnology

A Deep Look Into Population Variation In Gene Activity Provides Key Insight Into Cell Functions And Disease Susceptibility

2011-05-18T03:36:00.000-07:00

Our DNA contains the information needed to produce different proteins that are the building blocks and key components of cells. Instructions to synthesize such proteins are incorporated into DNA sequences defined as genes. This precious genetic material, however, never leaves the cell's stronghold nucleus. Instead, copies called RNA messengers are made and sent out to the tiny cell's protein factories located outside of the nucleus. Mutations in genes lead to a variation in the abundance or structure of these RNA messengers. This in turn is associated with changes in the protein content of cells, thereby influencing the way certain cellular processes are executed. Such DNA variations thus may contribute to differences in characteristics between individuals and may also cause or predispose to various diseases.

A new and detailed reality emerges through corrected vision

In order to elucidate the genetic nature of this variability, a collaboration of researchers from Switzerland, Spain and the UK, under the leadership of the Faculty of medicine of the UNIGE, have used novel technology to study RNA messengers. This cutting edge procedure, called "second generation sequencing", allows an unprecedented level of resolution to determine the abundance and structure of RNA messengers.

Previous studies merely informed us about rough individual differences in the quantity of RNA from each gene in the cell. Moreover, this was only the tip of the iceberg in terms of defining the exact molecular consequences. In this new research project, conducted using blood cells of 60 individuals of European descent, the scientists have obtained a much higher resolution of such processes that allow them to describe in detail the molecular differences in RNA among individuals. "For the first time we are able to "read" the sequence of almost all the RNA molecules in the cell and compare them among individuals" says Dr. Stephen Montgomery from the UNIGE.

The ability to read the RNA sequence in so many individuals is of unprecedented scale and brings the understanding of genetic variation to a new level. "The genome sequencing provided us with information to understand basic processes within the cell but the new mRNA study allows us to reach a new level on the understanding of variability between individuals" says Roderic GuigГі, coordinator of the Bioinformatics and Genomics Programme at the CRG.

Professor Emmanouil Dermitzakis from the Genetics Department of the Faculty of medicine of the UNIGE and the Frontiers in Genetics program states "Obviously, such an increase in resolution provides us with a major advance in understanding of cellular processes and the fine detail of differences between humans".

Sharper insight will pave the way to tailor made treatments

The results of this study, which has received financial support from the Wellcome Trust, the Louis-Jeantet Foundation and the Spanish Ministry of Science and Consolider program, have wider implications for human health. It is well known that DNA variants affecting gene activity may be responsible for disease susceptibility, primarily to common pathologies such as diabetes, cardiovascular diseases and asthma. The understanding of how such hitherto unknown subtle differences modulate gene expression is bound to accelerate the understanding of their mechanisms at the cellular level, enabling faster and more focused development of treatments.

As reported on line in this week's edition of Nature, this study provides a framework towards the full understanding of the impact of genetic variations in cellular interactions, which has very important implications for the understanding of human diseases.

The Ministry of Science and Innovation, the Ingenio Consolider 2010 Programme, the Wellcome Trust, the Louis-Jeantet Foundation and Swiss NSF Frontiers in Genetics have funded the project.

Source: Centre for Genomic Regulation

Nitrous Oxide: Definitely No Laughing Matter

2011-05-17T03:27:00.000-07:00

Farmers, food suppliers, policy-makers, business leaders and environmentalists are joining forces to confront the threat of the 'forgotten greenhouse gas' by taking part in an influential new forum at the University of East Anglia (UEA).

Launched on February 22, the Nitrous Oxide Focus Group will engage with many influential organisations including the National Farmers Union, Marks & Spencer, British Sugar, Defra, the Country Land and Business Association and Unilever.

The group will present and explore cutting edge research into the sources and sinks of nitrous oxide in the environment and discuss the prospects of mitigating the release of this destructive gas through re-shaping current policies and practice.

"People are becoming increasingly concerned about the immense problems associated with the unregulated release of this potent greenhouse gas," said Prof David Richardson, Dean of the Faculty of Science at UEA and co-ordinator of the Nitrous Oxide Focus Group.

"It is very encouraging that so many key figures from agriculture, industry and government are interested in mitigating nitrous oxide emissions by learning more about key research questions that are currently being addressed with government funding by groups within UEA, along with collaborating research groups across the UK and Europe."

Better known as 'laughing gas', nitrous oxide (N2O) accounts for 9 per cent of all greenhouse gases, yet is 300 times more potent than carbon dioxide (CO2). As a result its longevity in the atmosphere provides a potentially more damaging legacy than CO2.

Agriculture accounts for around 70 per cent of N2O emissions. The sources are mainly from soil micro-organisms that make N2O from nitrogen-rich fertilisers added to soils to maximise crop yields. Other significant biological sources of N2O come from the wastewater treatment industries where the greenhouse gas is again produced from micro-organisms.

The launch of the new consortium is underpinned by more than five years of interdisciplinary research at UEA and comes as significant new research on an N2O-generating enzyme from a widespread soil bacterium is published.

Published in the Journal of Biological Chemistry (February 15 2008), the research was done in collaboration with the University of Stockholm and largely carried out by UEA graduate Faye Thorndycroft under the guidance of Prof Richardson and Dr Nick Watmough.

For more information on the Nitrous Oxide Focus Group, please visit nitrousoxide/.

Source: Simon Dunford

University of East Anglia

Columbia University takes leading role in second phase of NIH protein structure initiative

2011-05-16T03:18:00.000-07:00

Researchers at Columbia University are taking a major role in the second phase of the National Institutes of Health's Protein Structure Initiative, leading or participating in three of the 10 new research centers announced Friday by the National Institute of General Medical Sciences (NIGMS).

The Protein Structure Initiative (PSI) is a national effort to determine the three-dimensional shapes of a wide range of proteins. This structural information will help reveal the roles that proteins play in health and disease and will help point the way to designing new medicines.

Selection of the centers, slated to receive about $300 million over the next five years, marks the second half of the decade-long initiative. Columbia University will receive about $25 million over five years to fund its research contributions.

"The overall idea of PSI is a bit like the Human Genome Project in that the information gained from these large-scale efforts will underpin a more efficient approach to medical research in the future," said Wayne Hendrickson, Ph.D., University Professor of Biochemistry and Molecular Biophysics at Columbia University Medical Center (CUMC) and leader of one of the new centers. "Drug discovery has been lagging in recent years, and many of us believe that the development of drugs based on a protein's structure is a much more efficient way to find the drugs we'd like to have."

The Protein Structure Initiative essentially starts from where the Human Genome Project left off. "Genes are important only in that they produce proteins, which are the tiny three-dimensional machines of life," says Lawrence Shapiro, Ph.D., associate professor in the Departments of Opthalmology and Biochemistry & Molecular Biophysics at CUMC, and a principal investigator of one of the new centers. "This project will enable us to see thousands of proteins in the form in which they actually do their work."

When the PSI established its pilot centers beginning in 2000, its goal was twofold: to develop innovative approaches and tools, such as robotic instruments, that streamline and speed many steps of generating protein structures, and to incorporate those new methods into pipelines that turn DNA sequence information into protein structures.

Now, according to the NIH, the focus shifts to a production phase during which the new centers will use methods developed during the pilot period to rapidly determine thousands of protein structures found in organisms ranging from bacteria to humans. These efforts will facilitate accurate structure prediction of a much larger number of proteins through computer modeling.

""We hope that the PSI will allow us to develop a new view of the relationships between protein sequence, protein structure, and protein function that will ultimately make the three-dimensional structures and functions of most proteins predictable from the protein sequence" said Barry Honig, Ph.D., professor of biochemistry and molecular biophysics at CUMC and the bioinformatics leader of the Northeast Structural Genomics Research Consortium.

"We are proud to be contributing to this important effort that is harnessing the brightest minds across a spectrum of scientific disciplines," said David Hirsh, Ph.D., executive vice president for research at Columbia University. "Through this collaborative research we will gain greater insight into how proteins function and their evolutionary interrelationships, ultimately leading to the identification of new targets for drug design."

Columbia researchers will play major roles in the following centers:

-- The New York Consortium on Membrane Protein Structure, led by Wayne Hendrickson, University Professor of Biochemistry and Molecular Biophysics at Columbia University Medical Center. Other Columbia researchers include: Drs. Burkhard Rost, Barry Honig, Lawrence Shapiro, Eric Gouaux, Ming Zhou, John Hunt, and Filippo Mancia.

-- The Rutgers-led Northeast Structural Genomics Consortium, led by Professor Gaetano Montelione of Rutgers University. Montelione and his consortium partners previously conducted a $36 million NIGMS pilot program that developed new tools that will now be utilized in this second phase of the project, which focuses on cancer-related proteins. Columbia contributors include bioinformaticians Burkhard Rost, Ph.D. and Dr. Honig, the consortium's director of bioinformatics; Dr. Hendrickson, the consortium's director of crystallography, and Drs. Peter Allen, Liang Tong, John Hunt, and Andrew Laine from Columbia University.

-- The New York Structural Genomics Research Consortium (led by Structural GenomiX, Inc, a company co-founded by Drs. Honig and Hendrickson). Dr. Shapiro, will help in high-throughput structure determination, focusing particularly on structures of phosphatases, a type of protein frequently important in disease.

Craig LeMoult

cel2113columbia

212-305-0820

Columbia University Medical Center

cumc.columbia

Fish Protein Link To Controlling High Blood Pressure, New Study

2011-05-15T03:09:00.000-07:00

Medical scientists at the University of Leicester are investigating how a species of fish from the Pacific Ocean could help provide answers to tackling chronic conditions such as hereditary high blood pressure and kidney disease.

They are examining whether the Goby fish can help researchers locate genes linked to high blood pressure. This is because a protein called Urotensin II, first identified in the fish, is important for regulating blood pressure in all vertebrates- from fish to humans.

The study is being carried out in the University's Department of Cardiovascular Sciences. Researcher Dr Radoslaw Debiec said: "The protein found in the fish has remained almost unaltered during evolution".

"This indicates that the protein might be of critical importance in regulation of blood pressure and understanding the genetic background of high blood pressure.

"Uncovering the genetic causes of high blood pressure may help in its better prediction and early prevention of its complications. My research at the University of Leicester has shown how variation in the gene encoding the protein may influence risk of hypertension."

Dr Debiec will be presenting his research at the Festival of Postgraduate Research which is taking place on Thursday 25th June in the Belvoir Suite, Charles Wilson Building at the University of Leicester between 11.30am and 1pm.

He added: "Drugs affecting the protein might be a novel alternative to the available therapies in particular in those patients who have chronic kidney disease coexisting with high blood pressure.

"Analysis of large cohort of families has provided us with evidence that genetic information encrypted in the protein travels together with the risk of high blood pressure across generations. Furthermore, the same genetic variant responsible for elevated blood pressure is responsible for the development of chronic kidney disease in this group of patients.

"The present findings may have an impact on the development of new blood pressure-lowering medications."

Dr Debiec's study was supervised Dr. M. Tomaszewski (Department of Cardiovascular Sciences, Cardiology Group,) and Professor D.G. Lambert (Department of Cardiovascular Sciences; Pharmacology and Therapeutics Group).

Source: Leicester University

Discovery Of New Step In DNA Damage Response In Neurons

2011-05-14T03:00:00.000-07:00

Researchers have identified a biochemical switch required for nerve cells to respond to DNA damage.

The finding, scheduled for advance online publication in Nature Cell Biology, illuminates a connection between proteins involved in neurodegenerative disease and in cells' response to DNA damage.

Most children with the inherited disease ataxia telangiectasia are wheelchair-bound by age 10 because of neurological problems. Patients also have weakened immune systems and more frequent leukemias, and are more sensitive to radiation.

The underlying problem comes from mutations in the ATM (ataxia telangiectasia mutated) gene, which encodes an enzyme that controls cells' response to and repair of DNA damage.

ATM can be turned on experimentally by treating cells with chemicals that damage DNA. After other proteins in the cell detected broken DNA needing repair, scientists had thought that the ATM protein could activate itself directly. Emory researchers have shown that an additional step is necessary first.

"In neurons that are not dividing anymore, we now know that another regulator is involved: Cdk5," says Zixu Mao, MD, PhD, associate professor of pharmacology and neurology at Emory University School of Medicine.

Working with postdoctoral fellows Bo Tian, PhD and Qian Yang, PhD, Mao found that the Cdk5 protein must activate ATM before ATM can do its job in neurons.

The results support the idea that Cdk5 may be a potential drug target. Cdk5 contributes to normal brain development, and aberrant Cdk5 activity is known to be involved in the death of neurons in several neurodegenerative diseases, including Alzheimer's, Parkinson's and amyotrophic lateral sclerosis.

"Cdk5 has a complex character," Mao says. "It can be bad for neurons if its activity is either too high or too low."

Mao says he and his colleagues were intrigued by reports that in these diseases, neurons that had stopped dividing appear to restart that process, copying their DNA, before dying.

"That's what really kicked us into high gear," he says.

The same process, called "mitotic catastrophe," occurs when neurons suffer DNA damage. Inhibiting either Cdk5 or ATM can reduce the number of neurons that suffer mitotic catastrophe after DNA damage, the authors found.

The National Institutes of Health and the Woodruff Health Sciences Center Fund supported the research.

Reference:

Tian, B., Yang, Q. and Mao, Z. Phosphorylation of ATM by CDk5 mediates DNA damage signaling and regulates neuronal death.

Nature Cell Biology, advance online publication.

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing, and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.

Source: Holly Korschun

Emory University

Cells That Avoid Suicide May Become Cancerous

2011-05-13T02:51:00.000-07:00

When a cell's chromosomes lose their ends, the cell usually kills itself to stem the genetic damage. But University of Utah biologists discovered how those cells can evade suicide and start down the path to cancer.

Details of how the process works someday may provide new ways to treat cancer.

The new study of fruit flies is the first to show in animals that losing just one telomere - the end of a chromosome - can lead to many abnormalities in a cell's chromosomes, which are strands of DNA that carry genes.

"The essential point is that loss of a single telomere may be a primary event that puts a cell on the road to cancer," says Kent Golic, a professor of biology at the University of Utah and senior author of the study, which will be published online this week in the December issue of the journal Genetics.

Fruit flies have four pairs of chromosomes. Humans have 23 pairs. Each chromosome has two ends, called telomeres, which often are compared with the plastic tips of shoe laces. When those tips are lost or break, the shoelace frays. Previous research has shown that aging and cancer often are associated with loss or shortening of telomeres.

Damaged Cells Usually Kill Themselves to Avoid Becoming Cancerous

To protect an organism against cancer, most cells with broken or missing telomeres undergo "apoptosis," also known as cell suicide. But Golic and Simon Titen, a postdoctoral fellow in biology, found how fruit fly cells with a missing telomere sometimes avoid suicide and instead continue to divide and develop early characteristics of cancer.

Normally when a chromosome is damaged, the cell carrying the chromosome turns on a gene named p53, which helps kill the cell. When mutated, p53 fails to carry out this vital function. That is why mutant p53 is a cancer-causing gene and is found in most human tumors.

Golic and Titen found that normal p53 and so-called "checkpoint" proteins named Chk1 and Chk2 are required for the suicide of fruit fly cells with a missing telomere.

They also found that a non-mutant cell lacking a telomere occasionally escapes suicide and divides. Then, its progeny accumulate defects, including the wrong number of chromosomes or chromosomes that have exchanged pieces with each other. Those defects are hallmarks of cancer cells.

One possible reason a cell avoids suicide even after telomere loss and other damage is that chromosomes in the cell's offspring regain telomeres.

"All cancer cells have figured out how to add new telomeres, which allows them to survive and divide indefinitely," says Titen. "By interfering with this process, it might be possible to provide a route therapeutically to treat cancer."

A telomere is made of short sequences of DNA repeated hundreds of times. Proteins bind to the DNA, forming a cap or telomere that protects the end of the chromosome.

In humans, cells in certain tissues, such as the skin, continue to divide over a lifetime. Each time a cell divides, the telomeres become shorter until, in rare cases, the rest of the chromosome is no longer protected. It has been proposed that this can trigger cancer, but previous studies have been done only in yeast or cultured animal cells that are grown in a dish. The new Utah study shows in flies that telomere loss can cause cancer-like changes in a cell.

When Cell Suicide is Blocked, Cells Start on the Road to Cancer

Fruit flies often are used for chromosomal studies because they share 60 percent of their genes with humans, and it is unethical to cause genetic abnormalities in humans. Also, the process by which fly cells grow and divide are comparable with human cells.

To trigger telomere loss, the researchers inserted into the flies a gene from common baker's yeast. The gene makes an enzyme that breaks and rejoins DNA. When they turned on the enzyme, it led to the loss of a single telomere in each affected fruit fly cell.

The researchers then looked at what happened to the cells that lost a telomere.

"When we looked to see what happens to cells [those lacking a telomere], we found that most died - which is good - because those that didn't die accumulated abnormal chromosomes, which is characteristic of cancer cells," Golic explains.

Next, they repeated the experiment using flies in which p53, Chk1 or Chk2 were mutated - thus crippling cells' ability to commit suicide. The net effect of crippling the cell suicide genes and then damaging the chromosomes was to allow more damaged chromosomes to survive instead of committing suicide.

In a normal fly, when a telomere is lost, only 10 percent to 20 percent of cells with such damage survive, with the rest killing themselves. But in flies whose suicide genes were crippled, up to 75 percent of cells survived despite lacking a telomere.

"Cells containing chromosomes with broken ends turn on a signal and Chk2 gets activated, and then that activates p53 which eventually leads to cell death," Golic says. "Chk1 also becomes activated and eventually activates p53."

Titen adds: "Chk1 and Chk2 were not previously known to be involved in cell death due to loss of a telomere."

The researchers found that if a damaged cell avoids suicide due to p53, Chk1 or Chk2, there is another way it can kill itself and avoid starting down the road to cancer.

This occurs when the damaged cell divides, and its progeny have the wrong number of chromosomes. The resulting genetic imbalance can cause cell suicide. Thus, telomere loss also is linked to this alternative form of cell suicide. The study shows for the first time that this type of cell death - which doesn't use p53 - is caused by gaining or losing copies of other important genes, Golic says.

Cells that bypass all of the protective suicide measures divide multiple times, accumulating more and more chromosomal abnormalities. In humans, such cells are likely to develop into cancer cells.

The study was funded by the National Institutes of Health.

University of Utah Public Relations

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Salt Lake City, Utah 84112-9017

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Source: Lee Siegel

University of Utah

Autotomy Reduces Immune Function And Antioxidant Defence

2011-05-11T02:33:00.000-07:00

In their struggle for life, many animals have evolved a fascinating mechanism to avoid being eaten: sacrificing a body part.

When a prey animal is grasped by a predator, the body part is amputated so that the animal itself can escape. Despite the obvious short-term survival benefit, there are long-term costs like reduced lifespan. These costs were traditionally explained by reduced locomotion after limb loss.

We identified a novel type of cost, impaired immunity, which should make prey more vulnerable to parasites. Trying to escape from one enemy can therefore drive prey in the arms of another one.

Royal Society Journal Biology Letters

Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.

publishing.royalsociety/biologyletters

Adolescent Smokers Prone To Drug Abuse

2011-05-10T02:24:00.000-07:00

It is common knowledge that smoking is a health risk but why do teens become addicted to smoking more easily than adults? In an evaluation for Faculty of 1000 Biology, Neil Grunberg looks into why adolescents are more prone to substance abuse.

Grunberg describes the study, published by Natividad et al. in Synapse journal, as "fascinating" and suggests it "may have implications to help understand why adolescents are particularly prone to drug abuse".

Nicotine increases the level of dopamine in the brain, a neurotransmitter that is responsible for feelings of pleasure and wellbeing. The study looked at dopamine levels in adolescent and adult rats after nicotine withdrawal. The authors found that the withdrawal signs (physical and neurochemical) seen in adolescent rats were fewer than those observed in adults.

The study provides previously unknown mechanisms as to why there are differences in nicotine withdrawal between adolescent and adult rats. The key here, as stated by Grunberg, is "age alters [neurological] systems and interactions relevant to nicotine".

The reason that adolescents are prone to drug abuse (in this case, nicotine) is that they have increased sensitivity to its rewarding effects and do not display the same negative withdrawal effects as adults do, due to an underdeveloped dopamine-producing system.

Since rats are not subject to cultural influences, "rat studies of nicotine ... have provided valuable insights that have led to practical behavioural and pharmacological interventions", says Grunberg.

The results of this study may not stop at nicotine. Grunberg continues, "these findings might also be relevant to other addictive and abuse drugs".

The full text of this article is available free for 90 days at f1000biology/article/d43fbwjsqtzb3f1/id/1166360

An abstract of the original article Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats is at ncbi.nlm.nih/sites/entrez/19771590

Source: Steve Pogonowski

Faculty of 1000: Biology and Medicine

Whole-Cell Computer Simulations

2011-05-09T02:15:00.000-07:00

Researchers have built a computer model of the crowded interior of a bacterial cell that - in a test of its response to sugar in its environment - accurately simulates the behavior of living cells.

The new "in silico cells" are the result of a collaboration between experimental scientists at the Max Planck Institute of Biology in Germany and theoretical scientists at the University of Illinois using the newest GPU (graphics processing unit) computing technology.

Their study appears in the journal PLoS Computational Biology.

"This is the first time that we're modeling entire cells with the complete contents of the cellular cytoplasm represented," said Illinois postdoctoral researcher and lead author Elijah Roberts. "We're looking at the influence of the whole cellular architecture instead of modeling just a portion of the cell, as people have done previously."

University of Illinois chemistry professor Zaida Luthey-Schulten, who led the research, had done molecular dynamics simulations of individual molecules or groups of molecules involved in information processing, but never of a system as large and complex as the interior of an entire cell.

Then in 2006 she saw a paper by Wolfgang Baumeister and his colleagues at Max Planck that located every one of a bacterium's ribosomes, its protein-building machines, inside the cell.

That image spurred Luthey-Schulten to think about modeling an entire cell, and she asked Baumeister and his colleague Julio Ortiz if they would repeat the study in Escherichia coli (E. coli), a bacterium that has been the subject of numerous molecular studies.

Once the new ribosome data were available, Roberts looked to other studies that described the size distribution of the rest of the molecules that take up space in the cell. By adding these to the ribosome data, he developed a three-dimensional model that showed the degree of "molecular crowding" in a typical E. coli cell.

Luthey-Schulten was amazed at how little "space" remained inside the cell, she said.

"I think, like everybody else, my perception of the cell up until Wolfgang and Julio's 2006 article had always been that it's a pretty big sack of water where a lot of chemical reactions occur," she said.

"But in fact there are a lot of obstacles in the cell, and that is going to affect how individual molecules move around and it's going to affect the reactions that occur."

Other researchers have begun studying the effects of molecular crowding on cellular processes, but never at the scale of an entire cell.

Those studying live cells can - by conducting fluorescence experiments - discover variations in the copy number of a particular protein in a population of cells. But they are less able to observe the microscopic details that give rise to such differences between genetically identical cells. Well-designed computer simulations of whole cells can track every reaction within the cells while also accounting for the influence of molecular crowding and other variations between cells, Luthey-Schulten said.

For example, by running simulations on models of two E. coli strains, the researchers were able to see that "bacterial cell architecture does indeed affect the reactions that occur within the cells," Luthey-Schulten said. When sugar was present in its environment, a longer, narrower E. coli strain was able to ramp up production of a sugar-transporter protein much more quickly than a bigger strain, the researchers found. That difference had a lot to do with the distribution of molecules in each cell type, Roberts said.

The computer simulation also showed how molecular crowding influences the behavior of a molecule that, when it binds to DNA, shuts down production of the sugar-transporter protein. Even when it wasn't bound to DNA, this repressor remained close to the binding site because other molecules in the cell blocked its escape. These intracellular obstacles reduced its ability to diffuse away.

The new model is only a first step toward an accurate simulation of a whole working cell, the researchers said. The development of better models will rely on the work of those conducting research on actual cells. Their data provide the framework for improving computer models, Luthey-Schulten said, and offer a real-world test of the in silico cells' ability to recreate the behavior of living cells.

Notes:

Future studies will further develop the E. coli models and will focus on methane-generating archaeal microbes.

This research was supported by the Department of Energy Office of Science, the National Science Foundation and the Foundation Fourmentin-Guibert. Computational resources were provided by the NSF through the TeraGrid and the National Center for Supercomputing Applications, and also by the CUDA Center of Excellence at Illinois.

The paper: "Noise Contributions in an Inducible Genetic Switch: A Whole-Cell Simulation Study"

Source:

Diana Yates, Life Sciences Editor

University of Illinois at Urbana-Champaign

Scientists Demystify An Enzyme Responsible For Drug And Food Metabolism

2011-05-08T02:06:00.000-07:00

For the first time, scientists have been able to "freeze in time" a mysterious process by which a critical enzyme metabolizes drugs and chemicals in food. By recreating this process in the lab, a team of researchers has solved a 40-year-old puzzle about changes in a family of enzymes produced by the liver that break down common drugs such as Tylenol, caffeine, and opiates, as well as nutrients in many foods. The breakthrough discovery may help future researchers develop a wide range of more efficient and less-expensive drugs, household products, and other chemicals. The scientists' findings were published in the journal Science on 12 November 2010.

Michael Green, an associate professor of chemistry at Penn State University and lead author of the study, explained that scientists have speculated for decades that, during the process of metabolizing chemicals in the human liver, enzymes in the family named P450 pass through a critical chemical phase-change called "Compound I," whereby an oxygen molecule is temporarily added. However, until now, no one had actually seen the process happen or even had proven that it existed. "This phase change happens quickly, and P450 just as quickly changes back to its original state," Green explained. "So the challenge was trapping the enzyme at the exact moment that it went through the Compound I stage." First, Green and his colleagues grew one of the P450 enzymes in E.coli - bacteria found in the human gut. They then developed a method to cool the enzyme at just the right rate - one one-thousandth of a second - to "freeze in time" the formation process of Compound I.

Green also explained that, while all humans have a gene responsible for making the P450 enzymes, different populations of humans vary in which version of the gene they carry, and thus, which version of P450 they produce. Such P450 variations lead to differences in the way people respond to particular drugs. "With a drug such as caffeine, for example, one population of people might be fast metabolizers, while another might metabolize the drug more slowly," Green explained. "Because the risk of caffeine-induced heart attack may be higher in slow metabolizers, the ability to actually take a snapshot of the phase changes of the P450 enzymes could help us to understand better how certain chemicals can affect people in vastly different ways."

Green's P40 research may also aid future scientific discoveries in the field of pharmacology. "Adverse drug-drug interactions are a well-known problem," Green explained. "The answer to why some people have bad interactions could be understood at the level of the P450 enzymes and their state changes. Now that we can see those state changes on a molecular level, a deeper investigation is finally possible."

Notes:

Green's co-author is Jonathan Little, who was an undergraduate student in Penn State's Department of Chemistry throughout the research study. Little is now a graduate student at the California Institute of Technology.

This research was supported by a grant from the National Science Foundation.

Source:

Barbara K. Kennedy

Penn State

Alternative To Embryonic Stem Cells Stem May Be Provided By Cells Found In Adult Hair Follicles

2011-05-07T01:57:00.000-07:00

Having recently identified the molecular signature of these epidermal neural crest stem cells in the mouse, their research resolves conflicting scientific opinions by showing that these cells are distinctly different from other types of skin-resident stem cells/progenitors. Their work provides a valuable resource for future mouse neural crest stem cell research.

A report on the research from Dr. Maya Sieber-Blum's laboratory, co-authored by Yao Fei Hu, Ph.D., and Zhi-Jian Zhang, Ph.D., researchers in cell biology, neurobiology and anatomy at the Medical College, was published in a recent issue of Stem Cells: The International Journal of Cell Differentiation and Proliferation.

Epidermal neural crest stem cells are found in the bulge of hair follicles and have characteristics that combine some advantages of embryonic and adult stem cells, according to lead researcher, Maya Sieber-Blum, Ph.D., professor of cell biology, neurobiology & anatomy. Similar to embryonic stem cells, they have a high degree of plasticity, can be isolated at high levels of purity, and can be expanded in culture. Similar to other types of adult stem cells, they are readily accessible through a minimally invasive procedure and could lead to using a patient's own hair as a source for therapy without the controversy or medical issues of embryonic stem cells.

"We see the potential for cell replacement therapy in which patients can be their own donors, which would avoid ethical issues and reduce the possibility of tissue incompatibility," says Dr. Sieber-Blum.

The Medical College team in collaboration with Prof. Martin Schwab, director of the Brain Research Institute of the University of Zurich, recently injected these cells in mice with spinal cord injuries. According to the study, when grafted into the spine, the cells not only survived, but also demonstrated several desirable characteristics that could lead to local nerve replacement and re-myelination (restoration of nerve pathways and sheaths).

Neural crest stem cells generate a wide array of cell types and tissues and actually give rise to the autonomic and enteric nervous systems along with endocrine cells, bone and smooth muscle cells. The cells can be isolated from the hair follicle bulge as multipotent stem cells, and then expanded in culture into millions of cells without losing stem cell markers.

"We grafted the cells into mice that have spinal cord injuries and were encouraged by the results. The cells survived and integrated into the spinal cord, remaining at the site of transplantation and not forming tumors," Dr. Sieber-Blum says.

According to Dr. Sieber-Blum, subsets of the epidermal neural crest stem cells express markers for oligodendrocytes, the nerve-supporting cells that are essential for proper neuron function. She has been awarded a grant from the Biomedical Technology Alliance, a Milwaukee inter-institutional research group, to determine in collaboration with Brian Schmit, Ph.D., associate professor of biomedical engineering at Marquette University, if the grafts lead to an improvement of spinal reflexes in the injured spinal cord of mice.

Dr. Sieber-Blum points out that the cells may also be useful to treat Parkinson's disease, multiple sclerosis, Hirschsprung's disease, stroke, peripheral neuropathies and ALS. Certain defects of the heart, and bone defects (degeneration, craniofacial birth defects) could also be treated through neural crest stem cell replacement therapy. Together, these conditions affect over 11 million people today in the US and are estimated to annually cost more than $170 billion.

Contact: Toranj Marphetia

Medical College of Wisconsin

Adult Skin Cellsturned Into Muscle And Vice Versa At Stanford

2011-05-06T01:48:00.000-07:00

In a study featured on the cover of the May issue of The FASEB Journal, researchers describe how they are able to reprogram human adult skin cells into other cell types in order to decipher the elusive mechanisms underlying reprogramming. To demonstrate their point, they transformed human skin cells into mouse muscle cells and vice versa. This research shows that by understanding the regulation of cell specialization it may be possible to convert one cell type into another, eventually bypassing stem cells.

"Regenerative medicine provides hope of novel and powerful treatments for many diseases, but depends on the availability of cells with specific characteristics to replace those that are lost or dysfunctional," said Helen M. Blau, Ph.D., the senior scientist involved in the study, Associate Editor of The FASEB Journal, Member of the Stem Cell Institute, and Director of the Baxter Laboratory in Genetic Pharmacology at Stanford. "We show here that mature cells can be directly reprogrammed to generate those necessary cells, providing another way besides embryonic stem cells or induced pluripotent stem cells of overcoming this important bottleneck to restoring tissue function."

The Stanford scientists sought to transform one specialized adult cell from one species into a different specialized adult cell of another species. To do this, they first used a chemical treatment to fuse skin and muscle cells together, producing cells that had nuclei from human skin cells and mouse muscle cells. By being encapsulated within the same cell wall, the human skin cells and mouse muscle nuclei could now "talk" to one another via chemical signals. Then, the scientists looked at the genes expressed from the human skin nuclei and mouse muscle nuclei. (This was possible because one cell type was human and the other was mouse, so the genes could be distinguished based on species differences.) After several experiments, they were able to induce the human skin nuclei to produce mouse muscle genes and induce the muscle nuclei to produce human skin genes - effectively transforming the cell from one type to the other.

"Reprogramming mature cells will likely complement the use of embryonic stem cells in regenerating tissues," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "By elucidating the regulators of reprogramming, as the Stanford group is doing, it may be possible to generate replacement cells in cases where stem cells are not present or not appropriate."

Source:
Cody Mooneyhan

Federation of American Societies for Experimental Biology

New Strategy To Create Genetically Modified Animals Reported By Penn Veterinary Medicine

2011-05-05T01:39:00.000-07:00

Researchers at the University of Pennsylvania School of Veterinary Medicine have demonstrated the potential of a new strategy for genetic modification of large animals. The method employs a harmless gene therapy virus that transfers a genetic modification to male reproductive cells, which is then passed naturally on to offspring.

Ina Dobrinski, associate professor and director of the Center for Animal Transgenesis and Germ Cell Research at Penn Vet, and her colleagues introduced adeno-associated virus, AAV, to male germline stem cells in both goats and mice. The study showed that AAV stably transduced male germ line stem cells and led to transgene transmission through the male germ line.

The findings, available online in The FASEB Journal and in the February 2008 print edition, are the first report of transgenesis via germ cell transplantation in a non-rodent species, a promising approach to germ line genetic modification. It also demonstrates that germline transduction and germ cell transplantation in large animals provides an approach that is potentially less costly than microinjection and cloning, the traditional methods used to generate transgenic large animal models for biomedical research.

Researchers used mouse germ cells harvested from experimentally induced cryptorchid donor testes that were then exposed in vitro to AAV vectors carrying a green fluorescent protein transgene and transplanted to germ cell-depleted recipient testes, resulting in colonization of the recipient testes by transgenic donor cells.

When researchers mated these recipient males with wild-type females, 10 percent of offspring carried the gene originally introduced into the transplanted germ cells, meaning the genetic modification had been passed on. To broaden the approach to non-rodent species, AAV-transduced germ cells from goats were transplanted to recipient males in which endogenous germ cells had been depleted by fractionated testicular irradiation. Transgenic germ cells colonized recipient testes and produced transgenic sperm. When semen was used for in vitro fertilization, 10 percent of embryos were transgenic.

"Initially, the team used the established germ cell transplantation model in the mouse to investigate whether AAV-mediated transduction of germ cells was possible and could result in transgene transmission," Dobrinski said. "To broaden the applicability of the results for different mammalian species, the approach was then applied to a large animal species in which germ cell transplantation-mediated transgenesis would provide an important alternate approach to the generation of transgenic animal models for biomedical research."

Currently, somatic cell nuclear transfer or pronuclear injection is used to generate transgenic animals. These inefficient and difficult methods also carry a risk of producing offspring with developmental abnormalities. The use of retroviral or lentiviral vectors has been reported in rodents, but it requires that animals be handled and maintained under higher biosafety precautions that render this approach less practical for transgenesis in large animal species. In contrast, animals exposed to AAV can be maintained under standard husbandry conditions.

AAV is a dependent virus that carries no disease and causes only a very mild response from the immune system. Because AAV can infect both dividing and non-dividing cells and passes its genome, it is considered an excellent candidate for use in gene therapy.

The research was performed as a collaboration between Dobrinski, Ali Honaramooz, Susan Megee, Jinping Luo, Hannah Galantino-Homer, Mark Modelski, Fangping Chen and Wenxian Zeng of the Center for Animal Transgenesis and Germ Cell Research at the New Bolton Center of the Penn School of Veterinary Medicine; Fang Yang and P. Jeremy Yang of the Department of Animal Biology at Penn Veterinary Medicine; Margret Destrempes, Stephen Blash, David Melican, William Gavin, Yann Echelard and Susan Overton of GTC Biotherapeutics Inc.; and Sandra Ayres of the Tufts Cummings School of Veterinary Medicine.

The research was supported by a grant from the National Institute of Child Health and Human Development and the National Center for Research Resources.

Source: Jordan Reese

University of Pennsylvania

Shift Work And Metabolic Disorders

2011-05-04T01:30:00.000-07:00

Scientists from Kiel and Odense/Denmark are currently jointly researching the influence that working shifts, the quality of sleep and nutrition has on metabolic disorders and gene activity. The Department of Human Biology in the Zoological Institute at Kiel University, the Institute of Human Genetics at the University Medical Center Schleswig-Holstein, Campus Kiel and the University of Southern Denmark in Odense are participating in the new project: "Sleep, work and their consequences for human metabolic disorders". The researchers are receiving support amounting to EUR 730,000 over a period of three years from the European Union as part of the INTERREG 4A South Denmark-Schleswig-K.E.R.N. programme, using funds from the European Regional Development Fund. The long-term objective of this study is to develop preventative measures in order to reduce the risk of metabolic and sleep disorders developing in future.

People who work shifts are not able to comply with the natural sleep/wake rhythm based on the cycle of day and night. Their internal body clock becomes unbalanced. The consequences of this can be a variety of metabolic disorders which, on a long-term basis, can be accompanied by a range of illnesses, psychological disorders and even the inability to work. In order to be able to investigate the extent of the changes to the human body and its cells which result from shift work, pairs of twins from Denmark are being examined using molecular-biological methods. From each pair, one twin works shifts. According to the Kiel human geneticist, Dr. Ole Ammerpohl, "The advantage of examining identical twins is that both are practically genetically alike and the effects of lifestyle can be identified more easily. That is why it is essential to work together with the national Danish twins register, which has been analysing twins with regard to medical and professional aspects for many years."

The effects of working shifts may well be far more fundamental than previously assumed. They may have a direct impact on our genetic make-up and the genes contained within this material. "Gene activity is controlled by small switches on the DNA, known as DNA methylation", explains Ammerpohl. "This DNA methylation adjusts to suit changes in environmental conditions and can even be passed on to subsequent generations."

Alongside shift work itself, nutritional and sleeping patterns also aid the development of metabolic disorders. Therefore the project does not only include DNA methylation and genetic variations, it also covers the twins' nutritional behaviour, the quality of sleep obtained as well as hormone and blood counts (blood sugar, blood lipids, etc.). For example, whether the levels of the stress-hormone "cortisol" change in people as a result of working shifts is being tested. All the features mentioned above are placed in relation to each other at the university in Odense and evaluated using special mathematical models.

Right up until a few generations ago, people got up at daybreak and went to bed when it got dark. "In order to adjust to this, our bodies have evolved over centuries to develop a sophisticated system of transmitters which control the sleep-wake cycle and enable the body to regenerate sufficiently", explains Professor Manuela Dittmar from Kiel University. However, over the last few decades our lifestyles have changed drastically. Working hours are no longer based on how long the day lasts. "More and more people are required to work shifts. The consequences for those affected include a higher incidence of typical civilisation diseases right up to burn-out syndrome and early disability", according to Dittmar.

Source: Christian-Albrechts-Universitaet zu Kiel, AlphaGalileo Foundation.

Human Glioblastoma Tumor Cell Size Reduced By 50 To 70 Percent In Rat Model

2011-05-03T01:21:00.000-07:00

In a landmark study, Medical College of Wisconsin researchers in Milwaukee report that drugs used to inhibit a specific fatty acid in rat brains with glioblastoma-like tumors not only reduced new blood vessel growth and tumor size dramatically, but also prolonged survival. The study is the featured cover story of the August, 2008 Journal of Cerebral Blood Flow & Metabolism.

"These rat model tumors were developed from human glioblastoma tumor cells and closely mimic human tumors in growth patterns and response to therapy," says lead researcher David Harder, Ph.D., Kohler Co. Professor in Cardiovascular Research. "The concept of targeting blood vessels that feed tumors as an approach to limit tumor growth is not a novel idea," he says. "However, blocking the specific fatty acid described in this study is novel, and holds great promise for use in humans."

Malignant gliomas are very aggressive tumors of the central nervous system, resistant to chemotherapy and radiation, and account for about half of the 350,000 brain tumors currently diagnosed in the U.S.

Dr. Harder is also professor of physiology, associate dean for research and director of the Medical College's Cardiovascular Research Center. He believes that further studies, demonstrating that such drugs work in humans may reveal that higher concentrations or infusions over longer periods of time may be more effective than the results reported in this study.

"If survival time could be extended, with a combination of surgical therapy and infusion with similar drugs, this could be a significant treatment option," he says.

Earlier studies from the Harder lab have shown that specific fatty acids generated in the brain induce new blood vessel growth known as angiogenesis. Harder and colleagues designed these studies on the premise that all cells, including cancer cells, require oxygen for growth and that blocking formation of specific fatty acids would decrease blood vessel growth and oxygen supply to tumors, retarding their growth.

In their current study, Dr. Harder and colleagues compared three sets of rats with induced tumors, two groups using either one of two inhibitor drugs, 17-ODYA or miconazole, to block the fatty acid CYP epoxygenase and a control group, receiving a placebo. Drugs were infused directly into the tumors over an extended period of time, using specially-designed miniature osmotic pumps and a very small burr hole in the skull. The pumps, similar to those used in humans, were buried just beneath the skin through a tiny incision.

Compared to the control group, tumor size in the drug-infused groups was reduced by an average 50 to 70 percent, and survival time increased by five to seven days, equivalent to three to four months in terms of human survival.

"These pumps have been used in humans for other diseases and can be designed for delivery of these drugs as well," says Dr. Harder. "We believe they can be used to deliver drugs to block angiogenesis in complex human tumors such as glioblastomas."

Dr. Harder's co-investigators in this study were Debebe Genremedhin, Ph.D., associate professor of physiology, and Medical College postdoctoral fellows Drazen Zagorac, Ph.D. and Danica Jakovcevic, Ph.D.

Source: Eileen La Susa

Medical College of Wisconsin

Sugar Molecule Can Protect Against HIV, Study Finds

2011-05-02T01:12:00.000-07:00

A sugar molecule called the Pk blood group antigen might provide a defense against HIV, according to a study published last week in the journal Blood, Toronto's Globe and Mail reports. Researchers from Toronto's Hospital for Sick Children and Lund University in Sweden studied the sugar molecule, which is found on the surfaces of some red and white blood cells. They found that Pk antigens act as magnets for HIV, neutralizing the virus once it attaches to the antigen and stopping its spread to other immune cells, the Globe and Mail reports.

The study's findings indicate that "the higher the level of [Pk] blood type you have, the less susceptible you are to HIV," according to Donald Branch of Canadian Blood Services, who led the study. Although most people have a certain amount of Pk in their blood supply, only about one in one million people have very high levels, making them "very resistant" to HIV, Branch said. The study "represents a breakthrough," he said, adding that he hopes other people could acquire the same protection against HIV by artificially boosting the Pk level in their blood. Researchers already have developed an artificial version of the antigen for possible use "to sop up the HIV," Branch said. Once the approach is tested in animals, Branch said researchers could move to clinical trials in humans (Taylor, Globe and Mail, 1/16).

An abstract of the study is available online.

Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Brawn Over Beauty In Human Mating Competition

2011-05-01T01:03:00.000-07:00

Male physical competition, not attraction, was central in winning mates among human ancestors, according to a Penn State anthropologist.

"There is sexual competition in many species, including humans," said David A. Puts, assistant professor of biological anthropology.

Many researchers have considered mate choice the main operator in human sexual selection. They thought that people's mating success was mainly determined by attractiveness; but for men, it appears that physical competition among males was more important. Puts sees humans as similar to many of the apes in using male competition to determine access to mates, the winning male choosing the women of his dreams. He reports his findings in the current issue of Evolution and Human Behavior.

"On average men are not all that much bigger than women, only about 15 percent larger," said Puts. "But, the average guy is stronger than 99.9 percent of women."

The problem is that men and women do not appear sexually dimorphic - different sexes having radically different sizes and weights. But Puts notes that women tend to store more body fat, while men have 60 percent more muscle mass than women.

Other traits indicate physical prowess was the major force in human mate competition through history. Men are far more aggressive than women, and approximately 30 percent of men in small-scale foraging communities die violently. Puts suggests that while a deep voice has been considered an appealing trait to women, it actually signals dominance.

"A deep voice makes men look dominant and older," said Puts. "A low voice's effect on dominance is many times greater than its effect on sexual attraction."

The main sticking point with human male competition compared to other species is that male humans do not possess inherent weapons.

"Other animals have antlers or long canines and claws," said Puts. "Why don't we have them?"

According to Puts, men do have weapons. They make them. Bows and arrows, spears, knives -- men have always manufactured weapons.

Other male traits also seem to imply competition. Males have thicker jawbones, which may have come from men hitting each other and the thickest-boned men surviving. Competition may explain why males have more robust skulls and brow ridges than women.

Another argument for male competition focuses on the environment. Puts suggests that species that live in three-dimensional space - birds and insects in the air or swimming creatures in the sea - tend not to compete for mates using physical competition because it would be very difficult for a male to defend females while fighting other males on all fronts. Species that live on the ground or the sea floor have it easier because there are only two dimensions to defend. Some insects that live in tunnels or burrows exhibit the most intense competition because it is impossible for the other male to get to the females except through the defender.

Male competition is rare among birds, occurring to a greater degree among large terrestrial species. Tree-living primates also show less physical competition. Humans living in a two-dimensional environment would experience substantial physical competition for mates.

According to Puts, humans and chimpanzees create male coalitions that are often strengthened by kinship. Coalitions can help males defend females from other males. However, when external forces are absent, these same males can compete with each other for mates.

These ideas may seem to paint a rather bleak picture of human nature with men duking it out among themselves for most of human evolution.

"Things are different for us now in many ways," said Puts. "It's heartening to think that human behavior is flexible enough that the right social institutions can increase equality and peace."

Source:

A'ndrea Elyse Messer

Penn State

Protein Roadmap For Inherited Eye Diseases

2011-04-30T00:54:00.000-07:00

Researchers at the University of Pennsylvania School of Medicine have identified proteins in the rod and cones of the eye that could lead to the discovery of the genetic causes of a host of inherited eye diseases. The investigators hope to gain a clearer understanding of what goes wrong at the most basic level in these diseases that cause blindness and other disorders.

Specifically, they have identified and measured the types and amounts of proteins in the light-sensing parts of the eye's retina. These light-sensitive structures, called photoreceptor sensory cilia, enable the rod and cone cells of the retina to detect light. While the proteins of cilia in single-celled organisms have been studied, this is the first time that a comprehensive description of the proteins of a mammalian cilium used for movement and sensing has been determined.

"We want to understand how cilia work normally and how their function is disrupted in disease, because their dysfunction is such an important cause of disease," says senior author Eric A. Pierce, MD, PhD, Associate Professor of Ophthalmology at the F.M. Kirby Center for Molecular Ophthalmology at Penn. "One of the first steps to achieve this is to put together a complete parts list. Now that we have that, we can figure out how all 2000 proteins we've identified fit together correctly."

The study will appear in the August print issue of Molecular & Cellular Proteomics and has been pre-published online.

Cilia, specialized structures that extend from cells, have recently taken the spotlight in studying genetic diseases. They are commonly used by cells for movement or sensory purposes, and, in many cases with mammals, have been thought to be remnants of evolution without much purpose. But new research has shown that mutations in genes that encode the proteins of cilia are common causes of a host of genetic diseases, including inherited retinal diseases and polycystic kidney disease.

Cilia diseases can also affect multiple organ systems in such disorders as Bardet-Biedl Syndrome, which causes kidney disease, obesity, polydactyly, diabetes, and retinal degeneration; Senior-Loken Syndrome, which causes kidney disease and retinal degeneration; Joubert Syndrome, which causes neurological disease, kidney disease, and retinal degeneration; Usher Syndrome, which causes deafness and blindness; and Meckel Syndrome, which causes kidney disease and neural tube defects.

Lead author Qin Liu, MD, PhD, Research Assistant Professor and Pierce collaborated with a team at the Wistar Institute led by David Speicher to perform the analyses for this study. The researchers used mass spectrometry to identify and measure the amounts of proteins in mouse photoreceptor sensory cilia. They found many proteins in the cilia that had not been identified in photoreceptors before. This includes proteins involved in intraflagellar transport, which is a process that moves materials from the cell body into the cilia. Mutations in proteins associated with this transport system lead to a number of cilia-related diseases.

The investigators also found 60 proteins encoded by genes on chromosomes implicated in 23 inherited cilia-related disorders. Armed with this knowledge, researchers hope to be able to more quickly find the exact genetic mutations that cause these 23 cilia diseases, which include eye and kidney diseases, among others.

Pierce is a pediatric ophthalmologist who specializes in caring for children with inherited retinal degenerations. He says that about half of his patients with degenerative eye diseases have a type of disease that can be identified according to its genetic mutation. He believes that this research will help identify the genetic causes behind the other half of his patients' conditions.

"We're narrowing the field," says Pierce. "This research in and of itself can't find a cure, but it's a great start because it tells you what proteins to study."

Co-authors also include Edward N. Pugh Jr. from Penn; Glenn Tan, Natasha Levenkova, and John J. Rux of the Wistar Institute; and Tiansen Li of Harvard Medical School. The National Eye Institute, the F.M. Kirby Foundation, Foundation Fighting Blindness, Research to Prevent Blindness, the Rosanne H. Silbermann Foundation, the Mackall Foundation Trust, and the Commonwealth University Research Enhancement Program provided funding for this research.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

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Controlling Schistosomiasis: Buffalo Or Snails?

2011-04-29T00:45:00.000-07:00

A parasitic infection common in China and Southeast Asia could be effectively reduced by controlling snail populations, according to research
published in PLoS Medicine.

Infection with schistosomes of various species affects some 200 million people worldwide, and can cause serious chronic illnesses, including liver
failure. Steven Riley of the University of Hong Kong and collaborators analyzed infection patterns of the parasitic worm Schistosoma japonicum in
fifty villages in Samar Province, the Philippines. Rates of infection among humans and animals have been found to differ among villages, and the
researchers developed a mathematical model incorporating fecal parasite test results from thousands of people and animals (including, cats, pigs,
dogs, water buffalo, and rats) to explain these differences.

Schistosomes are passed from mammals to fresh-water snails via feces, and then cycle back to infect mammals that contact water inhabited by infected
snails. Using the mathematical model, the team found that transmission from snails to mammals was a more important factor in explaining the
differences among villages than transmission from mammals to snails.

As with all scientific models, the findings of this one depend on the assumptions made to build the model. Nevertheless, the findings suggest that
interventions to reduce the size of the snail population and the exposure of mammals to parasite-containing water might reduce human infection levels
more effectively than interventions that interrupt other parts of the parasite's life cycle.

The results also indicate that the contribution of water buffaloes to human S. japonicum infection in the Philippines is not particularly important.
This finding contrasts with a recent study that identified water buffalo as the major mammalian reservoir for S. japonicum in China.
(who.int/bulletin/volumes/85/7/06-034033/en/index.html) , and suggests that further studies of the transmission of S. japonicum by water
buffalo are warranted before efforts are dedicated to treat or vaccinate water buffalo as a control measure against human S. japonicum infection.

In a related perspective article, Song Liang and Robert Spear, who were not involved in the study, discuss the findings and conclude that the
"modeling approach can be a useful tool in exploring schistosomiasis transmission in other settings, and may even apply to other macroparasites."

Click here to view article online.

About PLoS Medicine

PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of
human health and disease, together with commentary and analysis of important global health issues.

PLoS Medicine

About the Public Library of Science

The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.

Public Library of Science

Evolutionary Link To Modern-Day Obesity, Other Problems

2011-04-28T00:36:00.000-07:00

That irresistible craving for a cheeseburger has its roots in the dramatic growth of the human brain and body that resulted from environmental changes some 2 million years ago.

Higher quality, nutritionally dense diets became necessary to fuel the high-energy demands of humans' exceptionally large brains and for developing the first rudimentary hunting and gathering economy.

But the transition from a subsistence to a modern, sedentary lifestyle has created energy imbalances that have increased rapidly -- evolutionarily speaking -- in recent years and now play a major role in obesity.

Activity patterns must get every bit as much attention as consumption of unhealthy foods in any attempt to reverse the modern-day permeations of an evolutionary trend that now contributes to obesity worldwide, according to William Leonard.

Leonard, chair and professor of anthropology at Northwestern University, discussed his work during the 2009 American Association for the Advancement of Science (AAAS) meeting in Chicago at a press briefing on Feb. 12 and during a symposium from 8:30 to 11:30 a.m. Feb. 13.

Two million years ago shifts in foraging behavior and dietary quality helped to provide the energy and nutrition to support the rapid evolutionary increases in both the brain and body sizes of our ancestors.

Today modern humans use nearly a quarter of their resting energy needs to feed our brains, considerably more than other primates (about 8 to 10 percent) or other mammals (3 to 5 percent). To support the high-energy costs of our large brains, humans consume diets that are much richer in calories and nutrients than those of other primates.

"While our large-bodied ape relatives -- chimps, gorillas and orangutans -- can subsist on leaves and fruit, we needed to consume meat and other energy-rich foods to support our metabolic demands," Leonard said.

Staple foods for all human societies are much more nutritionally dense than those of other large-bodied primates. "To obtain these higher-quality diets, our foraging ancestors would have had to have moved over larger areas than our ape relatives, requiring large activity budgets," he said.

But substantial reductions of intense physical activities for adults living a modern lifestyle in the industrialized world have dramatically lowered the metabolic costs of survival.

The differences between energy in and energy out widen as we increase the nutritional density of our diets while reducing the time and energy associated with obtaining food. "Think about our ancestors," Leonard said. "Human hunter-gatherers typically move 8 miles per day in the search for food. In contrast, we can simply pick up the phone to get a meal delivered to our door."

That decline in daily energy expenditures contributes not only to obesity, but also to other chronic diseases of the modern world, such as diabetes and cardiovascular disease. "In a sense, those modern diseases represent where we started early in our evolutionary history," Leonard said.

The data clearly suggest the obesity epidemic cannot be understood solely by looking at consumption, he stressed. "Throughout most of our evolutionary history, the acquisition of our high-quality diets required substantial expenditure of energy and movement over much larger areas than for other primates."

The imbalance between energy intake and energy expenditure today, Leonard concludes, is the root cause of obesity in the industrialized world.

American Association for the Advancement of Science (AAAS), Hyatt Regency Chicago, 151 E. Wacker Drive, Acapulco Room

(Leonard's AAAS talks will highlight the work that he and his colleagues -- Marcia L. Robertson, Josh Snodgrass, Mark V. Sorensen and Northwestern's Christopher Kuzawa --have been doing on the evolution of human nutritional requirements over the last 15 years. The work has been featured in prominent publications such as Scientific American and the Annual Review of Nutrition, and in books, recent and forthcoming, on the evolutionary perspectives on health and nutrition.)

Source: Pat Vaughan Tremmel

Northwestern University

Skin Color Studies On Tadpoles Lead To Cancer Advance

2011-04-27T00:27:00.000-07:00

The humble tadpole could provide the key to developing effective anti-skin cancer drugs, thanks to a groundbreaking discovery by researchers at the University of East Anglia (UEA).

The scientists have identified a compound which, when introduced into Xenopus Laevis tadpoles, blocks the movement of the pigment cells that give the tadpoles their distinctive markings and which develop into the familiar greenish-brown of the adult frog.

It is the uncontrolled movement and growth of pigment cells (melanophore) in both tadpoles and humans that causes a particularly dangerous form of skin cancer. By blocking the migration of these cells, the development and spread of cancerous tumours can potentially be prevented.

Published in the Cell Press journal Chemistry & Biology, the findings are the culmination of several years' work by the UEA team. This unconventional study, which was initiated with funding from the UK Medical Research Council, identifies for the first time an effective new man-made MMP (metalloproteinase) inhibitor, known as 'NSC 84093'.

The work was led by the University of East Anglia, in partnership with the John Innes Centre (JIC) and Pfizer.

"This is an exciting advance with implications in the fight against cancer," said lead author Dr Grant Wheeler of UEA's School of Biological Sciences.

"The next step is to test the compound in other species and, in the longer term, embark on the development of new drugs to fight skin cancer in humans."

The species Xenopus Laevis (South African clawed frog) is more closely related to humans than one might expect. It only diverged from man 360 million years ago and has the same organs, molecules and physiology. This means that the same mechanisms are involved in causing cancer in both Xenopus tadpoles and humans.

Until the 1960s, Xenopus Laevis frogs were used as the main human pregnancy test. A woman's urine sample was injected into a live frog. If the urine contained the hCG (human chrionic gonadotropin) hormone, the frog would lay eggs within 24 hours, indicating that the woman was pregnant.

'A chemical genomic approach identifies matrix metallaoproteinases as playing an essential and specific role in Xenopus melanophore migration' by Grant Wheeler (UEA), Matthew Tomlinson (UEA), Carla Garcia-Morales (UEA), Robert Field (JIC), Pingping Guan ( JIC), Richard Morris (JIC), Martin Rejzek (JIC) and Mark Fidock (Pfizer) is published online on January 29 and in print on January 30.

Source: Simon Dunford, Press Officer

University of East Anglia

Cell Movements Totally Modular, Stanford Study Shows

2011-04-26T00:18:00.000-07:00

A study describing how cells within blood vessel walls move en masse overturns an assumption common in the age of genomics - that the proteins driving cell behavior are doing so much multitasking that it would be near impossible to group them according to a few discrete functions.

But now researchers at the Stanford University School of Medicine have shown that distinct groups of proteins each control one of four simple activities involved in the cells' collective migration. The findings will be published in the Dec. 1 issue of Genes and Development.

Graduate student Philip Vitorino, the study's first author, began the project in 2004 in the laboratory of senior author Tobias Meyer, PhD, professor of chemical and systems biology. The work is part of the Meyer lab's larger effort to find order in the overwhelming complexity of the inner workings of cells.

First they grew the cells (originally from umbilical cord tissue) into sheets and watched what happened when they scratched some of the cells away: They were looking to see the movements of individual cells and overall sheet movements as cells filled the open space.

"We stained the nuclei and took a movie under a microscope and watched what they did over a 15- to 20-hour period," said Vitorino. "That's when we noticed the cells moving inside the sheet, even in the absence of an open space. Not only were they moving, but they were moving in a flow-like pattern with neighboring cells moving as small collective groups. It looked like these groups were moving on invisible paths."

The cells moved at a rate of 10 microns an hour, pretty sprightly for a cell, Vitorino said. The researchers found they could break down movement into four processes: single cell movements, coordination of neighboring cells, directional sensing and cell division.

Vitorino went on to inactivate the more than 100 genes suspected of playing a role in controlling movement and watched how each change affected the cells' group behavior.

That's when he was able to show that the genes were acting in concert as distinct modules. "One hypothesis was, if you mess up one gene, everything gets messed up. That was a real possibility," said Vitorino. But he found that blocking a gene tended to disturb only one of the four processes - indicating a modular system at work.

"The cells don't need to activate and inactivate thousands of proteins to control sheet movements," Vitorino said. "Instead they simply coordinate the activity of four simple modules to generate efficient movements."

Vitorino also made some curious, though not immediately useful, observations about the impact of silencing genes for individual cells: "Some inactivations made them spiky, some made them long, some made them so they wouldn't stick together, some made them divide really fast, some, really slow," Vitorino said.

"The hardest part was organizing all of the data and making sense out of it," he added. Generating the data took only a year. Analyzing, retesting and making sense of these data took close to two more.

This discovery, at least in the case of blood vessel cell movement, marks a return to an earlier notion of modules in cell biology, prevalent before the 1990s and the advent of genomics, which led scientists to try to chart the individual actions of millions of genes.

Cell biologists have a penchant for comparing the cell's workings to auto mechanics and Vitorino is no exception. "Using the human genome, biochemical studies and proteomic approaches, scientists have generated a comprehensive list of parts and also some information about where the parts sit under the hood," he said.

"What we have done is organized these parts into those that are involved in generating forward movement, those that are important for steering, those that signal to other cars or those that are important for braking.

"Ultimately, this allows us to simplify very complex behaviors and provides a powerful tool for developing new therapeutics," said Vitorino. "With an understanding of the individual parts of the machine, it will be easier to effectively modify the system to change cell behaviors and ultimately treat human disease."

Notes:

This study was funded by the National Institutes of Health and the National Science Foundation Pre-Doctoral Fellowship Program.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital.

Source:

Rosanne Spector

Stanford University Medical Center

Rosalind Franklin University Cell Biology & Anatomy Professor's Results On Neural Plasticity

2011-04-25T00:09:00.000-07:00

The Chicago
Medical School (CMS) of the Rosalind Franklin University of Medicine and
Science (RFUMS) today announced that Assistant Professor of Cell Biology &
Anatomy, Athanasios Tzounopoulos, has uncovered novel forms of synaptic
plasticity that occur at the very first step in the processing of sound in
the central nervous system. His findings are being released today in
Neuron, one of two leading journals in Neuroscience.

"The ability to observe synaptic plasticity and uncover its cellular
mechanisms at such an early, relatively unprocessed stage allows us to
study the role of these mechanisms in sensory processing," said Professor
Tzounopoulos. "Our findings also show that the brain is able to change
itself as a result of previous experience at places where processing is
much simpler and better understood. This new capability could have a
significant impact on our understanding and cures for disorders caused by
neural plasticity-like mechanisms," he added.

These findings may be relevant for understanding the mechanisms of
human tinnitus. Tinnitus is the perception of ringing, buzzing, roaring, or
other noises in the ears or head - when there is no external source of the
noise. It is estimated that more than 50 million Americans experience
tinnitus to some degree. Of these, about 12 million have tinnitus severe
enough to seek medical attention. Many learn to ignore the sounds and
experience no major effects. However, about two million patients are so
seriously debilitated that they cannot function normally, finding it
difficult to hear, work or sleep. Though research is providing more
evidence for the causes and treatments of tinnitus, there is no real
understanding of the biological bases of tinnitus, nor are there any
treatments that help most sufferers. Recent studies point to the central
nervous system as the site for the maintenance of tinnitus. Moreover,
animal models of tinnitus indicate a role for the dorsal cochlear nucleus
(DCN, an auditory brainstem nucleus), the brain area where Professor
Tzounopoulos performed his studies.

"It is quite possible that transient exposure to intense sound might
induce long-term changes in the balance of excitation and inhibition in the
DCN, through the mechanisms described in our recent findings. Our studies,
by providing a detailed understanding on how this plasticity is induced,
expressed, and modulated at the cellular level may ultimately lead to
treatments for tinnitus," said Professor Tzounopoulos.

According to these recent findings, newly formed hypotheses suggest
that concerted operation of different forms of synaptic plasticity gate
sensory activation of the DCN and can lead to activity-dependent modulation
of timing precision. Timing is an important feature in the brain and
especially in the auditory system. Many neurons in the auditory system are
known for their ability to fire action potentials that occur in a precise
temporal relationship to the stimulus (phase locking). Activity-dependent
modulation of spike timing precision through these mechanisms is a new
concept that may allow sensory systems to adapt to different patterns of
sensory activity and to properly integrate and encode varying sensory
stimuli.

Recent studies have shown that more robust and faithful brainstem
timing encoding is observed in trained individuals (musicians) compared to
untrained individuals (non-musicians). While these types of learning
phenomena have been attributed to cortical plasticity until now, our
studies suggest that the brainstem itself has the mechanisms and the
capability to support such learning. Similar studies have established that
brainstem timing precision serves as a reliable marker of individuals with
learning disabilities. Faulty mechanisms of neural timing at the brainstem
may be the biological basis of malfunction in children with learning
disabilities. "Therefore, elucidation of mechanisms underlying synaptic
plasticity and timing precision in the brainstem may provide the cellular
basis for these learning disabilities," said Professor Tzounopoulos.

Rosalind Franklin University of Medicine and Science educates medical
doctors, health professionals, and biomedical scientists in a personalized
atmosphere. The University is located at 3333 Green Bay Road, North
Chicago, IL 60064, and encompasses Chicago Medical School, College of
Health Professions, Dr. William M. Scholl College of Podiatric Medicine,
and School of Graduate and Postdoctoral Studies. Visit us at
rosalindfranklin and lifeindiscovery.

Rosalind Franklin University of Medicine and Science

rosalindfranklin

Emerging Pathogens Revealed: Ticks, Flukes, And Genomics

2011-04-24T11:05:00.000-07:00

Ehrlichiosis is no star of science. This emerging disease has an awkward name, vague flu-like symptoms, and a nasty habit of being caused by bacteria that live inside ticks and flatworms. But in the current issue of the journal Public Library of Science Genetics (PLoS Genetics), scientists put ehrlichiosis under the genomic spotlight--and discover some brilliant biology.

Led by scientists at The Institute for Genomic Research (TIGR) and The Ohio State University (OSU), a team of researchers report the complete genomes of three emerging pathogens that cause ehrlichiosis--Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia sennetsu--and compare the genomes with those of 16 other bacteria with similar lifestyles. The study reports new genes that allow the bacteria to evade a host's immune system, adapt to new niches, and more. Finally, the report reconstructs the metabolic potential of five representative genomes from these bacteria.

"By comparing so many different pathogens, some closely related and others diverse, we're able to identify genes linked to different diseases and organisms," explains molecular biologist Julie Dunning Hotopp of TIGR, first author of the PLoS Genetics paper. Because the pathogens causing ehrlichiosis are obligate intracellular bacteria--able to thrive only inside host cells--they are hard to isolate and study in the lab, Hotopp adds. "How are these diseases different? How are they the same? Can we correlate certain genes with certain characteristics? For the first time, our comparative genomics database offers a resource for tackling these questions."

Recognized since at least the 1930s, ehrlichiosis sickens not only humans, but also dogs, cattle, sheep, and other animals. In Japan, human ehrlichiosis is commonly called sennetsu fever. In the U.S., most human cases have been linked to ticks.

In the new study, scientists uncovered a clue to how ehrlichiosis-causing bacteria infect such diverse animals. One of the three primary bacteria sequenced, A. phagocytophilum, contains roughly 1,400 genes--including more than 100 variations of a single gene that codes for a protein allowing the bacteria to evade the immune system of the organism it has infected. This protein sits on the bacteria's outer membrane surface. When the bacteria, through tick bites, transfers to a human, say, or horse, the bacteria chooses the protein variation needed to stay hidden from that particular host.

"These genome sequences have revolutionized the types of experiments [scientists] can perform to understand these diseases," says microbiologist Yasuko Rikihisa of OSU's College of Veterinary Medicine. "Already, at least four labs are performing, or planning to perform, whole genome DNA microarray analysis and proteomic analysis of these bacteria."

In addition to comparing genomes, the current study used those genomes to reconstruct the metabolic potential (the ability to use and produce energy and compounds) of five bacteria, representing the numerous organisms compared. With this final analysis, they gleaned new insight into the broader tactics used by different bacteria. Ehrlichiosis pathogens, for instance, appear capable of making vitamins that a host tick lacks in its regular diet.

"This study is a beautiful example of how in-depth comparative genomics can lead to the identification of molecular features that underlie the lifestyle of pathogens," says TIGR molecular biologist Hervщ Tettelin, senior author of the PLoS Genetics article. "We could not have reached these conclusions by independently studying the genome sequence of each individual pathogen," he adds. "Now we know how some of the pathogens studied infect or provide benefits to their hosts."

The scientists hope to build on this work, with potential studies to determine which bacterial genes are turned on during ehrlichiosis infection and to track the evolutionary differences between ehrlichiosis-causing organisms in different parts of the world. Other scientists can build on the new work as well, by accessing the comparative database now online at tigr/sybil/rcd/. This genome sequencing project work was funded by the National Institutes of Health.

The Institute for Genomic Research is a not-for-profit center dedicated to deciphering and analyzing genomes. Since 1992, TIGR, based in Rockville, Md., has been a genomics leader, conducting research critical to medicine, agriculture, energy, the environment and biodefense.

Delivering A Biochemical Payload To One Cell With Pinpoint Precision

2011-04-24T00:00:00.000-07:00

Imagine being able to drop a toothpick on the head of one particular person standing among 100,000 people in a stadium. It sounds impossible, yet this degree of precision at the cellular level has been demonstrated by researchers affiliated with the Johns Hopkins University Institute for NanoBioTechnology. Their study was published online recently in Nature Nanotechnology.

The team used precise electrical fields as "tweezers" to guide and place gold nanowires, each about one-two hundredth the size of a cell, on predetermined spots, each on a single cell. Molecules coating the surfaces of the nanowires then triggered a biochemical cascade of actions only in the cell where the wire touched, without affecting other cells nearby. The researchers say this technique could lead to better ways of studying individual cells or even cell parts, and eventually could produce novel methods of delivering medication.

Indeed, the techniques not relying on this new nanowire-based technology either are not very precise, leading to stimulation of multiple cells, or require complex biochemical alterations of the cells.

With the new technique the researchers can, for instance, target cells that have cancer properties (higher cell division rate or abnormal morphology), while sparing their healthy neighbors.

"One of the biggest challenges in cell biology is the ability to manipulate the cell environment in as precise a way as possible," said principal investigator Andre Levchenko, an associate professor of biomedical engineering in Johns Hopkins' Whiting School of Engineering. In previous studies, Levchenko has used lab-on-a-chip or microfluidic devices to manipulate cell behavior. But, he said, lab-on-a-chip methods are not as precise as researchers would like them to be. "In microfluidic chips, if you alter the cell environment, it affects all the cells at the same time," he said.

Such is not the case with the gold nanowires, which are metallic cylinders a few hundred nanometers or smaller in diameter. Just as the unsuspecting sports spectator would feel only a light touch from a toothpick being dropped on the head, the cell reacts only to the molecules released from the nanowire in one very precise place where the wire touches the cell's surface.

With contributions from Chia-Ling Chien, a professor of physics and astronomy in the Krieger School of Arts and Sciences, and Robert Cammarata, a professor of materials science and engineering in the Whiting School, the team developed nanowires coated with a molecule called tumor necrosis factor-alpha (TNF-alpha), a substance released by pathogen-gobbling macrophages, commonly called white blood cells. Under certain cellular conditions, the presence of TNF-alpha triggers cells to switch on genes that help fight infection, but TNF-alpha also is capable of blocking tumor growth and halting viral replication.

Exposure to too much TNF-alpha, however, causes an organism to go into a potentially lethal state called septic shock, Levchenko said.

Fortunately, TNF-alpha stays put once it is released from the wire to the cell surface, and because the effect of TNF-alpha is localized, the tiny bit delivered by the wire is enough to trigger the desired cellular response. Much the same thing happens when TNF-alpha is excreted by a white blood cell.

Additionally, the coating of TNF-alpha gives the nanowire a negative charge, making the wire easier to maneuver via the two perpendicular electrical fields of the "tweezer" device, a technique developed by Donglei Fan as part of her Johns Hopkins doctoral research in materials science and engineering.

"The electric tweezers were initially developed to assemble, transport and rotate nanowires in solution," Cammarata said. "Donglei then showed how to use the tweezers to produce patterned nanowire arrays as well as construct nanomotors and nano-oscillators. This new work with Dr. Levchenko's group demonstrates just how extremely versatile a technique it is."

To test the system, the team cultured cervical cancer cells in a dish. Then, using electrical fields perpendicular to one another, they were able to zap the nanowires into a pre-set spot and plop them down in a precise location. "In this way, we can predetermine the path that the wires will travel and deliver a molecular payload to a single cell among many, and even to a specific part of the cell," Levchenko said.

During the course of this study, the team also established that the desired effect generated by the nanowire-delivered TNF-alpha was similar to that experienced by a cell in a living organism.

The team members envision many possibilities for this method of subcellular molecule delivery.

"For example, there are many other ways to trigger the release of the molecule from the wires: photo release, chemical release, temperature release. Furthermore, one could attach many molecules to the nanowires at the same time," Levchenko said. He added that the nanowires can be made much smaller, but said that for this study the wires were made large enough to see with optical microscopy.

Ultimately, Levchenko sees the nanowires becoming a useful tool for basic research.

"With these wires, we are trying to mimic the way that cells talk to each other," he said. "They could be a wonderful tool that could be used in fundamental or applied research." Drug delivery applications could be much further off. However, Levchenko said, "If the wires retain their negative charge, electrical fields could be used to manipulate and maneuver their position in the living tissue."

The lead author for this Nature Nanotechnology article was Fan, a former postdoctoral fellow in the departments of Materials Science and Engineering and Physics and Astronomy. Additional authors included Zhizhong Yin, a former postdoctoral fellow in the Department of Biomedical Engineering; Raymond Cheong, a doctoral student in the Department of Biomedical Engineering; and Frank Q. Zhu, a former doctoral student in the Department of Physics and Astronomy. The research was funded by the National Science Foundation and the National Institutes of Health.

Source:

Mary Spiro

Johns Hopkins University