Proteins' 'Breaking Point' Found, UK

Scientists from Oxford University have discovered the watery secrets of what makes proteins unstable.

Their fundamental research into the 'critical condition' at which the biological function of proteins is destroyed could have a profound impact on many areas of science - including biology, materials science and medicine: In particular it could give fresh insights into diseases caused by proteins misfolding and how to mimic the properties of tissues such as cartilage and collagen.


The discovery comes from quantum mechanics simulations developed by Dr David Porter and Professor Fritz Vollrath of Oxford's Department of Zoology. 'The interaction of water with proteins is central to all biology, and the point at which water-protein interactions become unstable is arguably nature's most important 'critical condition',' said Dr David Porter. 'We can use these simulations to examine the physics and chemistry of hydrogen bonding between water and amide groups in a specific protein. The predictions from our models can then be translated into real biological stress conditions - of temperature, mechanical load and chemistry - that will cause this protein to become unstable and stop functioning.'


The new research also sheds light on how the amount of water in a protein tissue affects its relative 'softness' and overall structural properties. Proteins with relatively little water will be stiff but tough - like a hard plastic - whereas a larger fraction of water (above 30 per cent) makes tissues such as elastin highly flexible and strong.


Dr Porter and Professor Vollrath originally created the simulations to try to understand how spiders 'tease' a normally stable protein solution into a solid silk thread using a combination of stress mechanisms; temperature, mechanical load and chemistry. 'It soon became clear that our silk model could be applied to many other protein stability problems,' said Professor Fritz Vollrath. 'A key innovation is that our models can map how instability develops over a time period of anything from a few seconds to a hundred years. Understanding the role of water in biological materials will be very important as we try to create new materials with predictable properties.'


The innovative use of new ways to extract critical conditions from their quantum simulations could have many other important applications in materials science: They could be used to predict the conditions under which materials will melt or move between an ordered and a less ordered state. Professor Vollrath said: 'Clearly we can learn much more from spider silk than how to make a tough material.'


Notes:


- A report of the research, 'The role of kinetics of water and amide bonding in protein instability', is published in a forthcoming issue of the RSC journal Soft Matter, an advance copy of the article is available online here.




Oxford University

News From The Journal Of The National Cancer Institute, Sept. 9 JNCI

Bias Correction of Familial Risk Estimates Increases Estimated Melanoma Risk But Not Risk of Other Common Cancers



The relative risk of familial melanoma increases substantially when researchers account for a known potential bias in a large cohort study. The relative risk of familial lung, breast, prostate, and colorectal cancer do not change substantially with the correction.



Researchers have used the Swedish Cancer Registry and the Swedish MultiGenerational Register to estimate the relative risk of cancers for individuals who have an affected first-degree relative. However, Kamila Czene, Ph.D., of the Karolinksa Institute and colleagues recently determined that such database analyses may underestimate the risk because cancers that occur before the start of registration are not included.



In the current study, Czene and colleagues adjusted for the bias by using data from a simulated population and applying that information to the Swedish cohort.



The relative risk of familial melanoma increased from 2.68 to 3.18 following the adjustment for the bias. The impact was even greater when an affected parent was diagnosed at a young age, increasing the relative risk to 4.07. The relative risks for colorectal, lung, breast, and prostate cancer remained close to 2.



"The lack of bias for most of these cancers is due to the relatively low familial risk…and/or relatively low incidence in the population, combined with a reasonably high sensitivity of the observed family history," the authors write. "Because sensitivity depends on age at onset, it is not surprising that the lowest sensitivity was observed for melanoma, a cancer with relatively young age at onset."



Experts Call for Renewed Efforts in Gastroenteropancreatic Neuroendocrine Tumors



During a September 2007 summit on neuroendocrine and carcinoid tumor, clinicians and researchers presented the current standards of care and identified key areas that require investigation and development.



Over the last 30 years, the incidence of these tumors has steadily increased in the United States, but there have been no substantial improvements in survival during that same time period.



At a National Cancer Institute-sponsored meeting, basic science and clinical researchers identified specific areas in the field that need to be addressed, which are summarized in a commentary by Irvin M. Modlin, M.D., Ph.D., D.Sc., of Yale University in New Haven, Conn., and colleagues. Those issues include increased public and physician education, identification of molecular markers for diagnosis and disease monitoring during therapy, standardization of pathology classifications, creation of regional centers of excellence, and improved in vitro and animal models of disease.
















"The group of experts at the meeting considered that the increasing incidence and prevalence of neuroendocrine disease in the United States was of considerable concern, particularly in light of the lack of evidence of improvement of outcome and the lack of any tangible evidence of the development of demonstrably effective novel therapies," the authors write.



Confirmation of Association with Chromosome 15 Locus and Familial Lung Cancer



Two single-nucleotide polymorphism (SNP) variants on the short arm of chromosome 15 appear to be associated with familial lung cancer.



Several research groups recently reported an association between the 15q24-25.1 locus and sporadic lung cancer risk.



To confirm that association with familial lung cancer, Ming You, M.D., Ph.D., of Washington University in St. Louis and colleagues performed a genome-wide association study using SNPs on 194 case patients with familial lung cancer and 219 cancer-free individuals.



You and colleagues found a strong association between the 15q24-25.1 locus and familial lung cancer. Two SNP variants were associated with the risk of lung cancer, although the identity of a causal gene was not identified.



"Determination of a likely single candidate gene and further delineation of whether variants affect lung cancer directly or indirectly or both are warranted," the authors conclude.



Also in the September 9 JNCI:
Evaluation Of Quality Measure For Colon Cancer Care Suggests Considerable Improvements Needed


5- And 10-Year Survival Continues To Improve For US Children With Hematologic Malignancies


India: Breast Cancer Screening May Lower Mortality And Disease Burden





The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Visit the Journal online at jnci.oxfordjournals/.



Source: Liz Savage


Journal of the National Cancer Institute

Launch Of Stem Cell Study For Acute Stroke Patients, UT Houston

A first-of-its-kind stem cell study to treat acute stroke victims is being launched by investigators at The University of Texas Medical School at Houston.



The Phase I study, funded with a pilot grant from The National Institutes of Health, will use the patients' own stem cells. Researchers will enroll 10 patients who have just suffered a stroke and are being treated in the Emergency Center at Memorial Hermann - Texas Medical Center. Physicians will obtain permission from the patient or patient's surrogate.



"This will be our first attempt to look at the safety of using stem cells in acute stroke patients," said Sean I. Savitz, M.D., assistant professor of neurology at the medical school. "There's a lot of promise behind this but we want to do it in a slow, rigorous fashion. Because we are injecting them intravenously, these cells can disperse to lots of different parts of the body and that's why we're looking at safety parameters."



Stroke occurs when blood flow to the brain is interrupted by a blockage or a rupture in an artery, depriving brain tissue of oxygen. It is the third-leading cause of death behind heart disease and cancer. According to the American Stroke Association, nearly 800,000 Americans suffer a stroke each year - one every 40 seconds. On average, someone dies of stroke every three to four minutes.



The stem cells will be harvested from the bone marrow in the iliac crest of the leg, then separated and returned to the patient within three to six hours. Because they are the patient's own stem cells, rejection is not expected to be an issue.



"This study is the critical first step in translating laboratory work with stem cells into benefit for patients. If effective, this treatment could be helpful to a huge segment of stroke patients to reduce their disability," said James C. Grotta, M.D., Roy M. and Phyllis Gough Huffington Distinguished Professor of Neurology and chair of the Department of Neurology at the medical school. "We are fortunate here at UT Houston and the Texas Medical Center to have the resources needed to carry out this work, and to have attracted someone of Dr. Savitz's caliber to lead this study."



The clinical study builds on laboratory and animal research indicating that stem cells from bone marrow can migrate to the injured area of the brain and help repair the damage.



"Animal studies have shown that when you administer stem cells after stroke, the cells enhance the healing. We know that stem cells have some kind of guidance system and migrate to the area of injury," Savitz said. "They're not making new brain cells but they may be enhancing the repair processes and reducing damage."



A UT Medical School study involving acute brain-injured children using their own stem cells has been underway since 2006 at Children's Memorial Hermann Hospital. Principal investigator of the study is Charles Cox, M.D., The Children's Fund, Inc. Distinguished Professor in Pediatric Surgery and Trauma at the medical school. Co-investigator is James Baumgartner, M.D., research collaborator with the medical school and a pediatric neurosurgeon at Children's Memorial Hermann Hospital.



"It's beneficial for this study that we have precedence. Dr. Cox and Dr. Baumgartner have been great in guiding me. That study has served as a model for us," Savitz said.







Enrollment will begin mid-February. The study is only open to patients who are admitted to the Emergency Center at Memorial Hermann - TMC with symptoms of an immediate stroke.



Source: Deborah Mann Lake


University of Texas Health Science Center at Houston

Structure Of Protein That Mutates DNA Of The AIDS Virus HIV-1determined By U Of M Researchers

Understanding the structure of proteins involved in inhibiting HIV-1 infection could help in the battle against AIDS, and University of Minnesota researchers have taken a crucial step in that direction.



Hiroshi Matsuo, Ph.D., and Reuben Harris, Ph.D., co-investigators of the research and assistant professors in the Department of Biochemistry, Molecular Biology and Biophysics at the University of Minnesota have determined the structure of APOBEC3G - a protein that inhibits the AIDS virus, HIV. This discovery is the first to shed light on the atomic structure of the protein.



The research was released online Feb. 20, 2008 on the Nature Web site and it will be featured in an upcoming print publication of the journal.



Proteins could be compared to miniature machines, each of which carries out a specific function. The APOBEC3G "machine" is capable of modifying HIV DNA so that the virus is no longer infectious.



HIV-1, however, has unfortunately developed a way to evade this potent cellular protein with its own protein called Vif, which literally triggers the destruction of APOBEC3G.



The discovery will help researchers manipulate APOBEC3G to make it effective in combating HIV. Current studies also will help develop methods to neutralize Vif before it has a chance to destroy the protein.



"This new information is a crucial step toward understanding how APOBEC3G and Vif talk to each other," Harris said. "Furthermore this new information will undoubtedly help researchers identify candidate drugs for future novel HIV-1/AIDS therapies."







This research was funded by grants from the National Institutes of Health and from the Minnesota Partnership for Biotechnology and Medical Genomics and the Medica Foundation.



Source: Nick Hanson


University of Minnesota

Cost-Effective Technology For Disease Diagnosis And Biological Research Developed By Singapore Scientists

A novel electronic sensor array for more rapid, accurate and cost-efficient testing of DNA for disease diagnosis and biological research has been developed by scientists at Singapore's Institute of Bioengineering and Nanotechnology (IBN).



In a recent Journal of the American Chemical Society, IBN scientists reported that based on laboratory results, their Nanogap Sensor Array has shown "excellent" sensitivity at detecting trace amounts of DNA.



"By saving time and lowering expenses, our newly developed Nanogap Sensor Array offers a scalable and viable alternative for DNA testing," said Zhiqiang Gao, Ph.D., Group Leader at IBN, the world's first bioengineering and nanotechnology research institute.



The biosensor translates the presence of DNA into an electrical signal for computer analysis. The distinctively designed sensor chip has the ability to detect DNA more efficiently by "sandwiching" the DNA strands between the two different surfaces.



"The novel vertical nanostructure design and two different surfaces of the sensor allow ultrasensitive detection of DNA," added Dr. Gao. "This sensitivity is best-in-class among electrical DNA biosensors. The design of the sensor also took into consideration the feasibility of mass production in a cost-effective way for expanded usage."



Conventionally, human DNA is detected through the use of polymerase chain reaction (PCR), which while effective, is also expensive, cumbersome and time-consuming for widespread use. The PCR technique amplifies a single piece of DNA across several orders of magnitude, duplicating millions or more copies of a particular DNA sequence, in order to detect the genetic material more easily.



Although effective, tests involving PCR may not be optimal for situations such as a pandemic outbreak, where results are needed quickly because PCR devices tend to be bulky and costly.



The Nanogap Sensor Array has a unique, vertically aligned nanostructure design and a two-surface configuration based on electronic transduction. The sensor comes with a pair of micro-sized metal electrodes separated by a nanogap (5 - 20 nm or about 1/50,000 the width of a human hair).



Another distinctive feature of the biosensor is its ability to capture DNA strands more effectively. This is possible because the two surfaces of the sensor are coated with a chemically treated "capture probe" solution through an electrochemical technique specially developed by IBN. This allows DNA strands to "stick" more easily to the sensor, resulting in a faster and more accurate analysis.



"This new biosensor holds significant promise to speed up on-going efforts in the detection and diagnosis of debilitating diseases such as cancer, cardiovascular problems and infectious viruses. We aim to make healthcare accessible to the masses with early disease diagnosis as the critical driving force behind the research we undertake here at IBN," added Jackie Y. Ying, Ph.D., Executive Director of IBN, one of the research institutes of Singapore's Agency for Science, Technology and Research (A*STAR).



The research was published on Aug. 5, 2009, in a paper titled, "Mass-Produced Nanogap Sensor Arrays for Ultrasensitive Detection of DNA," in Journal of the American Chemical Society.



Source:
Elena Tan


Nidyah Sani


Cathy Yarbrough


Agency for Science, Technology and Research (A*STAR), Singapore

Birds Could Teach Us A Thing Or Two About Healthy Eating

Want to know what kinds of foods prevent disease? Then watch what migratory birds eat during their stopovers on Block Island.



Two University of Rhode Island scientists believe that birds choose certain berries because they offer protection against oxidative stress that occurs during long flights. Oxidative stress can lead to inflammation and a variety of diseases in birds and humans.



The team's preliminary findings show that birds stopping over on Block Island favor the arrow-wood berry, which contains more anti-oxidants and pigments than the 11 other island berries studied by the researchers.



Navindra Seeram, assistant professor of pharmacy and head of the Bioactive Botanical Research Laboratory at URI, and Scott McWilliams, URI professor of wildlife ecology and physiology, have teamed up to research migratory birds' eating habits and how their diets might be used to understand the role of berries rich in anti-oxidants in human health. Research has shown a diet rich in anti-oxidants can help prevent cancer and other serious illnesses.



Seeram reported the findings at the American Chemical Society's 239th national meeting in San Francisco.



"We're suggesting that birds choose deeply colored berry fruits in part because of their anti-oxidant properties," Seeram said.



About 11 years before Seeram arrived at URI, McWilliams began laying the foundation for the recent study.



"When I started studying birds during their migratory stopover on Block Island, I was impressed that most of the migratory birds ate berry fruits even though they usually eat insects or seeds at other times of the year," said McWilliams, who came to URI in 1999. "I began studying the relationship between the nutritional qualities of fruits and how those nutrients might fuel migration."



When Seeram arrived at URI two years ago, McWilliams saw a University story online that detailed Seeram's research interests.



"I saw the story about Navindra and in it he was talking about oxidative stress and inflammation and the effects berry fruits can have on reducing those impacts on people."



So McWilliams, who does his research and teaches in the College of the Environment and Life Sciences, tracked down Seeram, who works in the College of Pharmacy. They developed their mutual research interests into a successful collaboration that included URI graduate student Jessica Bolser and post-doctoral researcher Liya Li, who works in Seeram's lab.



Called the lynchpin between McWilliams and Seeram, Bolser spent months in the field on Block Island observing the birds' nutritional patterns and collecting batches of 12 different kinds of berries for their analysis of anti-oxidant levels.



The research indicates that birds prefer to eat certain fruits that have more antioxidants and key nutrients. In return, the seeds in the berries are dispersed by the birds. "It's the way plants ensure their survival. Birds eat the berries, digest them and defecate the seeds over wide areas," McWilliams said.



"Meanwhile, the birds are attracted to the berries because of their rich color, which we believe is a plant's response to the stress of constant exposure to the sun and other stresses. Berry color could be a plant's way of fighting oxidative stress. It's a partnership that benefits plant and bird."



The Seeram-McWilliams partnership will continue. "We've only measured a few of these anti-oxidants," Seeram said. "Our next step is to determine how birds can detect these compounds."



"Whenever we exercise, we undergo oxidative stress, and the same is true for birds," McWilliams said. "We're flying birds in wind tunnels to produce oxidative stress, and then we are going to see if anti-oxidants found in these berries alleviate that stress," McWilliams said.



The research may benefit human health as well as bird conservation. If further research shows the direct link between bird health and diet, then the findings will play a critical role in habitat protection for migratory birds, McWilliams said.



"That's what is so great about URI," Seeram said. "Because the University is small, without the usual bureaucratic walls, we can create these partnerships. This collaboration between professors in two separate colleges would not have happened so easily in other universities and produced results so quickly."



Source:

Dave Lavallee


University of Rhode Island

Union Of Chemistry And Nanotechnology Should Improve Identification And Treatment Of Bacterial Infections

A new technique developed by a University of Central Florida chemist will help physicians more quickly identify the bacterial infections patients have so they can be treated in hours instead of days.



As more bacterial strains resistant to many drugs emerge, it becomes more critical to quickly identify infections and the antibiotics that would most effectively treat them. Such quick identifications become even more important during epidemics because large numbers of samples would have to be tested at once.



Assistant Professor J. Manuel Perez's new technique also promises to give research institutes and pharmaceutical companies a quicker and cheaper way of developing new antibiotics to combat super bugs.



The results of Perez's study were recently published online in Analytical Chemistry. The research was funded in part by the National Institutes of Health.



"The method really gives doctors quicker access to test results so they can treat their patients more quickly," Perez said from his lab at the Nanoscience Technology Center at UCF. "But there are more applications. This method can also be used by research facilities and big pharmaceutical companies for the high throughput screening of drugs for antibacterial activity."



Perez uses gold nanoparticles coated with a sugar and a protein that binds to sugars. Meanwhile, a variety of antibiotics are placed in the same solution. A spectrophotometer reads optical variations in the gold nanoparticle solution as the sugar and protein shift , which in turn demonstrate which antibiotics effectively halt bacteria growth and which ones do not. Results can be obtained within a couple of hours, in contrast to the traditional methods, which can take days to complete. And hundreds of samples can be tested at once using this technique because the amount of bacteria and antibiotic needed is small.



Pharmaceutical companies can use existing equipment to read the variations, which means they do not have to buy new equipment. Perez's study also shows that the technique is as sensitive and accurate as the traditional, more time-consuming approach.



"We're very excited and very pleased with the results," Perez said.







The research was completed with the help of the UCF Chemistry Department and the Burnett School of Biomedical Sciences. Nanoscience Technology Center post-doctoral fellow Sudip Nath and graduate student Charalambos Kaittanis are co-authors of the study, as is Alisa Tinkham, formerly of the Burnett School.



UCF Stands for Opportunity -- Established in 1963, the University of Central Florida is a diverse metropolitan research university that ranks as the 6th-largest in the country with more than 48,000 students. Located in Orlando, Fla., UCF offers high-quality undergraduate and graduate education, student development, and continuing education, while conducting cutting-edge research that powers the region's economic development.



Source: Zenaida Gonzalez Kotala


University of Central Florida

5 Brown Faculty Elected To World's Largest Scientific Body

Five Brown University faculty have been awarded the distinction of fellow from the American Association for the Advancement of Science (AAAS).



The new fellows, among 486 chosen from the AAAS membership this year, include visual neuroscientist David M. Berson; marine ecologist Mark D. Bertness; brain scientist John P. Donoghue; cell biologist Susan A. Gerbi; and Jimmy Xu, a professor who focuses on laser science, nanotechnology and bio-nanoelectronics.



Fellows are elected by their peers in the AAAS,which is the world's largest general scientific society. The AAAS, founded in 1848, publishes the journal Science. The organization has chosen AAAS fellows since 1874.



New fellows were announced in the Dec. 19, 2008, issue of Science and honored during a formal ceremony at the AAAS annual meeting in Chicago in February.



David Berson: Neuroscientist, vision specialist David Berson Neuroscientist, vision specialist David M. Berson



Berson is the Sidney A. Fox and Dorothea Doctors Fox Professor of Ophthalmology and Visual Sciences and has been a neuroscience researcher for more than 30 years - 23 as a Brown professor. He is a 1975 Brown graduate with an A.B. in psychology.



Berson was recognized for his contributions to the field of visual neuroscience. His lab focuses on what the eye tells the brain. Specifically, he explores structural and functional diversity among the ganglion cells of the eye, the retinal neurons that communicate directly with the brain. Current research focuses on one very unusual type of ganglion cell that senses light directly. These neurons drive reflexive responses to daylight, such as synchronizing biological clocks to the rising and setting of the sun.



Berson's discovery of that third light-sensing cell in the eye was reported in Science on Feb. 8, 2002.



Berson's research is funded by the National Eye Institute of the National Institutes of Health. He has completed a number of research grants from the NIH and the National Science Foundation, among others.



Mark Bertness: Intertidal zone ecologist Mark Bertness Intertidal zone ecologist Mark D. Bertness



Bertness became an AAAS fellow for his contributions to marine ecology and for outstanding research mentoring. He is the Robert P. Brown Professor of Biology in the Department of Ecology and Evolutionary Biology at Brown. His research focuses on the ecology and conservation biology of marine shoreline communities, using salt marsh and rocky shore systems.



He and his students use manipulative field experiments in New England to develop general models of community organization and human impacts and then test the generality of their findings on Argentinean and Chilean shorelines with South American graduate student collaborators. His book Atlantic Shorelines (Princeton University Press, 2007) discusses his interests and approach to studying marine intertidal communities.
















Bertness has earned a number of honors and awards. He gave the 2004 distinguished ecologist lecture at Mt. Holyoke College, and was the 2004 visiting chair in ecology at the University of Groningen in Holland. In 1999, he won the Elizabeth Leduc Prize for Distinguished Teaching in the Life Sciences. He has written articles for numerous publications including the Journal of Ecology, Science, American Scientist and the Proceedings of the National Academy of Sciences.



John Donoghue: Neuroscientist, brain specialist John Donoghue Neuroscientist, brain specialist John P. Donoghue



Donoghue, the Henry Merritt Wriston Professor at Brown University, became an AAAS fellow because of his interdisciplinary work exploring how the brain converts intention into movement. From 1991 through 2006, Donoghue was chairman of the Department of Neuroscience, and since 1998 he has served as executive director of the Brain Science Program at Brown, which has now been transformed and renamed as the Brown Institute for Brain Science. The Institute brings together more than 10 departments and 100 faculty and fosters interdisciplinary research and training.



In a Nature paper (March 2002), Donoghue reported that a computer could use a reconstructed brain signal to accomplish immediate, complex goal-directed behavior. A device based on his research entered clinical trials on human subjects in April 2004, results of which were reported at the annual meeting of the American Academy of Physical Medicine and Rehabilitation in Phoenix that fall.



For more than 20 years, Donoghue has performed research on brain-computer interfaces, and his laboratory is internationally recognized as a leader in this field. His research has been funded by the National Institutes of Health (NIH), the National Science Foundation (NSF), and the Defense Advanced Research Projects Agency (DARPA), as well as private foundations.



Susan Gerbi: Molecular cell biologist Susan Gerbi Molecular cell biologist Susan A. Gerbi



Gerbi is the George Eggleston Professor of Biochemistry in the Division of Biology and Medicine at Brown, where she teaches molecular cell biology.



She was recognized for her ongoing research. Her lab is studying the initiation of DNA replication (doubling of the hereditary information of the cell), and has devised a method to map the start site of DNA replication at the nucleotide level. Her research in progress suggests that a steroid hormone receptor may play a direct role for initiation of DNA replication, which could help clarify the role certain hormones play in some cancers.



The Gerbi lab also studies the structure, evolution and biogenesis of ribosomes (the factories in the cell that make proteins), and her lab's work has opened the possibility for a new class of antibiotics.



Gerbi has also been very active in biomedical Ph.D. training. Among her activities: She served on NIH study sections reviewing training grants and participated in NIH workshops about training and careers. She was a member of the National Academy of Sciences committee that worked on the "Study of National Needs for Biomedical Research Personnel," and has testified about graduate education before both the House and Senate Subcommittees on Appropriations.



Gerbi has received several honors for her research, including the State of Rhode Island Governor's Award for Scientific Excellence and election as president of the American Society for Cell Biology.



Jimmy Xu: Nanoscientist Jimmy Xu Nanoscientist Jimmy Xu



Xu was recognized for his contributions to advances in laser science, nanotechnology and bio-nanoelectronics. Xu is the Charles C. Tillinghast Jr. '32 University Professor in the Division of Engineering and professor of physics. His interests include nanoscale science and technology, quantum photonics, aperiodic optics, semiconductor lasers, molecular electro-optics, and collective behaviors of large coupled systems.



Xu's ongoing research includes carbon nanotube structures, physics, and applications; silicon lasers and sub-wavelength photonics; synthesis and non-lithographic fabrication and sciences of quantum-arrays made from metals, superconducting, molecules and semiconductors; DNA conductivity; and the physics of redox processes in proteins and cells.







Source: Mark Hollmer


Brown University

Stigma Surrounding Mental Illness Remains Despite Abundant Pharmaceutical Ads

The medicalization of such mental illnesses as depression and bipolar disorder, which have seen prescription drug advertisements on TV skyrocket since such advertising became permissible in 1997, has done nothing to remove the harmful stigma attached to the illnesses, according to sociologists from Indiana University and the University of North Carolina in Chapel Hill.



"The findings fly in the face of current thinking about ways that stigma can be reduced," said Peggy Thoits, Virginia L. Roberts Professor of Sociology in IU's College of Arts and Sciences.



Stigma has posed a steadfast obstacle to the treatment of many mental health illnesses. Negative perceptions of mental illness color the support and advice people get from their friends, family and even their physicians and can create a reluctance to seek help.



The study by Thoits and lead author Andrew R. Payton, graduate student at University of North Carolina in Chapel Hill, sought to see if attitudes toward mental illness have changed since the U.S. Food and Drug Administration issued new guidelines allowing pharmaceutical companies to air TV ads.



Theoretically, when a condition such as depression comes to be viewed as a treatable medical condition instead of a moral failing or spiritual condition, this should reduce the blame and stigma attached to depression. The researchers examined the Mental Health Modules in the General Social Survey during these intervening years and saw no change in attitudes toward people with mental illness, specifically when they compared depression, which was a focus of many TV commercials, to schizophrenia, for which no drugs have been advertised.



"We're making a big assumption, that marketing drugs to treat some these conditions is actually penetrating the consciousness of viewers, giving them the ability to recognize symptoms and conceptualize them as disorders and to see that these disorders can be relieved essentially with drugs," Thoits said.



The study was presented in the session Medical Institutions and Mental Health at the American Sociological Association meeting.



Source:
Tracy James


Indiana University

First Large-Scale Formal Quantitative Test Confirms Darwin's Theory Of Universal Common Ancestry

More than 150 years ago, Darwin proposed the theory of universal common ancestry (UCA), linking all forms of life by a shared genetic heritage from single-celled microorganisms to humans. Until now, the theory that makes ladybugs, oak trees, champagne yeast and humans distant relatives has remained beyond the scope of a formal test. This week, a Brandeis biochemist reports in Nature the results of the first large scale, quantitative test of the famous theory that underpins modern evolutionary biology.



The results of the study confirm that Darwin had it right all along. In his 1859 book, On the Origin of Species, the British naturalist proposed that, "all the organic beings which have ever lived on this earth have descended from some one primordial form." Over the last century and a half, qualitative evidence for this theory has steadily grown, in the numerous, surprising transitional forms found in the fossil record, for example, and in the identification of sweeping fundamental biological similarities at the molecular level.



Still, rumblings among some evolutionary biologists have recently emerged questioning whether the evolutionary relationships among living organisms are best described by a single "family tree" or rather by multiple, interconnected trees - a "web of life." Recent molecular evidence indicates that primordial life may have undergone rampant horizontal gene transfer, which occurs frequently today when single-celled organisms swap genes using mechanisms other than usual organismal reproduction. In that case, some scientists argue, early evolutionary relationships were web-like, making it possible that life sprang up independently from many ancestors.



According to biochemist Douglas Theobald, it doesn't really matter. "Let's say life originated independently multiple times, which UCA allows is possible," said Theobald. "If so, the theory holds that a bottleneck occurred in evolution, with descendants of only one of the independent origins surviving until the present. Alternatively, separate populations could have merged, by exchanging enough genes over time to become a single species that eventually was ancestral to us all. Either way, all of life would still be genetically related."



Harnessing powerful computational tools and applying Bayesian statistics, Theobald found that the evidence overwhelmingly supports UCA, regardless of horizontal gene transfer or multiple origins of life. Theobald said UCA is millions of times more probable than any theory of multiple independent ancestries.



"There have been major advances in biology over the last decade, with our ability to test Darwin's theory in a way never before possible," said Theobald. "The number of genetic sequences of individual organisms doubles every three years, and our computational power is much stronger now than it was even a few years ago."



While other scientists have previously examined common ancestry more narrowly, for example, among only vertebrates, Theobald is the first to formally test Darwin's theory across all three domains of life. The three domains include diverse life forms such as the Eukarya (organisms, including humans, yeast, and plants, whose cells have a DNA-containing nucleus) as well as Bacteria and Archaea (two distinct groups of unicellular microorganisms whose DNA floats around in the cell instead of in a nucleus).
















Theobald studied a set of 23 universally conserved, essential proteins found in all known organisms. He chose to study four representative organisms from each of the three domains of life. For example, he researched the genetic links found among these proteins in archaeal microorganisms that produce marsh gas and methane in cows and the human gut; in fruit flies, humans, round worms, and baker's yeast; and in bacteria like E. coli and the pathogen that causes tuberculosis.



Theobald's study rests on several simple assumptions about how the diversity of modern proteins arose. First, he assumed that genetic copies of a protein can be multiplied during reproduction, such as when one parent gives a copy of one of their genes to several of their children. Second, he assumed that a process of replication and mutation over the eons may modify these proteins from their ancestral versions. These two factors, then, should have created the differences in the modern versions of these proteins we see throughout life today. Lastly, he assumed that genetic changes in one species don't affect mutations in another species - for example, genetic mutations in kangaroos don't affect those in humans.



What Theobald did not assume, however, was how far back these processes go in linking organisms genealogically. It is clear, say, that these processes are able to link the shared proteins found in all humans to each other genetically. But do the processes in these assumptions link humans to other animals? Do these processes link animals to other eukaryotes? Do these processes link eukaryotes to the other domains of life, bacteria and archaea? The answer to each of these questions turns out to be a resounding yes.



Just what did this universal common ancestor look like and where did it live? Theobald's study doesn't answer this question. Nevertheless, he speculated, "to us, it would most likely look like some sort of froth, perhaps living at the edge of the ocean, or deep in the ocean on a geothermal vent. At the molecular level, I'm sure it would have looked as complex and beautiful as modern life."


Source:

Laura Gardner

Brandeis University

Basic Math In Monkeys And College Students

Adult humans possess mathematical abilities that are unmatched by any
other member of the animal kingdom. Yet, there is increasing evidence that
the
ability to count sets of objects nonverbally is a capacity that humans
share with other animal species. This week in the open-access journal PLoS
Biology, Elizabeth Brannon and Jessica Cantlon set out to discover whether
humans and nonhuman animals also share a capacity for nonverbal
arithmetic.


The researchers tested monkeys and college students on a nonverbal
arithmetic task in which they had to add the numerical values of two sets
of dots
together and choose a stimulus from two options that reflected the
arithmetic sum of the two sets.

The results indicate that monkeys perform
approximate mental addition in a manner that is remarkably similar to the
performance of the college students. These findings support the argument
that humans and nonhuman primates share a cognitive system for nonverbal
arithmetic, which likely reflects an evolutionary link in their cognitive
abilities.



Citation: Cantlon JF, Brannon EM (2007) Basic math in monkeys and college
students. PLoS Biol 5(12): e328. doi:10.1371/journal.pbio.0050328
Please click here


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Structural Biologists Reveal The Workings Of 'Mother Nature's Blowtorch'

Using atom-level imaging techniques, University of Michigan researchers have revealed important structural details of an enzyme system known as "Mother Nature's blowtorch" for its role in helping the body efficiently break down many drugs and toxins.



The research has been detailed in a series of papers, the most recent published online this month in the journal BBA Biomembranes.



The system involves two proteins that work cooperatively. The first, cytochrome P450, does the actual work, but only when it gets a boost from the second protein, cytochrome b5. To complicate matters, the two proteins can interact only when both are bound to a cell membrane. That makes it difficult to use traditional techniques to discern the structural details that are crucial to the interaction, said Ayyalusamy Ramamoorthy, who leads the research group.



For instance, X-ray crystallography, often used to determine protein structures, requires separating the molecules from their membrane environment. Because part of cytochrome b5 sticks to the membrane, such separations involve breaking the molecule at the sticking point, which happens to be the part that controls its interaction with cytochrome P450. So while crystallography can offer some information on structure, it can't provide insights into exactly what goes on between P450 and b5 during their cozy, membrane-bound encounters, Ramamoorthy said.



However, the technique his lab uses---solid state NMR spectroscopy---can produce detailed images of proteins in the membrane environment, not only revealing molecular structure but also showing how a particular protein nestles into the membrane. Cytochrome b5 presented a challenge even to that versatile method, though, because the molecule has three parts that all behave differently: the rigid, sticky portion that buries into the cell membrane, a highly mobile, water-soluble portion, and a less mobile "linker" that connects the other two parts.



But by tweaking their technique, the researchers were able to get high-resolution images of all three portions.



"The challenge was something like having a room full of people and trying to get good photos of every one of them," said Ramamoorthy, an associate professor of chemistry and Biophysics. "With one picture, you probably can't do it. But if you say, 'Everyone over age 50 stand up,' and you take one picture, and then you ask for another age group and take another picture, and so on, you have a better chance."



By spinning their samples (or aligning the molecules in the magnetic field), the researchers were able to differentiate parts of the molecule based not on age group, as in the photo analogy, but by mobility. "With the techniques we designed, we were able to observe the rigid portion separately from the highly mobile and less mobile portions," Ramamoorthy said.



In the first part of the work, published in the Journal of the American Chemical Society in May, the researchers described the membrane-spanning segment of cytochrome b5, revealing for the first time its helical shape and the way it tilts in relation to the membrane. In the new work published in BBA Biomembranes, they determined that once both molecules are bound in the membrane, cytochrome b5 modulates the motion and the structure of cytochrome P450. More work is in progress to determine the detailed high-resolution structures of these two proteins.



Ramamoorthy's team also is studying other membrane-associated proteins, a group that includes many biologically important molecules.



"These proteins are involved in all major diseases, everywhere in the body, and are therefore primary targets for pharmaceutical applications," Ramamoorthy said. "In my opinion, solving the structures of membrane proteins should be the highest priority for structural biologists in the coming years."







Ramamoorthy collaborated on the most recent work with Lucy Waskell, a professor of anesthesiology and a physician at the Department of Veterans Affairs Medical Center.



A leader in this area of research, Ramamoorthy has organized several major international symposia on the field at the University of Michigan, edited a special issue in the journal BBA-Biomembranes, published a number of papers in leading journals, and brought out a book on NMR Spectroscopy of Biological Solids. Ramamoorthy said that this area of research will grow considerably at U-M from implementing plans to set up a high magnetic field solid-state NMR spectrometer facility and an NIH-funded program.



For more information on Ramamoorthy, visit: ns.umich/htdocs/public/experts/ExpDisplay.php?ExpID=1170



Source: Nancy Ross-Flanigan


University of Michigan

Fellowship To Advance Type 1 Diabetes Research

Dr. Wenbo Zhi, a postdoctoral fellow in the Medical College of Georgia Center for Biotechnology and Genomic Medicine, has received a two-year fellowship to study biomarkers associated with type 1 diabetes.



The fellowship is sponsored by the Juvenile Diabetes Research Foundation.



Dr. Zhi, who works with Dr. Jin-Xiong She, center director, uses proteomic techniques that enable rapid, simultaneous evaluation of thousands of proteins in human serum. He hopes the technology will help him identify biomarkers to improve the diagnosis and treatment of type 1 diabetes, in which the immune system inexplicably attacks insulin-producing cells.



"My current goal is to confirm protein biomarkers using efficient proteomic technologies," Dr. Zhi says.



Dr. Zhi has identified 50 protein biomarkers by comparing proteins in the serum of type 1 diabetics with that of non-diabetics and that of people who produce the implicated autoantibody but haven't yet been diagnosed with the disease.



Samples were taken from participants in an international study screening newborns for genes that increase their risk of type 1 diabetes. Dr. She, principal investigator, and his colleagues use a drop of blood taken at birth to identify children at high risk, then follow them until age 20 or until they develop the disease in hopes of better understanding genetic and environmental risk factors.



Dr. Zhi will use two biomarker-confirming techniques: one identifies possible diabetes-related proteins and one identifies structural and chemical properties of molecules while separating and quantifying proteins.



"These results will help hasten the biomarker development for type 1 diabetes," Dr. Zhi says.







Dr. Zhi, who came to MCG in 2005 from China, is the president of MCG's Chinese Student and Scholar Association. He earned a doctoral degree in biochemical engineering from the Chinese Academy of Sciences Institute of Process Engineering and a bachelor's degree in biochemistry from Wuhan University.



Source: Amy Connell


Medical College of Georgia

The Function Of NOD2 In Colonic Epithelial Cells

NOD2 is a cytosolic pattern recognition receptor similar in structure and function to Toll like receptors (TLRs). It can recognize and respond to a component found in the cell wall of bacteria, muramyl dipeptide (MDP), and has been shown to play an important role in the innate immune response of macrophages to bacterial infections. However, the function of NOD2 in the gastrointestinal tract and the colon and its contribution of mutant NOD2 alleles to the pathogenesis of CD is still unclear.



A research article to be published in the World Journal of Gastroenterology refers. The research team led by Professor Simon Carding from the University of Leeds used in vivo and in vitro studies to analyse the specific function of NOD2 in colonic epithelial cells.



They found that NOD2 was predominantly expressed in epithelial cells at the base of colonic crypts, where the majority of cells are undergoing proliferation. In addition, NOD2's ligand, MDP, stimulated the growth of in vitro cultures of colonic epithelial cells. Further evidence for the role of NOD2 in cell growth and survival was obtained using NOD2-deficient mice and RNA interference. In the absence of NOD2 colonic epithelial cells proliferation was reduced and apoptosis increased, which were exacerbated when challenged with the enteric pathogen, Salmonella typhimurium. Surprisingly the ability of NOD2 to promote cell growth and survival was also apparent in the colorectal cancer cells as the introduction of siRNAs specific for NOD2 resulted in an 80% decrease in survival compared to cells treated with control NOD2 siRNA.



These results highlight for the first time the importance of NOD2 in the regulation of epithelial cell growth and survival and consequently the integrity of the intestinal epithelial cell barrier, that is required for protection against pathogenic and opportunistic bacterial infections. further investigation is needed to assess if these receptors work alongside each other in the regulation of epithelial cell homeostasis.







Reference: Cruickshank SM, Wakenshaw L, Cardone J, Howdle PD, Murray PJ, Carding SR. Evidence for the involvement of NOD2 in regulating colonic epithelial cell growth and survival. World J Gastroenterol 2008; 14(38): 5834-5841 wjgnet/1007-9327/14/5834.asp



Correspondence to: Simon R Carding, Professor, The Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, United Kingdom.



About World Journal of Gastroenterology



World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2003-2000 IF: 3.318, 2.532, 1.445 and 0.993. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.



About The WJG Press



The WJG Press mainly publishes World Journal of Gastroenterology.



Source: Lai-Fu Li


World Journal of Gastroenterology

'Nanocantilevers' Yield Surprises Critical For Designing New Detectors

Researchers at Purdue University have made a discovery about the behavior of tiny structures called nanocantilevers that could be crucial in designing a new class of ultra-small sensors for detecting viruses, bacteria and other pathogens.


The nanocantilevers, which resemble tiny diving boards made of silicon, could be used in future detectors because they vibrate at different frequencies when contaminants stick to them, revealing the presence of dangerous substances. Because of the nanocantilever's minute size, it is more sensitive than larger devices, promising the development of advanced sensors that detect minute quantities of a contaminant to provide an early warning that a dangerous pathogen is present.


The researchers were surprised to learn that the cantilevers, coated with antibodies to detect certain viruses, attract different densities - or quantity of antibodies per area - depending on the size of the cantilever. The devices are immersed into a liquid containing the antibodies to allow the proteins to stick to the cantilever surface.


"But instead of simply attracting more antibodies because they are longer, the longer cantilevers also contained a greater density of antibodies, which was very unexpected," said Rashid Bashir, a researcher at the Birck Nanotechnology Center and a professor of electrical and computer engineering and biomedical engineering at Purdue University. The research also shows that the density is greater toward the free end of the cantilevers.


The engineers found that the cantilevers vibrate faster after the antibody attachment if the devices have about the same nanometer-range thickness as the protein layer. Moreover, the longer the protein-coated nanocantilever, the faster the vibration, which could only be explained if the density of antibodies were to increase with increasing lengths, Bashir said. The research group also proved this hypothesis using optical measurements and then worked with Ashraf Alam, a researcher at the Birck Nanotechnology Center and professor of electrical and computer engineering, to develop a mathematical model that describes the behavior.


The information will be essential to properly design future "nanomechanical" sensors that use cantilevers, Bashir said.


Findings are detailed in a research paper appearing online today (Monday, Aug. 28) in Proceedings of the National Academy of Sciences. The paper was authored by Amit K. Gupta, a former Purdue doctoral student working with Bashir and now a postdoctoral researcher at Harvard University; Pradeep R. Nair, a doctoral student in electrical and computer engineering; Demir Akin, research assistant professor of biomedical engineering; Michael Ladisch, Distinguished Professor of Agricultural and Biological Engineering with a joint appointment in the Weldon School of Biomedical Engineering; Steven Broyles, a professor of biochemistry; Alam and Bashir.


The work, funded by the National Institutes of Health, is aimed at developing advanced sensors capable of detecting minute quantities of viruses, bacteria and other contaminants in air and fluids by coating the cantilevers with proteins, including antibodies that attract the contaminants. Such sensors will have applications in areas including environmental-health monitoring in hospitals and homeland security. So-called "lab-on-a-chip" technologies could make it possible to replace bulky lab equipment with miniature sensors, saving time, energy and materials. Thousands of the cantilevers can be fabricated on a 1-square-centimeter chip, Bashir said.















The cantilevers studied in the recent work range in length from a few microns to tens of microns, or millionths of a meter, and are about 20 nanometers thick, which is also roughly the thickness of the antibody coating. A nanometer is a billionth of a meter, or approximately the length of 10 hydrogen atoms strung together.


A cantilever naturally "resonates," or vibrates at a specific frequency, depending on its mass and mechanical properties. The mass changes when contaminants land on the devices, causing them to vibrate at a different "resonant frequency, " which can be quickly detected. Because certain proteins attract only specific contaminants, the change in vibration frequency means a particular contaminant is present.


Ordinarily, when using cantilevers that are on a thickness scale of microns or larger, attaching mass causes the resonant frequency to decrease, which is the opposite of what occurs with the nanoscale-thickness cantilevers. Researchers believe the unexpected behavior is a result of the antibodies being about the same thickness as the ultra-thin nanocantilevers, meaning their vibration is more profoundly affected than a more massive cantilever would be by the attachment of the antibodies.


"The conclusion is that when the attached mass is as thick as the cantilever, then you not only affect the mass but you also affect a key property called the net stiffness constant and the resonant frequency can actually go up," Bashir said.


Gupta measured the cantilever's vibration frequency using an instrument called a laser Doppler vibrometer, which detects changes in the cantilever's velocity as it vibrates. The researchers then treated the antibodies with a fluorescent dye and took images of the proteins on the cantilever's surface, proving that the density increases with longer cantilevers.


Nair and Alam then developed a mathematical model to explain why the density increases as the area of the cantilever rises. The model uses a "diffusion reaction equation" to simulate the antibodies sticking to the cantilever's surface.



The research is based at the Birck Nanotechnology Center at Discovery Park, the university's hub for interdisciplinary research.


Related Web site


Purdue Laboratory of Integrated Bio Medical Micro/Nanotechnology & Applications:

https://engineering.purdue/LIBNA

New Data Demonstrating Radioprotection By Ex-RAD At RRS Annual Meeting

Onconova Therapeutics, Inc. is presenting new data in five posters and an oral presentation this week summarizing several studies with the company's radioprotectant Ex-RAD® at the 56th Annual Meeting of the Radiation Research Society (RRS), September 25-29 in Maui, Hawaii. In vivo studies show that Ex-RAD®, upon oral administration, produced a significant increase in survival versus placebo-treated groups in mice exposed to lethal whole body irradiation (WBI), for both prophylactic pre-treatment and mitigation post-treatment. Ex-RAD® is the only known oral radioprotectant that has shown such activity in animal model systems.



Collectively, these presentations demonstrate the ability of Ex-RAD® to provide radioprotective benefit by injection and oral delivery, an in-depth understanding of the kinetics and metabolism of Ex-RAD®, and radioprotective benefit to human bone marrow, as well as the gastrointestinal and hematopoietic systems in mice.



Onconova, a biopharmaceutical company developing novel chemical entities to treat cancer and protect normal cells, is developing Ex-RAD®, a novel radioprotectant with potential utility in bio-defense or bio-terrorism, which could prove useful as a prophylactic agent for first-responder protection from the harmful effects of radiation from nuclear accidents or weapons of mass destruction (WMD).



These presentations result from an on-going Onconova collaboration among investigators at a number of institutions: AFRRI, (The Armed Forces Radiobiology Research Institute) a part of the Uniformed Services University of the Health Sciences (USUHS); Georgetown University, Department of Biochemistry and Molecular & Cellular Biology; Long Island University, Arnold & Marie Schwartz College of Pharmacy; and the Department of Oncological Sciences, Mt. Sinai School of Medicine.



Summary of Oral Ex-RAD® Findings



The results from a prophylactic radioprotection study in mice demonstrated that Ex-RAD® dosed orally or by injection prior to lethal whole body irradiation (WBI) produced significant enhancement in survival for both Ex-RAD® treated groups versus placebo.



Results from the radiomitigation experiment (where the drug is administered after exposure to lethal radiation), using both injection and oral methods of delivery demonstrated that Ex-RAD® treated animals had comparably high rates of survival in both groups.



Hence, oral Ex-RAD® was found to be effective in both prophylactic pre-treatment and mitigation post-treatment settings.



"Years of collaborative work are resulting in great progress with Ex-RAD® in the laboratory and the clinic and Ex-RAD® is the focus of several posters and a key presentation within the RSS scientific and educational track," said Manoj Maniar, PhD, Senior Vice President for Product Development of Onconova. "We are very excited to see the acceleration and new developments within radioprotection, specifically in oral prophylaxis and treatment. Ex-RAD® holds a unique position among developing products with the potential to benefit people exposed to whole body radiation."
















Onconova oral presentation and poster sessions on Ex-RAD® at the Radiation Research Society meeting:



Oral Presentation



WEDNESDAY, SEPTEMBER 29, 2010
No. MS701 (Mini-Symposium Presentation, 10:15 AM-12:15 PM) - Radioprotection and Radiomitigation Properties of Ex-RAD® Upon Oral Administration Manoj Maniar1, Ramesh Kumar1, Bo-Hyun Moon2, David Taft3, Kamal Datta2; 1Onconova Therapeutics, Inc., 2Georgetown University, Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, 3Long Island University, Arnold & Marie Schwartz College of Pharmacy

Poster Sessions - Radiation Protection - Protection / Mitigators / Treatment



SUNDAY, SEPTEMBER 26, 2:00 pm-2:45 pm, 2010, Haleakala Foyer
PS.1.56 - Radioprotection and Radiomitigation Properties of Ex-RAD® Upon Oral Administration Manoj Maniar1, Ramesh Kumar1, Bo-Hyun Moon2, David Taft3, Kamal Datta2; 1Onconova Therapeutics, Inc., 2Georgetown University, Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, 3Long Island University, Arnold & Marie Schwartz College of Pharmacy
PS1.10 - Recovery from radiation-induced hematopoietic and gastrointestinal sub-syndromes by Ex-RAD™ in murine model, Sanchita P. Ghosh1, Shilpa Kulkarni1, Michael W. Perkins1, Kevin Hieber1, Ethery Amari1, Kristen Gambles1, Manoj M. Maniar2, Thomas Seed1, and K. Sree Kumar1; 1Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 2Onconova Therapeutics Inc.
PS1.73 - Radioprotection of human bone marrow by ON 01210.Na (Ex-RAD ®) through AKT-mediated signaling pathway Anthony D. Kang1,2, Stephen C.Cosenza1,3, Ramana Reddy1,3, E. Premkumar Reddy1,3 1Fels Institute for Cancer Research and Molecular Biologyand 2Armed Forces Radiobiology Research Institute, 3Department of Oncological Sciences, Mt. Sinai School of Medicine

Poster Sessions - Experimental Therapeutics and Translational Research
WEDNESDAY, SEPTEMBER 29, 5:30 PM-6:15 PM, 2010 Haleakala Foyer
PS7.64 - Disposition of Ex-RAD® (ON 01210.Na), a new radioprotectant, in the isolated perfused rat liver model; Chen Ren1, Mitalee Tamhane2, David Taft2, Manoj Maniar1, 1Onconova Therapeutics, Inc., 2Long Island University
PS7.20 - Metabolic disposition of Ex-RAD® (ON 01210.Na), a novel radioprotectant Chen Ren1, Mitalee Tamhane2, Glenn Fegley1, David Taft2, Manoj Maniar1; 1Onconova Therapeutics, Inc., 2Long Island University, Brooklyn, NY


About Ex-RAD®



Ex-RAD® is a novel radiation protection drug developed in collaboration with the U.S. Department of Defense to protect against (when given pre-exposure) and provide treatment for (when given post-exposure) lethal radiation in models of tissue and whole body radiation injury. Unlike most radiation protectors, Ex-RAD® is not a free-radical scavenger, chelator or cell cycle arrestor - instead, Ex-RAD® accesses a novel mechanism for radiation protection involving intracellular signaling, damage sensing, and DNA repair pathways. Ex-RAD-treated cells sustain less DNA damage upon exposure to irradiation.



Two Phase I safety trials of Ex-RAD® have been completed in healthy human volunteers. The development of Ex-RAD® is advancing according to the FDA Animal Rule, under which approval is based upon establishing safety in human volunteers coupled with demonstration of efficacy in well-characterized animal models.



Source:

Katrhyn Morris


PR on Call

A New Control Mechanism For Genetic Code Translation Discovered In Bacteria

Almost all organisms, from bacteria to human beings, share the same genetic code, a group of universal instructions used to convert DNA or RNA sequences into proteins, the "building blocks" of life. Identification of the evolutionary differences between the system for the translation of the genetic code in humans and other organisms, such as bacteria in this case, are useful, for example, for the design of new antibiotics. Researchers at the Institute for Research in Biomedicine (IRB Barcelona) have discovered that an essential molecular process, namely the determination of the start of protein synthesis, until now considered to be the same for all living organisms, differs in the bacteria Mycoplasma penetrans, a human pathogen that affects the respiratory tract. M. penetrans affects immuno-depressed patients, such as those infected by the HIV virus and some cancer patients. The results of this study have been published in the latest issue of Molecular Cell.



The leader of the study, LluГ­s Ribas de Pouplana, researcher at IRB Barcelona and head of the Gene Translation Laboratory, explains, "our work strengthens the theory that many of the components of the initial genetic code, established 3,500 million years ago, have matured separately between distinct branches of evolution: bacteria, archaea and eukaryotes". The origin of the genetic code is one of the issues in evolution biology in which most questions remain unanswered. "The translation machinery is so complex, so universal and so essential that it is difficult to imagine how it arose and how it has evolved. Thanks to these discoveries, we can observe that the genetic code and the protein translation system are not as universal as once thought and that some of the key components of the translation system appeared much later", concludes Ribas.



In fact, what these researchers have discovered is a difference in the mechanism used by bacteria to differentiate between methionine and isoluecine, two essential amino acids for protein formation. Specifically, methionine is the amino acid used universally to initiate protein formation.



An excessively large enzyme: a false clue for the discovery



As commonly occurs in science, the discovery of this new mechanism was by chance. The researchers were studying an enzyme called methionine-tRNA-synthetase (MetRS), which is found in all living organisms, but in the Mycoplasma bacteria it has an extension that makes it much larger. "We were studying this enzyme in order to elucidate the function of this extension", explains Ribas. The function of MetRS in all organisms is to take methionine and attach it to the RNA transcript of methionine in order to tell the cell when it must initiate the formation of a certain protein. This task is complicated because the RNA transcript of isoleucine is practically identical. "We then saw that the Mycoplasma enzyme distinguished between the RNA transcript of methionine and the transcript of isoleucine in a more simple and proficient manner that that observed to date in other organisms".



The most logical deduction was that the extension on this enzyme was a crucial part of this distinct recognition system. However, when the researchers removed this extension in the laboratory, the choice between the two RNA transcipt continued to operate flawlessly. "We still do now know the function of this extension of the enzyme in Mycoplasma, but in the meantime we have discovered a new mechanism of control in the translation system, which in addition, we have observed is shared by other bacteria". This discovery contributes to an improved understanding of the evolution of the genetic code and also demonstrates its plasticity. "In my opinion a certain degree of complexity shown by the genetic code is one of the main parameters that determines the point at which organisms begin to evolve", explains the researcher. The fundamental differences between the metabolism of human pathogens and the human being may represent the key for the development of new therapies to treat infection.







This release is available in Spanish.



Source: Sonia Armengou


Institute for Research in Biomedicine (IRB Barcelona)

Enzyme Modification Brings 'Corrective Genes' Closer

Scientists from the UniversitГ© de MontrГ©al and McGill University have re-engineered a human enzyme, a protein that accelerates chemical reactions within the human body, to become highly resistant to harmful agents such as chemotherapy, according to a new study published in The Journal of Biological Chemistry.



"Our team modified and decoded an enzyme structure," says Joelle Pelletier, a professor at the UniversitГ© de MontrГ©al's Department of Chemistry. "We discovered, to our surprise, that our intervention allowed the heart of the enzyme to increase its mobility. This unusual mobility caused the enzyme to resist the chemotherapy agent methotrexate - a result we never predicted and one that offers promise."



The research team made its discovery as it sought ways to help correct genetic diseases. "Our goal is to improve the injection of corrective genes in people suffering from genetic diseases," say Pelletier who is also co-director of PROTEO, a Quebec-based research group on the function, structure and engineering of proteins. "This discovery will lead to promising new avenues."



"We were intrigued to find the enzyme's internal flexibility was impacted by our modifications and that this fact played such a crucial role for resistance," says Albert Berghuis, a professor at the McGill University Department of Biochemistry and Canada Research Chair in Structural Biology. "We can now harness this insight to further advance therapies for genetic diseases such as leukemia."



Partners in research:


This study was funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.



About the study:


The paper, "Multiple Conformers in Active Site of Human Dihydrofolate Reductase F31R/Q35E Double Mutant Suggest Structural Basis for Methotrexate Resistance," published in The Journal of Biological Chemistry, was authored by Jordan P. Volpato, Elena Fossati Jonathan Blanchet, Lucie Poulin, Vanessa Guerrero and Joelle N. Pelletier of the UniversitГ© de MontrГ©al; Brahm J. Yachnin and Albert M. Berghuis of McGill University.



Source:
Sophie Langlois


University of Montreal

New Report: America's Scientific And Medical Progress Threatened By Flat Funding For NIH

Years of stagnant budgets outpaced by inflation threaten the progress of biomedical research and could thwart advances in treatments that are within reach, nine of the nation's most preeminent scientific and medical institutions told Congress. In a new report on the status of U.S. medical research and its funding, the group explained how perennially flat funding of the National Institutes of Health (NIH) has halted promising research in mid-stream, challenged seasoned researchers to continue to achieve scientific progress, and threatened the future of young investigators pursuing careers in academic research. And, if left unaddressed, these problems could undermine U.S. global leadership in biomedical research, the report warns.



"When scientists have to spend most of their time trying to get funded, caution wins out over cutting-edge ideas, creativity sacrifices to convention, and scientific progress gives way to meetings and grant applications," said report contributor and infectious disease expert Robert Siliciano, M.D., Ph.D., at The Johns Hopkins University School of Medicine. "Right now, very, very productive scientists are doing too little research. Instead, they are spending their time trying to get their labs funded again," he said.



The report was co-authored by The University of California, Columbia University, Harvard University, The Johns Hopkins University, Partners HealthCare, The University of Texas at Austin, Washington University in St. Louis, The University of Wisconsin Madison, and Yale University.



The group says that to fulfill the promise of previous investments by Congress the country needs to provide more consistent and robust funding of NIH. According to the report, Within Our Grasp - Or Slipping Away? Assuring a New Era of Scientific and Medical Progress, the doubling of NIH's budget between 1998 and 2003 enabled advances in basic research that transformed understanding of diseases affecting millions of Americans. But the NIH budget has been virtually frozen since 2003 and has shrunk by at least 8 percent after inflation is considered, with recent estimates up to 13 percent. Most recently, a small increase approved by Congress in the 2007 budget would be virtually wiped out by the Bush Administration's proposed 2008 budget, continuing the downward spiral in inflation-adjusted dollars. The implications are far-reaching for science, medicine, the economy and U.S. leadership in biomedical science, they add.



The 21-page report says that the country reaped a strong pay-off from previous years of robust funding of basic biomedical research, achieving progress in treating and preventing many devastating diseases and conditions. But the American public will ultimately pay the price for slowing the pace of research as scientists downsize their laboratories and abandon some of their most innovative work.



The report argues that research momentum gains have slowed, and in some cases may be lost, if flat funding continues. For example, in the fight against cancer, "The number of drugs moving into the pipeline that are based on our new, more profound genetic and molecular understanding of cancer is extraordinary - and there's no money to handle the testing of these compounds," said Joan Brugge, Ph.D., who chairs the Department of Cell Biology at Harvard Medical School.
















A similar situation faces the quest to cure spinal cord and brain injuries. "Ten years ago, the search for treatment of spinal cord injury was a daunting and hopeless task," said Stephen Strittmatter, M.D., Ph.D., a professor of neurology and neurobiology at Yale University's School of Medicine. Today that is changing, in part due to the discovery of NOGO, a molecule that prevents regeneration of spinal cord nerves. Scientists are investigating whether the molecule can be inhibited, allowing the spinal cord and neurons in the brain to repair themselves.



"The neurological sciences are on the launching pad of a revolution," according to Strittmatter. "We are at a juncture where we can begin identifying multiple molecular targets for the neurological diseases that have stymied us for so long. Without funding, they may go undiscovered, and we will have only weakly effective therapies."



The Threat to Future Scientific Endeavor



Despite the great push forward that accompanied the doubling of the NIH budget, subsequent flat funding has put many projects at risk. Today, eight of ten research grant applications are unfunded, according to the report. Those that are funded often require multiple submissions and suffer lapses in funding. Certain NIH institutes, such as the National Cancer Institute, report that they can only fund 11 percent of research project grant applications, rejecting many of exceptional quality.



The effects are being felt by both principal investigators and young researchers new to the field. For young researchers, the decreased funding contributes to another problem: a multi-year wait for receiving their first grant. In 1970, the average age recipient of a first grant was 34.2 years; today it is 41.7.



"Our product is not just our technology or medical breakthroughs," said Dr. Brent Iverson, Ph.D., The University of Texas at Austin. "Our College of Natural Sciences alone puts 1,000 undergrads in research situations in labs, most with NIH funding. That is a catalyst for creating innovative new scientists," he added.



Consequently, senior scientists fear that young people will turn away from science because the funding situation is so bleak. Scientists report that many of the brightest young minds no longer see the promise of a career in science, choosing law, business, and other professions. Losing young scientists today will cost the U.S. a lot later, the report warns. "That will have a generational impact that will take 15 years to fix," said Richard Davidson, Ph.D., University of Wisconsin-Madison.



In addition, scientists are increasingly having to abandon some of their most innovative and promising research in favor of more conventional projects with more predictable results that are more likely to be funded. Principal investigators also must spend enormous amounts of time fundraising and writing grants rather than conducting research.



Others are following research dollars overseas, to countries in Europe and Asia that are making investment in biomedical sciences high national priorities and actively recruiting star U.S. scientists, according to scientists interviewed for the report.



Said Nobel Laureate Eric Kandel at Columbia University Medical Center, who contributed to the report: "The scientific community is one of the driving forces of the economy. In biology, it helps drive the pharmaceutical industry, and helps people live longer in a productive way. Now, the rug has been pulled from under science in this country. We'll lose scientific manpower to European countries, and to India, China and Japan."



The funding problem is so great that the NIH's 2007 "Fiscal Policy for Grant Awards," urges decisionmakers to consider "the goal of not losing outstanding laboratories," as they allocate limited funds, says the report.



The group says that addressing the funding crisis now is imperative given the demographics of the population. "Medical treatments take decades to develop," says Harvard's Dr. Brugge. "If we wait until the baby boomers retire to find the most effective means for prevention and treatment for diseases like Alzheimer's and cancer, we will break the bank."







Within Our Grasp - Or Slipping Away? Assuring a New Era of Scientific and Medical Progress



The press conference is being live Web cast.



Contact: Janet Firshein


Burness Communications

African Scientists To Train In Latest Drug Discovery Techniques At Emory University

African scientists will soon begin training at Emory University as part of a unique partnership between Emory and the Republic of South Africa. The South Africa Drug Discovery Training Program will address the rising dangers of diseases that unduly affect developing countries. By training African scientists in drug discovery, the partnership is designed to give South Africans not only a voice but also a choice in how best to combat their disease epidemics.



"As part of this collaboration, the scientists will work with academic researchers in departments and schools throughout the Emory campus, including chemistry, pharmacology and other basic biomedical science departments," says Dennis Liotta, PhD, professor of chemistry. "The scientists will gain hands-on experience in translating research into healthcare solutions and will then return to their home countries to receive post-training placement in industrial or academic positions."



The visiting scholars will initially come from South Africa, but scientists from all over sub-Saharan Africa will soon take part in the training.



"To effectively battle the neglected infectious and immunologic diseases of poverty, the transfer of money and technology is not enough--it is expertise in the discovery and development of new medicines that is the intrinsic requirement," Dr. Liotta says. He and his colleagues have produced several new drugs, including crucial anti-HIV drugs used in the majority of AIDS cocktails today.



"By helping to shift early stage drug discovery to South Africa, this initiative will foster a viable research infrastructure that is capable of responding to global healthcare needs. The fact that several small pharmaceutical companies are beginning to spring up in Africa makes this an ideal time to develop a drug discovery training program," says Dr. Liotta.



Dr. Liotta and his colleagues recently formed iThemba, a start-up biotech company based in South Africa. By developing scientific, economic and educational alliances with Africa's scientists, industry and universities, iThemba will focus on developing affordable drugs to fight the diseases of poverty.



"We believe that we can develop affordable, effective drugs using a combination of relatively low operating costs and socially conscious investments. This is crucial because, for the most part, there is little incentive for pharmaceutical companies to invest in new medicines to treat diseases that have relatively small markets," Dr. Liotta says.



According to Dr. Liotta, HIV, tuberculosis (TB) and malaria are among the diseases most affecting Africa's impoverished populations.



"One of the issues with TB, for example, is that we know how to control the disease," says Liotta. "We have drugs that are 50 plus years old, and they work, but the problem is that patients have to take them for six to nine months. With such a prolonged dosing period, it is very difficult for people to remain compliant."



Dr. Liotta and his collaborators are hoping to develop anti-tuberculosis drugs that will require only two-week regimens.







Support for the South Africa Drug Discovery Training Program will come from the South African government and the Emory Global Health Institute, which was established to support Emory faculty, students and alumni in their work to find solutions to critical global health problems.



Contact: Holly Korschun


Emory University

Similarities Between Sleep-Deprived Humans And Insomniac Flies

Researchers at Washington University School of Medicine in St. Louis have created a line of fruit flies that may someday help shed light on the mechanisms that cause insomnia in humans. The flies, which only get a small fraction of the sleep of normal flies, resemble insomniac humans in several ways.



"Insomnia is a common and debilitating disorder that results in substantial impairments in a person's quality of life, reduces productivity and increases the risk for psychiatric illness," says senior author Paul Shaw, Ph.D. "We think this model has clear potential to help us learn more about the causes of insomnia and someday develop ways to test for or treat them in the clinic."



The findings are published June 3 in The Journal of Neuroscience.



One of Shaw's co-authors, Stephen Duntley, M.D., directs the Washington University Sleep Medicine Center.



"Insomnia is frustrating for clinicians for several reasons, including its high prevalence, uncertainties about how to define and categorize it, and how little we know about the pathophysiological mechanisms that can contribute to it," Duntley says. "The wonderful thing about this new model is that it lets us begin to sort out some of the many potential mechanisms, genetic and otherwise, that may underlie insomnia, hopefully leading to new interventions."



Shaw's lab was the first to show that fruit flies enter a state of inactivity comparable to sleep. The researchers demonstrated that the flies have periods of inactivity where greater stimulation is required to rouse them. Like humans, flies deprived of sleep one day will try to make up for it by sleeping more the next day, a phenomenon referred to as increased sleep drive or sleep debt.



As he studied the healthy flies, Shaw noticed that a few flies naturally slept less than others. He decided to take flies with insomnia-like characteristics and breed them to amplify those qualities. The flies he bred had difficulty falling asleep in normal circumstances, and their sleep was often interrupted or fragmented. He also used hyper-responsiveness to stimuli as a breeding guide. For example, if researchers turned on a light at night, insomniac flies woke and stayed up the rest of the night, while the healthy flies went back to sleep. The flies that stayed up were added to the breeding pool.



After generations of selective breeding, Shaw's group had produced a line of flies that naturally spent only an hour a day asleep - less than 10 percent of the 12 hours of sleep normal flies get. They quickly noticed an obvious and surprising behavioral change: even though flies have six legs, the insomniac flies fell over more often.



"We sent them to experts in neurodegeneration in flies to see if their lack of sleep or the breeding had somehow damaged their brains," Shaw says. "But the experts said there weren't any physical brain abnormalities."
















Shaw briefly entertained the possibility that the flies might be sleepwalking but realized that declines in balance have also been reported in sleep-deprived humans. In addition, other indicators suggested the flies weren't getting enough sleep. His lab previously isolated a biomarker for sleepiness that is present in flies and human saliva, and the insomniac flies had high levels of it. The flies also were slower learners and gained more fat, two indicators for fly sleep deprivation that Shaw identified earlier. Similar symptoms also occur in sleep-deprived humans.



Lead author Laurent Seugnet, Ph.D., says that while the insomniac flies "clearly suffer consequences" from their lack of sleep, they also show some resistance to the adverse effects of sleep deprivation. For example, while 70 hours of sleep deprivation will kill a normal fly, the insomniac flies can spontaneously go up to 240 hours without sleep and still survive.



"Overall, the flies are able to perform better than they should, given how much sleep they miss," says Seugnet. "That makes it tempting to speculate that insomnia is like drug addiction. As it increases the body's overall vulnerability and risk of collapse, it also seems to boost certain factors that help resist collapse."



When researchers screened the genome of the insomniac flies for changes in gene activity levels, they found altered activity levels for genes involved in metabolism, nerve cell activity and sensory perception. Shaw's lab had previously demonstrated that the activity levels of at least two of these genes are changed in sleep-deprived humans.



Researchers speculate that some genes altered by insomnia and sleep deprivation may simultaneously contribute to both detrimental and temporarily advantageous effects. Shaw has conducted follow-up studies of the altered genes and how restoring normal genetic activity levels affects insomnia and its symptoms. He will publish the results in a forthcoming paper.



Seugnet L, Suzuki Y, Thimgan M, Donlea J, Gimbel SI, Gottschalk L, Duntley SP, Shaw PJ. Identifying sleep regulatory genes using a Drosophila model of insomnia. The Journal of Neuroscience, June 3, 2009.



Source:
Michael C. Purdy


Washington University School of Medicine

Oncogene Overexpression Is Associated With Aggressive Glioma

Researchers have determined that the cell cycle-related kinase gene (CCRK) may be involved in the development of glioblastoma multiforme, the most aggressive form of a type of brain tumor called glioma.



The median survival for patients with glioblastoma multiforme is 12 to 15 months. Researchers hope that identifying the genes that control the progression of the disease will help them develop new therapies.



Samuel Ng, Ph.D., of the University of Hong Kong and colleagues analyzed the gene expression of CCRK in human glioma cell lines, in samples from glioma patients and normal brain tissue, and in mouse models.



They found that the overexpression of the CCRK gene was associated with a greater risk of developing glioma and increased tumor growth, whereas suppression of the gene was associated with the inhibition of tumor growth.



"Our results support the rationale for developing CCRK as a potential therapeutic and diagnostic target for glioblastoma multiforme, and, possibly, other cancers," the authors write.





Contact: Marie Lin, University of Hong Kong



Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Visit the Journal online at jnci.oxfordjournals/



Contact: Liz Savage


Journal of the National Cancer Institute

Leap Forward In Structural Biology Will Revolutionise Drug Making

A new method for determining the detailed architecture of key drug targets that relay vital messages into our cells could revolutionise the way we make and test drugs.


For decades it has been difficult to obtain information about the structure of proteins on the surface of cells that many drugs are designed to latch on to. However, a new approach, developed by scientists at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, can reveal the precise structures of recombinant G protein-coupled receptors (GPCRs), proteins that cross the cell membrane and are important targets for drug development. This novel method will allow scientists developing drugs to compare the structure of highly similar drug receptor proteins, called receptor subtypes, and produce more selective drugs. It is thought the findings, published in Nature, could also apply to many other key proteins associated with cell membranes, which mediate other important physiological processes.


Dr Gebhard Schertler who led the research on G protein-coupled receptors at the Laboratory of Molecular Biology said: "We have been looking at these drug target proteins for a long time trying to find a way to capture their shape. It's a bit like trying to find a way to take a non-blurry picture of a child at play. By using a new approach called conformational stabilisation we were able to trap the receptor in a form bound to a beta blocker. We then stabilised the receptor proteins enough to obtain crystals. Using very small X-ray beams we obtained an image of the Гџ1 adrenergic receptor. The level of precision that we reached will allow the creation of drugs which will be able to bind more specifically. This means medicines with fewer side-effects."


The specific structure reported in this Nature paper is that of the adrenalin stress hormone receptor (Гџ1 adrenergic receptor) which regulates heart rate and blood pressure. This receptor is targeted by drugs commonly referred to as beta-blockers, which are used in the treatment of hypertension and heart palpitations. The team at the MRC was able to compare the structure of Гџ1 with Гџ2 adrenergic receptor. The Гџ2 adrenergic receptor is the target for drugs in inhalers used to contain asthma attacks; these Гџ adrenergic receptor activators dilate the bronchial muscles in the lung and airways by acting on the Гџ2 adrenergic receptor.


Dr Schertler explains how these comparisons will be useful: "The Гџ1 and Гџ2 adrenergic receptor targets belong to the same receptor class and have very similar structures. Until now, drugs that affected one receptor also affected the other to some degree. So using an inhaler, which is intended to stimulate Гџ2 receptors to contain asthma attacks, also stimulates the Гџ1 adrenergic receptors and causes the heart to beat faster. Better targeting of new drugs using these new structural insights should allow us to avoid such side effects in the future."















Structure of the stress hormone receptor Гџ1 with a beta blocker bound to it


Dr Gebhard Schertler added: "The quality of the structural data we have been able to produce using this new approach is excellent and we feel the method is so robust there is no reason to think we would not be able to produce similar results with hundreds of other receptors. This will not only allow us to devise drugs that are much more selective for a single receptor, it could potentially turn the drug discovery process on its head, starting with the G protein-coupled receptor you wish to affect, and devising a drug to bind to it. This is important because there are still a significant number of human receptors where we do not know of a existing substance able to bind to them."


These latest findings are the culmination of decades of work by Richard Henderson, Chris Tate, Gebhard Schertler and other researchers at the Medical Research Council. Their steady progress led to the creation of a biotechnological spin out company Heptares Therapeutics, a new drug discovery company that was formed in 2007. The aim of the company is to support the translation of the successful long-term basic research results by providing it with the right infrastructure and fostering application. This means bringing together first-class investors and management while keeping the founding scientists at the core of the company's future
MRC/28/08


Background


- Structure of a b1-adrenergic G-protein-coupled receptor
Warne et al (2008)
Nature Online doi:10.1038/nature07101


- The more than 800 GPCRs in man belong to the largest family of membrane proteins in the human genome. Their function is to sense molecules outside the cell, hence 'receptors', and trigger cellular reactions. GPCRs are essential for the body to complete a wide range of physiological responses. They allow us to process light and smells, regulate our behaviour, mood and immune response. They are essential in autonomic nervous system transmission. They also control blood pressure, heart rate and digestive processes. This means GPCRs play a crucial role in many diseases and are targets of around a quarter of all modern drugs and GPCRS are a major focus for pharmaceutical companies. For more information, visit the Schertler Group page : www2.mrc-lmb.cam.ac.uk/SS/Schertler_G/


For more information about Heptares, please visit heptares

Medical Research Council

Designing A Cancer-Killing Virus

One new way to treat individuals with cancer that is being developed is the use of viruses that infect and kill cancer cells while leaving normal cells unharmed. These viruses are known as virotherapeutics. In a new study, David Kirn and colleagues at Jennerex Biotherapeutics, San Francisco, have described the development of a new virotherapuetic with antitumor effects in both mice and rabbits.



After selecting a highly potent strain of poxvirus that was able to traffic to tumors when administered intravenously to mice the authors engineered the virus such that it would target only specific cancer cells -- those with increased expression of a protein known as E2F and/or activation of signaling downstream of a protein known as EGFR. Further engineering to enable the virus to produce the soluble factor GM-CSF was designed to enhance the induction of anti-tumor immune responses. In addition to its antitumor effects in mice and rabbits, the virotherapeutic showed high selectivity for cancer cells in tumor-bearing rabbits and in human tissue samples, leading the authors to suggest that this virotherapeutic should be tested in clinical trials for the treatment of cancer.







TITLE: Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963



Author Contact:

David H. Kirn

Jennerex Biotherapeutics, San Francisco, California, USA.



Source: Karen Honey


Journal of Clinical Investigation