In Liver Cirrhosis Melatonin May Be Served As A Potential Anti-Fibrotic Drug

In China, the incidence of liver cirrhosis is still high. Liver cirrhosis results from fibrosis. If treated properly at fibrosis stage, cirrhosis can be prevented. However, no effective antifibrosis drugs are available at present. Several lines of evidences suggest that oxidative stress plays an important role in the etiopathogenesis of hepatic fibrosis. Melatonin can protect cells, tissues, and organs against oxidative damage induced by a variety of free-radical-generating agents and processes.



A research team led by Professor Jian-Ming Xu from the First Affiliated Hospital of Anhui Medical University, China evaluated the possible fibrosuppressant effect of melatonin in rat. Their study was published on March 28, 2009 in the World Journal of Gastroenterology.



In this study, hepatic fibrosis in rats was successfully induced by subcutaneous injection of sterile CCl4 twice weekly for a total of 12 wk. At the beginning of injection of CCl4, melatonin (2.5, 5, 10 mg/kg body weight) was intraperitoneally administered to the rats daily for 12 wk. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. The serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) were used to evaluate the hepatic injury. Hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA) and glutathione peroxidase (GPx) in liver homogenates. Serum hyaluronic acid (HA), laminin (LN), and procollagen 3 N-terminal peptide (P3NP) were determined as serum markers of hepatic fibrogenesis.



Their results suggested that treatment with melatonin (10 mg/kg) could decrease the scores of hepatic fibrosis grading, reduced the contents of HA, LN in serum and Hydroxyproline (HYP) in liver, treatment with melatonin (5,10 mg/kg ) could decrease serum levels of ALT, AST and blocked the increase in MDA in rats with hepatic injury caused by CCl4.



Their result indicated melatonin could ameliorate CCl4-induced hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be related to its antioxidant activities. This may provide a basis for further studies on the potentially protective effect of melatonin on liver function in cirrhotic patients


Notes:


Reference: Hong RT, Xu JM, Mei Q. Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats. World J Gastroenterol 2009; 15(12): 1452-1458
wjgnet/1007-9327/15/1452.asp



Correspondence to: Jian-Ming Xu, Professor, Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.



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

Too Much Of A Charge-Switching Enzyme Causes Symptoms Of Multiple Sclerosis And Related Disorders In Mouse Models

A new study highlights the role of a charge-switching enzyme in nervous system deficits characteristic of multiple sclerosis and other related neurological illness.



Multiple sclerosis (MS) is one of several diseases in which myelin - the insulator for electrical signaling in the nervous system - breaks down and causes severe deficits in brain and nerve function. Much like the rubber insulation on an electrical cord, myelin surrounds long projections from the body of a neuron, and allows signals to travel down the cell with speed and efficiency. Patients with MS and other "de-myelinating" diseases therefore suffer deficits in balance, coordination, and movement, as well as sensory disturbances, from the loss of this neuronal insulation.



A major research initiative in treating these diseases is identifying the molecular factors and changes that lead to myelin breakdown. In a new study published in Disease Models & Mechanisms (DMM), dmm.biologists/, a team of Canadian researchers report on a new mouse model of disease which will help in understanding how demyelination occurs. Previous research had identified that an enzyme known as peptidylarginine deiminase 2, or PAD2, is increased in patients with MS, and that PAD2 switches a charge on a protein key to myelin stability. Therefore, Abdiwahab A. Musse and colleagues at the University of Guelph and the Hospital for Sick Children in Ontario created a genetically modified mouse expressing too much of an enzyme known as PAD2. They found that these mice had significant loss of myelin, and also have behavioral deficits, such as abnormal movement, balance, and coordination.



Not only does this work present a new mouse model to study demyleinating disease, but it also stresses the importance of PAD in maintaining myelin integrity. Their work highlights PAD as a potential therapeutic target, as well as a potential marker for early detection of MS and other diseases characterized by a loss of myelin.







Commentary on this work by researchers Mario Moscarello and Fabrizio Mastronardi will be featured in the DMM Podcast for issue 4/5 of DMM. Podcasts are available via the DMM website at: dmm.biologists>dmm.biologists/.



The report was written by Abdiwahab A. Musse, Dorothee Bienzle, Roberto Poma, and George Harauz at the University of Guelph in Guelph, Ontario, and Zhen Li, Cameron A. Ackerley, Helena Lei, Mario A. Moscarello and Fabrizio G. Mastronardi at the Hospital for Sick Children in Toronto, Ontario. The report is published in the November/December issue of a new research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.



About Disease Models & Mechanisms:



Disease Models & Mechanisms (DMM) is a new research journal publishing both primary scientific research, as well as review articles, editorials, and research highlights. The journal's mission is to provide a forum for clinicians and scientists to discuss basic science and clinical research related to human disease, disease detection and novel therapies. DMM is published by the Company of Biologists, a non-profit organization based in Cambridge, UK.



The Company also publishes the international biology research journals Development, Journal of Cell Science, and The Journal of Experimental Biology. In addition to financing these journals, the Company provides grants to scientific societies and supports other activities including travelling fellowships for junior scientists, workshops and conferences. The world's poorest nations receive free and unrestricted access to the Company's journals.



Source: Donna Perry


The Company of Biologists

Prestigious Early Career Award Received By Clemson Bioengineer

Ning Zhang, assistant professor of bioengineering at Clemson University and the CU-MUSC Bioengineering Program, has received the prestigious 2008 Early Career Translational Research Award from the Wallace H. Coulter Foundation.



The foundation judged Zhang's research on an injectable hydrogel-based system for the treatment of stroke to be a highly promising technology that can progress towards commercial development and clinical practice. Zhang proposed the injectable hydrogel system to assist stem cell therapy for stroke treatment.



"This award exemplifies the strong leadership of Dr. Zhang in translational biomaterials research based on outstanding basic science," said Martine LaBerge, chair of Clemson's bioengineering department. "Our goal as bioengineers is to get potential life-saving treatments such as this from the research lab to the patient in an expedient manner."



The Early Career Translational Research Awards support biomedical engineering research that is translational in nature and encourage and assist eligible biomedical engineering investigators as they establish themselves in academic research careers with two years of funding.



Zhang's research on neurobioengineering has also been recognized by the 2007 Department of Defense Post-Traumatic Stress Disorder/Traumatic Brain Injury Research Program of the Office of the Congressionally Directed Medical Research Programs (CDMRP) with a Concept Award on "Brain Tissue Regeneration After Traumatic Brain Injury."



The Wallace H. Coulter Foundation is a private, nonprofit foundation in Miami dedicated to improving human healthcare by supporting translational research in biomedical engineering. Recipients of the Early Career Translational Research Awards are full-time, tenure-track faculty members with a primary appointment in biomedical engineering. They have received their doctoral degree no more than six years prior to their application, and they held a rank no higher than assistant professor at the time of application.



Wallace H. Coulter was an engineer, inventor and entrepreneur who applied engineering principles to biomedical problems. He founded Coulter Corp., which developed and marketed the first automated blood cell counters and flow cytometers, instruments that revolutionized healthcare diagnostics and therapeutics. Believing that the contributions of engineers to solving biomedical problems were generally under-recognized, Coulter mentored and encouraged young engineers to dream, take risks and be innovative.





Source: Martine LaBerge


Clemson University

TGen And Geisinger Health System Announce Strategic Partnership

The Translational Genomics Research Institute (TGen) and Geisinger Health System have announced the signing of a strategic research agreement that provides for a focused look at the gaps in clinical medicine where biomedical research can make a difference.



One of the first projects will focus on the causes of obesity, diabetes and other metabolic conditions. Researchers plan to look at the possible genetic reasons why so many Americans are overweight, and why diet, exercise and, specifically, bariatric surgery may fail to significantly reduce excess weight in some patients.



TGen, a non-profit biomedical research institute based in Phoenix, will pair its genomic and proteomic research expertise with the clinical excellence and research expertise of Geisinger, a non-profit medical and insurance provider based in Danville, Pa.



Geisinger's strength is its integrated healthcare delivery model, nontransitory population and advanced electronic health record (EHR) with nearly two decades of data. In addition to providing the clinical underpinnings for the study of obesity, the data within the EHR will provide researchers the evidence they need to make discoveries in future projects centered on cancer and other serious diseases.



"Merging Geisinger's wealth of clinical information with our genomic and proteomic expertise should provide researchers a richer framework for exploring the genetic origins of disease, and hopefully lead to improved treatments and outcomes," said Dr. Jeffrey Trent, Ph.D., TGen's President and Research Director.



TGen emphasizes a translational research process intended to quickly turn laboratory discoveries into new drugs and other treatments that can benefit patients, a goal shared by Geisinger.



"Given our unique research structure and a patient population that overwhelmingly supports cutting-edge research, I am confident that this partnership will allow us to test and apply new clinical translation theories to patient care," said Glenn D. Steele, Jr., M.D., Ph.D., Geisinger's President and CEO. "I look forward to the results of this first study, as I am confident we can greatly improve the outcomes for individuals coping with obesity and its many associated complications."



According to 2009 Census data, nearly one-third of the U.S. adult population is overweight and considered obese. The impact of obesity on one's health is great, often leading to a shortened lifespan. A disease, obesity is not always caused by overeating or lack of exercise, and research has shown there is often an underlying genetic component leading to excess weight gain.



David Carey, Ph.D., Director of the Sigfried and Janet Weis Center for Research, located on the campus of the Geisinger Medical Center, agreed that the collaboration should advance patient care. "Identification of patients at risk for chronic metabolic diseases would provide enormous benefit to health care. Geisinger's ability to obtain detailed, electronic health information in real time for a large, stable patient population will significantly accelerate this research effort."



Johanna DiStefano, Ph.D., Director of TGen's Diabetes, Cardiovascular & Metabolic Diseases Division, will lead TGen's efforts to understand the genetic basis of obesity and liver disease. She said research strategies would capitalize on the synergistic strengths of a large multidisciplinary research program in obesity at Geisinger. "I am confident that the long-term results of this collaboration will yield improved diagnostic and therapeutic outcomes for countless individuals suffering from chronic metabolic diseases."



TGen also plans to bring to bear its collaboration with the Partnership for Personalized Medicine (PPM), which includes TGen, Arizona State University's Biodesign Institute and the Fred Hutchinson Cancer Research Center. The PPM's mission is to improve medical outcomes and reduced costs through more effective diagnosis of disease risk, early stage, and matching patients to therapies.



"Working with Geisinger will provide yet another significant opportunity for the Partnership for Personalized Medicine to provide better evidence to meet the specific medical needs of individual patients," said Lee Hartwell, Ph.D., a 2001 Nobel laureate and Executive Committee Chairman of PPM.



The research partnership between TGen and Geisinger will also address some of the nation's other critical health challenges. Preliminary discussions covered such research areas as genetic variations that predispose individuals to disease, congestive heart failure, abdominal aortic aneurysms, and the potential side effects of prescription drugs.



Source:

Steve Yozwiak

The Translational Genomics Research Institute

Caltech Scientists Control Complex Nucleation Processes Using DNA Origami Seeds

The construction of complex man-made objects--a car, for example, or even a pizza--almost invariably entails what are known as "top-down" processes, in which the structure and order of the thing being built is imposed from the outside (say, by an automobile assembly line, or the hands of the pizza maker).



"Top-down approaches have been extremely successful," says Erik Winfree of the California Institute of Technology (Caltech). "But as the object being manufactured requires higher and higher precision--such as silicon chips with smaller and smaller transistors--they require enormously expensive factories to be built."



The alternative to top-down manufacturing is a "bottom-up" approach, in which the order is imposed from within the object being made, so that it "grows" according to some built-in design.



"Flowers, dogs, and just about all biological objects are created from the bottom up," says Winfree, an associate professor of computer science, computation and neural systems, and bioengineering at Caltech. Along with his coworkers, Winfree is seeking to integrate bottom-up construction approaches with molecular fabrication processes to construct objects from parts that are just a few billionths of a meter in size that essentially assemble themselves.



In a recent paper in the Proceedings of the National Academy of Sciences (PNAS), Winfree and his colleagues describe the development of an information-containing DNA "seed" that can direct the self-assembled bottom-up growth of tiles of DNA in a precisely controlled fashion. In some ways, the process is similar to how the fertilized seeds of plants or animals contain information that directs the growth and development of those organisms.



"The big potential advantage of bottom-up construction is that it can be cheap"--just as the mold that grows in your kitchen does so for free--"and can be massively parallel, because the objects construct themselves," says Winfree.



But, he adds, while bottom-up approaches have been extremely useful in biology, they haven't played as significant a role in technology, "because we don't have a great grasp on how to design systems that build themselves. Most examples of bottom-up technologies are specific chemical processes that work great for a particular task, but don't easily generalize for constructing more complex structures."



To understand how complexity can be programmed into bottom-up molecular fabrication processes, Winfree and his colleagues study and understand the processes--or algorithms--that generate organization not just in computers but also in the natural world.



"Tasks can be solved by carrying out well-defined rules, and these rules can be carried out by a mindless mechanism such as a computer," he says. "The same set of rules can perform different tasks when given different inputs, and there exist 'universal programs' that can perform any task required of it, as specified in its input. Your laptop is such a universal computer; it can run any software that you download, and in principle, any feasible task could be programmed."
















These principles also have been exploited by natural evolution, Winfree says: "Every cell, it appears, is a kind of universal computer that can be instructed in seemingly limitless ways by a DNA genome that specifies what chemical processes to execute, thus building an active organism. The aim of my lab has been to understand algorithms and information within molecular systems."



Winfree's investigations into algorithmic self-assembly earned him a MacArthur "genius" prize in 2000; his collaborator, Paul W. K. Rothemund, a senior research associate at Caltech and a coauthor of the PNAS paper, was awarded the same no-strings-attached grant in 2007 for his work designing scaffolded "DNA origami" structures that self-assemble into nearly arbitrary shapes (such as a smiley face and a map of the Western Hemisphere).



The structures designed by Rothemund, which could eventually be used in smaller, faster computers, were used as the seeds for the programmed self-assembly of DNA tiles described in the current paper.



In the work, the researchers designed several different versions of a DNA origami rectangle, 95 by 75 nanometers, which served as the seeds for the growth of different types of ribbon-like crystals of DNA. The seeds were combined in a test tube with other bits of DNA, called "tiles," heated, and then cooled slowly.



"As it cools, the first origami seed and the individual tiles form, as their component DNA molecules begin sticking to each other and folding into shape--but the tiles and origami don't stick to each other yet," Winfree explains.



"Then, at a lower temperature, the tiles start to stick to each other and to the origami. The critical concept here is that the DNA tiles will only form crystals if the process gets started by a seed, upon which they can grow," he says.



In this way, the DNA ribbons self-assemble themselves, but only into forms such as ribbons with particular widths and ribbons with stripe patterns prescribed by the original seed.



The work, Winfree says, "exhibits a degree of control over information-directed molecular self-assembly that is unprecedented in accuracy and complexity, which makes me feel that we are finally beginning to understand how to program information into molecules and have that information direct algorithmic processes."


Notes:


The paper, "An information-bearing seed for nucleating algorithmic self-assembly," was published in the March 24 issue of the Proceedings of the National Academy of Sciences.



The other authors of the paper are undergraduate Robert D. Barish and visiting scholar Rebecca Schulman. The work was supported by grants from the National Aeronautics and Space Administration's astrobiology program, the National Science Foundation, and the Focus Center Research Program, and a gift from Microsoft Research.



Source:
Kathy Svitil


California Institute of Technology

Eating And Weight Gain Not Necessarily Linked, Study Shows

You may not be what you eat after all.



A new study shows that increased eating does not necessarily lead to increased fat. The finding in the much-studied roundworm opens the possibility of identifying new targets for drugs to control weight, the researchers say.



The discovery reveals that the neurotransmitter serotonin, already known to control appetite and fat build-up, actually does so through two separate signaling channels. One set of signals regulates feeding, and a separate set of signals regulates fat metabolism. The worm, known scientifically as Caenorhabdtis elegans, shares half of its genes with humans and is often a predictor of human traits.



The signaling pathways are composed of a series of molecular events triggered by neurons in the brain that ultimately "instruct" the body to burn or store fat.



If the "separate-channel" mechanism is also found in humans, weight-loss drugs might be developed to attack just the fat-deposition channel rather than the hunger-dampening pathway that has met with limited success, says Kaveh Ashrafi, PhD, assistant professor of physiology at UCSF and senior author on the scientific paper reporting the study.



"It's not that feeding isn't important," Ashrafi says. "But serotonin's control of fat is distinct from feeding. A weight-loss strategy that focuses only on eating can only go so far. It may be one reason why diets fail."



The research was reported online June 3 by the journal Cell Metabolism and in the print edition June 4.



The finding does not challenge the view that hunger, feeding and fat are all linked in a feedback loop under the influence of serotonin and other neurotransmitters that act on neurons in the brain. But the discovery shows that this is not the whole story, according to Ashrafi.



Various weight-loss drugs have been developed to boost serotonin and thereby suppress appetite. But the cutback in eating tends to be short-term - often a matter of days, based on animal research, Ashrafi says. Drugs that block the brain's separate fat-deposition signaling pathway might be a boon to controlling obesity, type 2 diabetes, cardiovascular disease and other threats, he adds.



The scientists studied more than 250 genes to identify those that underlie serotonin's effects on fat and feeding. They found that serotonin controls feeding by docking with receptors on neurons that are distinct from those that control fat. In turn, these fat- controlling neurons send signals to sites of fat storage to rev up metabolism.



It is widely believed that environments that encourage excessive food intake and little physical activity promote development of obesity. However, extensive studies have revealed that body weight is not merely a passive consequence of environmental conditions but that a physiological system coordinates the complex mechanisms that regulate food intake and energy expenditure, Ashrafi says.
















This physiological system is thought to involve genes that operate in various tissues such as fat, muscle, and brain. In fact, the genetic contribution to body weight is estimated to be between 40 and 70 percent. The molecular mechanisms that link excess fat to various diseases such as type 2 diabetes are not understood.



To help decipher the complex relationships between behavioral and metabolic pathways that control body weight, Ashrafi and his team began analyzing serotonin-induced regulation of fat and feeding in the microscopic C. elegans worm. They took advantage of a powerful and relatively new technique known as RNA interference, or RNAi, which allowed them to inactivate hundreds of genes one at a time to determine the effect of these gene inactivations on serotonin's actions on fat regulation.



"Obesity and thinness are not solely determined by feeding behavior," the scientists conclude in their paper. "Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability."







Lead author on the paper is Supriya Srinivasan, PhD, a postdoctoral fellow in Ashrafi's lab. Co-author at UCSF is Leila Sadegh, BS, staff research assistant.



Other co-authors are Ida C. Elle, BS, graduate student; Anne G.L. Christensen, BS, staff research assistant; and Nils J. Faergeman, PhD, associate professor, all at the University of Southern Denmark.



Research support includes the National Institutes of Health, the Sandler Opportunity Fund and the Richard and the Susan Smith Family Foundation Pinnacle Program Project Award.



UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.



Source: Wallace Ravven


University of California - San Francisco

Protein Isolated That May Be 'Boon' To Medicine

Scientists at UC Santa Barbara have isolated a unique protein that appears to have a dual function and could lead to a "boon in medicine." The findings are published in the August issue of the Journal of Cell Biology.



The protein that the researchers studied, named mDpy-30, affects both the expression of genes and the transport of proteins. "We first found that this protein has a dual location in the cell," said Dzwokai Ma, senior author and assistant professor in UCSB's Department of Molecular, Cellular and Developmental Biology. "That spurred us to investigate this protein further, because location is always linked to function."



Proteins that are most sensitive to mDpy-30 are pivotal to the movement of a cell, according to the current study and unpublished results from the Ma lab. "Indeed, we have obtained preliminary evidence that mDpy-30 is an important regulator of cell movement," said Ma. "The movement of a cell is essential to myriad biological functions such as neural networking, proper immunological function, and wound healing. Consequently, when these processes go awry, they can result in the development or progression of human disease, including cancer metastasis."



What remains enigmatic, Ma added, is the particular role of mDpy-30 in protein transport regulation, and whether or how this function is coordinated with gene expression during cell movement. "Further study could lead to a boon in medicine," he said.



First authors from UCSB who contributed equally to the paper, are: Zhuojin Xu, Qiang Gong, and Bin Xia. Additional co-authors are Benjamin Groves, Mark Zimmerman, Brian Matsumoto, and Chris Mugler, of UCSB; Dezhi Mu of Sichuan University, Chengdu, China; and Matthew Seaman of the University of Cambridge, Cambridge, U.K.



Source:
Gail Gallessich


University of California - Santa Barbara

Researchers simulate molecular biological clock, New York University

Researchers at New York University have developed a model of the intra-cellular mammalian biological clock that reveals
how rapid interaction of molecules with DNA is necessary for producing reliable 24-hour rhythms. They also found that without
the inherent randomness of molecular interactions within a cell, biological rhythms may dampen over time. These findings
appeared in the most recent issue of the Proceedings of the National Academy of Sciences (PNAS).


Daniel Forger, an NYU biologist and mathematician, and Charles Peskin, a professor at NYU's Courant Institute of Mathematical
Sciences and Center for Neural Science, developed a mathematical model of the biological clock that replicates the hundreds
of clock-related molecular reactions that occur within each mammalian cell.


Biological circadian clocks time daily events with remarkable accuracy--often within a minute each day. However,
understanding how circadian clocks function has proven challenging to researchers. This is partly because the 24-hour rhythm
is an emergent property of a complex network of many molecular interactions within a cell. Another complication is that
molecular interactions are inherently random, which raises the question how a clock with such imprecise components can keep
time so precisely. One way to combat molecular noise is to have large numbers of molecular interactions, but this is limited
by the small numbers of molecules of some molecular species within the cell (for instance, there are only two copies of DNA).



To simulate the random nature of the biochemical interactions of the mammalian intra-cellular circadian clock, Forger and
Peskin used the existing Gillespie method. The method tracks the changes in the integer numbers of each type of molecule of
the system as these biochemical reactions occur. Modeling each type of molecule separately helped avoid mathematical
assumptions in their model that may not be valid in real-life cells. Their model was validated with a large library of data
on the concentrations of the molecular species within the mouse molecular clock at different times of the day and data on the
behavior of mice with circadian clock mutations.


The results of their computer simulations showed that reliable 24-hour timekeeping can only be achieved if the regulatory
molecules that influence gene expression bind and unbind to DNA quickly--typically, within a minute. In this way, the large
number of bindings and unbindings helps to compensate for the small numbers of molecules involved. The researchers also found
that having more molecules in the cell does not necessarily lead to more accurate timekeeping. Removing all the CRY1
molecules (CRY1 mutant) or removing all the CRY2 molecules (CRY2 mutant), while keeping all other molecular species
unchanged, leads to more accurate timekeeping. While simulating the PER2 mutation, they found that circadian oscillations
could only be sustained in the presence of molecular noise. This may help explain some of the conflicting experimental
reports about the PER2 mutant.


"Without the rapidity of molecular interactions within these cells, the precision of the biological clock would be lost,"
explained Forger. "It is remarkable that a process occurring on the time scale of minutes can have such a profound effect on
one that occurs over 24 hours."


James Devitt

jamesvittnyu

New York University

In Organisms, Molecular Middle Managers Make More Decisions Than Bosses

Organisms are structured at the molecular level in ways similar to social hierarchies. In some, master genetic regulators call most of the shots, and in others most of life's activities are carried out by more egalitarian collaborations.



Knowing these organizational rules will help us understand biological systems and our social interactions, argues Mark Gerstein, A L Williams professor of biomedical informatics, molecular biophysics and biochemistry, and computer science. He is the senior author of a paper on the subject published online the week of March 29 in the Proceedings of the National Academy of Sciences.



Gerstein and postdoctoral associate Nitin Bhardwaj analyzed regulatory networks of five diverse species, from E. coli to human, and rearranged those systems into hierarchies with a number of broad levels, including "master regulators," "middle managers" and "workhorses." In most organisms, master regulators control the activity of middle managers, which in turn govern suites of workhorse genes that carry out instructions for making proteins.



As a general rule, the more complex the organism, the less autocratic and more democratic the biological networks appear to be, researchers report. In both biological systems and corporate structures, interactions between middle managers are often more critical to functioning than actions by bosses. "If my department chair takes another job, the emphasis of my lab might change, but it will survive," Gerstein said. "But if my systems administrator leaves, my lab dies."



In simpler organisms such as E. coli, there tends to be a simple chain of command in which regulatory genes act like generals, and subordinate molecules "downstream" follow a single superior's instructions. Gerstein calls these systems "autocratic." But in more complex organisms, most of these subordinate genes co-regulate biological activity, in a sense sharing information and collaborating in governance. Gerstein labels these systems "democratic." If they share some qualities of both they are deemed "intermediate."



The interactions in more democratic hierarchies lead to mutually supporting partnerships between regulators than in autocratic systems, where if one gene is inactivated, the system tends to collapse. This is why Gerstein and colleagues in earlier work found that when they knocked out a master regulating gene in a complex organism, the "effects were more global, but softer" than when a key middle manager gene in a simpler life form was inactivated, which led to the death of the organism.



"Regulators in more complex species demonstrate a highly collaborative nature. We believe that these are due to the size and complexity of these genomes," Gerstein said. For example, about 250 master regulators in yeast have 6000 potential targets, a ratio of about one to 25. In humans, 20,000 targets are regulated by about 2,000 genes, a ratio of one to 10.



The work was funded by the National Institutes of Health.



Source:

Bill Hathaway


Yale University

Drug Combination Halts Tumor Growth Better Than Single Agent

Treatment with three drugs that inhibit the human epidermal growth factor receptor (HER) stops HER2-positive breast cancer tumor growth in mice better than treatment with just one or two of the drugs.



Grazia Arpino, M.D., Ph.D., of Baylor College of Medicine in Houston, and colleagues measured tumor growth in mice with human breast cancer tumors that overexpress HER2. Some mice received one of three HER inhibitors - pertuzumab, trastuzumab, or gefitinib - or a combination of two or three of the drugs. The mice also received different combinations of hormonal therapy, including estrogen supplements, estrogen withdrawl, and tamoxifen.



A combination of all three HER inhibitors was more effective at slowing tumor growth than a single drug or combination of two drugs. The tumors grew after 49 days in mice that received all three drugs, compared with 21 days for mice in the estrogen-only group and 28 days for mice that got estrogen and pertuzumab. The addition of tamoxifen to any of the three drugs also inhibited tumors growth in the mice, but after two months the tumors grew resistant to the treatment. In mice treated with all three HER inhibitors plus tamoxifen or estrogen withdrawal, most tumors completely disappeared and did not progress for more than 189 days after treatment.



"These results support the hypothesis that acquired resistance to the individual agents is the result of [an] incomplete blockade of this complex network at the receptor level and not activation of a different survival pathway," the authors write.



Contact: Kimberlee Barbour







Other highlights in the May 2 JNCI



Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jnci.oxfordjournals/.



Contact: Liz Savage


Journal of the National Cancer Institute

Sensitivity To Appetite Suppressant Fat Hormone Restored By Approved Drugs

A new study in the January 7th issue of Cell Metabolism, a Cell Press publication, helps to explain why obese people and animals fail to respond to leptin, a hormone produced by fat that signals the brain to stop eating. What's more, they show that two FDA-approved drugs might restore leptin sensitivity, offering a novel treatment for obesity.



" Most importantly, our study is the first success in sensitizing obese mice on a high-fat diet to leptin," said Umut Ozcan of Harvard Medical School. "If it works in humans, it could treat obesity."



When leptin was first discovered some 13 years ago, it led to great excitement in the field, Ozcan said. Studies showed that leptin administered to obese mice that lacked the hormone lost weight. The buzz over leptin's potential as an obesity therapy soon waned, however, because obese animals and people don't respond to the hormone. Efforts to find drugs that act as leptin sensitizers over the years have also failed.



However, the underlying reason why obese individuals become leptin resistant in the first place remained open to question. The new study by Ozcan's team has shed some light on that issue.



Recent studies by him and his colleagues showed that a condition known as endoplasmic reticulum (ER) stress in peripheral organs plays an important role in obesity-induced insulin resistance and type 2 diabetes. Ozcan describes ERs as protein factories within cells. Within those cellular components, molecular chaperones, which serve as the factory workers, facilitate the folding and transport of proteins. When the chaperones can't keep up, it triggers a stress response known as the unfolded protein response (UPR).



Ozcan suspected that ER stress and the UPR response might also lead to leptin resistance in the brain's hypothalamus. The hypothalamus is the primary brain region that responds to leptin, sending a signal that curbs appetite. Mice engineered to have reduced ER capacity or increased ER stress throughout their bodies do gain more weight on a high-fat diet, according to earlier studies.



Ozcan now reports that obese mice manipulated to have increased ER stress only in the hypothalamus show less response to leptin. The animals are not only more leptin resistant, but they also grow significantly more obese on a high-fat diet.



The question then became whether the animals could be resensitized by treating them with either of two pre-existing drugs (4-Phenyl Butyric Acid [PBA] and Tauroursodeoxycholic acid [TUDCA]) that act as ER stress reducers. And the answer, they report, is yes.



" It was very exciting," Ozcan said of the discovery. "Normal mice treated with the drugs dropped some weight and quickly rebounded, but the knockout mice [that were genetically predisposed to ER stress in the brain] continued to lose weight. It shows that ER stress relievers are leptin sensitizers."



That makes PBA and TUDCA the first leptin sensitizers, Ozcan emphasized.



" A leptin-sensitizing agent has not been previously described despite the long-standing efforts in both academia and industry," he wrote. "The results presented in this study provide evidence that chemical chaperones, particularly the PBA and TUDCA, can be used as leptin-sensitizing agents. When the high safety profiles of PBA, TUDCA, and leptin are taken into consideration, our results may define a novel treatment option for obesity."







The researchers include Lale Ozcan, Children's Hospital Boston, Harvard Medical School, Boston, MA; Ayse Seda Ergin, Children's Hospital Boston, Harvard Medical School, Boston, MA; Allen Lu, Children's Hospital Boston, Harvard Medical School, Boston, MA; Jason Chung, Children's Hospital Boston, Harvard Medical School, Boston, MA; Sumit Sarkar, Children's Hospital Boston, Harvard Medical School, Boston, MA; Duyu Nie, Children's Hospital Boston, Harvard Medical School, Boston, MA; Martin G. Myers, Jr., University of Michigan Medical School, Ann Arbor, MI; and Umut Ozcan, Children's Hospital Boston, Harvard Medical School, Boston, MA.



Source: Cathleen Genova


Cell Press

Mutation In Bone Marrow Cancers Blocked By Promising New Drug , May Also Help Patients With Rheumatoid Arthritis

Oregon Health & Science University Knight Cancer Institute researchers have found that an experimental drug successfully blocks an enzyme that causes some bone marrow cancers.



The oral drug, called CYT387, was tested in mice as well as in human cells. In both cases, it blocked the growth of certain bone marrow cancers called myeloproliferative disorders, also referred to as MPDs.



The research was presented Tuesday, Dec. 9, at 7 a.m. during the 50th annual American Society of Hematology conference in San Francisco.



"The drug was found to be very effective against a specific type of cancer cells, cancer cells which are driven by an enzyme mutation called JAK2-V617F. In the mouse model, the drug blocked JAK2-V617F, normalized blood counts and reduced enlarged spleens back to a normal size. It is a very promising compound," said Thomas Bumm, M.D., Ph.D., a member of the research team.



The drug works by binding to the V617F mutation in the JAK2 enzyme. Without this drug, the mutated JAK2 enzyme leads to MPDs. The "big three" MPDs include polycythemia vera, essential thrombocythemia and primary myelofibrosis. Until now there have been no FDA-approved targeted treatments for these diseases.



"Based on the efficacy that we demonstrated in the mouse model, there is a good chance that CYT387 will enter clinical trials as early as 2009. Those in greatest need include patients with myelofibrosis, a relentless disease for which there is currently no effective therapy. It is likely that JAK2 inhibitors will change the standard of care for these patients," said Michael Deininger, M.D., Ph.D., principal investigator and Head of the Hematological Malignancies Program Ph.D. He also is an associate professor of medicine (hematology/medical oncology), OHSU School of Medicine and a Scholar of the Leukemia & Lymphoma Society.



Researchers also discovered that CYT387 effectively blocks overproduction of inflammatory cytokines. Abnormal cells carrying the JAK2-V617F mutation produce a large amount of different inflammatory cytokines that help the cancer cells to grow and repress normal cells. In mice, the drug normalized 19 different inflammatory cytokine levels in the blood. The overproduction of cytokines can also be found in inflammatory conditions such as rheumatoid arthritis. This drug's effect on cytokines could benefit patients with inflammatory diseases, especially rheumatoid arthritis.



The next likely step will be to open clinical trials for people with MPD as soon as 2009 once formal preclinical toxicology studies are completed.







The investigational drug is made by Cytopia Research Pty Ltd, a publicly registered drug company from Australia. Cytopia sponsored this trial.



Other researchers include: Jeffrey Tyner, Ph.D.; Jutta Deininger, M.D., senior research assistant; Jonathan Van Dyke, research assistant; Marc Loriaux, M.D., Ph.D., assistant professor of pathology (anatomic pathology) and assistant professor of medicine (hematology/medical oncology); and Brian Druker, M.D., director of the OHSU Knight Cancer Institute, JELD-WEN Chair of Leukemia Research, Howard Hughes Medical Institute Investigator and a member of the National Academy of Sciences.



About the OHSU Knight Cancer Institute



The OHSU Cancer Institute is the only National Cancer Institute-designated center between Sacramento and Seattle. It comprises some 200 clinical researchers, basic scientists and population scientists who work together to translate scientific discoveries into longer and better lives for Oregon's cancer patients. In the lab, basic scientists examine cancer cells and normal cells to uncover molecular abnormalities that cause the disease. This basic science informs more than 300 clinical trials conducted at the OHSU Cancer Institute.



About OHSU



Oregon Health & Science University is the state's only health and research university and Oregon's only academic health center. OHSU is Portland's largest employer and the fourth largest in Oregon (excluding government), with 12,400 employees. OHSU's size contributes to its ability to provide many services and community support activities not found anywhere else in the state. It serves patients from every corner of the state, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state.



Source: Christine Decker


Oregon Health & Science University

Breast Cancer: Discovery Leads To Rapid Mouse 'Personalized Trials'

One person's breast cancer is not the same as another person's, because the gene mutations differ in each tumor. That makes it difficult to match the best therapy with the individual patient.



Using a finding that the genetic complexity of tumors in mice parallels that in humans, researchers at the Duke University Institute for Genome Sciences and Policy and Duke University Medical Center are starting trial studies in mice, just like human clinical trials, to evaluate whether understanding tumor diversity can improve cancer treatment.



"Giving everyone the same few current treatments doesn't take the very different types of tumors into account," said Joseph Nevins, Ph.D., Barbara Levine University Professor of Breast Cancer Genomics at Duke, who directs the Center for Applied Genomics & Technology at Duke. "It's like trying to treat a virus infection without recognizing that it may be HIV, influenza or cold virus."



For a study appearing this week in the Proceedings of the National Academy of Sciences, Nevins and colleagues painstakingly examined a large number of mouse breast tumors and performed genomic analyses to differentiate the tumors.



"The genetic pathways in the tumors determine the sensitivity to drugs," Nevins said. "We still have so much to learn about this."



All of the mice were bred to have a Myc gene variant that gave them tumors; however, additional gene mutations are acquired that contribute to the development of the tumor, including mutations in the Ras gene and others. The spectrum of tumor variation at the genetic level mimicked the complexity of human cancers.



"If we are going to successfully treat a tumor, we must recognize the extensive heterogeneity of what we call breast cancer and match drugs carefully to the characteristics of that particular tumor," Nevins said. "Today breast tumors may be sorted by whether they are estrogen-sensitive or HER-2 sensitive, but that is about the extent of it. We are performing human trials to look at the underlying biological pathways and examine how best to match therapies with the individual patient. But, these are lengthy studies. Now we can develop new strategies to match a therapy with a mouse tumor subtype and have results in a much shorter period of time."



Nevins and colleagues plan to conduct trials in the mice just as they would in humans: find the tumor, perform a needle biopsy, learn all they can about the tumor, and match it to a drug based on scientific data. The mouse studies don't replace human trials, but they can be an important component of advancing a strategy, Nevins said.



"This work highlights the importance of both biological and computational model systems to unravel the complexities and heterogeneity of human cancer," said Daniel Gallahan, Ph.D., program director for the Integrative Cancer Biology Program at the National Cancer Institute. "This type of analysis can be exploited to better align a therapeutic strategy with an individual's specific cancer."



Running parallel to human trials, the mouse trials will show what works well and what doesn't in the trial methods, data collection, analysis and other aspects of the trials. Researchers can then translate these findings immediately to keep the human clinical trials advancing as effectively as possible.



With so much mouse model research happening around the globe, why weren't these mouse tumor differences noted before? The gene expression analyses performed on mouse tumors simply haven't been large enough, Nevins said.



"We examined a large number, up to 80 samples of mouse tumors. And in the same way that a picture gets clearer when you add more pixels, the information about the tumors became clearer as we examined more samples," he said. "In effect, we went to a higher resolution and could begin to see patterns more clearly."



The study was funded by the National Institutes of Health and the V Foundation for Cancer Research, named in honor of the late North Carolina State basketball coach Jim Valvano.



Other authors include Eran R. Andrechek, Jeffrey T. Chang, Michael L. Gatza, Chaitanya R. Acharya, and Anil Potti of the Duke Institute for Genome Sciences and Policy, and Robert D. Cardiff of the Center for Comparative Medicine at the University of California at Davis.



Source:
Mary Jane Gore


Duke University Medical Center

Cause Of Cartilage Degeneration In Osteoarthritis Discovered By Scripps Research Scientists

The scientists describe their work in this week's Early Edition of the Proceedings of the National Academy of Sciences. In the study, the team shows how the loss of the protein HMGB2, found in the surface layer of joint cartilage, leads to the progressive deterioration of the cartilage that is the hallmark of osteoarthritis.



"We have found the mechanism that begins to explain how and why aging leads to deterioration of articular cartilage," says Scripps Research Professor Martin Lotz, M.D., a world-renowned arthritis researcher who led the study with Noboru Taniguchi, M.D., Ph.D., a senior research associate in his lab. "Our findings demonstrate a direct link between the loss of this protein and osteoarthritis."



Osteoarthritis typically begins with a disruption of the surface layer of cartilage. The cartilage surface layer, called the superficial zone, is the most important functionally of the four layers of cartilage present in joints. In normal joints the cartilage surface is perfectly smooth, enabling joints to slide across one another without friction. Once the cartilage of the superficial zone starts to deteriorate, though, osteoarthritis sets in, triggering an irreversible process that eventually leads to the loss of underlying layers of cartilage until bone begins to grind painfully against bone. Osteoarthritis most commonly affects the spine, temporomandibular joints, shoulders, hands, hips and knees.



"We knew that the first phase of osteoarthritis is the destruction of cartilage in the superficial zone," says Lotz, who has spent the past five years studying the role of HMGB2 in osteoarthritis. "Now we know that before this layer is destroyed, there is loss of the critical DNA binding protein HMGB2 and that this loss is directly related to aging."



The team found that the protein HMGB2 is uniquely expressed on the surface layer of cartilage in joints, where it supports the survival of chondrocytes, the cells that produce and maintain cartilage. Aging is associated with the loss of HMGB2 and an accompanying reduction or total elimination of chondrocytes in the superficial zone. The scientists provided further links between HMGB2 and osteoarthritis by breeding mice to be genetically deficient in HMGB2; these mice had an earlier and more severe onset of osteoarthritis.



The findings, made in collaboration with colleagues from Scripps Research, San Raffaele University in Milan, Italy, and Kagoshima University in Kagoshima, Japan, provide a promising avenue to explore the development of new osteoarthritis treatment options.



"If small molecules can be found to prevent or stop the loss of HMGB2, or conversely, to stimulate the production of this protein, then it is possible that osteoarthritis may one day either be prevented or reversed," Lotz says.



The discovery also will impact research on the use of stem cells in tissue regeneration. Because cartilage is unable to heal itself, scientists have been searching for ways to use stem cells to grow replacement cartilage in the lab that could be used to surgically replace damaged or non-existent cartilage. With the discovery of the link between HMGB2 and surface layer protein, scientists now have a clue about how they might be able to engineer the surface layer cartilage.
















"As our population ages, osteoarthritis will become an ever-greater health issue," Lotz says. "Everyone eventually gets osteoarthritis; even those people who are not functionally impaired by the disease are found to have cartilage damage. And it all starts with the loss of cells in the superficial layer. We now have a starting point for potential prevention, diagnosis, and treatment."







In addition to Lotz and Taniguchi, co-authors of the paper, titled, "Aging-related loss of chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis," are Beatriz Carames and Ulrich Ulmer from the Scripps Research Institute; Lorenza Ronfani and Marco E. Bianchi from San Raffaele University in Milan; and Setsuro Komiya from the Department of Orthopaedic Surgery, Kagoshima University in Japan.



This work was supported by the National Institutes of Health, and by grants from the Arthritis National Research Foundation and the Japan Orthopaedics and Traumatology Foundation, Inc.



About The Scripps Research Institute



The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is currently in the process of moving from temporary facilities to its permanent campus in Jupiter, Florida. Dedication ceremonies for the new campus will be held in February 2009.



Source: Keith McKeown


Scripps Research Institute

Unravelling The Wolbachia Evolutionary Role: The Reprogramming Of The Host Genomic Imprinting

In this paper we provide the first evidence that a bacterium modulates its host genomic imprinting, influencing the expression of genes involved in sex differentiation and development.



In the leafhopper Zyginidia pullula, males feminized by the endosymbiont Wolbachia pipientis display phenotypic features that are typical of females, including female gonads, and a female genomic imprinting. Interestingly, some rare feminized males, which are characterised by an extremely low bacterium density, maintain testes and a male genome-methylation pattern.



Our data show that Wolbachia infection disrupts male imprinting, and the alteration occurs only if the bacterium exceeds a threshold density.


Proceedings of the Royal Society B: Biological Sciences


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


rspb.royalsocietypublishing

Sandoz Receives Positive EU Opinion For Approval Of Epoetin Alfa Biosimilar

Sandoz is the first company to receive a positive opinion from European Union regulators supporting the approval of a biosimilar version of epoetin alfa, achieving another important milestone in its efforts to bring follow-on biological medicines to patients.



More than 250,000 patients in Europe are estimated to be treated with epoetin alfa, which is marketed under various brand names, and similar medicines to regulate the formation of red blood cells. Worldwide annual sales are estimated at more than USD 7 billion, including USD 600 million in Europe.



The Committee on Medicinal Products for Human Use (CHMP), which reviews medicines scientifically in the European Union, has now for the second time issued a positive opinion for a Sandoz biosimilar. In a precedent-setting decision in April 2006, Sandoz was the first company to get European approval for such a medicine, the human growth hormone Omnitrope, while US approval was granted in May 2006.



The European Commission will now decide on granting approval for this biosimilar developed by Sandoz.



"The positive opinion is another important milestone for Sandoz as we lead the way to bring high-quality and cost-effective biosimilars to the market following the expiry of patents," said Andreas Rummelt, CEO of Sandoz.



"We look forward to receiving European Commission approval for this medicine and providing patients and healthcare payors a high quality treatment that will improve access for patients and also contribute significant savings to healthcare budgets. We are committed to further developing these types of medicines and have several projects in the pipeline," Rummelt said.



The CHMP recommendation supports the use of epoetin alfa for indications approved for the reference product at the time of the Sandoz application for EU approval. These include the use in treating patients with renal anemia as well as those receiving chemotherapy, and specifically excludes the subcutaneous administration for patients with chronic kidney disease and the use to increase the yield of autologous blood from patients in a predonation program.



Biopharmaceuticals are medicinal products manufactured by biotechnology methods. They are complex protein molecules with a high molecular weight derived from living organisms that have been genetically modified to produce the desired protein. Using advanced product development, analytical methodologies and manufacturing processes, companies like Sandoz can manufacture high quality medicines and bring them to market with savings for patients and payors.



Sandoz has been on the forefront of efforts to support the creation of regulatory review procedures to enable the approval of biosimilar medicines. Rigorous scientific criteria should be consistently applied to the approval process for these types of medicines. However, the unnecessary or unethical duplication of animal studies and human trials should be avoided, as is the case with other types of subsequent versions of medicinal products.
















As more biopharmaceuticals lose patent protection in the coming years, these products are expected to play a key role in the growth strategy of Sandoz.



About Sandoz


Sandoz, a division of the Novartis group, is a global leader in the field of generic pharmaceuticals, offering a wide array of high-quality, affordable products that are no longer protected by patents. Sandoz has a portfolio of more than 840 compounds in over 5 000 forms worldwide and sells its products in more than 110 countries. Key product groups include antibiotics, treatments for central nervous system disorders, gastrointestinal medicines, cardiovascular treatments and hormone therapies. Sandoz develops, produces and markets these drugs along with pharmaceutical and biotechnological active substances and anti-infectives. In addition to the strong organic growth in recent years, Sandoz has made a series of acquisitions including Lek (Slovenia), Sabex (Canada), Hexal (Germany) and EonLabs (US) In 2006, Sandoz employed around 21,000 people worldwide and posted sales of USD 6 billion.



Disclaimer


This release contains certain "forward-looking statements" such as "estimated," "expected," "will" or similar expressions, or by express or implied discussions regarding potential regulatory filings or approvals or future sales of epoetin alfa. Such forward-looking statements reflect the current plans or views of Sandoz with respect to future events and involve known and unknown risks, uncertainties and other factors that may cause actual results with epoetin alfa to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that epoetin alfa will be approved for sale in the EU or any other additional markets or that epoetin alfa will will reach any particular sales levels. In particular, management's expectations regarding the approval and commercialization of epoetin alfa could be affected by, among other things, additional analysis of clinical data; new clinical data; unexpected clinical trial results; unexpected regulatory actions or delays or government regulation generally; competition in general, as well as other risks referred to in Novartis AG's Form 20-F on file with the U.S. Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Sandoz is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.


Sandoz

us.sandoz/site/en/index.shtml

Flexible Electronics For Medical Sensors

They've made electronics that can bend. They've made electronics that can stretch.



And now, they've reached the ultimate goal -- electronics that can be subjected to any complex deformation, including twisting.



Yonggang Huang, Joseph Cummings Professor of Civil and Environmental Engineering and Mechanical Engineering at Northwestern University's McCormick School of Engineering and Applied Science, and John Rogers, the Flory-Founder Chair Professor of Materials Science and Engineering at the University of Illinois at Urbana-Champaign, have improved their so-called "pop-up" technology to create circuits that can be twisted. Such electronics could be used in places where flat, unbending electronics would fail, like on the human body.



Their research is published online by the Proceedings of the National Academy of Sciences (PNAS).



Electronic components historically have been flat and unbendable because silicon, the principal component of all electronics, is brittle and inflexible. Any significant bending or stretching renders an electronic device useless.



Huang and Rogers developed a method to fabricate stretchable electronics that increases the stretching range (as much as 140 percent) and allows the user to subject circuits to extreme twisting. This emerging technology promises new flexible sensors, transmitters, new photovoltaic and microfluidic devices, and other applications for medical and athletic use.



The partnership -- where Huang focuses on theory, and Rogers focuses on experiments -- has been fruitful for the past several years. Back in 2005, the pair developed a one-dimensional, stretchable form of single-crystal silicon that could be stretched in one direction without altering its electrical properties; the results were published by the journal Science in 2006. Earlier this year they made stretchable integrated circuits, work also published in Science.



Next, the researchers developed a new kind of technology that allowed circuits to be placed on a curved surface. That technology used an array of circuit elements approximately 100 micrometers square that were connected by metal "pop-up bridges."



The circuit elements were so small that when placed on a curved surface, they didn't bend -- similar to how buildings don't bend on the curved Earth. The system worked because these elements were connected by metal wires that popped up when bent or stretched. The research was the cover article in Nature in early August.



In the research reported in PNAS, Huang and Rogers took their pop-up bridges and made them into an "S" shape, which, in addition to bending and stretching, have enough give that they can be twisted as well.



"For a lot of applications related to the human body -- like placing a sensor on the body -- an electronic device needs not only to bend and stretch but also to twist," said Huang. "So we improved our pop-up technology to accommodate this. Now it can accommodate any deformation."



Huang and Rogers now are focusing their research on another important application of this technology: solar panels. The pair published a cover article in Nature Materials this month describing a new process of creating very thin silicon solar cells that can be combined in flexible and transparent arrays.







Source: Megan Fellman


Northwestern University

Zebrafish Model Of Human Melanoma Reveals New Cancer Gene

Looking at the dark stripes on the tiny zebrafish you might not expect that they hold a potentially important clue for discovering a treatment for the deadly skin disease melanoma. Yet melanocytes, the same cells that are are responsible for the pigmentation of zebrafish stripes and for human skin color, are also where melanoma originates. Craig Ceol, PhD, assistant professor of molecular medicine at the University of Massachusetts Medical School, and collaborators at several institutions, used zebrafish to identify a new gene responsible for promoting melanoma. In a paper featured on the cover of the March 24 issue of Nature, Dr. Ceol and colleagues describe the melanoma-promoting gene SETDB1.



"We've known for some time that there are a number of genes that are responsible for the promotion and growth of melanoma," said Ceol, who completed the research while a postdoctoral fellow in the lab of Howard Hughes Medical Institute investigator Leonard Zon, MD, at Children's Hospital Boston. "With existing methods, it had been difficult to identify what those genes are. By developing the new approach described in this paper, we were able to isolate SETDB1 as one of those genes."



Cases of melanoma, an aggressive form of skin cancer, have been on the rise in the United States: in 2009 alone, 68,000 new cases were diagnosed and 8,700 people died of the disease. Though it accounts for less than 5 percent of all skin cancers, it is responsible for the majority of deaths from skin cancers and has a poor prognosis when diagnosed in its advanced stages. Early signs of melanoma include changes to the shape or color of existing moles or the appearance of a new lump anywhere on the skin.



Approximately 60 percent of human melanoma cases are caused by a mutation in the BRAF gene that drives proliferation of melanocytes, the cells responsible for skin pigmentation. Because the BRAF mutation is also found in benign moles, scientists hypothesized that the single mutation alone wasn't sufficient enough to cause melanoma. Ceol and colleagues set out to locate other genes implicated in this disease by focusing on areas of the genome that were overrepresented in melanoma cells, hypothesizing that there were genes in these regions that enabled cells to grow unchecked, leading to cancerous tumors. To evaluate genes from an overrepresented region of chromosome 1, Ceol created a technique called MiniCoopR to deliver the test genes, one-by-one, to transgenic zebrafish models with the melanoma-causing BRAF mutation. These fish also lacked the tumor suppressing gene p53.



"The MiniCoopR technique allows us to build melanocytes with whatever genes we want," said Ceol. "With it, we can test individual genes by placing them in the melanocytes and observing how those genes affect melanoma growth."



Painstakingly analyzing more than 2,100 tumors from more than 3,000 zebrafish, researchers found that in fish with the SETDB1 gene, melanoma not only appeared earlier, but grew faster and invaded more deeply into the neighboring muscle and spinal tissue. With this new information, researchers screened 100 human melanomas for the SETDB1 gene. In 70 percent of the sample tumors, SETDB1 was present at high levels, indicating that SETDB1 may be involved in the formation of a majority of human melanomas."



Further analysis showed that SETDB1 produces an enzyme that turns other genes on or off and is overrepresented in other forms of cancer, such as ovarian, breast and liver cancer. "It's clear that SETDB1 is up-regulated and that it's altering the activity levels of other genes," said Ceol. "Because SETDB1 regulates several genes, we still don't know which of its targets promote melanoma."



An abnormally high level of the SETDB1 enzyme may provide clinicians a means of identifying melanoma before patients experience symptoms. It may also provide an enticing target for pharmaceutical intervention. "Enzymes like SETDB1 are particularly attractive as drug targets because they are so amenable to inhibition by small molecules, which could potentially block the cancer causing activity," said Ceol.



Source:

Jim Fessenden

University of Massachusetts Medical School

Close-Up View Of Poliovirus Linked To Host Cell Receptor

Researchers from Purdue and Stony Brook universities have determined the precise atomic-scale structure of the poliovirus attached to key receptor molecules in human host cells and also have taken a vital snapshot of processes leading to infection.



The virus binds to a receptor on the cell to form a single complex.



"This structure had been predicted, but the predictions were not as accurate as we had thought," said Michael Rossmann, Purdue's Hanley Distinguished Professor of Biological Sciences. "What we have now is the real structure, as opposed to a prediction of the receptor molecule. We also have a much higher resolution view of the complex of the receptor when bound to the virus."



The work was carried out by Ping Zhang, a Purdue doctoral student, and others working in Rossmann's laboratory in collaboration with the group at Stony Brook University in New York.



"These findings show the detailed relationship between atoms in the receptor and atoms in the virus," Rossmann said.



The research, which was funded by the National Institutes of Health, is not immediately geared toward medical applications. However, such findings might one day help scientists design better vaccines for the poliovirus and aid in research into the infection processes of other viruses, Rossmann said.



The findings are detailed in a research paper that appeared on Nov. 25 in the journal Proceedings of the National Academy of Sciences.



The poliovirus has three "serotypes," which cause different effects in people. All three serotypes use the same receptor, and Zhang studied how each serotype binds to the receptor.



The virus is roughly spherical and is made up of 60 triangular facets forming a geometric shape called an icosahedron. Each of the 60 units contains a site that can attach to a host cell's receptor molecules. The receptor molecules are called CD155, for cellular differentiation protein, and are made up of a single protein bound to the membrane that envelops a cell. The part outside the cell is divided into three sections, or domains.



The virus binds to a specific domain, and the new high-resolution analysis shows the atomic structure at this attachment point.



Zhang used a method called X-ray crystallography to visualize and study the atomic structure of CD155 and electron microscopy to study the combined virus and CD155 receptor molecule.



Though cellular receptors are designed to carry out specific chemical processes for the cell, viruses have developed ways to use them for gaining entry into cells.



"The virus has learned, to the disadvantage of the cell and human beings, to attach itself to this particular receptor molecule in order to enter the cell," Rossmann said.



The researchers also found what happens next by looking at how the virus disintegrates in the cell in order to deliver its genetic material to infect the host.



"These research results provide a detailed analysis of how a virus can enter its host cell," Rossmann said.



Polioviruses cause poliomyelitis, a human disease that affects the central nervous system, injuring or destroying the nerve cells that control the muscles. Though effective vaccines have been developed against polioviruses, scientists do not have a clear understanding of how these viruses attach to receptor molecules on cells to initiate infection.







The authors listed on the paper are Zhang; Steffen Mueller, a postdoctoral research associate at Stony Brook; Marc Morais, a former Purdue postdoctoral research associate; Carol M. Bator, a technical research assistant at Purdue; Purdue electron microscopist Valorie D. Bowman; Susan Hafenstein, a postdoctoral research associate at Purdue; Eckard Wimmer, a distinguished professor of molecular genetics and microbiology at Stony Brook; and Rossmann.



Related Web site:



Michael Rossmann



Abstract on the research in this release



Source: Emil Venere


Purdue University

Array CGH Used To Examine Human Embryonic Stem Cell Genome

Stem cell researchers from UCLA used a high resolution technique to examine the genome, or total DNA content, of a pair of human embryonic stem cell lines and found that while both lines could form neurons, the lines had differences in the numbers of certain genes that could control such things as individual traits and disease susceptibility.



The technique used to study the genome, which contains all the genes on 46 chromosomes, is called array CGH. The use of higher resolution techniques, such as array CGH and, soon, whole genome sequencing, will enhance the ability of researchers to examine stem cell lines to determine which are best - least likely to result in diseases and other problems - to use in creating therapies for use in humans.



Array CGH provided a much better look at the gene content on the chromosomes of human embryonic stem cells, with a resolution about 100 times better than standard clinical methods. Clinical specialists commonly generate a karyotype to examine the chromosomes of cancer cells or for amniocentesis in prenatal diagnosis, which has a much lower resolution than Array CGH, said Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the senior author of the study. Small defects that could result in big problems later on could be missed using karyotyping for stem cells.



"Basically, this study shows that the genetic makeup of individual human embryonic stem cell lines is unique in the numbers of copies of certain genes that may control traits and things like disease susceptibility," said Teitell, who also is an associate professor of pathology and laboratory medicine and a researcher at UCLA's Jonsson Comprehensive Cancer Center. "So, in choosing stem cell lines to use for therapeutic applications, you want to know about these differences so you don't pick a line likely to cause problems for a patient receiving these cells."



The study appears in the March 27, 2008 express edition of the journal Stem Cells.



Differences between individual DNA sequences provide the basis for human genetic variability. Forms of variation include single DNA base pair alterations, duplications or deletions of genes or sets of genes, and translocations, a chromosomal rearrangement in which a segment of genetic material from one chromosome becomes heritably linked to another chromosome. These changes can be benign, but they can also promote diseases such as certain cancers, or confer increased risk to other diseases, such as HIV infection or certain types of kidney ailments.



In this study, Teitell and his team sought to determine copy number variants (CNVs), or differences in the numbers of certain genes, in two embryonic stem cell lines. The CNVs provide a unique genetic fingerprint for each line, which can also indicate relatedness between any two stem cell lines. Teitell used embryonic stem cell lines that made different types of neurons and studied them with array CGH for comparison. His team found CNV differences between the two lines in at least seven different chromosome locations below the level of detection using standard karyotype studies. Such differences could impact the therapeutic utility of the lines and could have implications in disease development. More studies will be required to determine the effect of specific CNVs in controlling stem cell function and disease susceptibility, he said.
















"In studying embryonic stem cell lines in the future, if we find differences in regions of the genome that we know are associated with certain undesirable traits or diseases, we would choose against using such stem cells, provided safer alternative lines are available," Teitell said.



Large genome-wide association studies are underway in a variety of diseases to determine what genetic abnormalities might be at play. When the genetic fingerprint or predisposing genes for a certain disease is discovered, it could be used as key information in screening embryonic stem cell lines.







The Institute for Stem Cell Biology and Medicine was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the Institute. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding human adult and embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at stemcell.ucla/.



Source: Kim Irwin


University of California - Los Angeles

Children With Juvenile Arthritis May Have Increased Cancer Risk But Anti-TNF Therapy Doesn't Appear To Be Lone Culprit

Children with juvenile idiopathic arthritis have a two to threefold increased risk of developing cancer compared to similarly-aged children without JIA, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta. The same study also reported no cases of cancer in children with JIA who were exposed to anti-TNF therapy.


TNF antagonists, also called biologics or anti-TNF therapy, are a class of drugs that have been used since 1998; overall, they have been given to more than 600,000 people worldwide. These drugs are given by injection and lessen inflammation by interfering with biologic substances that cause or worsen the inflammatory process.


"These findings are likely to mitigate concern that arose in 2009 after a study by the Food and Drug Administration raised the possibility that children treated with anti-TNF therapy had an increased risk of developing malignancy compared to children in the general population," says Timothy Beukelman, MD, MSCE, assistant professor of pediatrics in the Division of Pediatric Rheumatology at the University of Alabama at Birmingham and lead investigator in the study. "This study led the FDA to issue a "black box" warning regarding the risk of pediatric malignancy for all of the anti-TNF agents," he says.


About one child in every 1,000 develops some type of juvenile arthritis. These disorders can affect children at any age, although rarely in the first six months of life. It is estimated that around 300,000 children in the U.S. have been diagnosed with JIA. There are several types of JIA, all involving chronic (long-term) joint inflammation. This inflammation begins before patients reach the age of 16, may involve one or many joints, and can cause other symptoms such as fevers, rash and/or eye inflammation and even cause inflammation of the internal organs.


Dr. Beukelman's research team recently used National Medicaid Administrative Claims data from all 50 U.S. states collected between 2000 and 2005 to identify 7,321 children with JIA confirmed by both a doctor's diagnosis and based on taking medications used to treat the disease. Among these children, 3,194 were taking methotrexate, a disease-modifying antirheumatic drug, and 1,413 were exposed to TNF antagonists.


The rate of cancer among all children with JIA was approximately 59 per 100,000 person-years (number of patients multiplied by number of years of observation). By comparison, the standardized rates of cancer in two groups of children without JIA were approximately 23 to 27 per 100,000 person years. Researchers identified no malignancies in participants with JIA who had been exposed to anti-TNF therapy, though the number of children treated was relatively small.


"I believe that many people agree that there's increased risk [of malignancy in JIA patients], but it's not all attributable to TNF inhibitors. At least part of the increased risk, and perhaps even all of it, appears to be attributable to the disease itself," says Dr. Beukelman.


There have been few studies investigating the relationship between JIA and cancer. However, efforts to establish the background risk of cancer associated with JIA have increased since the FDA issued its findings that TNF inhibitors are associated with an increased risk of cancer. Efforts are also underway to prospectively collect data on all children who are exposed to TNF inhibitors.


"How disease activity in JIA influences the risk of cancer is not known. We did not have access to that kind of clinical information in this type of administrative database," Dr. Beukelman explains. "TNF inhibitors may possibly be associated with an increased risk of cancer; our study did not have enough patients to definitively answer this question. But based on our findings, the amount of risk that the TNF inhibitors may be responsible for appears to be much smaller than initially suspected."


Source: American College of Rheumatology (ACR)

Researchers in Italy produce a mouse that can regenerate its tissues

Making new muscle


Rome (Italy) - Researchers at the European Molecular Biology Laboratory (EMBL) and the University of Rome "La Sapienza" have found a way to restore some of the "regenerative" ability of tissues, which happens naturally in animals at the embryonic stage of development, but is lost shortly after birth.


The scientists' work, published this week in PNAS, gives new insight into how stem cells can be mobilized across the body, and how they take on specialized functions in tissue.


"Many labs have reported the integration of stem cells into various types of tissues, but on a small scale," says Prof. Nadia Rosenthal, Coordinator of EMBL's Mouse Programme in Monterotondo, Italy.


"This is the first study to show that stem cells can be mobilized to achieve a major regeneration of damaged tissue."


In a collaboration with the group of Antonio Musarт at the University of Rome, the scientists investigated muscle tissue in mice, discovering that stem cells can travel large distances to reach an injury.


They also found a special form of a protein called mIGF-1 induces the muscle to send the distress signal that summons them.


"This form of IGF-1 is produced in the cells of embryos, but that production shuts down quickly after birth," says Rosenthal.


"It is also produced in quick bursts when muscles are injured. This made us think it might play a role in regenerating damaged tissues."


They created a strain of mouse whose muscle cells continue to produce mIGF-1 throughout its lifetime.

In order to study the activity of stem cells at the injury site and to trace those cells back to their source, the authors generated a second strain of mouse whose bone marrow produced stem cells that bore a distinctive, fluorescent tag.


"mIGF-1 is acting like a megaphone," Musarт says. "If there's an injury, muscles expressing mIGF-1 send out a very loud signal, and stem cells respond from quite far away. After birth, most animals lose the signal, which may be one of the key reasons that our tissues don't regenerate as quickly when we age."


The result is a high level of muscle regeneration, which doesn't happen in normal mice that have stopped producing IGF-1.

Muscle regeneration can also be boosted in aging mice, or animals with a form of muscular dystrophy, whose muscles are undergoing steady deterioration. Stem cells are recruited to the tissue and can significantly reverse the process.


This study also provides insight into how stem cells lose their generic quality and become specialized.

Some researchers have maintained that upon reaching a tissue, they simply fuse to existing cells and acquire some of their characteristics.


However as Prof. Rosenthal notes, "The cells we observed went through all of the typical steps of specialisation before becoming fully integrated into the new tissue.'















EMBL Press Release

European Molecular Biology Laboratory

Monterotondo Mouse Biology Programme


Prof. Nadia Rosenthal, Coordinator of the EMBL-Monterotondo Research Programme


Dr. Antonio Musarт and his research group at the University of Rome "La Sapienza"



Press Contact: Trista Dawson, EMBL Press Officer

Meyerhofstrasse 1, 69117 Heidelberg, Germany, Tel: +49 6221 387 452, Fax: +49 6221 387 525, dawsonembl


Source article: Antonio Musarт, Cristina Giacinti, Giovanna Borsellino, Gabriella Dobrowolny, Laura Pelosi, Linda Cairns, Sergio Ottolenghi, Giulio Cossu, Giorgio Bernardi, Luca Battistini, Mario Molinaro, Nadia Rosenthal. Stem cellmediated muscle regeneration is enhanced by mIgf-1. PNAS. February 3, 2004. Issue 5.


17 EMBL Member States: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom


About EMBL:


The European Molecular Biology Laboratory is a basic research institute funded by public research monies from 17 member states, including most of the EU, Switzerland and Israel. Research at EMBL is conducted by approximately 80 independent groups covering the spectrum of molecular biology. The Laboratory has five units: the main Laboratory in Heidelberg, and Outstations in Hinxton (the European Bioinformatics Institute), Grenoble, Hamburg, and Monterotondo near Rome. The cornerstones of EMBL's mission are: to perform basic research in molecular biology, to train scientists, students and visitors at all levels, to offer vital services to scientists in the member states, and to develop new instruments and methods in the life sciences. EMBL's international PhD Programme has a student body of about 170. The Laboratory also sponsors an active Science and Society programme. Visitors from the press and public are welcome.


About EMBL-Monterotondo:


The EMBL Mouse Biology Programme based in Monterotondo (Rome), is a recently established basic research center of excellence and innovation in mouse genetics and functional genomics, capturing new opportunities and applications of mouse genetic manipulation and becoming a hub for the international mouse research network. Alliances with other EMBL research units, neighboring facilities in the European Mutant Mouse Archive (EMMA) and Italian national research (CNR) groups, and European academic research and clinical centers has resulted in the participation of EMBL in several EU-wide initiatives to establish an international research and knowledge database, linking information on genetics/genomics, phenotyping/physiology and biomedical features. EMBL Monterotondo currently has six research groups, with a staff of close to 80 people.


About the University of Rome:


The University of Rome 'La Sapienza' is one of the oldest universities in Italy and in Europe, celebrating its 700th anniversary this year. As the 'Studium Urbis', the University traces its origins to April 20, 1303, with Pope Bonifacio VIII's Papal Bull entitled 'In Supremae'. The mandate of Studium Urbis was to develop the legal doctrine and the arts. In the last century, considerable efforts have been made to increase the prestige of the University of Rome in the field of basic and clinical science, creating specific research centers of excellence. The University of Rome 'La Sapienza' has 21 faculties with 4,767 lecturers and 147,000 students.


Policy regarding use:


EMBL press releases may be freely reprinted and distributed via print and electronic media. Text, photographs and graphics are copyrighted by the EMBL. They may be freely reprinted and distributed in conjunction with this news story, provided that proper attribution to authors, photographers and designers is made. High-resolution copies of the images can be downloaded from the EMBL web site: embl

Medicine Reaches The Target With The Help Of Magnets

If a drug can be guided to the right place in the body, the treatment is more effective and there are fewer side-effects. Researchers at Lund University in Sweden have now developed magnetic nanoparticles that can be directed to metallic implants such as artificial knee joints, hip joints and stents in the coronary arteries.


Associate Professor Maria Kempe, her brother and colleague Dr Henrik Kempe and members of staff at SkГҐne University Hospital have shown that the principle works in animal experiments. They have succeeded in attaching a clot-dissolving drug to the nanoparticles and, with the help of magnets, have directed the particles to a blood clot in a stent in the heart to dissolve it. Thus the nanoparticles have been able to stop an incipient heart attack.


A stent is a tube-shaped metal net used to treat narrowing of the coronary arteries. First the artery is expanded using a balloon catheter, then a stent is inserted to keep the artery open. However, the method is not without problems: depending on the type of stent inserted, the cells of the artery wall can grow and again obstruct the artery or a blood clot can develop in the stent.


In the Lund researchers' experiments, the nanoparticles were coated with a drug used to treat blood clots. The particles could also carry other drugs, e.g. drugs to stop the cell growth that makes an artery become narrower.


"They could also carry antibiotics to treat an infection developed after insertion of an implant. We have developed polymer materials that can be loaded with antibiotics these could produce interesting results in this context", says Maria Kempe.


Guiding drug-loaded magnetic particles using a magnet outside the body is not a new idea. However, previous attempts have failed for various reasons: it has only been possible to reach the body's superficial tissue and the particles have often obstructed the smallest blood vessels.


The Lund researchers' attempt has succeeded partly because nanotechnology has made the particles tiny enough to pass through the smallest arteries and partly because the target has been a metallic stent. When the stent is placed in a magnetic field, the magnetic force becomes sufficiently strong to attract the magnetic nanoparticles. For the method to work the patient therefore has to have an implant containing a magnetic metal.


"It takes many years to develop a treatment method that can be used on patients. But the good initial results make us hopeful", says Maria Kempe.


An article about the results, entitled 'The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy', has recently been published in the journal Biomaterials.


Sources: Lund University, AlphaGalileo Foundation.

Unlocking The Secrets Of Cross-Species Rabies Transmission

Like most infectious diseases, rabies can attack several species. However, which species are going to be infected and why turns out to be a difficult problem that represents a major gap in our knowledge of how diseases emerge. A paper just published in the journal Science by a team of researchers led by Daniel G. Streicker, a PhD student at the University of Georgia Odum School of Ecology, has begun to close that knowledge gap.



The paper, co-authored by researchers from the U.S. Centers for Disease Control and Prevention, the University of Tennessee-Knoxville and Western Michigan University, provides among the first estimates for any infectious disease of how often a disease can be transmitted across species in complex, multi-host communities and the likelihood of disease establishment in a new host species.



"Rabies happens to be an ideal system to answer these questions," said Streicker. "Rabies occurs across the country, affects many different host species and is known to mutate frequently." Although cases of rabies in humans are rare in the U.S., bats are the most common source of these infections, according to the CDC.



To determine the rate at which rabies infects multiple species, Streicker and his colleagues used an enormous dataset, unprecedented in its scope, containing hundreds of rabies viruses from 23 North American bat species. They used gene sequencing and tools from population genetics to quantify how many cross-species transmission (CST) events were expected to occur between each pair of species from any infected individual. Their analysis showed that, depending upon the species involved, a single infected bat may infect between 0 and 2 members of a different species; and that, on average, the probability of cross-species transmission occurs only once for every 73 transmissions within the same species.



"What's really important about this is that molecular sequence data, an increasingly cheap and available resource, can be used to quantify CST," said Streicker.



Associate professor Sonia Altizer, Streicker's advisor at the Odum School, agreed. "This is a breakthrough," said Altizer. "The team defined, for the first time, a framework for quantifying the rates of CST across a network of host species that could be applied to other wildlife pathogens, and they developed novel methods to do it."



The researchers also looked at what factors allow diseases to move across species, such as foraging behavior, geographic range and genetics.



"There's a popular idea that because of their potential for rapid evolution, the emergence of these types of viruses is limited more by ecological constraints than by genetic similarity between donor and recipient hosts," explained Streicker. "We wanted to see if that was the case."



They found, instead, that rabies viruses are much more likely to jump between closely related bat species than between ones that diverged in the distant past. Overlapping geographic range was also associated with CST, but to a lesser extent.



"CST and viral establishment do not occur at random, but instead are highly constrained by host-associated barriers," Streicker said. "Contrary to popular belief, rapid evolution of the virus isn't enough to overcome the genetic differences between hosts."



Streicker believes that what he and his colleagues have learned about bat rabies will be influential in understanding the ecology, evolution and emergence of many wildlife viruses of public health and conservation importance. "The basic knowledge we've gained will be key to developing new intervention strategies for diseases that can jump from wildlife to humans," he said.



Streicker is continuing his work with rabies and bats, with funding for a three-year study from the National Science Foundation. He and Altizer, in collaboration with investigators at the CDC, University of Michigan and the Peruvian Ministries of Health and Agriculture, will explore how human activities affect the transmission of the rabies virus in vampire bats in Peru and how those changes might feed back into altering the risk of rabies infection for humans, domesticated animals and wildlife.



"This kind of synthetic, interdisciplinary work is precisely what we aim for in the Odum School," said John Gittleman, Odum School dean. "The success of this research hinges on bringing together the fields of genetics, evolution and disease in a large-scale ecological context. Big problems in ecology will be solved in this way."



Source:

Daniel G. Streicker

University of Georgia