Visualizing Protein Interaction That May Initiate Viral Infection

Biologists at Purdue University have taken a "snapshot" of a Velcro-like protein on a cell's surface just after it attached to the dengue virus, a linkup thought to initiate the early stages of infection.


The virus, which is spread by mosquitoes, infects more than 50 million people annually, killing about 24,000 each year, primarily in tropical regions.


During the earliest stages of infection, the dengue virus attaches to the "carbohydrate recognition domain," or CRD, of a key binding protein called DC-SIGN, located on a host cell's surface.



Using a powerful imaging tool called cryo-electron microscopy, the biologists took a picture of the virus attached to the CRD shortly after the two joined together. It is the first time scientists have visualized the virus and CRD binding.


"We formed the virus-CRD complex, took a snapshot and determined its structure," said Michael Rossmann, the Hanley Distinguished Professor of Biological Sciences in Purdue's College of Science. "Ultimately, researchers might want to find ways to treat or prevent viral infections, but in order to do that we first have to learn how viruses work and how they initiate infection."


The findings are detailed in a research paper to appear on Feb. 10 in the journal Cell. The research was carried out by Elena Pokidysheva and Ying Zhang, post-doctoral research associates working with Rossmann and Richard J. Kuhn, a professor and head of Purdue's Department of Biological Sciences.


Researchers from the Howard Hughes Medical Institute at Columbia University provided a cloned gene that enabled the Purdue scientists to produce the CRD.


The CRD is part of a protein receptor molecule called DC-SIGN - or dendritic cell-specific ICAM3 grabbing non-integrin. ICAM stands for intercellular adhesion molecule, a family of cell proteins that viruses bind to, and the number 3 defines a specific protein.


"The binding occurs on dendritic cells, which are usually one of the first lines of defense in the immune system," Kuhn said. "The first step in a virus infecting a cell is usually the attachment of the virus to the receptor. That's essentially what we are looking at, except in this case, instead of having the receptor, which is normally bound or attached to the cell, we have just a portion of the receptor, the CRD, which we produced separately."


Dengue belongs to a family of viruses known as flaviviruses, which includes a number of dangerous insect-borne diseases such as West Nile, yellow fever and St. Louis encephalitis. These diseases, however, use different biological mechanisms than dengue to infect host cells. Dengue is prevalent in Southeast Asia, Central America and South America. Mosquitoes transmit the virus to people, setting in motion the infection process.















"We and others think that this CRD acts sort of like Velcro to get the virus to stick to the surface of the cell, although this has not been proven," Kuhn said. "Once the virus and protein receptor are linked, perhaps the virus then moves across the cell surface to find a second protein, attaching to that receptor and entering the cell.


"One of the things that this study shows is that only a very small portion of the cell's surface is occupied by the DC-SIGN molecule, which means a significant amount of space is still available for that other receptor protein that people don't know about yet."


Zhang said that the initial binding of the CRD and the virus might result in a "signaling event between the DC-SIGN molecule and the other primary receptor, leading to activating the other protein and promoting the cell for infection."


The virus has a diameter of 50 nanometers, or billionths of a meter, and the CRD is 3 nanometers wide.


In cryo-electron microscopy, specimens are first frozen before they are studied with an electron microscope. The method enables scientists to study details as small as 8 angstroms, or .8 nanometers, resolution high enough to see groups of atoms. An angstrom is one ten-billionth of a meter, or roughly a millionth as wide as a human hair.


Zhang discovered that the CRD attaches to a structure on the virus surface that contains two carbohydrates a distance of 18 angstroms apart. This feature apparently is essential for the binding to take place, she said.


"Why doesn't the binding happen at other sugar-binding sites?" she asked. "The answer is that we need two carbohydrate sites that are 18 angstroms apart. There are no other sites that are 18 angstroms apart."


Each virus particle contains 60 of the features, each having two carbohydrates 18 angstroms apart, representing 60 potential binding sites for the CRD.


The research has been funded primarily through a grant from the National Institutes of Health.


The paper was co-authored by Pokidysheva; Zhang; Anthony J. Battisti, a graduate student; Carol M. Bator-Kelly, a technical assistant; Paul R. Chipman, an electron microscopist; and post-doctoral researcher Chuan Xiao, all at Purdue University; G. Glenn Gregorio, a graduate student at the Howard Hughes Medical Institute at Columbia University; Wayne A. Hendrickson, a researcher at the Howard Hughes institute and a professor of biochemistry and molecular biophysics at Columbia University's College of Physicians and Surgeons; as well as by Kuhn and Rossmann.


Writer: Emil Venere


Related Web sites:

Michael Rossmann:

biology.purdue/people/faculty/rossmann/index.htm

Richard Kuhn:

biology.purdue/people/faculty/kuhn/index.htm


A publication-quality graphic is available.


Emil Venere

venerepurdue

Purdue University

purdue

Landscape Of Human-Pathogen Protein Interactions Unveiled By Researchers

Researchers at the Virginia Bioinformatics Institute (VBI) and the Department of Computer Science at Virginia Tech have provided the first global analysis of human proteins interacting with viral proteins and proteins in other pathogens. The scientists examined publicly available experimental data for 190 different pathogens that comprise 10,477 interactions between human and pathogen proteins. This approach provides a highly detailed network map of human proteins interfacing with proteins in different pathogens. The network of interactions, published in the journal PLoS Pathogens, reveals possible key intervention points for the future development of therapeutics against infectious diseases.



Matt Dyer, a bioinformatician at VBI and a graduate student in Virginia Tech's Genetics, Bioinformatics, and Computational Biology Program, remarked: "Infectious diseases result in millions of deaths each year. Although much effort has been directed towards the study of how infection by a pathogen causes disease in humans, only recently have large data sets for protein interactions become publicly available. We have leveraged this opportunity to compare protein interactions between human and pathogen proteins from 190 different pathogens to provide important insights into the strategies used by pathogens to infect human cells."



The researchers paid particular attention to two networks of human proteins - proteins that interact with at least two viral pathogens and proteins that interact with at least two bacterial pathogens. Gene Ontology (GO) terms computed for both sets of proteins provided key information on the functions of the different proteins. Some of the striking findings of the study included a clear demonstration that pathogens preferentially interact with two classes of human proteins referred to as hubs and bottlenecks. Hubs are popular proteins that interact with many other proteins in the human protein interaction network. Bottlenecks are proteins that lie on many of the shortest paths in the network. Pathogens appear to maximize their likelihood of success by targeting these high-impact, influential proteins during infection. In many cases, human proteins that mediate pathogen effects are proteins that are known to be involved in cancer pathways, for example, the transcription factor STAT1 or the tumor suppressor protein TP53. This finding suggests interesting parallels between pathogen infection and cancer and opens up future areas for research.



T. M. Murali, an assistant professor in the Department of Computer Science at Virginia Tech, added: "Previous studies have suggested that protein interaction networks have topologies that are resilient to attacks on random nodes but are susceptible to targeted attacks, for example on hubs. Our results provide a striking example of how pathogens may have evolved the ability to exploit the structure of interactions between human proteins in order to promote infection. This global study also suggests that many viruses share similar strategies to control the human cell cycle, regulate programmed cell death, and transport viral genetic material across the nuclear membrane in the human cell."
















Bruno Sobral, executive and scientific director of the Virginia Bioinformatics Institute, commented: "Infectious diseases are placing a huge burden on public health systems around the globe. At the same time, the pharmaceutical and biotechnology industries are facing the daunting challenge of increasing innovation and productivity in their drug and vaccine discovery and development pipelines. This groundbreaking study provides an exciting strategic tool for anyone in the scientific community interested in prioritizing anti-viral and anti-bacterial targets."







VBI researchers Matt Dyer and Bruno Sobral, and Department of Computer Science researcher T. M. Murali contributed to the paper, "The Landscape of Human Proteins Interacting with Viruses and other Pathogens." The paper will be featured in the February 15, 2008 edition of PLoS Pathogens 4(2): e32. doi:10.1371/journal.ppat.0040032



About VBI


The Virginia Bioinformatics Institute (VBI) at Virginia Tech (vbi.vt) has a research platform centered on understanding the "disease triangle" of host-pathogen-environment interactions in plants, humans and other animals. By successfully channeling innovation into transdisciplinary approaches that combine information technology and biology, researchers at VBI are addressing some of today's key challenges in the biomedical, environmental and plant sciences.



About the Department of Computer Science


The Department of Computer Science at Virginia Tech (cs.vt/) was established in 1971 and is part of the College of Engineering (eng.vt/), the premier engineering school in the Commonwealth of Virginia. The college has a history of innovation, including cost-effective supercomputing (System X) and entrepreneurial research innovation, leading to 3 new buildings for research in critical technologies and applied science. The Department of Computer Science is distinguished by interdisciplinary research in high-end computing systems, computational biology and bioinformatics, and human-computer interaction as well as core areas in computing. The graduate program, offering M.S. and Ph.D. degrees in Blacksburg and at the Northern Virginia Center, was ranked among the top 30 programs as measured by the most recent study of Ph.D.s awarded. The graduates of the accredited undergraduate program are highly sought by industry and well prepared for further study.



About the Genetics, Bioinformatics and Computational Biology Program


The new research paradigm exemplified by the Human Genome Project requires a new academic training, one that creates team-oriented researchers who may be specialists in one area but who are literate in several other disciplines. The transdisciplinary Ph.D. program in Genetics, Bioinformatics, and Computational Biology at Virginia Tech encompasses applications of molecular biology, genomics, mathematics, statistics and computer science to all areas of the life sciences. Transdisciplinary programs span traditional departmental boundaries and allow students enrolled in a program to study with faculty from many departments and colleges.



Source: Barry Whyte


Virginia Tech

Research Into Trace Minerals' Nutritional Alliance Boosted By Grant

Iron is the workhorse of trace minerals. An essential component of red blood cells, disruption of iron levels in the body will result in a myriad of serious conditions, and life cannot be sustained without it.


In novel research, investigators at the University at Buffalo's School of Public Health and Health Professions, have learned that iron is only one half of an all-important duo of trace minerals -- the other being copper -- that work in tandem to maintain proper iron balance, or homeostasis. It appears the workhorse has a helper. James F. Collins, Ph.D., UB assistant professor of exercise and nutrition sciences and biochemistry, discovered that when iron-absorption by cells lining the small intestine decreases during iron-deficient states, copper absorption increases.



Collins now is exploring the relationship between these two trace minerals through a $1.38 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The work will be carried out using established models of intestinal iron absorption in humans, including iron and iron/copper-deficient rodents and cultured intestinal epithelial cells.



"This project is intended to test the overall hypothesis that increased copper transport during iron-deficiency is critical to enhance certain aspects of intestinal iron absorption," said Collins. "Iron or copper deficiency causes anemia, and abnormal intestinal iron transport is associated with several common human pathologies, including anemia of chronic disease (ACD) and hereditary hemochromatosis (HH), different forms of which result from several common genetic defects."



HH is an inherited metabolic disorder characterized by abnormally high absorption of dietary iron, which is deposited in body tissues and organs, where it may become toxic. ACD is a blood disorder caused by low body iron levels resulting from any medical condition that affects the production and lifespan of red blood cells, such as chronic infection, chronic immune activation resulting in inflammation, or malignancy.



"In collaboration with Dr. Zihua Hu, Ph.D., a computational scientist at UB's New York State Center of Excellence in Bioinformatics and Life Sciences, we determined that several genes related to iron and copper homeostasis were strongly induced by iron deprivation across different developmental stages in the rat small intestine," said Collins. "We will concentrate on understanding the role of two key proteins encoded by these genes: an intestinal iron transporter called divalent metal transporter 1 (Dmt1) and an intestinal copper transporter, the Menkes copper ATPase (Atp7a)."



The overall goal of the project is to answer three specific questions regarding the role of copper in intestinal iron transport, Collins noted:

Are Atp7a and Dmt1 solely responsible for enhancing dietary copper absorption during iron-deficiency?
What are the molecular mechanisms leading to induction of the Atp7a and Dmt1 genes?
Which physiological processes related to intestinal iron ion homeostasis are enhanced by increased copper levels in enterocytes (cells of the superficial layer of the intestines) and in the liver?
"We also expect to learn more about the mechanisms of dietary copper absorption, which currently are not well defined," Collins said. "Furthermore, studies addressing the impact of increased enterocyte and liver copper levels during iron-deficiency have not been reported in the scientific literature to date, so this investigation is novel. "






Key collaborators at UB are Hu, Michael D. Garrick, Ph.D., professor of biochemistry, and Laura M. Garrick, Ph.D., research associate professor of biochemistry. The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities. The School of Public Health and Health Professions is one of five schools that constitute UB's Academic Health Center.



Source: Lois Baker


University at Buffalo

Synthetic Enzymes Could Help ID Proteins

Using a rare metal that's not utilized by nature, Rice University chemists have created a synthetic enzyme that could help unlock the identities of thousands of difficult-to-study proteins, including many that play key roles in cancer and other diseases.



The research was published online this week in the Journal of the American Chemical Society.



"We have combined the chemical capabilities of rhodium with what biology already knows about recognizing and selecting specific proteins," said study co-author Zachary Ball, assistant professor of chemistry at Rice. "The result is a tool that, in many ways, is more powerful than any biological or chemical approach alone."



Ball began studying dirhodium catalysts more than three years ago. He did not start out trying to create enzymes with them, but he was intrigued by a study that showed dirhodium catalysts could be used to modify tryptophan, one of the 21 amino acids that are the basic building blocks of life.



Catalysts enhance chemical reactions by increasing the rate of reaction without being consumed themselves. In living things, proteins called enzymes serve the same purpose. But unlike many inorganic catalysts, enzymes are very selective. In a process that biologists often liken to a "lock and key," enzymes associate only with molecules that match their shape exactly. This prevents them from spurring extraneous reactions throughout the cell.



Ball and postdoctoral research associate Brian Popp wondered if they could marry the selectivity of enzymatic reactions with a rhodium-based catalyst. They tested the idea by attaching their catalyst to a short segment of protein that can wrap with other proteins, like strands of rope fiber. This "coiled coil" wrapping motif is common in biology, particularly in signaling proteins. Signaling proteins are those that activate or deactivate key processes like apoptosis, the "programmed death" response that's known to play a key role in cancer.



"Signaling pathways are like a trail of dominos," Ball said. "Dozens of proteins can be involved, and they interact one after the other in a cascade. In most cases, the interactions are both fleeting and weak. They are difficult to observe with traditional methods, and as a result we are still in the dark about the roles that key signaling proteins play in health and disease."



Ball said his and Popp's synthetic enzyme strategy might help solve that problem. In their tests, the chemists were able to develop synthetic enzymes that could selectively bind with proteins and attach tags that would allow biologists to identify them.



In addition to tryptophan, the method worked with phenylalanine and tyrosine, two amino acids commonly found in signaling proteins. And recent unpublished studies indicate the researchers' strategy might work for even more amino acids.



Ball said the process must be refined before it can be used in the majority of biology labs, but he and Popp are already working toward realizing broad applications of the strategy.



The research was funded by the Welch Foundation and Rice University.



Source:

Jade Boyd

Rice University

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Discovery May Lead To Treatments For Chronic Sensitivity Caused By Cold Temperatures

Researchers at Johnson & Johnson Pharmaceutical Research & Development, L.L.C., today announced that they have discovered a biological basis for explaining how people sense cold temperatures.


Ultimately, these findings may be a critical step in developing treatments for patients who suffer from hypersensitivity to cold, such as occurs in neuropathic pain and complex regional pain syndromes. This research is published in the May 3, 2007 issue of Neuron.


In the study, researchers sought to understand the mechanisms underlying cold sensitivity. Scientists used a line of mice that lacked a critical ion channel receptor called TRPM8, also referred to as the cold menthol receptor 1. Then, they tested how these mice reacted to cold stimuli, and found that not having these receptors reduced their adverse reactions to the cold, both under normal and pathological conditions. Results suggest that TRPM8 modulation could play an important role in certain types of cold-induced pain in humans and could hold therapeutic potential in the treatment of many chronic, painful conditions for which there are currently limited effective treatment options.


"This work represents the culmination of a multi-year collaborative effort on the part of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., scientists to help explain fundamental mechanisms involved in human pain states and may lead to the development of innovative medicines to relieve patient suffering," said Christopher Flores, Ph.D., biology team leader for Analgesics, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. "Although preliminary, these findings provide compelling initial evidence toward validating TRPM8 as an analgesic drug target and addressing major unmet medical needs of pain patients."


Ion channels are proteins that form tiny openings through the membrane of a cell and allow the passage of certain ions that regulate cellular activities. Some of these channels are opened by chemicals, some by changes in voltage and others by various temperatures. TRPM8 is a member of the thermo-TRP family of ion channels that respond to temperatures ranging from noxious heat to noxious cold. Many scientists think that modulating the signals carried through such channels represents an important strategy for designing drugs to treat a host of conditions, including pain.


"We have a long history of bringing patients innovative treatments for pain, from TYLENOL®, which was first introduced in the 1950s, to JURNISTA™, which was launched in Europe in 2006," said Paul Stoffels, M.D., company group chairman, Pharmaceutical Research and Development, Johnson & Johnson. "Our ability to bring innovative treatments for these evolving needs starts with the understanding that not all pain is the same. Distinct biological mechanisms cause different kinds of pain, which means that while one drug target may be best for treating the neuropathic pain of a diabetes patient, another target may be better for easing the chronic pain of a patient with advanced osteoarthritis. We are committed to the discovery and development of new medicines to treat pain, and this initial discovery reflects the important research into many disease treatments being explored in our labs."


About Johnson & Johnson Pharmaceutical Research & Development, L.L.C.


Johnson & Johnson Pharmaceutical Research & Development, L.L.C., is part of Johnson & Johnson, the world's most broadly based producer of health care products. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., is headquartered in Raritan, New Jersey (USA), and has facilities throughout Europe and the United States. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., is leveraging drug discovery and drug development in a variety of therapeutic areas to address unmet medical needs worldwide.


Johnson & Johnson

jnj/home.htm

Los Angeles Society Of Pathologists Honors Dr. Samuel W. French

The Los Angeles Society of Pathologists, Inc. presented its Lifetime Achievement Award to Samuel W. French, MD, a principal investigator at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed), on Jan. 15.



The Society is an organization of more than 350 members from throughout Southern California seeking to improve the practice of pathology. Dr. French has been affiliated with LA BioMed and Harbor-UCLA Medical Center for more than two decades, leading the way in research and training in pathology.



"Congratulations to Dr. French for this recognition of a lifetime of achievements," said LA BioMed President and CEO David I. Meyer, PhD. "Dr. French is renowned for his extensive research and scholarship in pathology and for the invaluable training he's provided to residents. His dedication and his many years of service are appreciated by all of us at LA BioMed."



Dr. French has authored or co-authored more than 800 research papers, book and book chapters, case studies and abstracts in his field. He has been Harbor-UCLA Medical Center's chief of the Division of Anatomic Pathology since 1990.



He is a distinguished professor of pathology at UCLA and has received numerous honors, including seven "Best Teacher" awards from senior pathology residents at Harbor-UCLA Medical Center and the Distinguished Teaching Award from Harbor-UCLA's Clinical Faculty in the Department of Medicine.



Source:

Laura Mecoy

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed)

Major Public-Private Biomedical Research Partnership, The Biomarkers Consortium, Totals 30 Companies And Nonprofits

Contributing membership in The Biomarkers Consortium now totals 30 companies and non-profit trade associations and advocacy groups, it has been announced. To date, these organizations have committed an aggregate of nearly $2 million to fund the first year of the central activities of the consortium which is managed by the Foundation for the National Institutes of Health.



A major public-private biomedical research partnership unprecedented in breadth, The Biomarkers Consortium embraces government, industry, patient advocacy and other non-profit private sector organizations. In addition to the Foundation for NIH, founding members include: the National Institutes of Health, the Food and Drug Administration, and the Pharmaceutical Research and Manufacturers of America.



The 30 contributing members are: the Academy of Molecular Imaging; the Advanced Medical Technology Association; the Alzheimer's Association; the American Association for Cancer Research; the American Cancer Society; the American College of Neuropsychopharmacology; the American Society of Clinical Oncology; the Association of Clinical Research Organizations; AstraZeneca; BG Medicine; the Biotechnology Industry Organization; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb; EMD Serono; the Michael J. Fox Foundation for Parkinson's Research; GlaxoSmithKline; GVK BIOSciences; Johnson & Johnson, the Kidney Cancer Association; The Leukemia & Lymphoma Society; Eli Lilly & Company; Luminex Corporation; Merck & Co., Inc.; Novartis; Novo Nordisk; Pfizer Inc; the Pharmaceutical Research and Manufacturers of America; the Radiological Society of North America; F. Hoffmann-La Roche; and, the Society of Nuclear Medicine.



As previously reported, this large-scale, public-private biomedical research partnership was formally launched in late 2006 to identify and qualify new, quantitative biological markers ("biomarkers"), for use by biomedical researchers, regulators, and health care providers. The Biomarkers Consortium will harmonize approaches to identifying viable biomarkers, verify their individual value, and formalize their use in research and regulatory approval.



The overall aim of The Biomarkers Consortium is to accelerate delivery of technologies, medicines, and therapies for successful prevention, early detection, diagnosis, and treatment of disease. The identification of biomarkers is an essential element for the new era of predictive, preventive, and personalized medicine in which the accuracy of individual health assessments will exceed those of today. Biomarkers will accelerate basic and translational research and the development of safe and effective medicines and treatments for a wide range of diseases and help guide clinical practice.



The Biomarkers Consortium is now actively soliciting biomarker project concepts from the biomedical research community. If adopted by the consortium, concepts are developed into formal project proposals. Upon approval of project plans by the consortium's executive committee, the Foundation for the National Institutes of Health then undertakes fund-raising for project implementation. For example, to date over $6 million has been raised from the private sector to support the consortium's lung cancer and lymphoma cancer biomarker projects, the first projects approved for execution by the consortium.



Concept submissions must succinctly and clearly define the background and rationale for the proposed project and describe findings that demonstrate the feasibility of the proposed study and the likelihood of the expected outcome. Complete information on The Biomarkers Consortium, including its online project concept submission process and how organizations can become involved in the consortium through its contributing membership program,is available at: biomarkersconsortium/.






The Foundation for the National Institutes of Health was established by the United States Congress to support the mission of the National Institutes of Health -- improving health through scientific discovery. The foundation identifies and develops opportunities for innovative public-private partnerships involving industry, academia, and the philanthropic community. A non-profit, 501(c)(3) corporation, the foundation raises private-sector funds for a broad portfolio of unique programs that complement and enhance NIH priorities and activities. The foundation's Web site address is fnih/.



Source: Charles Pucie

NIH/Foundation for the National Institutes of Health

Spinal Cord Repair May Be Hindered By Damaging Inflammatory Response

The inflammatory response following a spinal cord injury appears to be set up to cause extra tissue damage instead of promoting healing, new research suggests.



Scientists analyzing this inflammatory response in mice discovered that the types of cells recruited to the site of the injury are dominated within a week by those that promote inflammation. When chronic, inflammation can prevent healing, and these inflammatory cells are believed to remain at the injury site indefinitely.



Meanwhile, similar cells that are typically involved in a later phase of injury repair and that are anti-inflammatory were found to promote effective growth of axons that connect nerve cells. However, these cells disappear shortly after an injury, making it unlikely that they get a chance to complete their work under naturally occurring circumstances.



All of the responding cells in question are macrophages, but the study revealed that they have slightly different characteristics that define their functions. The research suggests that changing the balance of how these cells are activated in favor of the anti-inflammatory macrophages could be a potential treatment strategy for spinal cord injury.



Currently, no Food and Drug Administration-approved treatment exists for spinal cord injury, and scientists have not discovered a way to repair nerve cells that are damaged or killed when the spinal cord is injured. An estimated 1.3 million people in the United States are living with a spinal cord injury, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.



"If these pro-inflammatory macrophages are a big part of the reason cells are dying, and we can figure out how to shut off that death cascade that they start, we might be able to minimize the amount of tissue damage," said senior study author Phillip Popovich, a professor of neuroscience and molecular virology, immunology and medical genetics at Ohio State University.



"If that could be achieved by injecting a drug or giving a patient a pill for a set number of days after injury, that could improve a lot of function and quality of life for people who suffer a spinal cord injury."



The research was presented Wednesday during a poster session at the Society for Neuroscience annual meeting in Chicago.



Popovich has known about the presence of macrophages after spinal cord injury for a long time. What he didn't know was exactly what they did, or how they did it, or whether there could be more than one function among these cells.



"I've always been of the mind that if nature requires these cells to be there, we must figure out if it's advantageous or disadvantageous for spinal cord function," said Popovich, also director of Ohio State's Center for Brain and Spinal Cord Repair.



"If what they do is disadvantageous, how can we change that without completely removing them? Because if we remove them, it will probably change a lot of other things and that is not going to be beneficial."
















In this study, he and colleagues compared the spinal cords of mice with injury to the spinal cords of uninjured mice. The mouse injuries resembled the most common contusion/compression spinal cord damage in humans that occurs when a vertebral bone or a disc bumps into the cord, causing a lesion and bleeding.



The researchers used chemicals to stain the spinal cords with markers that would indicate what types of cells were active at the injury site. They named the pro-inflammatory macrophages M1 cells and anti-inflammatory macrophages M2 cells.



Immediately after the injury, the researchers observed an intermingling of M1 and M2 cells at the site of the spinal cord injury. In just a few days, all of the anti-inflammatory M2 cells had disappeared. The pro-inflammatory M1 population persisted for a month after injury - the longest period scientists have ever observed.



Popovich said he and colleagues used recent principles learned by others in models of repair of injured heart muscle to predict how the inflammatory response to spinal cord injury would occur. After the heart is damaged, macrophages migrate to the site to clean up debris and protect against any invading bacteria or other pathogens. Signals are eventually sent out to initiate a next phase, which prepares the site for repair. Then new cells are recruited, blood vessels grow and other macrophages facilitate closure of the wound.



In the spinal cord, the long-term presence of pro-inflammatory M1 cells appears to prevent the shift into a repair phase.



"What we've done is overly simplistic, but it's an advance conceptually from where we were because we're saying that even though it looks like a homogeneous response, not all macrophages are created equal," Popovich said.



Once they knew how M1 and M2 cells were distributed at an injury site, the researchers sought to determine what those two types of macrophages could do.



They created in vitro models - essentially, test tube experiments - in which they examined the effects of M1 and M2 macrophages on neurons, the cells that make up most of the spinal cord and brain.



The M1 macrophages killed neurons or stimulated a sprouting type of growth among their axons, which function as arms on neurons that reach out to connect with other cells or to send and receive signals. This type of sprouting of axons is associated with misguided circuits and can actually cause chronic pain.



The M2 cells, on the other hand, promoted long-distance axon growth without causing toxicity. This is the kind of axon growth required to regenerate spinal cord tissue and is the type of axon growth that is normally inhibited by proteins and cells that accumulate in the spinal cord after injury.



Popovich speculates that the immune system normally inhibits axon regeneration because its primary goal is to keep the injured spinal cord free from infection.



"The injury opens tissue to the external environment, increasing the potential to be exposed to pathogens. The immune system doesn't care that the spinal cord is damaged - it just wants to keep the organism alive," he said. "And neurons want to regrow, but when they try to grow their axons, they hit a wall of inflammatory cells that they can't get past or that are working against them."



One class of drugs - PPARgamma agonists, used to treat diabetes - is known to promote recruitment of M2 macrophages and has appeared in previous research to protect neurons in models of spinal cord injury, Popovich said. But before pursuing drug therapies, researchers must determine whether changing the balance of macrophages in an injured spinal cord to favor the activation of M2 cells would actually be beneficial in a human body.



"The only benefits we've shown so far were in vitro," he said. "There's a chance we'll never be able to figure out how to regenerate an axon. But if we could minimize damage caused by inflammation, that would be helpful. Each axon that dies gets you closer to a threshold where you lose function. If we could just keep axons and neurons alive, we may have a better chance at promoting recovery."



The National Institutes of Health and the National Institute of Neurological Disorders and Stroke supported this research.



Popovich conducted the work with postdoctoral researchers Kristina Kigerl and John Gensel, and research scientist Daniel Ankeny, all of Ohio State's Department of Molecular Virology, Immunology and Medical Genetics; Jessica Alexander of the Neuroscience Graduate Studies Program; and graduate student Dustin Donnelly of the Medical Scientist Program. All of the co-authors also are also investigators in the Center for Brain and Spinal Cord Repair.



Source:
Phil Popovich


Ohio State University

Launch Of New BioInterfaces Research Program

With an annual budget of 20 Million Euro, 67 research groups develop new tools to control cells



This will lead, for example, to new ways of growing stem cells, or manipulating cells in the organism and in bioreactor systems. These key technologies will ultimately contribute to the development of new therapies for many degenerative diseases that affect muscle, the retina or the central nervous system. In addition, BioInterfaces aims to control or inhibit bacterial cells that form biofilms on man-made surfaces, another area of immense technical relevance.



"The basic philosophy of the BioInterfaces programme is to learn from nature and then copy it. So, the first stage of our strategy involves a focused, innovative, large-scale analysis to learn more about the natural control mechanisms of cells and how optimally to manipulate them", says Professor Uwe Strähle, speaker of the program and head of the Institute of Toxicology and Genetics. "This will be achieved by a close partnership between biologists and technology developers. In the subsequent stages, multifunctional molecular devices or advanced surface modifications will be designed and built in order to target and interact with the key molecular control points and thereby to control cell behaviour."



The interdisciplinary nature of the BioInterfaces programme demands a new generation of scientists. The programme has therefore just launched the BioInterfaces Postgraduate School that will provide interdisciplinary training for approximately 90 PhD students. Students will be offered introductory courses covering all the participating disciplines. This school will foster cross-talk between the BioInterfaces research fields through the funding of interdisciplinary and "twinning" student projects.



Reflecting the Helmholtz research philosophy, the BioInterfaces researchers have access to or operate large scale infrastructures such as the largest fish facility in Europe, the ANKA synchrotron radiation source, a large computing and data storage facility, microand nano-fabrication facilities, and advanced surface analysis technology. The programme is based at the campus north of KIT, the Forschungszentrum Karlsruhe. This large Helmholtz research center encompasses a research expertise in micro- and nanotechnology but is also the home for basic biology research. Importantly, BioInterfaces establishes a regional focus since it involves a strong partnership with the University of Heidelberg, recently promoted to the "elite class" of German universities. Strategically, BioInterfaces represents a key programme that demonstrates the great potential offered by KIT.



Source:
Dr. Elisabeth Zuber-Knost


Helmholtz Association of German Research Centres

Studies Of OrthoLogic's Chrysalin(R) (TP508) Show Specific Receptor Binding Activity And Effects In Human Endothelial Cells

OrthoLogic Corp. (Nasdaq:
OLGC) today announced results of experiments that advance the basic science
supporting its novel synthetic peptide Chrysalin (TP508). Two posters are
being presented at the American Society for Cell Biology 46th Annual
Meeting in San Diego, CA (December 9 - 13, 2006).



"The experiments being presented at this year's ASCB Annual Meeting
help to further our understanding of the basic science behind this exciting
molecule," said Darrell H. Carney, Ph.D., Professor of Biochemistry and
Molecular Biology at The University of Texas Medical Branch, Galveston. "We
have gained greater insight into how TP508 stimulates repair and
revascularization of tissues; we believe that endothelial cells play a key
role in a number of TP508 effects."



The first presentation demonstrates binding and chemical cross-linking
of TP508 to specific molecules on the surface of endothelial cells. This is
the first identification of what may be a specific TP508 receptor. It
therefore represents a significant step in understanding how TP508
activates cells.



Dr. Carney and colleagues have explored the signals that are stimulated
by TP508 binding to endothelial cells. Their studies, as described in the
second presentation, show that TP508 increases the ability of endothelial
cells to produce nitric oxide and that TP508 prevents negative effects
caused by oxygen deprivation, a condition found in myocardial ischemia and
chronic wounds. This discovery may provide a unifying hypothesis to explain
how TP508 stimulates tissue repair, and raises the possibility that TP508
could be useful in treating a number of vascular diseases associated with
aging where endothelial cells fail to produce nitric oxide.



About the Receptor Binding Presentation



"Demonstration of Specific Binding of TP508 to Receptors on Fibroblasts
and Coronary Artery Endothelial Cells by Photo-Affinity Cross-Linking"




TP508 is a non-proteolytic synthetic peptide representing the portion
of human thrombin originally identified as the fibroblast high-affinity
receptor binding domain. TP508 initiates cellular effects distinct from
those of proteolytically active thrombin and has been postulated to bind a
non-proteolytically activated thrombin receptor (NPAR). TP508 has been
shown to accelerate revascularization and repair of animal tissues and to
accelerate healing of bone fractures (based on x-ray evidence) and diabetic
foot ulcers. The data presented show that TP508 specifically binds to one
or more cell surface receptors. The data also provide initial
characterization of receptor molecules that appear to be distinct from the
PAR1 thrombin receptor. Ongoing characterization and sequencing will
provide additional answers to advance the understanding of how these
molecules relate to TP508 signaling.
















About the eNOS Presentation



"Thrombin Peptide, TP508, Upregulates Expression and Activation of eNOS
and Prevents Hypoxia-Induced eNOS Downregulation in Human Endothelial
Cells"



TP508 is being evaluated in preclinical tests for potential use in
myocardial revascularization and other vascular indications. In animal
models, TP508 accelerates repair and revascularization of dermal and
musculoskeletal tissue and increases the density of blood vessels in
ischemic myocardium. This abstract describes experiments in which the
authors studied the effects of TP508 on endothelial cell nitric oxide (NO)
signaling and the enzyme that produces NO (eNOS). Impaired NO production
reduces the responsiveness of endothelial cells to angiogenic factors and
causes loss of endothelial function in ischemic and inflamed blood vessels
contributing to a number of chronic diseases. The authors hypothesized that
TP508 may accelerate tissue repair by stimulating NO production or
restoring the ability of dysfunctional cells to make NO. If so, TP508 may
have potential therapeutic value in tissues and diseases exhibiting
endothelial dysfunction. The studies show that in human coronary artery
endothelial cells, TP508 increased phosphorylation of eNOS. This effect of
TP508 was observed in normal cells and those cultured in low oxygen. TP508
also increased eNOS expression and prevented low oxygen-induced decreases
in eNOS expression. Therefore, TP508 may exert its effects in a number of
tissues by modulating eNOS activity and NO production in endothelial cells.



About OrthoLogic



OrthoLogic is a biotechnology company committed to developing a
pipeline of novel therapeutic peptides and other molecules aimed at helping
patients with under-served medical conditions. The Company is focused on
the development and commercialization of two product platforms:


Chrysalin(R) (TP508) and AZX100.



Chrysalin, the Company's novel synthetic 23-amino acid peptide, is
being studied in two lead indications, both of which represent areas of
significant unmet medical need -- fracture repair and diabetic foot ulcer
healing. Based on the Company's pioneering scientific research of the
natural healing cascade, OrthoLogic has become a leading company focused on
bone and tissue repair. The Company owns exclusive worldwide rights to
Chrysalin.



AZX100 is a novel synthetic pre-clinical 24-amino acid peptide, one of
a new class of compounds in the field of smooth muscle relaxation called
Intracellular Actin Relaxing Molecules, or ICARMs(TM). AZX100 is currently
being evaluated for commercially significant medical applications, such as
the treatment of vasospasm associated with subarachnoid hemorrhage, the
prevention of keloid scarring and the treatment of asthma. OrthoLogic has
an exclusive worldwide license to AZX100.



OrthoLogic's corporate headquarters are in Tempe, Arizona. For more
information, please visit the Company's website: orthologic.



Statements in this press release or otherwise attributable to
OrthoLogic regarding our business that are not historical facts are made
pursuant to the safe harbor provisions of the Private Securities Litigation
Reform Act of 1995. These forward-looking statements, which include the
timing and acceptability of FDA filings and the efficacy and marketability
of potential products, involve risks and uncertainties that could cause
actual results to differ materially from predicted results. These risks
include: delays in obtaining or inability to obtain FDA, institutional
review board or other regulatory approvals of pre-clinical or clinical
testing; unfavorable outcomes in our pre-clinical and clinical testing; the
development by others of competing technologies and therapeutics that may
have greater efficacy or lower cost; delays in obtaining or inability to
obtain FDA or other necessary regulatory approval of our products; our
inability to successfully and cost effectively develop or outsource
manufacturing and marketing of any products we are able to bring to market;
changes in FDA or other regulations that affect our ability to obtain
regulatory approval of our products, increase our manufacturing costs or
limit our ability to market our products; our possible need for additional
capital in the future to fund the continued development of our product
candidates; and other factors discussed in our Form 10-K for the fiscal
year ended December 31, 2005, and other documents we file with the
Securities and Exchange Commission.


OrthoLogic Corp.

orthologic

Worm Species Adapts To Pesticides In 80 Days

A new study published in the open-access journal PLoS ONE
finds that populations of the worm Caenhorabditis elegans
need 20 generations to become resistant to pesticides - that is just 80
days. The study, conducted by researchers at the Instituto Gulbenkian
de Ciencia (IGC) and the Faculty of Science of the University of
Lisbon, Portugal, furthers understanding of how pests and
parasites respond to pesticides and antibiotics.



Levamisole is a widely used pesticide that is lethal to the nervous
system of the worm C. elegans if exposed to high
enough doses. In lower doses, the pesticide merely affects fecundity
and mobility of the worm. Following 20 generations of the
Levamisole-exposed worm, PatrГ­cia Lopes and colleagues discovered that
the pesticide significantly reduced fecundity, survival, and the
frequency of males. Although males started out as about 30% of the
population, they numbered 0% by the 10th generation. The researchers
note that males were not necessarily more susceptible to Levamisole
than females. However, the worms were less mobile after exposure to the
pesticide and were unable to find mates.



This lack of males did not, though, lead to the demise of the entire
worm population. As the worms adapted to this new Levamisole
environment, they began to show a revival in survival and fecundity
from the 10th to the 20th generation, and the number of males increased
again. How was it possible to reproduce without any males? C.
elegans is a hermaphrodite species, and so some worms in the
population are both male and female and could breed on their own (a
process called "selfing").



The researchers then put the adapted worms into an environment with out
pesticides, and the worms were able to survive without any problems.
This means that there were no adaptation costs to the population.
"These findings have implications for managing the application of
pesticides: if we had found that the survival of adapted worms in the
original environment was impaired too, this would have meant that, by
maintaining areas where the pesticide is not spread, resistance to the
pesticide could be controlled, and the efficacy of the pesticide
increased," said Elio Sucena (group leader at IGC and
co-author of this study).



Group leader at the University of Lisbon Sara MagalhГЈes concludes that,
"As a result of the widespread use of pesticides and antibiotics,
resistance to these chemicals has developed in many species. Our
ability to manage this resistance entails being able to dissect the
genetic changes underlying the acquisition of resistance. Our approach,
using experimental evolution, allows us to manipulate several factors,
such as population size, environmental stability and genetic background
in our efforts to tackle and understand pesticide resistance, not only
of C. elegans but also other pests and parasites."



Rapid Experimental Evolution of Pesticide Resistance in C.
elegans Entails No Costs and Affects the Mating System

Lopes PC, Sucena Г‰, Santos ME, MagalhГЈes S

PLoS ONE (2008). 3(11): e3741.

doi:10.1371/journal.pone.000374

Click
Here to View Article



About PLoS ONE



PLoS ONE is the first journal of primary research
from all areas of science to employ both pre- and post-publication peer
review to maximize the impact of every report it publishes. PLoS
ONE is published by the Public Library of Science (PLoS), the
open-access publisher whose goal is to make the world's scientific and
medical literature a public resource.



About the Public Library of Science



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



Written by: Peter M Crosta

Cellular Decision On The Computer

Scientists of the Division of Theoretical Bioinformatics at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg have simulated on the computer how cells decide whether or not to migrate. Using their results, the researchers were able to predict the molecular targets within a cell that have to be hit so that its behavior changes in a particular direction. This method may help to develop new treatments against cancer metastasis. The scientists have published their results in the latest issue of Molecular Systems Biology.



One hundred and thirty years ago, Paul Ehrlich, pioneer of chemotherapy, speculated that when a cell gets sick, this is caused by a molecular change that has taken place inside the cell. Ehrlich surmised that if one could specifically hit this place of change, i.e. the "molecular target", then the disease could be cured.



When it comes to cancer, this concept has only limited applicability, because tumor cells are altered in many places. For cancer treatment to be successful, it needs to hit several molecular targets - and in a specific order, too. However, with the number of targets growing, the number of possible combinations of hits increases exponentially. If one aims to influence the genetic activity of a cell, there are several thousand targets to choose from. In this case it is impossible to test all possible combinations experimentally in order to find an efficient therapy. In this area, biologists and medical researchers are seeking help from mathematicians or physicists. They provide computer models that simulate a cell's behavior and, thus, make "testing" possible at all. This new research field is called systems biology.



In an interdisciplinary collaboration, research groups at DKFZ have now succeeded in elucidating the process underlying a cell's decision about how it is going to behave. Scientists in the teams of biologist Dr. Axel Szabowski, physicist Dr. Hauke Busch and mathematician Professor Roland Eils have investigated what makes human skin cells migrate into a wound to make it heal. They showed that the cells take several steps to decide to "start moving", how fast to do so, where to go and when to stop again. For the process to start, various external signals have to be received in a particular order. The scientists subsequently simulated this process on the computer. In doing so, they succeeded in predicting the molecular targets by which a cell's behavior can be changed in a particular direction.



Metastasizing cancer cells, too, migrate through the body - though in their case, it is undesired. They decide to migrate even when normal cells would not move. Using the new simulation method developed by the DKFZ researchers, it is possible to simulate how the genes involved in this process interact and, thus, find out the molecular targets and the order in which they need to be hit so that tumor cells stop migrating. Therefore, the method is relevant not only for basic medical research, but also forges new paths in cancer medicine.



H. Busch et al. Gene network dynamics controlling keratinocyte migration. DOI:10.1038/msb.2008.36 The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V.).







Source: Dr. Stefanie Seltmann


Helmholtz Association of German Research Centres

News From The Journal Of Neuroscience

1. Targeting Arc to Synaptic Sites

Fen Huang, Jennifer K. Chotiner, and Oswald Steward



Arc/Arg 3.1 is not only an immediate early gene, but its mRNA is also targeted to dendrites. Thus it has become a focus of studies linking neural activity to changes in synaptic efficacy. This week, Huang et al. further explored the signaling cascade involved in the targeting of Arc mRNA and protein to active synaptic sites. The authors induced long-term potentiation in adult anesthetized rats by stimulating the medial perforant path and recording the response in the dentate gyrus. High-frequency stimulation was continued for periods of up to 90 min. Polymerized actin, measured by phalloidin staining, colocalized with Arc/Arg 3.1 mRNA in the activated dendritic lamina within the molecular layer of the dentate gyrus. This colocalization was blocked by inhibition of Rho kinase or inhibition of actin polymerization with latrunculin B. ERK1 phosphorylation induced by high-frequency stimulation was also required for the targeting of Arc/Arg 3.1 mRNA.



2. Retraction Bulbs and Microtubule Networks

Ali Ert'rk, Farida Hellal, Joana Enes, and Frank Bradke



It's not altogether clear why injured peripheral axons can regenerate relatively easily, whereas central axons have a much rougher time. This week, Ert'rk et al. decided to take a comparative look at microtubules in the business end of the axon: the tip or growth cone. Rather than growth cones, injured central axons have swellings at their tips called retraction bulbs that are the hallmark of a failed growth response. The authors lesioned the dorsal column or the sciatic nerve in 2-to 3-month-old mice and tracked axon tips with a fluorescent reporter. In central axons, retraction bulbs continue to increase in size after injury and contained disorganized microtubule networks compared with the sleek and organized regenerating peripheral axons. Disruption of microtubules with nocodazole caused retraction bulb formation in peripheral axons in vivo and in cell culture. In contrast, stabilizing microtubules with taxol prevented retraction bulbs.



3. Mapping Fingerpads in S1 with Positive BOLD

Li M. Chen, Gregory H. Turner, Robert M. Friedman, Na Zhang, John C. Gore, Anna W. Roe, and Malcolm J. Avison



Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to map functional brain activity in humans, whereas optical imaging of intrinsic signals (OIS) has been used for similar purposes in animals. Most BOLD studies use the 'positiveВ± signal', rather than much smaller early negative BOLD that likely corresponds to the signal detected by OIS. OIS is generally regarded as having higher spatial resolution on the order of 100 m and higher time resolution on the order of 100 ms. This week, Chen et al. compared the two techniques by mapping single distal fingerpad activation in the somatosensory cortex (S1) of anesthetized squirrel monkeys. Using a 9.4 T magnet, the authors report that positive BOLD signals without contrast agents could resolve submillimeter shifts in activation in area 3b, similar to what was detectable with OIS. Coregistration of fMRI and OIS maps in the same monkeys showed close agreement.



4. The Time Course of the Phenotype in HD Mice

Mary Y. Heng, Sara J. Tallaksen-Greene, Peter J. Detloff, and Roger L. Albin



The long latency, measured in decades, before onset of symptoms is a hallmark of adult-onset Huntington's disease (HD). Yet putative treatments would best be tested before overt clinical symptoms emerge in man or in mouse models of the human disease. This week, Heng et al. tracked the time course of changes in behavior and in the striatum of the Hdh-(CAG150) knock-in mouse model of HD. All mice survived to 100 weeks, but by that point, they had a tremor, unsteady movements, and a staggering gait. A battery of behavioral tested revealed motor abnormalities at 70 and 100 weeks. There were also losses in striatal dopamine D1 and D2 receptors at 70 and 100 weeks and a loss of striatal neuron number at 100 weeks. These longitudinal studies not only validate this mouse model as exhibiting features consistent with HD but also provide a benchmark for its use in studies of pathogenesis and treatment.





Source: Sara Harris


Society for Neuroscience




View drug information on Taxol.

Specific Lung Cancer Susceptibility Gene Identified By Researchers

University of Cincinnati (UC) cancer cell biologists have identified a distinct gene linked to increased lung cancer susceptibility and development. They say this gene - known as RGS17 - could result in a genetic predisposition to develop lung cancer for people with a strong family history of the disease.



With further investigation, they believe the gene could be used to identify high-risk patients who may benefit from earlier, more aggressive lung cancer screening.



Marshall Anderson, PhD, and his colleagues report their findings in the April 15, 2009, issue of the journal Clinical Cancer Research.



"Understanding how the RGS17 gene impacts cancer development could change clinical diagnosis and treatment as radically as discovery of the breast cancer genes (BRCA1 and BRCA2) did," explains Anderson, who has led the multi-institutional Genetic Epidemiology of Lung Cancer Consortium (GELCC) studying the genetic basis of lung cancer since 1997. "A proven genetic test could help us identify people at risk before the disease progresses."




According to the American Cancer Society, lung cancer is the leading cause of cancer related disease and death. Although tobacco smoke is the primary environmental cause of the disease, science has shown there is also a strong genetic component to the disease.



"This study represents a significant contribution to our understanding of lung cancer susceptibility and is another step toward to the goal of preventive medicine," says David Christiani, MD, MPH, a professor of occupational medicine and environmental health at the Harvard School of Public Health, whose two-page commentary on the study is published in conjunction with the GELCC team's scientific findings. "The authors undertook a daunting challenge of performing a family-based study of lung cancer in an effort to identify specific causal genes."



Genes, which are located in fixed positions on the cell's chromosomes, carry the DNA code that determines inherited characteristics, including a risk of certain diseases.




For this study, Anderson and his multi-institutional team collected biological samples from numerous multigenerational families with five or more members who were affected by lung cancer. Through a combination of what is known as "fine mapping" - where genetic information is dissected and analyzed - and genetic association studies, researchers identified RGS17 as a major candidate susceptibility gene for familial lung cancers.



Research has shown that lung cancer can occur sporadically - where people have no known risk factors or family history - or hereditarily, occurring in multiple members of the same family. In 2004, Anderson's team reported the first genetic evidence of a major lung cancer "susceptibility locus" on chromosome 6, and evidence of a susceptibility region on three other chromosomes.




The region of the original chromosome where the lung cancer markers were found contained about 100 genes, including several genes suspected to be involved in tumor suppression and cell growth.




Using a genetically altered mouse model, researchers determined that when RGS17 was suppressed, lung tumors shrank, proving the gene was involved in cancer development and must be present for cancer growth.




"What was most interesting is that this same gene was over-expressed in 60 percent of the samples from non-hereditary lung tumors," explains Anderson. "This suggests that perhaps epigenetic factors may be contributing to abnormal genetic development."



The UC-led team will conduct additional research to investigate how environmental factors may influence familial cancer development.


Notes:


Funding for this research comes from the National Institutes of Health through the Genetic Epidemiology of Lung Cancer Consortium, a collaborative research effort established in 1997 to research the genetic origins of familial lung cancers. Anderson serves as principal investigator. Collaborating institutions include Washington University-St. Louis, Mayo Clinic-Rochester, University of Colorado, University of Texas Southwestern Medical Center, Louisiana State University, Saccomanno Research Institute, National Cancer Institute, National Human Genome Research Institute, Karmanos Cancer Institute, University of Toledo and M.D. Anderson Cancer Center-Houston.



The team continues to collect information from families and patients with a history of lung cancer.



Source:
Amanda Harper


University of Cincinnati

Mystery Of How Largest Cellular Motor Protein Powers Movement Solved By UNC Scientists Solve

Scientists now understand how an important protein converts chemical energy to mechanical force, thus powering the process of cell division, thanks to a new structural model by University of North Carolina at Chapel Hill researchers.



The structural model helps solve a scientific mystery: how the protein dynein fuels itself to perform cellular functions vital to life. These functions include mitosis, or cell division into identical cells.



Dynein uses energy derived from ATP, or adenosine triphosphate, a molecule that is the principal form of energy for cells. The lack of a comprehensive and detailed molecular structure for dynein has kept scientists largely in the dark about how the protein converts ATP into mechanical force, said Dr. Nikolay V. Dokholyan, assistant professor of biochemistry and biophysics in the UNC School of Medicine.



Dokholyan said the dynein puzzle is similar to figuring out how auto engines make cars move.



"You have an engine up front that burns gas, but we didn't know how the wheels are made to move."



Dr. Timothy Elston, associate professor of pharmacology and director of the School of Medicine's bioinformatics and computational biology program, explains further. "One of the unknowns about dynein was that the molecular site where chemical energy is initially released from ATP is very far away from where the mechanical force occurs. The mechanical force must be transmitted over a large distance."ќ



The study was published online in the Proceedings of the National Academy of Sciences Early Edition. The work was supported in part by grants from the Muscular Dystrophy Association and the American Heart Association.



Using a variety of modeling techniques that allowed resolution at the level of atoms, Adrian W.R. Serohijos, a graduate student in Dokholyan's lab and first author of the study, identified a flexible, spring-like "coiled-coil" region within dynein. It couples the motor protein to the distant ATP site.



"This dynein coiled-coil was completely missing from all previous studies. We saw it could allow a very rapid transduction of chemical energy into mechanical energy," Dokholyan said.



Conversion to mechanical energy allows dynein to transport cellular structures such as mitochondria that perform specific jobs such as energy generation, protein production and cell maintenance. Dynein also helps force apart chromosomes during cell division.



"Dividing cells must separate their chromosomes and something has to generate the force to move chromosomes apart. Dynein provides the mechanical energy to do that," Doholyan said.



While the research offers no immediate application to human disease, the authors noted that mutations of dynein have been implicated in some neurodegenerative and kidney disorders. Dokholyan pointed out that disruption of dynein's interaction with a particular regulator protein causes defects in nerve cell transmission and mimics the symptoms of people with amyotrophic lateral sclerosis (ALS).







Study co-authors include Dr. Feng Ding, research associate in biochemistry and biophysics, and Yiwen Chen, graduate student in physics and astronomy.



Contact: Les Lang


University of North Carolina School of Medicine

People Vary Widely In Ability To Eliminate Arsenic From The Body

Large variations exist in peoples' ability to eliminate arsenic from the body, according to a new study that questions existing standards for evaluating the human health risks from the potentially toxic substance. The study found that some people eliminate more than 90 percent of the arsenic consumed in the diet. Others store arsenic in their bodies, where it can have harmful effects. The research, based on the first application of new methods for studying arsenic, is scheduled for the Sept. 21 issue of ACS's Chemical Research in Toxicology, a monthly journal.



In the study, Kevin Francesconi and colleagues point out that drinking water in many parts of the world, including some regions of the United States, contain amounts of arsenic that exceed the World Health Organization's maximum acceptable levels. Consumption of seafood, the article notes, is another major source of arsenic contamination. Health effects from chronic arsenic exposure include skin and internal cancers, cardiovascular disease, and possibly diabetes, it adds.


The scientists describe monitoring arsenic excretion in the urine of human volunteers. They found that ability to eliminate arsenic from the body varied greatly, with some participants excreting up to 95 percent of the ingested arsenic but others eliminating as little as four percent. "This observed individual variability in handling [arsenic] exposure has considerable implications for the risk assessment of arsenic ingestion," the paper states. It adds that further study is needed to assess potential risks to humans consuming seafood products. "The data presented here suggest that the long held view that seafood arsenic is harmless because it is present mainly as organoarsenic compounds needs to be reassessed."


Source
Chemical Research in Toxicology

Targeting Nicotine Receptors To Treat Cognitive Impairments In Schizophrenia

Smoking is a common problem for patients with schizophrenia. The increased tendency of patients diagnosed with this disorder is to not only smoke, but to do so more heavily than the general public. This raises the possibility that nicotine may be acting as a treatment for some symptoms of schizophrenia.


Nicotine acts through two general classes of brain receptors, those with high and low affinity for nicotine. The low affinity class of nicotinic receptors contains the alpha-7 subunit, which is present in reduced numbers in people with schizophrenia.


Two papers published in the January 1st issue of Biological Psychiatry suggest that drugs that stimulate these alpha-7 subunit-containing nicotinic receptors might enhance cortical function and treat cognitive impairments associated with schizophrenia.


In their study of healthy monkeys, Graham Williams and colleagues at Yale University and AstraZeneca found that very low doses of AZD0328, a novel drug that acts as an alpha-7 agonist, produced both acute and persistent improvements in their performance on a spatial working memory task.


"Our work demonstrates that that the neuronal nicotinic alpha-7 receptor plays a critical role in the core cognitive function of working memory, which is a key indicator of outcome in patients with schizophrenia," explained Dr. Williams. "The function of the alpha-7 receptor may account for the ability of a partial agonist to induce long-term beneficial changes for high-order cognition at such low doses."


This influence on cortical function has been exemplified by the work of Jason Tregellas and colleagues. These researchers examined the effects of DMXB-A, a novel alpha-7 partial agonist, on the brain's 'default network' in people with schizophrenia. Function of the default network, which is likely a major contributor to the intrinsic neuronal activity that accounts for 60-80% of the brain's energy use, is different in people with schizophrenia.


Dr. Tregellas summarized their findings: "We found that DMXB-A altered default network activity in people with schizophrenia in a pattern consistent with improved function of the network. We also found that these neuronal differences were related to the genotype of the alpha-7 nicotinic receptor and to drug-related improvements in symptoms."


Together, "these two studies provide additional support for a novel pharmacologic approach to treat cognitive impairments in schizophrenia", observed Dr. John Krystal, Editor of Biological Psychiatry.


Sources: Elsevier, AlphaGalileo Foundation.

Ancient DNA Traces The Woolly Mammoth's Disappearance

Some ancient-DNA evidence has offered new clues to a very cold case: the disappearance of the last woolly mammoths, one of the most iconic of all Ice Age giants, according to a report published online in Current Biology, a publication of Cell Press.



DNA lifted from the bones, teeth, and tusks of the extinct mammoths revealed a "genetic signature" of a range expansion after the last interglacial period. After the mammoths' migration, the population apparently leveled off, and one of two lineages died out.



"In combination with the results on other species, a picture is emerging of extinction not as a sudden event at the end of the last ice age, but as a piecemeal process over tens of thousands of years involving progressive loss of genetic diversity," said Dr. Ian Barnes, of Royal Holloway, University of London. "For the mammoth, this seems much more likely to have been driven by environmental rather than human causes, even if humans might have been responsible for killing off the small, terminal populations that were left."



Barnes, along with Dr. Adrian Lister of the University College London and the Natural History Museum in London and others, had earlier found evidence that bison, bears, and lions underwent major population shifts twenty-five to fifty thousand years ago. Those results came as a surprise, the researchers said, because scientists tended to think that the major environmental changes happened about fifteen to twenty-five thousand years ago, when the glaciers reached their fullest extent. The findings also offered early human hunters a potential alibi; they didn't come on the scene in large numbers until even later.



In search of a general pattern in the new study, Barnes and Lister's team looked to the extinct woolly mammoth. What they found, however, was an "interesting pattern, not like those of the other species."



Their genetic data indicate that Siberian mammoths expanded from a small base some time before sixty thousand years ago. Moreover, they found two distinct genetic groups, implying that mammoths had diverged in isolation for some time before merging back into a single population. The DNA further suggests that no later than forty thousand years ago, one of the groups died out, leaving only the second alive at the time of the mammoth's last gasp.



"At a time when we should be very concerned about the potential extinction of many existing large mammals, studying those that occurred in the geologically recent past can provide many insights," Lister said. "Our work, together with that of others, shows that the conditions for extinction can be set up long before the actual extinction event."







The researchers include Ian Barnes of Royal Holloway, University of London in Surrey, UK; Beth Shapiro of University of Oxford in Oxford, UK; Mark G. Thomas of University College London in London, UK; Adrian Lister of the Natural History Museum and University College London in London, UK;Tatiana Kuznetsova of Moscow State University in Moscow, Russia; Andrei Sher of Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences in Moscow, Russia; Dale Guthrie University of Alaska in Fairbanks, Alaska.



This work was supported by the UK Natural Environment Research Council (IB), the Royal Society (BS), and the Russian Foundation for Basic Research (AS).



Barnes et al.: "Genetic Structure and Extinction of the Woolly Mammoth, Mammuthus primigenius." Publishing in Current Biology 17, 1-4, June 19, 2007. DOI 10.1016/j.cub.2007.05.035. current-biology/



Contact: Erin Doonan


Cell Press

Cancer Therapy Using Nanosystems Featured At Major Energy And Nanotech Meeting

AVS holds its annual International Symposium and Exhibition in Seattle October 14-19, 2007. Formerly called the American Vacuum Society, AVS is a professional society devoted to scientific research in a number of technology fields, such as surface science, nanotechnology, and controlled environments, including the creation and manipulation of vacuum or plasmas. Highlights from the 1,200 papers will be provided below. Click here to access the full meeting program.



The symposium features sessions on a wide variety of high-tech areas, especially those based on equipment at the microscopic and nanoscopic level. Indeed the proliferation of tiny electronic and other gadgets sometimes overwhelms meeting attendees. Consequently there will be an "ask-the-experts" booth in the exhibit area. So save up your questions (Exhibit Hall Aisle 100 Booth 126).



A meeting within the AVS meeting, the Industrial Physics Forum (IPF), sponsored by the American Institute of Physics (AIP), is dedicated this year to energy research and policy (the website for sessions is aip/ipf). See more details below. A topical conference on a related topic considers energy efficiency. Another self-contained conference is devoted to the homely but important topic of marine anti-fouling treatments.



HIGHLIGHTS OF THE MEETING



PLENARY TALKS



The main plenary will be delivered by James Heath (Caltech) who, as a graduate student, was involved in the discovery of carbon-60 fullerene molecules. He will discuss the use of nanosystem tools in the study of cancer. (Lab website; recent press release concerning Heath's research). In addition, there will be a session of plenary talks devoted to biomaterials. R.V. Durvasula (University of New Mexico) will speak on the use of genetic modification of symbiotic bacteria associated with the vectors that carry deadly diseases; W.R. Rodriguez (Harvard) on the use of nanotechnology---especially MEMS, microfluidics, and nanosensing-for mitigating the huge toll on global health of certain infections, such as HIV and TB; and P. Yager (University of Washington) on using cheap point-of-care diagnostics methods in the developing world.



INDUSTRIAL PHYSICS FORUM



The Industrial Physics Forum meeting-within-a-meeting is grouped around four energy sessions.


1. The automotive session features invited talks on low-carbon fuels, hydrogen, and the "re-electrification of the automobile."















2. The energy efficiency session features talks on solar cells, thermoelectric materials (which turn heat directly into electricity), solid state lighting (set to break through into use in general lighting), and energy policy.


3. Nuclear energy talks concern fusion reactors, high-temperature gas, nuclear waste, and nuclear policy.


4. Cleaner energy talks: ethanol biorefineries, wave power, and the geology of carbon sequestration.



FRONTIERS OF PHYSICS



The Industrial Physics Forum also hosts a Frontiers in Physics Symposium, showcasing some of the top speakers on some of the hottest topics in physics. This year's symposium speakers are as follows: Gerald Gabrielse (Harvard) about establishing a much more precise value for the fine structure constant, the parameter that sets the inherent strength of the electromagnetic force; Nader Engheta (Univ Penn) about electronic circuits that operate at optical frequencies; William Bottke (Southwest Research Institute) on near Earth objects; J.J. Kasianowicz (NIST) on nanopores & systems biology.



NEUTRALIZING BENZENE'S TOXIC EFFECTS



At the nanoscale, a particle's size, shape, and even orientation can have a significant impact on a material's resulting properties. Scientists at the University of California at Berkeley have found that size, shape and orientation can also have a significant impact on catalytic processes, such as benzene hydrogenation. Benzene is a colorless, flammable liquid industrial solvent used as a precursor in the production of drugs, plastics, synthetic rubber, and dyes, as well as detergents, explosives, pesticides, and napalm. It is sometimes used as an additive in gasoline, to increase octane levels and reduce knocking, although federal regulations currently limit the amount of allowable levels. However, benzene is also a toxic carcinogen that can lead to leukemia, among other adverse health effects, so finding better ways to convert benzene and other aromatic hydrocarbons into less harmful hydrocarbons is a critical issue in terms of both human health and environmental concerns.



Two common byproducts of benzene hydrogenation are cyclohexene and cyclohexane, solvents commonly used in industrial manufacturing. The UC Berkeley work builds on previous studies of benzene hydrogenation on two types of single platinum crystals: Pt(111) and Pt(100). (Platinum is a popular, environmentally friendly catalyst used in fuel cells, for example.) Those earlier studies found that while cyclohexane is produced on both surfaces during the hydrogenation process, cyclohexene was only produced on the Pt(111) surface. Ultimately, the UC Berkeley researchers are interested in better understanding chemical catalysis at the molecular level by conducting spectroscopic studies to determine which surface chemical intermediates are present during the catalytic process. "If we can understand which surface intermediates are responsible for different catalytic processes, we will better understand how catalysis works and, perhaps, better engineer new catalysts for specific reactions," said UC Berkeley team member Kaitlin Bratlie.



MINI-VACUUM PUMP GOES TO MARS



Engineers at Creare Incorporated are developing miniaturized vacuum pumping technologies for NASA and other organizations. Tiny mass spectrometers and other analytical instruments have already been developed for space-based missions such as the Mars Science Lab. However, the vacuum systems required to support these instruments are still too big, heavy, and power hungry for feasible use in space. Among the engineering challenges to be overcome are designing small diameter vacuum pumps, precision machining of various components, and building very high-speed, efficient electric motors to power such vacuum systems.



R.J. Kline-Schoder and P.H. Sorenson will report on their recent progress designing two small prototype high vacuum pumps ideal for space-based missions. One is the size of a soda can and is slated for use on the Mars Science Lab mission in 2009, while the other is about the size of a C-cell battery. The smaller version could be ideal for portable applications here on earth, such as detecting hazardous materials or detecting leaks in commercial settings.



TROJAN HORSE FOR CHAGAS' DISEASE



Chagas' Disease is a vector-borne illness transmitted by blood-feeding insects called traitomines, commonly known as "kissing bugs." After feeding on the victim's blood, they will leave a "fecal droplet" at the site. The droplet is mostly water, but it also contains a parasite, T. cruzi that flourishes in the insect's gut. If the victim scratches the site or rubs his eyes, the parasite enters the bloodstream. Between 16 and 18 million infected persons worldwide. Several countries managed to almost eradicate Chagas' disease by spraying households in endemic areas" with pesticides. But the toxic pesticides cause health problems in human inhabitants, including pediatric asthma and neurological problems such as weakness and numbness. Also, the insects gradually develop resistance to the pesticides. Ravi Durvasula of the University of New Mexico has developed an alternative control measure that focuses on the transmission phase. Using a process known as paratransgenesis, he and his colleagues have created a genetically altered version of T. cruzi that acts as a kind of Trojan Horse, producing a protein that destroys the parasite.



The tricky part is getting the genetically modified version into the gut of the kissing bug. Kissing bugs need the T. cruzi and other gut-friendly bacteria, just like human beings need certain types of "good" bacteria in our own digestive systems. Baby kissing bugs aren't born with said bacteria: they acquire them shortly after birth by probing the fecal droplets left by adults nearby. This gave Durvasula and his colleagues the idea for an innovative delivery mechanism: a decoy version of the fecal droplets. They created Cruzigard, a synthetic, dung-like paste, which contains a massive dose of the transgenic bacteria. Those altered bacteria take up residence in the insect's gut; should the Chagas parasite appear, it is quickly wiped out. On a broader scale, paratransgenesis is a potentially powerful technique for combating the spread of all manner of so-called vector-borne diseases. Click here for more information.



MEMS IN EXTREMIS



Just as living organisms are now known to thrive in extreme environments, so too the microscopic minions of the electronic world must also be able to sustain harsh environments such as high temperatures, high pressure and corrosive media. Microelectromechanical systems (MEMS), which included tiny sensors and labs-on-a-chip, have to be hardened to some demanding conditions. One example from the MEMS Reliability in Harsh Environments session is Roya Maboudian's resonant sensor that can survive corrosive environment and still operate reliably. In collaboration with Prof. Pisano at Berkeley and Prof. Mehregany at Case Western Reserve, the team has also demonstrated strain and pressure sensors that can survive high temperature and high g shock. Maboudian (UC Berkeley) says that these developments pave the way for a variety of devices for extreme conditions, such as in-cylinder sensors. (Lab website).







ABOUT AVS



AVS is a not-for-profit professional society that promotes communication between academia, government laboratories, and industry for the purpose of sharing research and development findings over a broad range of technologically relevant topics. Founded in 1953, AVS was originally a group of scientists, technicians, and equipment manufacturers focused on the rapidly emerging field of vacuum science and technology. Over the years AVS has broadened and evolved into an interdisciplinary society covering topics related to both vacuum and emerging technologies in the materials, interfaces, and processing fields.



Today, AVS papers showcase experiments not only in vacuums but also in many other "controlled environments." These controlled environments include so-called "underwater surfaces," or carefully prepared samples immersed in liquids, which are the natural environment for many biological structures. In addition, AVS members study and manipulate the boundaries or "interfaces" between liquids and solids to make state-of-the-art fuel cells and better batteries. Crucial processes for making computer chips, such as chemical vapor deposition, are now being done at atmospheric pressure where vacuum pressure was once necessary. Add to the list atomic- and molecular-scale microscopy, which is routinely done in air and liquid, and you'll get a sense of the many controlled environments that AVS members create and study for a whole host of applications over the entire spectrum of science and technology.



Source:



Phillip Schewe

American Institute of Physics



Della Miller


American Vacuum Society

Royal Society Responds To HFEA Papers, UK

In response to the publication of the HFEA papers relating to policy on Human Animal Embryos Martin Rees, President of the Royal Society, said:


"The HFEA's consultation reveals welcome recognition of the potential of this research. 61% of the general public agreed with the creation of human-animal embryos - if it may help understand diseases - with only a quarter opposed to this research.


"It is heartening that the wider public agree with the scientific community that human-animal embryos offer the potential to better understand incurable illnesses such as Parkinson's and Motor Neuron Disease.


"Human-animal embryos allow some very promising experiments to be done. Specifically, the creation of cytoplasmic hybrid embryos - using the plentiful supplies of animal eggs from abattoirs - reduces the need for human eggs in stem cell research - which is currently limiting progress in this rapidly developing field."


The Royal Society is an independent academy promoting the natural and applied sciences. Founded in 1660, the Society has three roles, as the UK academy of science, as a learned Society, and as a funding agency. It responds to individual demand with selection by merit, not by field. As we prepare for our 350th anniversary in 2010, we are working to achieve five strategic priorities, to:


-- Invest in future scientific leaders and in innovation

-- Influence policymaking with the best scientific advice

-- Invigorate science and mathematics education

-- Increase access to the best science internationally

-- Inspire an interest in the joy, wonder and excitement of scientific discovery

royalsoc.ac.uk

Yale Study May Lead To Better Traps, Repellents Fo Mosquitoes

Yale University researchers have found more than two dozen scent receptors in malaria-transmitting mosquitoes that detect compounds in human sweat, a finding that may help scientists to develop new ways to combat a disease that kills 1 million people annually.



These olfactory receptors in the mosquito Anopheles gambiae offer scientists potential new targets for repelling, confusing or attracting into traps the mosquitoes that spread a disease afflicting up to 500 million people across a broad swath of the world's tropical regions, according to authors of the article published online Feb. 3 in the journal Nature.



"The world desperately needs new ways of controlling these mosquitoes, ways that are effective, inexpensive, and environmentally friendly," said John Carlson, the Eugene Higgins Professor of Molecular, Cellular, and Developmental Biology at Yale and senior author of the study. "Some of these receptors could be excellent targets for controlling mosquito behavior."



While it has long been known that mosquitoes are attracted to human scents, just how the mosquito's olfactory system detects the different chemical elements of human odor has been unknown.



"Mosquitoes find us through their sense of smell, but we know very little about how they do this," Carlson said. "Here in the United States, mosquitoes are a source of annoyance, but in much of the world they're a source of death."



Carlson's lab identified the first insect odor receptors in 1999 in studies of the fruit fly. The Yale team then found an ingenious way to use the fruit fly to study how the mosquito olfactory system works: They used mutant flies that were missing an odor receptor. Under the leadership of Allison Carey, an M.D./Ph.D. candidate in Carlson's lab and lead author of the study, the researchers systematically activated genes of 72 mosquito odor receptors in fruit fly olfactory cells that lacked their own receptors. The engineered flies were then exposed to a battery of scent compounds, and the responses conferred by each receptor were analyzed. Over the course of the project, Carey recorded 27,000 electrical responses in the genetically engineered fly/mosquito olfactory system to the library of scents.



Particularly strong responses were recorded from 27 receptors - and most of these receptors responded to chemical compounds found in human sweat.



"We're now screening for compounds that interact with these receptors," Carlson said. "Compounds that jam these receptors could impair the ability of mosquitoes to find us. Compounds that excite some of these receptors could help lure mosquitoes into traps or repel them. The best lures or repellents may be cocktails of multiple compounds."



Carey says that more knowledge about mosquito behavior and odor reception will help develop more effective traps and repellents.



Other authors were Guirong Wang and Laurence Zwiebel of Vanderbilt University, and Chih-Ying Su of Yale University. The Vanderbilt team is also pursuing additional strategies to characterize mosquito odor receptors and together with colleagues at Yale and other institutions, pursue the development of novel attractants and repellents.



The study was funded by the Foundation for the National Institutes of Health (NIH) through the Grand Challenges in Global Health Initiative to Vanderbilt.



Source:

Bill Hathaway

Yale University

How A Protein Stabilises Microtubules By Binding To Their Weakest Point

A cell is a busy place. In a permanent rush hour, molecules are transported along a dynamic motorway system made up of filaments called microtubules. Microtubules constantly grow and shrink and are rapidly assembled wherever a cargo needs to go, but during this transportation process they need to be kept stable. Researchers from the European Molecular Biology Laboratory (EMBL) have discovered for the first time that a protein stabilises microtubules by binding to their weakest part, the so-called lattice seam. The study, which appears in this week’s issue of the journal Cell, also suggests that the protein creates a special surface along the seam that offers an alternative track for transportation.


The basic building blocks of microtubules are proteins called tubulins. They assemble in a single line to form so-called protofilaments, of which several combine to build a large tubulin sheet. Investigating how this sheet folds into the tube-like structures of microtubules in yeast, researchers have now discovered that a protein called Mal3p is crucial. Combining molecular techniques with a unique Electron Microscope setup based at the ETH in ZГјrich, they found that Mal3p binds to the seam of the microtubule, which forms as the two sides of the tubulin sheet fold into a tube. The protein binds in a single line along the seam, seals the tube and stabilises it at its weakest point.


“It is the first time that we’ve found a protein that specifically binds to the microtubule seam,” says Andreas Hoenger, former group leader at EMBL who has just moved to head a lab at the University of Colorado. “Until now the function of the seam has been unknown and it has been largely ignored as an odd and irrelevant part of the microtubule lattice. Our experiments now reveal it as a central spot where microtubule stability can be regulated.”


Without Mal3p, microtubules are unstable and likely to disassemble, while in its presence they grow into long filaments. Mal3p could function as a key regulator of microtubule behaviour. Controlling its presence allows fast switches between growth and shrinkage of microtubules, which are essential for rapid and flexible cellular transport. Mal3p’s location along the microtubule seam is crucial, because here it can confer stability without obstructing the traffic of motor proteins along the filament. Apart from its stabilising role Mal3P could also play a more active role in transportation.


“Motor proteins move along microtubules through direct interaction with tubulin. They transport cargo similarly to trucks driving on motorways,” explains Damian Brunner, group leader at EMBL. “The line of Mal3p along the seam potentially creates an alternative track on the filament, along which a specialised type of motor protein could move, just like creating a railway track along a motorway. This dual system could make transport more diverse and efficient.”


The new insights gained into cellular transport and the stabilisation of microtubules in yeast might help shed light on how similar processes work in humans. Mal3p is highly conserved across species and its human counterpart plays a role in various clinical conditions, such as colon cancer or neurodegenerative diseases.


embl/downloads