Study Advances Evidence For Receptor's Role In Alcohol Pleasure And Problems

A genetic variant of a receptor in the brain's reward circuitry heightens the stimulating effects of early exposures to alcohol and increases alcohol consumption, according to a new study by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH). Conducted in rhesus monkeys, the study extends previous research that suggests an important role for a similar brain receptor variant in the development of human alcohol use disorders. A report of the findings is published in the March, 2007 issue of the Archives of General Psychiatry.



"Although the pathway to alcoholism is influenced by many factors, our findings affirm that individuals who possess this receptor variant may experience enhanced pleasurable effects from alcohol that could increase their risk for developing alcohol abuse and dependence," notes Markus Heilig, M.D., Ph.D., NIAAA Clinical Director and the study's senior author.



Molecules known as opioid peptides bind to opioid receptors in the brain to signal experiences of reward and reinforcement, as well as the euphoria and other positive subjective effects produced by alcohol. Previous studies have shown that, among the brain's various subtypes of opioid receptors, the mu-subtype is most likely responsible for transmitting alcohol's positive effects.



"We also know that there are several genetic variants of the human mu-opioid receptor," notes first author Christina Barr, V.M.D., Ph.D., a lead investigator in NIAAA's Laboratory of Clinical and Translational Studies and Laboratory of Neurogenetics. "One of these, designated 118G, has a greatly enhanced ability to bind opioid peptides. People who have this variant of the receptor have reported increased euphoria following alcohol consumption."



Drs. Barr, Heilig, and their colleagues note that recent studies have linked the 118G mu-opioid receptor with alcohol dependence in humans. In the current study, the researchers explored the link between genetic variants of mu-opioid receptors and alcohol-related behaviors in a group of 82 rhesus monkeys.



"A mu-opioid receptor variant that is functionally similar to the human 118G variant occurs in these animals," explained Dr. Barr. "That is, it also has a greatly enhanced ability to bind opioid peptides. We hypothesized that monkeys that had the gene for this receptor variant would experience enhanced alcohol stimulation and, therefore, consumption.



Groups of monkeys had access to both alcoholic and non-alcoholic solutions for one hour per day for a period of six weeks. Researchers measured the animals' alcohol intake and post-intake activity, and determined which monkeys carried the gene for the mu-opioid receptor similar to the human 118G receptor. Activity measures are commonly used in animal studies to assess alcohol's pleasurable effects. As predicted, the researchers found that monkeys with the variant gene showed increased activity following alcohol consumption. They also found that male animals with the variant had a clear preference for the alcohol solution and consumed on average almost twice as much alcohol as other animals. Males with the variant also became intoxicated on almost 30 percent of testing days, while other animals did so only on an average of 8 percent of testing days.
















"The male-restricted effect of this gene is interesting, and parallels other recent evidence that opioid transmission may play a greater role in alcohol problems among some males than among females," explained Dr. Heilig. This information also complements recent data suggesting that alcohol-dependent people with the gene for the 118G receptor have a better therapeutic response to medications that block opioid receptors. More broadly, the finding underscores the important role that the pleasurable and stimulating initial effects of alcohol play in the subsequent development of alcohol problems."






The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at niaaa.nih/. The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.



References:



Barr CS, Schwandt M, Lindell SG, Chen SA, Goldman D, Suomi SJ, Higley, JD, Heilig M. Association of a Functional Polymorphism in the Г¬-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques. Archives of General Psychiatry. 2007;64:369-376



Ray LA, Hutchison KE. A polymorphism of the mu-opioid receptor gene (OPRM1)
and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res. 2004; 28:1789-1795.



Contact: John Bowersox


NIH/National Institute on Alcohol Abuse and Alcoholism

NCI-Penn Collaboration Finds Targeted Immune Cells Shrink Tumors In Mice

Researchers have generated altered immune cells that are able to shrink, and in some cases eradicate, large tumors in mice. The immune cells target mesothelin, a protein that is highly expressed, or translated in large amounts from the mesothelin gene, on the surface of several types of cancer cells. The approach, developed by researchers at the University of Pennsylvania School of Medicine and the National Cancer Institute (NCI), shows promise in the development of immunotherapies for certain tumors. The study appears online this week in the Proceedings of the National Academy of Sciences.



Expression of mesothelin is normally limited to the cells that make up the protective lining (mesothelium) of the body's cavities and internal organs. However, the protein is abundantly expressed by nearly all pancreatic cancers and mesotheliomas and by many ovarian and non-small-cell lung cancers. Although the biological function of mesothelin is not known for certain, it is thought to play a role in the growth and metastatic spread of the cancers that express it.



"Since tumor cells are derived from the body's normal cells, the immune system often does not recognize tumor molecules as dangerous or foreign and does not mount a strong attack against them," said Ira Pastan, M.D., chief of the Laboratory of Molecular Biology in NCI's Center for Cancer Research, a study collaborator. Moreover, even though it is possible to genetically engineer immune system cells to recognize molecules on tumor cells, most of the molecules found on tumor cells are also found on normal cells. But, Pastan notes, "Mesothelin is a promising candidate for generating tumor-targeting T cells, given its limited expression in normal tissues and high expression in several cancers."



Previous laboratory research has shown that certain immune system cells, called T cells, can kill tumor cells that express mesothelin. In addition, studies in both animals and humans have shown that antibodies directed against mesothelin protein can shrink tumors.



In the new study, the research team genetically engineered human T cells to target human mesothelin. To produce them, a modified virus was used as a delivery vehicle, or vector, to transfer synthetic genes to T cells. These genes directed the production of hybrid, or chimeric, proteins that can recognize and bind to mesothelin and consequently stimulate the proliferation and cell-killing activity of the T cells. In laboratory studies, the team found that the engineered T cells proliferated and secreted multiple cytokines when exposed to mesothelin. Cytokines are proteins that help control immune functions. The cells also expressed proteins that made them resistant to the toxic effects of tumors and their surrounding tissues.
















To study the effects of the engineered T cells on tumor tissue, the researchers implanted human mesothelioma cells underneath the skin of mice. About six weeks later, when tumors had formed and progressed to an advanced stage, the engineered T cells were administered to the mice. Direct injection of the T cells into tumors or into veins of the mice resulted in disappearance or shrinkage of the tumor.



"Based on the size of the tumors and the number of cells administered, we estimate that one mesothelin-targeted T cell was able to kill about 40 tumor cells," said study leader Carl H. June, M.D., Professor of Pathology and Laboratory Medicine and director of Translational Research at Penn's Abramson Cancer Center. "This finding indicates that small doses of these cells may have potential in treating patients with large tumors. Clinical trials are being developed to investigate this approach in patients with mesothelioma and ovarian cancer."







PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.



Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.



The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.



Source: Karen Kreeger


University of Pennsylvania School of Medicine

Synthetic Platelets Halve Clotting Time

Blood loss is a major cause of death from roadside bombs to freeway crashes. Traumatic injury, the leading cause of death for people age 4 to 44, often overwhelms the body's natural blood-clotting process.



In an effort to enhance the natural process, a team led by Erin Lavik, a new Case Western Reserve University biomedical engineering professor, and her former doctoral student, James P. Bertram, built synthetic platelets that show promise in halting internal and external bleeding.



Their work is published in Science Translational Medicine.



The researchers were inspired by studies showing there are few options to treat soldiers suffering from internal injuries in Afghanistan and Iraq. They wanted to develop a treatment medics can keep in their field packs.



"The military has been phenomenal at developing technology to halt bleeding, but the technology has been effective only on external or compressible injuries," Lavik said. "This could be a compliment to current therapies."



Blood platelets are the structural and chemical foundation of blood clotting, a complex cascade of events that works well with normal cuts and scrapes but can be overmatched by serious injury.



Using other's platelets can enhance clotting but carries risks of several complications. And these platelets must be refrigerated and have a short shelf life.



Bertram and Lavik developed platelets made from biodegradable polymers. The synthetic platelets are designed to home in and link up with natural platelets at the site of an injury.



In essence, adding artificial platelets to a traumatic injury site is akin to adding sand bags to a levy along a flooding river.



The natural platelets, activated by injury, emit chemicals that bind natural platelets and the additional synthetics into a larger clot that quickly stems the bleeding.



In testing, rat models injected with synthetic platelets prior to injury stopped bleeding in half the time of untreated models. Untreated models injected 20 seconds after injury stopped bleeding in 23 percent less time than models left untreated.



In another comparison, the artificial platelets resulted in clotting times about 25 percent faster than wounds treated with recombinant factor VIIa, which is the current state of the art treatment for uncontrolled bleeding in surgery and emergency rooms. While the recombinant factor is used on various injuries, its cost can be in the tens of thousands of dollars per treatment and is not used in patients suffering head or spinal cord injuries, due to risk of complications.



Lavik said her team made platelets from polymers already used in treatments approved by the Food and Drug Administration in hopes the new treatment might be approved faster. They also built the parts of the synthetic platelets that bind to natural platelets from relatively short pieces of proteins because they're more stable than longer pieces and cheaper.



To avoid formation of an artificial clot, each synthetic platelet is built with a surrounding water shield. Fluorescing compounds showed the synthetic platelets not bound in clots were flushed from the rat model's system in a day. No ill effects were seen in the following week.



Testing also showed the synthetic platelets remain viable after sitting on a shelf for at least two weeks.



Lavik is seeking grants to further test the platelets.



Source: Kevin Mayhood


Case Western Reserve University

$500,000 Gruber Neuroscience Prize Awarded To Hall, Rosbash And Young

The 2009 Neuroscience Prize of The Peter and Patricia Gruber Foundation is being awarded to Jeffrey Hall, professor of neurogenetics at the University of Maine; Michael Rosbash, professor and director of the National Center for Behavioral Genomics at Brandeis University; and Michael Young, professor and head of the Laboratory of Genetics at Rockefeller University. On October 18, at the annual meeting of the Society for Neuroscience in Chicago, Illinois, these three distinguished scientists will receive this prestigious international award for their groundbreaking discoveries of the molecular mechanisms that control circadian (daily) rhythms in the nervous system. Their research was the first to establish a simple relationship between single genes and a complex behavior.



"The combined discoveries of Jeffrey Hall, Michael Rosbash and Michael Young are stunning in their creativity, breadth and significance. These researchers began with a complicated animal behavior, established that single genes can define specific aspects of this behavior and determined mechanistically how such genes act," says H. Robert Horvitz, David H. Koch Professor of Biology at MIT. "Hall, Rosbash and Young have not only defined the genetic, molecular and biochemical bases of a complex animal behavior but have also established a paradigm for how such analyses should be done."



Before Hall, Rosbash, and Young published their seminal studies on the molecular underpinnings of the circadian rhythms of the fruit fly, Drosophila melanogaster, many people questioned whether a compelling relationship between genes and behavior could be established. By the early 1970s, the first fruit fly mutants with altered circadian rest/active cycles had been identified - making a case for the genetic control of behavior - but the mechanism behind the phenomenon remained unknown. What was running the internal biological clock in Drosophila?



In 1984 came the first breakthrough. That year Hall and Rosbash, working at Brandeis University, and Young, working at Rockefeller University, simultaneously cloned the period (per) gene of Drosophila. That pivotal discovery led to subsequent studies from all three labs that eventually unmasked the general molecular mechanism for circadian clocks: a transcriptional feedback loop that oscillates during the 24-hour cycle.



Hall and Rosbash demonstrated, for example, that per gene products exhibit oscillations for their concentrations and that during a daily cycle the per protein represses transcription of the very gene that specifies that "final" product. (Transcription is a gene's ability to copy its DNA sequence into messenger RNA, a necessary step for translating the gene into a protein that performs a specialized function in the cell). Young identified per's partner gene, timeless (tim), and then showed that when these two genes' protein products (PER and TIM) reach certain levels, they bind together in the cell's cytoplasm and are transported back into the nucleus, where primarily PER shuts down the genes that made them. After a few hours, the proteins degrade, the genes start up again - and the cycle begins anew.



As Hall, Rosbash, and Young continued their research, the fundamental workings of this complex feedback system came into even sharper focus. They discovered other genes and protein products that play critical roles in regulating the loop. They found that mutations affecting any of these genes had effects on Drosophila's molecular rhythms - and on its behavior. They also identified how certain stimuli, most notably the light-dark cycle, help regulate the feedback loop in order to reset the clock everyday to operate in synch with natural environmental cycles (a key and universal feature of daily rhythms).



When other researchers investigated the clock mechanisms in mammals, they found them to be strongly analogous to what Hall, Rosbash, and Young had found in Drosophila. Thus, the uncovering of the mechanism in the fruit fly - a tour de force of genetics and molecular biology - has paved the way for the study of human circadian genetics.



"Practically all biological creatures thus display a circadian rhythm, whether fruit fly or man, as some species are active during night and others during daytime. This astounding ability depends on an intricate molecular mechanism that, once developed, has been conserved throughout evolution," says Sten Grillner, Director of the Nobel Institute for Neurophysiology at the Karolinska Institutet. "To reset the biological clock takes many days, as all intercontinental travelers are forced to experience - for shift-workers it is more serious, it creates stress and fatigue that over many years can lead to harmful medical conditions."



Source:
Alyson O'Mahoney


Robin Leedy & Associates, Inc.

Mechanism In Memory Development Discovered In Flies That May Help Parkinson's Patients

Before swatting at one of those pesky flies that come out as the days lengthen and the temperature rises, one should probably think twice. A University of Missouri researcher has found, through the study of Drosophila (a type of fruit fly), that by manipulating levels of certain compounds associated with the "circuitry" of the brain, key genes related to memory can be isolated and tested. The results of the study may benefit human patients suffering from Parkinson's disease and could eventually lead to discoveries in the treatment of depression.



"The implication for human health is that it could influence our understanding of the cognitive decline associated with Parkinson's disease and depression in humans," said Troy Zars, MU assistant professor of biological science in the College of Arts and Science.



The idea that animals have a system that can match the quality of a memory with the significance of the memory is well established. If the event is significant, the memory and detail surrounding it is much stronger, lasts longer and is more easily recalled compared to more insignificant or common events. The problem the study addresses is the understanding of the mechanism by which that occurs.



"We have developed a strategy to address how this matching occurs, so we can 'turn that crank' over and over again. It allows us to answer the questions, 'What gene is it" How does it function" How does it interact with other proteins"' We can find brand-new, completely unexpected things," Zars said.



A major goal of neuroscience is to discover and study memory-forming structures within a brain. Zars said he works with Drosophila because they are a well-established genetic model, have a relatively less complex brain than the mouse or human (250,000 neurons versus 100 billion neurons), and have a broad repertoire of behaviors.



Memory in the flies was tested using a specialized chamber in which single flies were allowed to wander freely. The chamber was outfitted with heating elements. When the fly moved to a particular side, the whole chamber rapidly heated to an uncomfortable temperature. The flies eventually learned, or remembered, to avoid that half if brain "circuitry" is functioning properly. A mutation in certain flies, however, altered the levels of serotonin and dopamine, which resulted in lower memory scores.



"This research is important because by studying a simple brain it will help us ultimately understand complex neural systems," Zars said. Zars' study was published this week in Proceedings of the National Academy of Sciences.







Source: Bryan E. Jones

University of Missouri-Columbia

Discovery Of Protein That Contributes To Cancer Spread

In an important finding published online in Developmental Cell, researchers at Albert Einstein College of Medicine of Yeshiva University, along with collaborators at Massachusetts Institute of Technology, have identified a protein likely responsible for causing breast cancer to spread.



Metastatic cancer occurs when cancer cells from the original tumor travel to distant sites via the blood system. Most cancer deaths are due to cancer that has spread to other organs. Trying to stop cancer before it metastasizes is the main goal of cancer treatments. Upon diagnosis, 6 out of 10 breast cancer patients have cancer that is still in its primary location making the potential discovery of a marker for invasive cancer of tremendous value that could better inform treatment options.



Until now, early markers of metastatic breast cancer have been hard to find. However, in the Einstein-led study, researchers have identified a protein that is a promising candidate for a metastatic breast cancer marker.



The protein, called Menainv is present in invasive cells within a breast tumor. These cells move into surrounding tissue and eventually to blood vessels. Menainv is not on breast tumor cells that stay put (resident cells). This is the first time that a protein has been shown to contribute to the invasive and metastatic ability of tumor cells, rather than just being an 'innocent bystander' that shows up when cells are invading, strengthening the potential use of this protein as a marker.



The research was conducted under the direction of and in the laboratories of John S. Condeelis, Ph.D., Einstein professor and co-chair of anatomy and structural biology and co-director of Gruss Lipper Biophotonics Center and Frank B. Gertler, Ph.D., Ross Scholar Professor of Biology at MIT.



The latest research was aided considerably by the work of Jeffrey B. Wyckoff, principal associate, department of anatomy and structural biology at Einstein who, with Dr. Condeelis, developed the in vivo invasion assay used to isolate metastatic tumor cells from breast tumors thereby implicating Mena as an important gene for metastasis.



Evanthia T. Roussos, an M.D.-Ph.D. student in Dr. Condeelis' lab and primary co-author of the study, explains, "We have micro-needles filled with growth factors and tissue that we insert into a tumor on an anesthetized mouse. If a cell is invasive, within four hours, it will crawl into the needles. We found that mouse breast tumor cells that we engineered to contain Menainv were invasive whereas cells that did not have Menainv were not."



Another finding from the study that has important implications for patient treatment is that tumor cells harboring Menainv are less likely to be responsive to newer breast cancer treatments that inhibit epidermal growth factor receptors (EGFR). Epidermal growth factor (EGF) has been shown to increase a breast cancer cell's invasive potential. The study investigators propose that drugs which inhibit EGF may lack effectiveness on tumor cells that express Menainv. That's because Menainvcells are so sensitive to EGF that even the small amount of EGF signal that the drugs fail to block may be enough to stimulate EGF receptor and promote tumor cell migration and metastasis.
















If Menainv behaves similarly in humans as it does in mice, it would be an especially attractive marker for metastatic breast cancer because the structure of Menainv would enable an antibody or a PCR assay to be developed to identify it. Such an antibody or PCR assay could be used to diagnose the presence of Menainv in biopsies and blood samples allowing doctors to identify breast cancer patients who are more likely to have progressive disease and recommend the appropriate treatment.



The current study builds on previous research by Dr. Condeelis' group which identified Menainv as the isoform of Mena that is over expressed in the invasive and metastatic subpopulation of tumor cells in breast tumors. The current study shows that Menainv forces tumor cells in mammary tumors of mice to become invasive and eventually metastasize to the lung.







The primary co-authors of the paper are Ulrike Philippar, MIT, Merck Research Laboratories and Evanthia Roussos, Albert Einstein College of Medicine, Department of Anatomy and Structural biology, Gruss Lipper Biophotonics Center. Other authors include Matthew Oser, Yarong Wang and Jeffrey B. Wyckoff of Einstein; Sumanta Goswami of Einstein and Department of Biology, Yeshiva University; Hideki Yamaguchi, Einstein and now at Tokyo University of Pharmacy and Life Sciences; Hyung Do Kim and Douglas A. Lauffenburger, MIT; Silvia Giampieri, Cancer Research UK, London Research Institute; and Erik Sahai, Einstein and Cancer Research UK, London Research Institute.



About Albert Einstein College of Medicine of Yeshiva University



Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Last year, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island - which includes Montefiore Medical Center, Einstein's officially designated University Hospital - the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit aecom.yu.



Source: Michael Heller


Albert Einstein College of Medicine

Efficacy Of M2 Vaccines Increased By Cell Death Suppression

Significant public attention has recently been focused on the development of new anti-influenza (flu) vaccines that provide protection against a broad spectrum of viral strains. One proposed strategy is to utilize conserved viral protein, M2. Clinical trials of M2-containing influenza vaccines were recently initiated by US and European companies.



Scientists from Cure Lab, Inc. in collaboration with Boston University School of Medicine published new findings indicating that unmodified M2 may have a negative effect on anti-influenza vaccination. The researchers also demonstrated how this detrimental effect of M2 can be eliminated, thereby allowing any future M2-containing vaccine to be both broadly protective as well as safe. This study appears in the January 16th issue of the online journal PLoS ONE, which provides free access of its publications to scientists and the general public.



Annual vaccinations against seasonal flu are known to be insufficient to fully prevent disease. The cause of this is a single predicament: current vaccines predominantly target two viral surface proteins, hemaglutinin and neuraminidase that are constantly mutating. Thus, a particular vaccine can be protective against a viral strain carrying matching hemaglutinin and neuraminidase, but will lose efficacy as soon as these proteins change (gradually or even in a single step). The latter process is known to continuously occur in nature.



In their attempts to make current strain-specific vaccines effective, the World Health Organization (WHO) has to annually predict the most likely viral strains that will be responsible for the next seasonal flu outbreak. This process takes place just a few months before flu season starts. This process is error prone, that is, it is possible that the vaccine may be manufactured against non-matching viral strains and not the one that may actually cause the epidemic. Moreover, as long as vaccines remain to be strain specific, it will be impossible to both manufacture them in advance and to enable their stockpiling. This, in turn, drives up the vaccine cost and makes its efficient world-wide distribution almost impossible.



Finally, the new strains of flu virus usually emerge in Asia and then migrate to Europe and North America. Recently, Indonesia demonstrated its reluctance to cooperate with WHO and restricted information exchange regarding the nature of a novel influenza strain. Several other countries in the region were sympathetic to Indonesia's actions. These and many other problems will never be fully resolved until anti-flu vaccines cease to be strain-specific.



However, all of the problems mentioned above could be alleviated by the development of a new generation of vaccine. Such a vaccine should be based on conserved flu proteins, which to a significant degree remain constant among all flu strains.
















In addition to continuously mutating proteins, flu virus also possesses nucleoprotein (NP), and major matrix protein (M1), that reside inside the viral particle, and do not generate a strong antibody response. This may be the reason why these proteins do not naturally undergo significant mutagenesis and posses a striking degree of similarity among all influenza strains. Another conserved flu protein that is strongly expressed in virus-infected cells is a nonstructural protein 1 (NS1).



In the March issue of the scientific journal Influenza and Other Respiratory Viruses, Massachusetts-based biotech company Cure Lab, Inc. reported that vaccinating mice with a combination of genes encoding these three conserved proteins of flu virus, NP, M1 and NS1, protected mice against human as well as avian strains of flu virus. In particular, this included an experiment demonstrating protection against bird flu virus that encodes type 5 hemaglutinin or H5. The challenge with this viral strain was used as a model of potential pandemic outbreak, which many believe may be caused by spreading of avian H5N1 virus to the human population. Moreover, in the same paper, Cure Lab reported that the same combination of three conserved viral genes provided significant protection against H5-carrying influenza strain in the chicken model.



In addition to Cure Lab, several other companies are also pursuing attempts to utilize genes encoding conserved flu proteins as vaccine components. This includes the California-based company Vical, known for its chemical adjuvant Vaxfectin. Vical included another extremely conserved flu protein, M2 into its proposed anti-flu product. M2 is present in low copy numbers at the surface of influenza viral particles, but is expressed abundantly on the surface of infected cells. Most of the research groups, including British biotech company, Acambis, have attempted to utilize only an extracellular domain of M2 protein called M2e. Despite some encouraging results demonstrating that if used at very high doses, M2e may induce a protective antibody response, the current opinion in the field is that it should be used only as a supplement to more potent antigens. One of the reasons may be that M2e lacks possible protective epitopes located within the intracellular and trans-membrane parts of M2. In addition, at least one recent report demonstrated that vaccination with M2e-encoding gene used in combination with the NP gene, exacerbated disease and increased mortality in pigs. In contrast to the Acambis strategy, Vical has included the gene encoding a full-size M2 into its vaccine prototype. The company reported that it had initiated clinical trials already.



"As it often happens, path-finding research starts as a result of an unexpected failure," said Dr. Alex Shneider, the senior author on the PLoS ONE paper and Cure Lab's CEO. "Initially, we believed that simply adding a gene encoding the full size M2 to our previously developed vaccine prototype would further increase the protective properties of the vaccine. Instead, we observed exactly the opposite".



Puzzled with such a counterintuitive result, Cure Lab went from product development to a basic science approach and asked the question: "Why would M2 decrease the efficiency of influenza vaccination?" Interestingly, for a number of years M2 was known to be insufficiently immunogenic in vaccine studies, which in fact, necessitated the utilization either of high doses of M2 or the shift to M2e-peptide as mentioned above. Earlier, Cure Lab demonstrated that M2 on its own may kill the cells producing this protein (uninfected with influenza). The scientists hypothesized that this is the underlying reason for the undesirable effect of M2 on vaccination. If this assumption was correct, then it would immediately suggest how to resolve the problem.



In order for M2 not to be able to exercise its negative functions, the protein should be "trapped" or neutralized in such a manner that prevents it from cell killing. Therefore, Cure Lab fused M2 with other proteins constituting a vaccine in such a way that NP, M1 and NS1 proteins restrict M2 functionality. This specific composite poly-protein, which did not kill the host cells, was selected based on its biochemical properties and cell-based assays.



Further animal testing demonstrated that the fusion construct containing all four conserved influenza proteins including "neutralized" M2, possesses much more promising protective properties than the same poly-protein without M2. "It shows us that the M2-gene can indeed be a valuable component of a novel anti-influenza vaccine if its negative effect is eliminated. One such approach is delineated in the PLoS ONE publication. Other possibilities are prevention of M2-induced cell death by introduction of specific mutations into the M2 gene or combining vaccination with drugs targeting M2, for example, amantadine." said Dr. Alex Shneider.



"Our data does not necessarily indicate that clinical trials of vaccines utilizing genes encoding a full-size influenza M2 protein is unsafe." stated Dr. Petr Ilyinskii, Principal Scientist at Cure Lab. "At the same time, it may suggest that the efficacy of M2-containing vaccines is not optimal for clinical trials and medical applications".



Meanwhile, pandemic flu continues to be one of the major threats to society. It remains to be seen whether it will be eliminated through the development of novel vaccines similarly to smallpox and polio or, at least, becomes controllable.







Citation: Ilyinskii PO, Gambaryan AS, Meriin AB, Gabai V, Kartashov A, et al (2008) Inhibition of Influenza M2-Induced Cell Death Alleviates Its Negative Contribution to Vaccination Efficiency. PLoS ONE 3(1): e1417. doi:10.1371/journal.pone.0001417



Click here to link to the published article online.



Disclaimer


This press release refers to an upcoming article in PLoS ONE. The release has been provided by the article authors and/or their institutions. Any opinions expressed in this are the personal views of the contributors, and do not necessarily represent the views or policies of PLoS. PLoS expressly disclaims any and all warranties and liability in connection with the information found in the release and article and your use of such information.



Source: Helen Kress


Public Library of Science

Illumina Announces Delivery Of The First Genome Through Its Individual Genome Sequencing Service

Illumina, Inc. (NASDAQ:ILMN) announced that it has delivered Hermann Hauser's genome sequence. Dr. Hauser, Partner, Amadeus Capital Partners Ltd, is the first consumer to purchase Illumina's individual genome sequencing service working with his physician, Michael Nova, MD, of Pathway Genomics. The genome was completed in Illumina's CLIA-certified and College of American Pathologists (CAP) accredited laboratory using the Genome Analyzer technology. Over 110 billion base calls were generated, delivering over 30X coverage of the genome. Data analysis showed 300K novel SNPs in the genome that have not been documented elsewhere. This discovery demonstrates the power of whole genome sequencing as an exploratory tool, as these SNPs were novel but not necessarily unique.


"We are very excited to be delivering our first individual genome sequence to Hermann Hauser," said Jay Flatley, President and CEO of Illumina. This is a landmark since just two months ago we launched the availability of this service from Illumina. The experience we created for Hermann was not only one of personal genetic exploration, but one that points to a future where genome sequencing will become a routine practice and the information generated will enable physicians to make better healthcare decisions for the individual. This information has long term value for Hermann as he can continue to access it and gain personal genomic insights as new discoveries are made.


Dr. Hauser's genome was delivered by a team consisting of his physician, Dr. Michael Nova, a bioinformatics specialist and geneticist at Illumina's San Diego headquarters on Thursday, August 20, 2009. The visit included a consultation, facility tour and ceremony during which Dr. Hauser's genome was delivered on an iMac® computer using GenomeStudio® software as a genome browsing interface.


Hermann Hauser is one of the first of a small, select group of individuals who have had their genome sequenced. "Going through Illumina's process was very exciting for me personally. I am looking forward to the information on gene variants that will give my doctors guidance on effective treatments and drug dosage based on pharmacogenetic information, for any future medical condition I may develop. This is the beginning of personalized medicine and I am delighted to be there at the start of it. As an early investor in the gene sequencing technology used in this work, I am proud that Illumina has introduced this service to consumers. It fulfills an early dream to substantially reduce the cost of whole genome sequencing," said Hauser.


Dr. Hauser is a pioneer member of a growing community that is driving education and exchange of information for those who have had their genomes sequenced. As more information becomes available, participants will be in a position to mine their personal genome sequence data to understand their identity in ways which have never been possible before. For more information about Illumina's individual genome sequencing service, please visit everygenome.


Source

Illumina

Breaking The Nanometer Barrier In X-ray Microscopy

Argonne National Laboratory scientists in collaboration with Xradia have created a new X-ray microscope technique capable of observing molecular-scale features, measuring less than a nanometer in height. Combining x-ray reflection together with high resolution x-ray microscopy, scientists can now study interactions at the nanometer-scale which often can exhibit different properties and lead to new insights. Improving our understanding of interactions at the nanoscale holds promise to help us cure the sick, protect our environment and make us more secure.



This novel technique will lead to a better understanding of interfacial reactions at surfaces, such as ion adsorption, corrosion, and catalytic reactions. In particular, this method extends the capability of x-ray microscopy to observe sub-nanometer-sized interfacial features directly and in real time. This non-invasive approach complements the more widely used scanning probe microscopies and can image the topography of a solid surface without using probe-tips near the surface.



Argonne researchers together with Xradia, a firm specializing in x-ray optics and x-ray microscope systems, have achieved sensitivity to sub-nanometer sized features by using a phenomenon known as phase contrast. This breakthrough makes it possible to look directly at individual steps on a solid surface, borrowing a technique used previously in electron microscopy, "The ability to see individual nanometer-scale features is an important benchmark for X-ray microscopy" states Paul Fenter, Argonne National Laboratory Physicist. "Understanding interfacial reactivity is vital to many areas of science and technology, from the corrosion of metals to the transport of contaminants in the environment." Steve Wang of Xradia adds, "This technique opens up the possibility of watching these processes directly and will provide fundamentally new opportunities for understanding them."



This is a significant advance towards understanding the reactivity of solid-surfaces. Future studies will extend these measurements to the observation of real-time processes of mineral surfaces in contact with water. Employing a novel x-ray microscope setup developed by Xradia, and measurements performed at Argonne's Advanced Photon Source, home of the most brilliant X-ray source in the Western Hemisphere, was central to the teams' success.







The research, funded by the U.S. Department of Energy's Office of Basic Energy Sciences, was carried out by a team at Argonne National Laboratory Chemistry Division, scientists including Paul Fenter, Changyong Park, Zhan Zhang, in collaboration with Steve Wang from Xradia. The results were recently published in Nature Physics (VOL 2, pages 700-704, 2006).



Xradia, Inc. is a privately held company established in 2000 to commercialize high-resolution x-ray microscopy systems for nondestructive inspection and nano-scale imaging. Initially targeted at failure analysis in the semiconductor IC industry, subsequent developments have led to a suite of commercial x-ray imaging products that have permitted expansion into markets that include metrology in semiconductor IC production, scientific equipment, biomedical research and nanotechnology development.



The nation's first national laboratory, Argonne National Laboratory conducts basic and applied scientific research across a wide spectrum of disciplines, ranging from high-energy physics to climatology and biotechnology. Since 1990, Argonne has worked with more than 600 companies and numerous federal agencies and other organizations to help advance America's scientific leadership and prepare the nation for the future. Argonne is managed by the UChicago Argonne, LLC for the U.S. Department of Energy's Office of Science.



Contact: Eleanor Taylor


DOE/Argonne National Laboratory

News From The American Chemical Society June 18, 2008

Prions are not degraded by conventional sewage treatment processes



Scientists in Wisconsin are reporting in a paper scheduled for the July 1 issue of ACS' Environmental Science & Technology that typical wastewater treatment processes do not degrade prions. Prions, rogue proteins that cause incurable brain infections such as Mad Cow disease and its human equivalent, variant Creutzfeldt-Jakob Disease, are difficult to inactivate, resisting extreme heat, chemical disinfectants, and irradiation. Until now, scientists did not know whether prions entering sewers and septic tanks from slaughterhouses, meatpacking facilities, or private game dressing, could survive and pass through conventional sewage treatment plants.



Joel Pedersen and colleagues used laboratory experiments with simulated wastewater treatment to show that prions can be recovered from wastewater sludge after 20 days, remaining in the "biosolids," a byproduct of sewage treatment sometimes used to fertilize farm fields.



Although emphasizing that prions have never been reported in wastewater treatment plant water or biosolids, the researchers note that existing tests are not sufficiently sensitive to detect the extremely low levels of prions possible in those materials. - AD



ARTICLE: "Persistence of Pathogenic Prion Protein during Simulated Wastewater Treatment Processes" dx.doi/10.1021/es703186e



CONTACT:

Joel A. Pedersen, Ph.D.

University of Wisconsin

Madison, Wisconsin



New test for more reliable product expiration labels



Beer gets a "skunky" taste. Wine develops an unpleasant flavor termed "light-struck." And exposure to light causes off flavors, colors, and aromas in hundreds of other foods and beverages and decreases shelf life. Now, researchers in Italy report development of a more reliable method for predicting shelf-life that accounts for light sensitivity for the first time and may help consumers choose fresher, tastier food products. Their study is scheduled for the June 25 issue of ACS' Journal of Agricultural and Food Chemistry, a bi-weekly publication.



In the new study, Lara Manzocco and colleagues note that the bright, intense light of retail displays is widely known to cause the formation of off-flavors, loss of nutrients, and color fading in food and beverages. But conventional methods to test the shelf-life of these products focus on the effect of heat and ignore the effect of light, leading to underestimations in shelf-life shown on product expiration labels. A more reliable test is needed, the researchers say.



The scientists exposed a soft drink containing saffron, which contains light-sensitive substances, to different levels of light at increasing temperatures. They found that the beverage grew lighter in color as light intensity increased, confirming that light can cause a dramatic decrease in beverage quality. Based on these observations, the scientists developed a new mathematical model that measures light-sensitivity as well as temperature to provide a more reliable method for predicting shelf-life. - MTS
















ARTICLE: Shelf Life Modeling of Photosensitive Food: The Case of Colored Beverages" dx.doi/10.1021/jf800072u



CONTACT:

Lara Manzocco, Ph.D.

UniversitГ  di Udine

Udine, Italy



New research reports that 12 million molecules share 143 basic shapes



Chemists in Ohio have discovered that half of all of the known chemical compounds in the world have an amazing similarity in sharing only 143 basic molecular shapes. That sharply limits the number of molecular building blocks that chemists often deploy in efforts to develop new drugs and other products, the researchers say in a study scheduled for the June 20 issue of the bi-weekly ACS' Journal of Organic Chemistry.



Alan H. Lipkus and colleagues note that researchers have known for years that certain features of molecules, such as rings of atoms and the bonds than link them together, appear time after time in hundreds of life-saving medications, food additives, and other widely used products.



Scientists often tend to focus on these well-known types of molecular scaffolding in their quest to select the most promising rings, linkers, and other components for building new drugs while overlooking less familiar structures, the researchers say.



In the new study, they analyzed the chemical frameworks of more than 24 million organic substances found in the ACS' Chemical Abstracts Service (CAS) Registry, the world's most comprehensive database of disclosed molecules. They found that half of the substances could be described by only 143 basic framework shapes. By paying more attention to a multitude of other molecular shapes, chemists might discover an array of useful rings, linkers, and other building blocks for tomorrow's drugs and other medical, commercial, and industrial products, the study concluded. - MTS



ARTICLE: "Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry" dx.doi/10.1021/jo8001276



CONTACT:

Eric Shively

Chemical Abstracts Service

Columbus, Ohio 43210



Building giant 'nanoassemblies' that sense their environment



Researchers in Texas are reporting the design, construction, and assembly of nano-size building blocks into the first giant structures that can sense and respond to changes in environmental conditions. The study, scheduled for the July 9 issue of ACS's Nano Letters, a monthly journal, terms those structures "giant" because they are about the size of a grain of rice - millions of times larger than anything in the submicroscopic realm of the nanoworld.



In the new study, Pulickel M. Ajayan and colleagues point out that such structures are a step toward the development of futuristic nanomachines with practical applications in delivering medicines to patients, labs-on-a-chip, and other products. Until now, scientists have had difficulty in using nanomaterials to build more complex, multifunctional objects needed for those applications.



The researchers describe development of a hybrid nanowire consisting of segments with water-repelling carbon nanotubes on one end and water-attracting metal nanowires on the other end. In laboratory tests, they showed that the nanowires could assemble themselves into larger, more complex structures when placed in water. The structures also sensed and responded to their environment by making movements when exposed to chemicals, magnets, and light. The findings "could lead to the creation of smart materials that are a cornerstone for the development of nanotechnology-based applications," the study notes.



ARTICLE: "Controlled Manipulation of Giant Hybrid Inorganic Nanowire Assemblies" dx.doi/10.1021/nl080407i



CONTACT:


Pulickel M. Ajayan, Ph.D.

Rice University

Houston, Texas 77251-1892



Chemists develop healthier foods



From carrots to grapefruits to tortillas, researchers worldwide are giving common foods a more nutritious makeover by removing unhealthy substances and adding or enhancing those that may help fight diseases such as cancer and heart disease, according to an article scheduled for the June 23 issue of Chemical & Engineering News. Some of these products could soon appear at a grocery store near you.



In the C&EN cover story, Associate Editor Rachel Petkewich points out that, amid growing consumer interest in leading a healthier lifestyle, scientists are identifying an increasing number of disease-fighting substances in foods and using them to enhance food crops. As evidence for this skyrocketing interest in healthier foods, the article notes that the number of published papers exploring the disease-fighting properties of food components has quintupled since 2003. Scientists have already developed carrots with super-high antioxidant levels. Other foods designed to target cancer, high cholesterol, and other health conditions may soon be on the way.



But creating healthier foods that are still appealing to consumer taste can be tricky, as changing certain food components makes flavor and texture unappetizing. Scientists are now working on creating substances that can boost nutrition without loosing the qualities consumers find appealing.



ARTICLE: "Devising Healthier Foods" pubs.acs/cen/coverstory/86/8625cover.html







The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.



Source: Michael Woods


American Chemical Society

Gene Therapy Of AIDS

Specialists of the V.A. Engelgardt Institute of Molecular Biology, Russian Academy of Sciences, and the "Vector" Main Research Center of Virology and Biotechnology created and tested on the cell culture three genetic structures capable to suppress reproduction of human immunodeficiency virus (HIV-1) in human cells.


At present, the virus is fought against by chemical agents. The drugs subscribed to the patients act predominantly on key HIV-1 enzymes - reverse transcriptase, invertase and protease. There are a lot of antiviral drugs, but they are often ineffective as HIV mutates quickly and acquires drug resistance. And these drugs are, one should note, toxic and very expensive.


Meanwhile, the human organism's cells possess powerful natural mechanism which should regulate the work of genes including viral ones. It is called RNA-interference. In an extremely simplified form, RNA-interference is damage to a certain RNA sequence with participation of a different, "defending" RNA molecule. This system prevents viral infection, unless viruses had learned to cut it off in the course of evolution. Researchers from countries including Russia are developing the artificial RNA-interference system. It is non-injurious to the patient and, due to high specificity of action, does not damage its own RNA in cells infected by the virus.


To fight against HIV, Russian biologists have created three genetic structures. These structures contain short nucleotide sequences that find the most conservative molecules among all RNA molecules, that is, sequences that do not change quickly and are important to the virus. These sequences are then "damaged". The structure also includes the gene of green fluorescent protein, which allows to determine is the gene structure has entered the cell or not.


The researchers embedded the gene structures created by them into cultivated lymphoid cells. Cells which have been penetrated by the fluorescent protein begin to glow with green. Within 24 and 72 hours after introduction of genetic structures, the cells were infected by human immunodeficiency virus (GKV-4046 culture), and several days later the researchers assessed the degree of viral welfare by specific antigen accumulation. It has turned out that the genetic structures significantly suppress viral reproduction.


The extent of damage to viral RNA depends on the viral dose received by the cell itself and on the sequence of the structure per se. The sequence aimed at the reverse transcriptase area of viral genome turned out to be the most efficient, being capable of suppressing the viral production in the cells by 91 to 98 percent within three days.


In the researchers' opinion, similar genetic structures can be used in AIDS gene therapy. At present, the researchers continue the effort on creation of efficiently operating structures, including the ones that are able to overcome high virus mutation.


INFORMNAUKA (INFORMSCIENCE) AGENCY

informnauka.ru/

Smell Is 'Noisy' And 'In Shades Of Grey' - Scientists Debunk Ancient Lock-And-key Theory

University of Manchester scientists have overturned the 2,500-year-old theory that smell is detected by simple lock-and-key codes - using maggots with only one working olfactory sensory neuron (OSN), a nose with one nerve cell.



It was thought that smells are detected by simple lock-and-key codes. Instead it appears that there is a combination of precise and 'fuzzy' coding that allows organisms to sharpen their response to odours, rather like the dither that is famously used to improve computer performance. Whilst fuzzy coding is known to occur in the central brain, this is the first time it has been shown in the periphery.



Dr Matthew Cobb, at the University's Faculty of Life Sciences, explains: "We have been able to address a problem that people have been trying to resolve for 2,500 years, since the Greek philosopher Democritus suggested that nice smells came from smooth, round atoms and bad smells came from spiky atoms.



"Until now, people have thought that smell works by a simple lock-and-key code where each smell molecule fits into one or more receptors that recognise it. If the smell is there, then the receptors will respond.



"However we have found this to be an over-simplification. It is not just a lock-and-key system. Sometimes a smell comes along and doesn't 'turn the lock'.



"We first set out thinking we would crack the code of locks and keys but we were driven to a new conclusion by the data. We tested for everything, controlled everything, but we found our starting place was wrong. It was a very exciting turn of events."



Dr Cobb and his colleague Dr Cathy McCrohan, together with their PhD student Derek Hoare, have published their study in Journal of Neuroscience. They used Drosophila larvae (maggots) with only one working olfactory sensory neuron (OSN) - a nose with one nerve cell. Although it might seem an unlikely animal to study, the "wiring diagram" of a maggot's nose is exactly the same as that in a human, but much simpler. The scientists recorded the activity in the maggot's nose, to see exactly how smells were detected. The test group was compared to a control group of normal maggots with a full complement of twenty-one working OSNs.



As expected, some OSNs showed consistent, precise lock-and-key responses - either excitation or inhibition - in response to a given odour. But to the scientists' surprise, most cells also showed variable responses - "fuzzy coding"; sometimes they responded to a given odour and sometimes they did not. This variability was real: it was not related to odour type, concentration, stimulus duration, or the genetic make-up of the individual maggot, and it was seen in both test and control groups. They concluded that the peripheral code combines precise coding with fuzzy, stochastic responses in which neurons show apparent unpredictability in their responses to a given odour.



They now believe that fuzzy coding occurs in other organisms, is translated into differing degrees of activation in the brain, and forms a key component of odour recognition in the first stages of olfactory processing.
















Dr McCrohan explains: "The nose gives us insight into the brain - it's not a computer, it's not precise, it's fuzzy. This may be a consequence of way the receptors are built and must be used in some way as part of the process by which the brain perceives an almost infinite variety of odours.



She adds: "These data explained previously mysterious findings that people had reported but were unable to fit into the 'lock and key' model.



"These findings had people scratching their heads, now we can explain them. Fuzziness is true, a real phenomenon that forms a key part of how we detect smells."



The pair now plans to take the research further. So far they have been using pure smells but real smells are highly complex mixtures of chemicals. In addition the single cell maggot nose is extremely simple; many animals possess hundreds of thousands of OSNs and humans have millions.



Dr Cobb says: "We've been using pure smells but real smells are complicated blends; for example a cherry has 200 different molecules. Maybe when you detect a real smell, you use a combination of precise and fuzzy responses - to give yes/no/maybe - forming overall recognition. This is rather like face recognition in which you recognise the same face, even from different angles. So we would like to see how maggots respond with blends.



"We also want to extend the study to other organisms such as beetles, which have nearly as many olfactory receptor types as humans. Other scientists who work with mice or humans could rise to the challenge. I presented this study to a scientific meeting on the sense of smell in Slovenia. It was controversial but well received. People went away convinced they need to look again at data that they have thrown away or ignored.



"Science works by analogy. In the past, people believed the body was like a machine. Then, with the advent of technology, we first thought the brain was like a computer, then like the worldwide web. What we've found here is that these analogies can be misleading. Animals are not machines: information processing in the nervous system involves a huge amount of unpredictability - even in a maggot."




A copy of the paper 'Precise and Fuzzy Coding by Olfactory Sensory Neurons' by Derek J. Hoare, Catherine R. McCrohan and Matthew Cobb is also available here.



The University of Manchester Faculty of Life Sciences, with more than 1,000 people involved in research, 1,700 undergraduate students and an annual total budget of ВЈ65 million, is one of the largest and most successful unified research and teaching organisations of its kind in Europe. See ls.manchester.ac.uk.

New Model Of Muscle Function From Toad Research

A toad sits at a pond's edge eyeing a cricket on a blade of grass. In the blink of an eye, the toad snares the insect with its tongue. This deceptively simple, remarkably fast feeding action offers a new look at how muscles work.



This fresh perspective could lead to designing more efficient electric motors, better prostheses and new medical treatments for neuromuscular diseases like Parkinson's.



Science has long held that muscles behave largely like motors. Northern Arizona University researcher Kiisa Nishikawa suggests that muscle acts more like a spring.



"Existing theories don't explain how muscles shorten rapidly," Nishikawa said. "Muscles can only shorten to do work; they can't do work by lengthening." A spring also can only do work by shortening.



By example, Nishikawa explains that the jaw muscles in toads and chameleons shorten in the lower jaw, and the opening of the jaws causes the tongue to stretch by its own momentum.



"When a toad or chameleon captures prey with its tongue, it exerts force over a distance. Figuring out how they do it has immense application to any device that actually moves."



A toad's jaw muscles can produce forces greater than 700 times the animal's weight. "The best electric motor achieves about one-third of that force-to-weight ratio," Nishikawa noted.



Muscles also function as self-stabilizing springs.



"They have built-in self-correcting mechanisms. Before the brain can even react, muscles are changing their elasticity adaptively," she said. Think of walking down a flight of steps and missing a step. Leg muscles instantly become less stiff to afford better shock absorption. "It's an intrinsic property of muscle," Nishikawa said.



Tom Sugar and his colleagues Arizona State University have been inspired by biology in designing a robotic tendon. After meeting with Nishikawa about her work, Sugar said, "We were amazed at the speed, energy storage and power of muscle. We learned how a frog tongue will store energy and release it in a powerful burst."



At ASU's Human Machine Integration Laboratory, Sugar and his team are building "SPARKy" (Spring Ankle with Regenerative Kinetics) that mimics biology by storing and releasing energy during the ankle gait cycle.



"Energy is stored as the leg and body rolls over the ankle, and then this energy is released in a powerful burst to propel the user forward. By mimicking biology, we are able to build a very lightweight and functional device," Sugar said.



"Putting motors and springs together in a smart way is something nature hit on about 600 million years ago (with the earliest vertebrates)," Nishikawa said.



It's a notion that captured the interest of Discovery Channel Canada, which spent a day at NAU and a day at ASU taping for a segment of its Daily Planet show that will air in the fall.



The NAU researcher wants to know more about how the brain controls movement. About decade ago Nishikawa realized that how the brain and body work together to produce coordinated movement means understanding what muscles contribute to the whole process.



"Understanding what the neurological part is and what the muscular part is can help establish cause and effect," she said. Identifying these mechanisms at the molecular level might aid medical research in developing better treatments for sufferers of Parkinson's, whose low force output results in stiff movements.



Nishikawa's studies of the neuromuscular basis for extremely rapid movements in animals, such as the toad snaring prey with its tongue, could leapfrog to a new model of muscle function, changing the standard representation of muscle as a motor.






Source: Lisa Nelson


Northern Arizona University

Animal Study Of Alzheimer's-Associated Plaques Shows New Plaques Develop In 24 Hours, Neuronal Changes Soon After

The amyloid plaques found in the brains of Alzheimer's disease patients may form much more rapidly than previously expected. Using an advanced microscopic imaging technique to examine brain tissue in mouse models of the devastating neurological disorder, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), working with colleagues from Washington University School of Medicine, find that plaques can develop in as little as a day and that Alzheimer's-associated neuronal changes appear soon afterwards. Their report will appear in the Feb. 7 issue of Nature.



"While we've known for a long time what amyloid plaques and other changes seen in the brains of Alzheimer's patients look like, we didn't know in what order and at what speed those changes occur," says Bradley Hyman, MD, PhD, director of the Alzheimer's Unit at MGH-MIND and senior author of the Nature paper. "Understanding the rules that govern plaque formation may lead us to ideas about how to intervene in the process."



To investigate the timing of these brain changes, the researchers used a novel technique for microscopically imaging the brains of living animals. Using several strains of transgenic mice destined to develop amyloid plaques, they imaged initially plaque-free areas of the brain on a regular basis - first weekly and, in subsequent experiments, daily. Although plaques formed rarely, they could appear as little as 24 hours after a previous plaque-free image was taken. The new plaques were similar in appearance to those seen in the brains of Alzheimer's patients and in the mouse models, and subsequent imaging showed little change in the size of plaques once they had formed.



Earlier investigations have shown that levels of microglia - neuronal support cells that react to inflammation and other damage - rise in the vicinity of amyloid plaques. Imaging an Alzheimer's mouse model that expresses a fluorescent marker in microglia showed that the cells were attracted to new plaques within a day of formation. Although there was no evidence that microglia were actively removing the plaques, the investigators hypothesize that they may help restrict further plaque growth. Examining neurons adjacent to plaques showed that the kind of changes associated with Alzheimer's - distortions in the projections through which neuronal signals pass - appear rapidly and approach maximum effect within five days.



"These results confirm the suspicion we've had that plaques are a primary event in the glial and neuronal changes that underlie Alzheimer's dementia," Hyman says. "We hope that what we've learned about the time frame and sequence of events will help us find ways to keep plaques from forming." Hyman is the John Penny Professor of Neurology at Harvard Medical School.







Melanie Meyer-Luehmann, PhD, of MGH-MIND is the first author of the Nature report; Washington University School of Medicine co-authors Jessica Koenigsknecht-Talboo, PhD, and David Holtzman, MD, provided the transgenic mice and collaborated on the microglial experients. Aditional co-authors are Tara Spires-Jones, Claudia Prada, MD, Monica Garcia-Alloza, Alix de Calignon, Anete Rozkalne, and Brian Bacskai, PhD, all of MGH-MIND. The study was supported by grants from the National Institutes of Health and the Alzheimer's Association.



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



Source: Sue McGreevey


Massachusetts General Hospital

Similarities Found In Dog And Human Breast Cancer Pre-Malignant Lesions

Pre-malignant mammary lesions in dogs and humans display many of the same characteristics, a discovery that could lead to better understanding of breast cancer progression and prevention for people and pets, said a Purdue University scientist from the School of Veterinary Medicine.



A group of scientists including Sulma Mohammed have found similarities between benign lesions that are considered to carry risk for developing breast cancer in both canines and humans. Breast cancer is the second leading cause of cancer deaths in women.



"Dogs develop these lesions spontaneously in contrast to other available models and are exposed to the same environmental risk factors as humans," said Mohammed, an associate professor in comparative pathobiology. "These shared features make the dog an ideal model to compare the breast lesions that will progress to cancer and those that will regress. Such a model will facilitate customized treatment and prevention strategies."



Due to the success of mammographic screening and awareness by women, abnormal cell growth within breast tissues is frequently diagnosed, Mohammed said. These intraepithelial lesions are recognized risk factors for invasive cancer, and their presence affects patient management decisions.



"Once a lesion is identified, it can be treated with hormonal therapy if it is estrogen receptor (ER)-positive, but for low-risk and ER-negative lesions, we can't do anything but wait and watch to see if it grows into a tumor," Mohammed said. "With a dog model, we could study these lesions and test different prevention modalities before it becomes a cancer."



The research appears in this month's issue of the Journal of Cancer Epidemiology, Biomarkers, and Prevention. Mohammed's co-authors include Sunil Badve from Indiana University; Margaret (Peg) Miller, Jun Xie and Elisabetta Antuofermo from Purdue; and Salvatore Pirino from the Sassari University School of Veterinary Medicine in Sardinia, Italy.



The scientists studied 212 tissue biopsies from 200 female dogs with tumors that were retrieved from the archives of the Purdue Animal Disease Diagnostic Laboratory and the Veterinary Teaching Hospital as well as from the Institute of General Pathology and Anatomical Pathology at Sassari University.



The canine slides were compared to human specimens collected from the Department of Pathology at the IU School of Medicine. Mohammed said the focus of the study was not on the tumor but on the precancerous, or preneoplasia, lesions in tissue around the tumor.



"We found that preneoplasia lesions are virtually identical, microscopically, in dogs and women," she said. "In fact, many of the slides were so similar it was often difficult to determine if they were from dogs or people without looking at the label."
















In particular, Mohammed said, they wanted to examine each type of mammary intraepithelial lesion for estrogen receptors expression. Recently, scientists have concluded that breast cancer is not a single disease, but a group of malignancies.



"Establishing an animal model is paramount for testing new treatment and prevention modalities, especially for lesions that express none of the targeted receptors, such as triple-negative types, before human clinical trials," Mohammed said.



The team determined that because of the frequency of lesions, their association with spontaneous mammary cancer and the resemblance to human lesions, dogs may be the ideal model to study human breast cancer progression as well as prevention and treatment. Mohammed emphasized that the research results would benefit both dogs and humans.



According to the American Cancer Society, 62,030 cases of precancerous malignant lesions and 178,480 new cases of breast cancer will be diagnosed. There will be 70,880 women who die from breast cancer this year.



Much of the difficulty in research on dogs with breast cancer is that the data is outdated, Mohammed said. According to a 1969 study of female dogs over 4 years old that were not spayed, one out of four were expected to develop mammary neoplasia, or abnormal cell growth that may progress to cancer. Thirty percent to 50 percent of canine mammary tumors were malignant, and 50 percent to 75 percent of these recurred or metastasized within one to two years.



"Women have become more aware and conscientious of conducting their own breast self-exams, and pet owners also are more aware to check their animals," Mohammed said. "With better diagnostic tools and early detection, we are able to give dogs the same treatment that we give humans."



Mohammed said the dogs provide a more realistic comparison to humans than the mice and rat models, in part because the tumors developed spontaneously, just as in humans. Dogs have been evaluated in a few studies, but rodent research is more common, she said.



"This is a very large, untapped resource for comparative oncology research," Mohammed said. "Unlike laboratory rodents, dogs share a common environment with people and, therefore, may be exposed to some of the same carcinogens. Also, because dogs have a shorter life span than people, it is possible to study mammary lesions and invasive tumors that develop after a few years instead of decades."



Miller, a veterinary pathologist in the Animal Disease Diagnostic Laboratory, said that mammary cancer in dogs is one of the most common forms of cancer studied at the Animal Disease Diagnostic Laboratory.



"We already had hundreds of mammary tumor specimens archived in the diagnostic laboratory," Miller said. "It's a wonderful thing when we're able to collaborate with other departments at Purdue and Indiana University with these specimens. There's so much to be learned from these types of studies."



Tissue samples are kept indefinitely at the Animal Disease Diagnostic Laboratory, but most of the samples in this study were less than a year old, she said. The records kept for each sample provide opportunities for follow up if necessary in future studies.



"Diseases such as this are important to a diagnostic laboratory," Miller said. "Through diagnostic pathology, we gain knowledge that's useful for veterinarians and animals, as well as collecting information that's helpful for people."



The main form of treatment of breast cancer tumors has been surgical removal. Both Mohammed and Miller would like to find out if there is a way to identify the lesion early with noninvasive screening, such as ultrasound or magnetic resonance imaging.



As a next step, Mohammed will determine the prevalence of lesions in dogs with no tumors. In addition, she and Miller are looking at cats, which have a 90 percent malignancy rate when they are diagnosed with breast cancer.







This research was funded by the U.S. Department of Defense.



Writer: Maggie Morris



Related Web site:


School of Veterinary Medicine: vet.purdue/



Click here to access abstract on the research in this release.



Source:

Sulma Mohammed

Maggie Morris


Purdue University

Animal Studies In The Land Of The Midnight Sun Illuminate Biological Clocks

The temperature hovers around freezing, but the sun is up for 24 hours each day. How do animals living in the continuous light of the Arctic summer know when to sleep and when to be active? Do they maintain a 24-hour cycle of rest and activity, or does living in continuous light alter their circadian rhythm?



Answering these questions may improve our understanding of biological clocks -- the internal, genetically programmed cycle of rest and activity that affects the behavior, metabolism and physiology of all animals, including humans. A better understanding may also help solve problems -- such as shift-work fatigue, jet lag and even seasonal affective disorder -- that are associated with disruptions of biological clocks.



One scientist who has spent a lifetime pursuing these questions and finding answers that have helped build the field of biological clock research is G. Edgar Folk, Ph.D., emeritus professor of molecular physiology and biophysics at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.



Folk notes that humans have a natural circadian rhythm of close to, but not exactly, 24 hours. Importantly, all biological clocks are adjustable and respond to environmental cues such as sunrise or sunset, which continuously reset the clock and keep us on a regular 24-hour schedule.



However, previous research, including studies in Folk's lab, has shown that lab rats kept in continuous light develop a 26-hour cycle of rest and activity, meaning their peak of activity travels around our usual daily 24-hour clock. This phenomenon is called the "Aschoff Effect" after a German scientist who first recorded it in the 1960s. Folk sometime ago set out to determine if this effect was also seen in wild animals during the continuous light of the Arctic summer.



"In continuous light in the lab, the animal's clock changes depending on the intensity of the light," Folk explained. "We thought that would also happen in the Arctic. "Much to our surprise, the Arctic animals maintained a very crisp 24-hour period of activity."



Working at Folk's permanent Arctic field lab at Barrow, Alaska, the research team studied two types of Arctic rodent: nocturnal porcupines and day-living ground squirrels.



Heart rates -- a good measure of metabolism and activity -- from four porcupines and direct observation of nine squirrels' activity showed that both creatures retained a 24-hour rhythm of behavior, just as they would if they were living under a normal day/night situation. The study results were published in Biological Rhythm Research.



It seemed that although the scientists were very careful not to provide time cues of any sort, the animals had managed to latch onto something that gave them regularity.
















"I have written for years that experimental animals seem to be hungry for cues, or time signals, to keep on a regular cycle," Folk said. "So we tried to figure out what cue the wild animals were using, and we could find only one thing that kept a 24 hour periodicity. At Barrow, the sun travels in a circle overhead for 82 days, but at midnight the circle is tipped to the north.



"We postulate that the animals are conscious of where the sun is in the sky and that the nearness of the sun to the horizon could be a clue to animals, and even plants, to keep on a 24-hour schedule."



Folk found that several other scientific teams have also proposed the same theory.



"Our work shows that clocks are important, and for me it means that you get surprises -- I thought that we would see drift in the times the animals, slept, but we didn't. The broad implication is that, when possible, animals like humans, like to have regularity."



Sixty years of study have not diminished Folk's fascination with biological clocks, and he says the field still produces surprising results and raises new questions.



"There is a lot more to be done," he said. "For example, birds haven't been studied enough - I first got interested in this study when I was listening to birds singing in the Arctic and trying to figure out if they always sang at the same time of day even when the light was continuous. I'm pretty sure that as a species they must learn to resist the Aschoff effect, but no one has studied it."



Although Folk has not visited his Arctic lab in several years, the heart rate data he has collected in Arctic animals, including hibernating bears, continues to provide a goldmine of information. Folk is currently involved in a collaborative project with Eric Dickson, M.D., UI professor and head of emergency medicine, examining the cardiology of hibernating animals and looking at what application that information might have in human emergency medicine.







Folk's UI research colleagues include, Diana Thrift, a research assistant in Folk's lab, Bridget Zimmerman, Ph.D., clinical associate professor in the UI College of Public Health, and Paul Reimann in anatomy and cell biology.



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



Contact: Jennifer Brown


University of Iowa

Steroids In Female Mouse Urine Light Up Nose Nerves Of Male Mice

A group of steroids found in female mouse urine goes straight to the male mouse's head, according to researchers at Washington University School of Medicine in St. Louis. They found the compounds activate nerve cells in the male mouse's nose with unprecedented effectiveness.



"These particular steroids, known as glucocorticoids (GCCs), are involved in energy metabolism, stress and immune function," says senior author Timothy E. Holy, Ph.D., assistant professor of neurobiology and anatomy. "They control many important aspects of the mouse's physiology and theoretically could give any mouse that sniffs them a detailed insider's view of the health of the animal they came from."



Holy plans further research to see if activating the nerves in the male mouse's nose leads to particular behavioral responses. He probes the male mouse's reaction to chemical signals from female mice to advance understanding of pattern recognition and learning in the much more complex human brain. In 2005, he found that female mice or their odors cause male mice to sing. He doesn't know yet if the GCC steroids' effects on the male mouse nose help to trigger this behavior.



Science has long recognized that urine, sweat and other bodily fluids contain chemical communication signals called pheromones that can influence the biology or behavior of others. Most mammals use the information in these signals for social purposes, such as establishing territory or dominance, or in courtship and mating. In many cases, though, the specific chemical identities of the signals are unknown.



The new study, published in The Journal of Neuroscience and led by graduate student Francesco Nodari, identified compounds that are unusually potent stimulators of the mouse nose. The pheromones activate nerve cells 30 times as often as all the other pheromones previously identified in female mouse urine combined. In addition, several of the new signals activate specific nerve cells. This may mean the male mouse's brain can assess different aspects of female mouse health by selectively analyzing individual pheromones.



Stressing female mice led to a threefold increase in the levels of GCCs in their urine, directly linking the female mouse's health and the GCC pheromones.



The GCC pheromones that Nodari identified were sulfated, which means they had a chemical attachment comprised of sulfur and oxygen atoms. This attachment is added to deactivate the steroids prior to excretion in the urine. When Nodari used an enzyme to remove these attachments, the GCCs lost their ability to activate nerves, further suggesting that the link between the sulfated GCCs and the nerve cells is a channel fine-tuned by evolution to carry information from female mice to male mice.



The nerves researchers studied in the male mouse nose are located in an area known as the accessory olfactory system. Humans and many closely related apes don't have an accessory olfactory system, but most other mammals and some reptiles do. The system, found in a structure called the vomeronasal organ, sends its outputs to a different part of the brain than the main olfactory system. Like the main olfactory system, it's dedicated to detecting airborne particles. But researchers believe the accessory olfactory system focuses on compounds from sources that are physically very close to or touching the animal.
















According to Holy, this focus on scents from nearby sources makes the accessory olfactory system "halfway between a taste system and a sense of smell." He believes the GCC pheromones account for approximately 75 percent of the signals detected in female urine by the male accessory olfactory system.



"Because these new pheromones are so good at activating the accessory olfactory system, they will be very helpful in efforts to better understand what this system does," he says. "That high degree of activation likely also means they have much potential for advancing the general study of pheromones."



To follow up, Holy's lab is testing to see how mice change their behavior when they smell these compounds. They are also searching for additional pheromonal cues that the accessory olfactory system can detect in female urine.







Nodari F, Hsu F-F, Fu X, Holekamp TF, Kao L-F, Turk J, Holy TE. Sulfated steroids as natural ligands of mouse pheromone-sensing neurons. The Journal of Neuroscience, June 18, 2008.



Funding from the United States Public Health Service supported this research.



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



Source: Michael C. Purdy


Washington University School of Medicine

Discovery Of A New Ally In The Battle Against Cocaine Addiction

A recent study shows that a bacterial protein may help cocaine addicts break the habit.



Cocaine esterase (CocE) is a naturally-occurring bacterial enzyme that breaks down cocaine, thereby reducing its addictive properties. The efficacy of CocE in animals and its suitability for treatment of addiction has been limited by its short half-life in the body.



A recent study, published in the Journal of Pharmacology and Experimental Therapeutics and reviewed by Faculty of 1000 Medicine's Friedbert Weiss, demonstrates that a more stable version of CocE, double mutant or DM CocE, significantly decreased the desire for cocaine and prevented death from cocaine overdose.



In the study, rats were trained to self-administer cocaine by pressing a button in their cage, mimicking the need for regular doses of the drug during addiction. Rats treated with the double mutant form of CocE pressed the button to receive cocaine less often, suggesting that DM-CocE broke down the drug and dampened addiction.



DM-CocE decreased the rats' urge for cocaine but not for an addictive analogue, highlighting the degree of specificity for cocaine. Weiss notes that the DM-CocE enzyme also provides "long-lasting protection" against the toxic effects of a potentially lethal dose.



Though the effects of CocE can be overcome by a sufficiently large dose of cocaine, the present findings suggest that CocE has great promise as a drug abuse treatment.



Weiss says, "These therapeutic approaches may therefore not be "fail-safe" for reducing cocaine intake by determined users" but "long-acting forms of CocE represent potentially valuable treatment approaches not only for the prevention of cocaine-induced toxicity but also for ongoing cocaine abuse in humans."



The full text of this article is available free for 90 days at f1000medicine/article/017fjm0nn9jlk80/id/1167997/evaluation/sections



Source: Steve Pogonowski


Faculty of 1000: Biology and Medicine

Genetic Patterning In Fruit Fly Development Identified By Rutgers-Camden Scholar

No matter the species, from flies to humans, we all start the same: a single-cell fertilized egg that embarks on an incredible journey. The specifics of this journey are being uncovered at Rutgers University-Camden, where a biologist is researching how from one cell a jumble of many are able to organize and communicate, allowing life to spring forth.



According to Nir Yakoby, a recently appointed assistant professor of biology at Rutgers-Camden, his work on cell communication is a lot like genetic play dough. His medium however is fruit flies, thousands and thousands of them from various genetic backgrounds.



Yakoby knows that manipulating certain genes in the fruit fly egg will result in very specific consequences in the development of its shell. He and his colleagues' research has been published this month in the prestigious journal Developmental Cell.



"Most people work on one gene at a time, but we're interested in gene networks," explains Yakoby, who earned his undergraduate and doctoral degrees from Hebrew University in Israel. "While riding on the new wave of biology, systems biology, we are still keeping the fundamentals of developmental biology by asking how many genes are expressed over time and space."



After four years of post-doctoral research at the Lewis-Sigler Institute for Integrative Genomics at Princeton University, the Rutgers-Camden scholar is interested in how Drosophila cells communicate and create genetic patterning during its eggshell formation. To gain this knowledge, Yakoby has studied eggshells from a range of Drosophila species for insight on how variations of patterns could reflect how actual structures have evolved.



Titled "A combinatorial code for pattern formation in Drosophila oogenesis," the Developmental Cell article offers precise outcomes for the tens of genes and hundreds of patterns involved in four developmental stages of the fruit fly's eggs. As part of a research team, Yakoby developed an innovative new coding language to formally follow and manage the dynamics of hundreds of gene-patterns. The team concentrated on the two main patterning pathways of the Drosophila egg development: bone morphogenetic protein and epidermal growth factor receptor. Most developmental and other diseases, such as cancer, are associated with these universal pathways.



Yakoby teaches a course on genetics at Rutgers-Camden, where the newly created Center for Computational and Integrative Biology will offer doctoral and graduate programs in computational and integrative biology. The Rutgers-Camden research center aims to determine the quantitative organizational principles of complex biological systems, using a combination of theoretical and experimental approaches.






The Camden Campus of Rutgers, The State University of New Jersey, offers 34 undergraduate and 16 master's-level programs, as well as the nation's first PhD program in childhood studies. Located in the heart of the vibrant Camden Waterfront, Rutgers-Camden is home to 260 faculty whose research, teaching, and service endeavors are respected worldwide.



Source: Cathy Donovan


Rutgers University

Nanoparticle 'Smart Bomb' To Target Cancer Cells Created From Novel Bee Venom Derivative

New research in the FASEB Journal shows that a peptide derived from bee venom can deliver liposomes bearing drugs or diagnostic dyes to specific cells or tissues



The next time you are stung by a bee, here's some consolation: a toxic protein in bee venom, when altered, significantly improves the effectiveness liposome-encapsulated drugs or dyes, such as those already used to treat or diagnose cancer. This research, described in the August 2010 print issue of the FASEB Journal, shows how modified melittin may revolutionize treatments for cancer and perhaps other conditions, such as arthritis, cardiovascular disease, and serious infections.



"This type of transporter agent may help in the design and use of more personalized treatment regimens that can be selectively targeted to tumors and other diseases," said Samuel A. Wickline, Ph.D., a researcher involved in the work from the Consortium for Translational Research in Advanced Imaging and Nanomedicine (C-TRAIN) at the Washington University School of Medicine in St. Louis, Missouri.



To make this discovery, Wickline and colleagues designed and tested variations of the melittin protein to derive a stable compound that could be inserted into liposomal nanoparticles and into living cells without changing or harming them. They then tested the ability of this protein, or "transporter agent," to attach to different therapeutic compounds and enhance drug therapy without causing harmful side effects. In addition, their results suggest that the base compound which is used to create the transporter agent may improve tumor therapy as well.



"Our journal is abuzz in a hive of bee-related discoveries. Just last month, we published research showing for the first time how honey kills bacteria. This month, the Wickline study shows how bee venom peptides can form "smart bombs" that deliver liposomal nanoparticles directly to their target, without collateral damage," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal.



Details:
Hua Pan, Jacob W. Myerson, Olena Ivashyna, Neelesh R. Soman, Jon N. Marsh, Joshua L. Hood, Gregory M. Lanza, Paul H. Schlesinger, and Samuel A. Wickline. Lipid membrane editing with peptide cargo linkers in cells and synthetic nanostructures. FASEB J. 2010 24: 2928-2937. doi: 10.1096/fj.09-153130



Source:

Cody Mooneyhan

Federation of American Societies for Experimental Biology

Your Body Recycling Itself - Captured On Film

Discovery shows how cells decide what to recycle, unlocking debilitating disease's secret


Our bodies recycle proteins, the fundamental building blocks that enable cell growth and development. Proteins are made up of a chain of amino acids, and scientists have known since the 1980s that first one in the chain determines the lifetime of a protein. McGill researchers have finally discovered how the cell identifies this first amino acid - and caught it on camera.


"There are lots of reasons cells recycle proteins - fasting, which causes loss of muscle, growth and remodeling during development, and normal turnover as old proteins are replaced to make new ones," explained lead researcher, Dr. Kalle Gehring, from McGill's Department of Biochemistry. "One way that cells decide which proteins to degrade is the presence of a signal known as an N-degron at the start of the protein. By X-ray crystallography, we discovered that the N-degron is recognized by the UBR box, a component of the cells' recycling system." The powerful technique can pinpoint the exact location of atoms and enabled the team to capture an image of the UBR box, providing insight to this incredibly tiny yet essential part of our bodies' chemical mechanics.


Aside from representing a major advance in our understanding of the life cycle of proteins, the research has important repercussions for Johanson-Blizzard syndrome, a rare disease that causes deformations and mental retardation. This syndrome is caused by a mutation in the UBR box that causes it to lose an essential zinc atom. Better understanding of the structure of the UBR box may help researchers develop treatments for this syndrome.


The research was published in Nature Structural & Molecular Biology and received funding from the Canadian Institutes of Health Research.


Source:

Department of Biochemistry, McGill University