William C. Reeves New Investigator Award Won By UC Davis Malaria Researcher Win Surachetpong

Malaria researcher Win Surachetpong, a doctoral candidate at the University of California, Davis, is the 2009 winner of the William C. Reeves New Investigator Award, given to the best scientific paper presented at the annual Mosquito and Vector Control Association of California (MVCAC) meeting.



Surachetpong received $1000 and a plaque at the 77th annual MVCAC meeting, held in Burlingame. His scientific paper focused on regulating the development of malaria parasites.



"Win is a very talented, dedicated student and I have been extremely fortunate to have him in my lab," said his major professor and malaria researcher Shirley Luckhart, an associate professor of medical microbiology and immunology at the UC Davis School of Medicine, and a faculty member of the Graduate Groups of Biochemistry and Molecular Biology; Microbiology; Immunology; and the Graduate Program in Entomology.



"His work," she said, "has been the foundation of the development of a completely new area of work for us that will probably keep us busy for years to come."



The award memorializes a renowned entomologist and professor at UC Berkeley who was widely regarded as the world's foremost authority on the spread and control of mosquito-borne diseases. Reeves (1916-2004) was a frequent visitor to the UC Davis campus.



Surachetpong said that malaria "remains an enormous public health burden, especially in developing countries." Malaria, caused by the parasite Plasmodium and transmitted by infected anopheline mosquitoes, strikes some 350 to 500 million people a year, killing more than a million, according to the Centers for Disease Control and Prevention.



"New strategies including integrated vector management in combination with current conventional malaria control efforts such as drug treatment and bednet usage could synergistically reduce malaria transmission," Surachetpong said.



"However, our current knowledge of vector-host-parasite interactions is limited," he noted. "For example, how mosquito innate immune responses control malaria parasite development and how blood-derived factors modulate mosquito biology remain interesting topics."



"In this study, we reveal the role of MEK-ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling in regulation of malaria parasite development by an ingested blood-derived, mammalian cytokine in the mosquito host."



The results, the researchers said, "provide new insights into the host-parasite-vector relationship that could be utilized as a foundation for new strategies to reduce malaria transmission."



Surachetpong titled his paper "MAPK/ERK Signaling Regulates the TGF-Betal Dependent Mosquito Response to Plasmodium falciparum." TGF-beta is a transforming growth factor beta synthesized by skeletal cells and found in most species.



A native of Thailand, Surachetpong joined the Luckhart lab and the Immunology Graduate Group in 2005. He is seeking his doctorate in immunology, with a designated emphasis in vectorborne diseases. His doctoral thesis is "MAPK Signaling Pathways Regulate Anti-Malarial Response in Anopheles Mosquitoes."







Last year Surachetpong was awarded a prestigious Bill and Melinda Gates Foundation health travel award to present his research at a Keystone Symposia conference in Bangkok, Thailand. The meeting focused on the pathogenesis and control of emerging infections and drug-resistant organisms.
Surachetpong received his doctorate of veterinary science degree at Chulalongkorn University, Bangkok in 2000, ranking first in his class, and his master of science degree in pathobiology in 2005 from the University of Arizona, with high honors.



Source: Kathy Keatley Garvey


University of California - Davis

New Protein Tag Enhances View Within Living Cells

The view into the inner world of living cells just got a little brighter and more colorful. A powerful new research tool, when used with other labeling technologies, allows simultaneous visualization of two or more different proteins as well as the ability to distinguish young and old copies of a protein within one living cell. The research is published by Cell Press in the February issue of Chemistry and Biology.



Scientists have developed innovative technologies that make use of fluorescent molecules to visualize proteins and biochemical processes in living cells. Various technologies exist that allow transfer of fluorescent properties to specific proteins of interest. One such method, developed by Dr. Kai Johnsson and colleagues at Ecole Polytechnique FГ©dГ©rale de Lausanne, is derived from the human DNA repair enzyme alkylguanine-DNA alkyltransferase (AGT). This tool, called SNAP-tag, can be covalently labeled in living cells using benzylguanine (BG) derivatives bearing a chemical probe.



Now, Dr. Johnsson's group has modified SNAP-tag to generate a new AGT-based tag, named CLIP-tag, which reacts specifically with benzylcytosine (BC) derivatives. "Use of SNAP-tag in conjunction with CLIP-tag permits simultaneous labeling of two proteins with different molecular probes for multiparameter imaging of cellular functions in living cells," explains Dr. Johnsson.



The researchers demonstrate that SNAP-tag and CLIP-tag have some significant advantages over existing labeling methods for conducting multi-protein studies within living cells. Both tags can label proteins in any cellular compartment, have very high specificity towards their native substrates, low reactivity to other BC and BG derivatives and have similar properties that will aid in comparison of one fusion protein to another. Further, chemical labeling methods allow for visualization of proteins in organisms that are not suitable for expression of autofluorescent proteins and are well suited for experiments that make use of other biochemical characterizations after imaging.



"The labeling of CLIP-tag fusion proteins is highly specific and mutually independent from other existing labeling approaches, making the method a highly valuable tool for chemical biology," concludes Dr. Johnsson. "Furthermore, we show for the first time simultaneous pulse-chase experiments to visualize different generations of two different proteins in one sample, allowing concurrent investigation of two different dynamic processes."







The researchers include Arnaud Gautier, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Alexandre Juillerat, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Christian Heinis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Ivan Reis Correa, Jr., Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Maik Kindermann, Covalys Biosciences, Witterswil, Switzerland; Florent Beaufils, Covalys Biosciences, Witterswil, Switzerland; and Kai Johnsson, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.



Source: Cathleen Genova


Cell Press

Computational Quantum Chemical Methods Promising For Drug Development

Research, led by a Virginia Tech chemist, may someday help natural-products chemists decrease by years the time it takes to develop certain types of medicinal drugs. The research by T. Daniel Crawford, associate professor of chemistry, involves computations of optical rotation angles on chiral non-superimposable molecules


Many chiral molecules are important for medical treatment for illnesses ranging from acid-reflux to cancer. The term "chiral" means that two mirror images of a molecule cannot be superimposed onto each other. In other words, some are "left-handed" and some are "right-handed."


"Most drugs have this handedness property," Crawford said, "and for many of these drugs, even though both hands can cause a reaction, it is a situation where one hand does a good thing and one does a bad thing." He used thalidomide as an example. A mixture of both hands of the drug was used in the late 1950s and early 1960s to treat morning sickness in pregnant women. Later studies revealed that, while one of the two hands acted as the desired sedative, the other hand was found to cause significant birth defects. Thalidomide was never approved by the FDA in the United States and was eventually taken off the market in Europe.


For chemists, therefore, it is often vital to determine which hand of a molecule they are using. In other words, when you have a sample of a chiral molecule, how do you distinguish between the left and right hand?


This is where a technique called polarimetry comes in to play. By shooting plane-polarized light through a sample of one hand, the chiral molecule in question will rotate to a characteristic angle either clockwise or counterclockwise, and the two hands of a chiral molecule produce opposite rotations.


"So if we figure out the direction and rotation of the light or each hand, we have a frame of reference for determining whether we have the left or right hand of a molecule," Crawford said.


The problem with this method is that synthesizing the two hands of chiral molecules is often extremely time consuming. "It can take anywhere from weeks to years," Crawford said.


Crawford's research applies the theory of quantum mechanics to devise computational methods in order to eliminate having to create a synthetic molecule. "The hope is that this will allow us to calculate things like optical rotation very accurately," he said. "So when an organic chemist has a molecule and doesn't know if it is left- or right-handed, we can calculate that directly on the computer."


Crawford said the ultimate goal in his research is to be able to provide organic chemists with computational tools to determine the handedness of a particular molecule they are working with. He said that such tools could speed up the drug development process by years.


The research titled, The Current State of 'Ab Initio' Calculations of Optical Rotation and Electronic Circular Dichcoism Spectra, by Crawford and Mary C. Tam of Virginia Tech and Mica Abrams of the University of Central Arkansas, appeared as the cover article in the November 2007 Journal of Physical Chemistry A. Get the complete article at: pubs.acs/cgi-bin/article.cgi/jpcafh/2007/111/i48/html/jp075046u.html


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Chemists Concoct New Agents To Easily Study Critical Cell Proteins

They are the portals to the cell, gateways through which critical signals and chemicals are exchanged between living cells and their environments.



But these gateways -- proteins that span the cell membrane and connect the world outside the cell to its vital inner workings - remain, for the most part, black boxes with little known about their structures and how they work. They are of intense interest to scientists as they are the targets on which many drugs act, but are notoriously difficult to study because extracting these proteins intact from cell membranes is tricky.



Now, however, a team of scientists from the University of Wisconsin-Madison and Stanford University has devised a technology to more easily obtain membrane proteins for study. Writing this week (Oct. 31) in the journal Nature Methods, the group reports the development of a class of agents capable of extracting complex membrane proteins without distorting their shape, a key to understanding how they work.



"The proteins are embedded in the membrane to control what gets into the cell and what gets out," explains Samuel Gellman, a UW-Madison professor of chemistry and a senior author of the paper along with Brian Kobilka of Stanford and Bernadette Byrne of Imperial College London. "If we want to understand life at the molecular level, we need to understand the properties and functions of these membrane proteins."



The catch with membrane proteins and unleashing their potential, however, is getting insight into their physical properties, says Gellman.



Like other kinds of proteins, membrane proteins exhibit a complex pattern of folding, and determining the three-dimensional shapes they assume in the membrane provides essential insight into how they do business.



Proteins are workhorse molecules in any organism, and myriad proteins are known. Structures have been solved for many thousands of so-called "soluble" proteins, but only a couple of hundred membrane protein structures are known, Gellman notes. This contrast is important because roughly one-third of the proteins encoded in the human genome appear to be membrane proteins.



To effectively study a protein, scientists must have access to it. A primary obstacle has been simply getting proteins out of the membrane while maintaining their functional shapes. To that end, Gellman's group has developed a family of new chemical agents, known as amphiphiles, that are easily prepared, customizable to specific proteins and cheap.



"These amphiphiles are very simple," says Gellman. "That's one of their charms. The other is that they can be tuned to pull out many different kinds of proteins."



The hope, according to Gellman, is that the new technology will facilitate research at the biomedical frontier.



The development of the amphiphiles was conducted in close collaboration with groups like Kobilka's, which specializes in techniques that help resolve the three-dimensional structures of proteins found in cell membranes.



The lead author of the new study is Pil Seok Chae, a postdoctoral fellow in Gellman's lab. The work was supported primarily by the U.S National Institutes of Health.


Source:

Samuel Gellman

University of Wisconsin-Madison

Researcher Wjho Established A Paradigm Shift In The Regulation Of Neuronal Cell Development Awarded 2008 EMBO Gold Medal

The European Molecular Biology Organization (EMBO) announced that James Briscoe of the Medical Research Council's National Institute for Medical Research will receive the prestigious EMBO Gold Medal for 2008.



Briscoe receives the award in recognition of his discovery that cells integrate time of exposure and concentration of a morphogen to subsequently mount a graded response.



Awarded annually, the EMBO Gold Medal recognises the outstanding contributions of young researchers in the molecular life sciences. Widely regarded as the most prestigious award of its kind in Europe, the Gold Medal highlights the high standards of Europe's best scientists.



"James Briscoe has revolutionized our understanding of the specification of cell identity in a given spatial setting," said Hermann Bujard, EMBO Executive Director. "His work exemplifies how talented scientists are advancing the field of molecular biology."



Four years at Columbia University in New York as a postdoc in Thomas Jessell's lab laid the foundation for Briscoe's career as a developmental biologist. James says he "learned" developmental biology from working alongside Jessell and a "great" postdoc in the lab at the time, Johan Ericson.



While at Columbia University, Briscoe began to unravel the control mechanisms of neuronal cell identity in the ventral neural tube - a research theme sustained in his own lab at NIMR since taking up a group leader position in 2000. Specifically, the Briscoe lab studies the central role of the morphogen Sonic Hedgehog (Shh) to specify the position and subtype identity of neurons in the ventral spinal cord.



"We want to understand how neurons - nerve cells - are arranged in the spinal cord," explains the EMBO Gold Medal winner for audiences other than his peers. "Specifically we are looking at the molecular basis of how different neuronal cells are organized in a developing embryo as a result of signals received from an important molecule called Sonic Hedgehog, or Shh, that is secreted from a particular region in the spinal cord."


Briscoe and his group discovered a novel mechanism that allows cells to integrate the time of exposure and the concentration of the morphogen Shh to subsequently mount a graded response. In other words, different concentrations of the morphogen activate a signal within the receiving cell for different periods of times. Cells in turn respond to different durations of the signal by activating different genes and therefore becoming different types of nerve cells.



"The discovery that concentration is effectively converted into time is a major shift in our understanding of how a graded signal acts to regulate genes," stated David Wilkinson, Head of Genetics and Development at NIMR, in his nomination of Briscoe for the EMBO Gold Medal.



James Briscoe's contribution to the understanding of how cell identity is specified in a given spatial setting has established a new paradigm that may also apply in many other contexts. In addition to Shh, a number of other secreted molecules - members of different protein families - have also been implicated in acting as morphogens to pattern other tissues. "It is possible that other morphogens could use a similar mechanism to control cells, for example early in embryo development during gastrulation," explains the Gold Medal winner.
















"James's discoveries have revealed general principles that may apply to many other contexts in which graded signals and downstream transcription factors control cell identity," confirmed David Wilkinson.



Robb Krumlauf, former Head of Division at NIMR who helped to recruit Briscoe to the institute, points out his outstanding qualities at the bench: "At NIMR James rapidly established an independent and creative line of research in his own group. His work is highly rigorous, hits the heart of a problem, and continues to be timely and of wide general interest."



Jim Smith of the Gurdon Institute agrees with Krumlauf that Briscoe's work "has been remarkably creative and imaginative while retaining characteristic levels of careful experimentation and scholarship."



On hearing the news of the EMBO Gold Medal Briscoe referred to the success of his team of researchers: "I have been very fortunate working with very talented and smart people. They taught me a lot, supported me fantastically, and made many significant contributions."



In 2000, James Briscoe was selected to benefit from the highly competitive EMBO Young Investigator Programme, then in its first year and now renowned for its scientific excellence.



James Briscoe will receive the EMBO Gold Medal and an award of 10,000 euro on 6 September 2008 at the EMBO Members Workshop, Frontiers of Molecular Biology, in Tampere, Finland.







Source: Suzanne Beveridge


European Molecular Biology Organization

Scripps Scientists Develop New Tests That Identify Lethal Prion Strains Quickly And Accurately

One of the new in vitro tests, called the Standard Scrapie Cell Assay, measures prion infectivity levels in a highly accurate and extremely rapid way, producing results in less than two weeks. The second test, called the Cell Panel Assay, allows researchers to quickly distinguish between several prion strains in various cells lines. Using the new assays, the scientists were able to show that four different cell lines exhibited widely different responses to four different strains of the infectious protein particles.



The research is being published in an advanced online edition of the Proceedings of the National Academy of Sciences the week of December 3, 2007.



"These new assays vastly accelerate the measurement of prion infectivity and the determination of those cell lines that are able to sustain high infection rates of some prion strains," said Sukhvir P. Mahal, an author of the study who is a senior staff scientist in the laboratory of Charles Weissmann, chair of the Scripps Florida Department of Infectology. "The current test, which takes anywhere from 150 to 250 days and involves large numbers of laboratory mice, is slow, imprecise, and expensive. Our new assays will replace the current mouse brain-bioassays."



The current method of measurement and identification involves injecting a prion-containing sample into the brains of mice and then waiting to see how long it takes for the animals to succumb to disease; the higher the prion level, the less time it takes for them to become lethally infected.



In contrast, the new Standard Scrapie Cell Assay is based on prion-susceptible cell lines. In the test, cells are exposed to prions and then the infected cells are identified and counted using automated imaging equipment.



A Unique Pathogen



Prions (the name stands for proteinaceous infectious particles) are unique infectious pathogens associated with some 15 different diseases, including Bovine Spongiform Encephalopathy ("mad cow") and its rare human form, variant Creutzfeldt-Jacob disease. Infectious prions, which are thought to consist mainly of an abnormally structured or misfolded protein, have the ability to reproduce, despite the fact that they contain no nucleic acid genome as do viruses or bacteria.



Mammalian cells normally produce what is known as cellular prion protein; during infection, the abnormal protein converts production of normal host prion protein to its infectious form. The full details of this process are still not understood.



Prions develop in distinct strains, initially characterized by incubation time and the pattern of brain damage that develops during infection. It is currently thought that strain-specific properties of prions are determined by the three-dimensional structure of the misfolded protein, although the amino acid sequence remains the same. During infection with a single type of prion, several different prion strains can be propagated indefinitely in a single host.
















"Some cell lines can be persistently infected by prions and show preference for certain strains," Mahal said. "One intriguing finding of our new study is that a cell line's ability to replicate a particular prion strain is a trait that varies significantly among the members of the cell population-even sibling cell lines may show different relative susceptibilities to various prion strains."



This suggests that the capacity of a cell line to replicate a particular prion strain is controlled epigenetically without any changes to the DNA sequence, she said.



Another fascinating question raised by the study is how cells come to distinguish between prion strains; that is, between the various proteins that differ only in the way they are folded. The exact nature of that recognition process is now the target of a new Scripps Research study using the Cell Panel Assay.







Other authors of the study, Prion Strain Discrimination In Cell Culture: The Cell Panel Assay, include Christopher A. Baker, Cheryl A. Demczyk, Emery W. Smith, and Charles Weissmann of the Department of Infectology, Scripps Florida; and Christian Julius of the Institute of Neuropathology, University Hospital of ZГјrich, ZГјrich, Switzerland.



The study was supported by The Scripps Research Institute and the Alafi Family Foundation.



About The Scripps Research Institute



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



Source:

Keith McKeown

Scripps Research Institute

Nitric Oxide: Key To Cardiovascular And Pulmonary Function And Drug Effectiveness

A naturally occurring molecule in the body appears to control whether certain medications, such as beta adrenergic receptor agonists used in acute heart failure or in inhalers for asthma, lose their effectiveness over time.



Nitric oxide is a molecule produced by the body that controls many functions, including the contraction or dilation of blood vessels.



New experiments conducted by Duke University Medical Center and Howard Hughes Medical Institute researchers have shown that specialized forms of nitric oxide called SNOs may be the key to a problem that has stumped physicians for years -- why specific drugs for such diseases as heart failure or asthma lose their effectiveness over time.



Almost half of all drugs on the market today, as well as many hormone and neurotransmitters, target a specific family of cell surface receptors known as G-protein coupled receptors. The researchers believe that the presence or absence of nitric oxide or SNOs determines whether these receptors continue to function properly. This action is controlled by the ability of nitric oxide to inhibit a key regulatory system which ordinarily shuts the receptors off after they are stimulated



The researchers report their latest findings in the journal Cell.



"This work is significant in that it demonstrates how two of the most pervasive physiological systems -- G-protein coupled receptors and nitric oxide -- come together to influence one another," said Erin Whalen, Ph.D., who spent six years focusing on the link between the two biological systems. Whalen is a postdoctoral fellow in the laboratory of Robert Lefkowitz, M.D., a Howard Hughes Medical Institute investigator at Duke who first cloned these receptors in 1986. The link was cemented through a collaboration with Matt Foster, a post-doctoral fellow in the laboratory of Jonathan Stamler M.D.



G-protein coupled receptors reside on the cell surface where they interact with all manner of stimuli, including circulating factors such as adrenaline, as well such diverse sensory signals as odorants and light. The activation of these receptors leads to the propagation of intracellular signals. Once activated the receptors are quickly turned-off by an enzyme called a G protein-coupled receptor kinase. This process is called desensitization and can limit the effectiveness of many drugs, such as opiates for pain and adrenaline for asthma, and is further associated with numerous diseases including those of the cardiovascular and pulmonary systems. If activated for a long period of time the receptors are carried into the cell and are "turned off."



In animal, cellular and biochemical experiments, the researchers found that a lack of nitric oxide leads to a decrease in beta adrenergic receptor number and function. Also, the researchers found that when SNO compounds were administered to mice they could prevent the receptors from being "turned off" by the drugs.



The researchers said these findings, if confirmed in humans, open up new avenues for the development of non-desensitizing drugs not only for heart failure and asthma but also for other conditions such as pain and high blood pressure.



"We demonstrated that when one of the systems goes awry, so does the other," said Stamler, whose laboratory has made many fundamental discoveries about the role of nitric oxide in human biology, including the discovery of SNOs' ubiquitous role in human health and disease. "When nitric oxide function is impaired by disease, therapeutic agents like beta-agonists in asthma and adrenergic stimulants in heart failure will work less well. The key now is to determine how best to manipulate these ubiquitous receptors, together with nitric oxide for the treatment of human diseases."



"In broad terms, the results of these experiments present a novel role for nitric oxide in regulating the activity of G-protein coupled receptors," Lefkowitz said. "Also, the findings point to the possibility that deficiencies in the activity of nitric oxide, which occurs in common disorders such as high blood pressure, diabetes, atherosclerosis, cystic fibrosis and neurodegenerative conditions, as well as in aging, may interfere with the G-protein coupled receptor signaling."







Other Duke members of the team were Akio Matsumoto, Kentaro Ozama, Jonathan Violin, Loretta Que, Chris Nelson, Moran Benhar and Howard Rockman. Yehia Daaka of the Medical College of Georgia, and Janelle Keys and Walter Koch, both of Jefferson Medical College, in Philadelphia, were also members of the team.



Contact: Richard Merritt


Duke University Medical Center

Journal Of The National Cancer Institute July 29

The Same Dose of Anthracycline Is Not Safe for Everyone



Not all patients can tolerate the currently recommended cumulative dose of epirubicin. New models can help physicians calculate the epirubicin dose associated with a 5 percent risk of cardiotoxicity for individual patients.



Oncologists frequently use anthracyclines, including epirubicin and doxorubicin, to treat breast cancer patients. However, the drugs cause lasting heart problems in a substantial number of patients. To limit the problem, current treatment guidelines suggest that patients receive no more than 900 mg/m2 epirubicin over the course of their cancer care.



In the current study, Marianne Ryberg, M.D., of the University of Copenhagen and colleagues followed 1,097 patients with metastatic breast cancer who were treated in a single hospital near Copenhagen between 1983 and 2003. The researchers assessed patients' risk factors for cardiotoxicity and corrected for the risk of death from all other competing causes of death, including cancer. (The studies that have previously concluded that the upper safe limit of epirubicin is 900 mg/m2 have not generally corrected for other causes of death.) Using these data, they calculated the maximum cumulative dose of epirubicin that is associated with a 5 percent risk of developing heart disease.



Ryberg and colleagues found that patient age, predisposition to heart disease, previous chest irradiation, and prior hormonal cancer therapy were associated with an individual's risk of developing heart problems following epirubicin treatment. By contrast, the researchers found that treatment with less epirubicin, a higher tumor burden, prior chemotherapy, and older age of the patient were associated with an increased risk of death from other, non-cardiac, causes.



Based on these data, the researchers lowered the cumulative dose recommended for most patients, with maximum doses ranging from 300 mg/m2 to 900 mg/m2. "Treatment with a potentially cardiotoxic drug may often be inevitable to extend survival for a cancer patient. However, it is essential to be aware of the risk of cardiotoxicity, not only because cardiotoxicity can progress to a potentially fatal out
come if not treated but also because it lowers the quality of patient life," the authors write.



In an accompanying editorial, Dawn Hershman, M.D., and Alfred I. Neugut, M.D., Ph.D., of Columbia University Medical Center in New York write that it has been difficult to predict which patients are most likely to develop cardiotoxicity following anthracycline therapy. Neither randomized clinical trials nor studies that rely on large administrative databases are adequate for addressing the issue. Therefore, Ryberg's study is an important step to helping physicians personalize cancer care for their patients.
















"If we can better predict who is at greatest risk for toxicity and who is not, we may be able to comfortably offer standard treatment to a larger percentage of the population," the editorialists write.



Lapatinib Reduces Brain Metastases in Mouse Model of Metastatic Breast Cancer



Lapatinib reduces the number of large brain metastases in a mouse model of metastatic breast cancer, relative to untreated mice.



Symptomatic brain metastases affect between 10 and 20 percent of women with metastatic breast cancer, and the problem is particularly common for women whose tumors overexpress the HER2 protein. However, trastuzumab, an antibody that blocks the HER2 protein activity and is the standard of care for HER2-positive disease, does not cross the blood-brain barrier. Therefore, other therapies are needed to reduce the brain metastases in patients with HER2-positive disease. Lapatinib, a small-molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR), is able to cross the blood-brain barrier.



In the current study, Patricia Steeg, Ph.D., of the National Cancer Institute and colleagues injected mice with a breast cancer cell line that preferentially gives rise to metastases in the brain, called MDA-MB-231-BR. The researchers engineered some of the cells to overexpress the HER2 protein. Five days after the mice were injected with the cancer cells, the researchers started treating them with lapatinib or a placebo. After 24 days of therapy, the investigators measured and counted brain metastases.



Among mice injected with the HER2-overexpressing cells, those treated with lapatinib developed fewer than half of the large metastases as those that did not receive the drug. A similar reduction occurred among mice injected with the unmodified cells, although a higher dose of lapatinib was required. Lapatinib did not completely prevent the formation of brain metastases, suggesting that some of the tumor cells are resistant to the drug.



"We propose a scenario in which standard treatments such as neurosurgery and stereotactic radiosurgery are used to treat clinical metastases and currently unavailable molecular therapeutics are then used to hold the remaining micrometastases in check. One possible molecular therapeutic is lapatinib, a dual inhibitor of EGFR and HER2 kinases," the authors write



Mitochondrial DNA Copy Number Associated with Risk of Kidney Cancer



Genetic factors were shown to influence the number of copies of mitochondrial DNA (mtDNA) in healthy cells. A lower mtDNA copy number was associated with an increased risk of renal cell cancer in a case-control study.



The degree to which mtDNA copy number is controlled genetically has been unknown. Previous studies have suggested that low mtDNA copy number may be associated with an increased risk of a variety of cancers, but researchers have not explored its possible association with kidney cancer.



In the first portion of the study, Xifeng Wu, M.D., Ph.D., of the University of Texas M. D. Anderson Cancer Center in Houston and colleagues analyzed mtDNA copy number from the peripheral blood cells of more than 300 identical and non-identical twins to estimate the influence of genetics on copy number. In the second portion of the study, the researchers analyzed mtDNA copy number from 260 renal cell cancer patients and 281 control subjects to examine the association between copy number and renal cancer risk.



The investigators estimate that genetics accounts for 65 percent of the variation in mtDNA copy number in the population. On average, renal cancer patients had a lower mtDNA copy number in peripheral blood cells than did control subjects. They also observed a statistically significant trend for increased risk of renal cell cancer with decreasing mtDNA copy number.



"To the best of our knowledge, this is the first molecular epidemiological study to evaluate mtDNA content in lymphocytes as a susceptibility biomarker for cancer," the authors write.



Modified Salmonella Slows Tumor Growth



Attenuated Salmonella bacteria engineered to express the Fas ligand (FasL) accumulate in tumors and reduce their growth.



Salmonella typhimurium concentrates in tumors following intravenous injection in mice. Taking advantage of that observation, Markus Loeffler, M.D., and John Reed, M.D., Ph.D., of the Burnham Institute for Medical Research in La Jolla, Calif., engineered a genetically modified, less pathogenic strain of Salmonella to express FasL, a signaling protein that can attract neutrophils and can promote tumor cell killing by cytotoxic T cells. Although FasL is toxic when injected into the bloodstream, the authors hypothesized that Salmonella might be used to safely target this protein to tumors.



In the current study, Loeffler, Reed, and colleagues injected mice with tumors derived from mouse breast and colon cancers with attenuated FasL-expressing Salmonella.



Following the treatment, primary tumor growth was substantially inhibited in mice with either breast or colon tumors and lung metastases were reduced in the mice with breast cancer. The anti-cancer effect appeared dependent on the presence of inflammatory cells called neutrophils.



Although toxicology and other studies are needed before the approach can be tested in human clinical trials, "these results from murine cancer models suggest that FasL-expressing [Salmonella] could offer an acceptable strategy for employing FasL and possibly other toxic cytokines for cancer therapy," the authors conclude.







Also in July 29 JNCI:



Despite Hazards, 1/5 Of British Adult Survivors Of Childhood Cancer Are Smokers



Breast Cancer Screening: Two Strategies Are Equally Effective



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



Source: Liz Savage


Journal of the National Cancer Institute

Transplanted Embryonic Cells Create New Period Of Brain "Plasticity"

UCSF scientists report that they were able to prompt a new period of "plasticity," or capacity for change, in the neural circuitry of the visual cortex of juvenile mice. The approach, they say, might some day be used to create new periods of plasticity in the human brain that would allow for the repair of neural circuits following injury or disease.



The strategy - which involved transplanting a specific type of immature neuron from embryonic mice into the visual cortex of young mice - could be used to treat neural circuits disrupted in abnormal fetal or postnatal development, stroke, traumatic brain injury, psychiatric illness and aging.



Like all regions of the brain, the visual cortex undergoes a highly plastic period during early life. Cells respond strongly to visual signals, which they relay in a rapid, directed way from one appropriate cell to the next in a process known as synaptic transmission. The chemical connections created in this process produce neural circuitry that is crucial for the function of the visual system. In mice, this critical period of plasticity occurs around the end of the fourth week of life.



The catalyst for the so-called critical period plasticity in the visual cortex is the development of synaptic signaling by neurons that release the inhibitory neurotransmitter GABA. These neurons receive excitatory signals from other neurons, thus helping to maintain the balance of excitation and inhibition in the visual system.



In their study, published in the journal Science, (Vol. 327. no. 5969, 2010), the scientists wanted to see if the embryonic neurons, once they had matured into GABA-producing inhibitory neurons, could induce plasticity in mice after the normal critical period had closed.



The team first dissected the immature neurons from their origin in the embryonic medial ganglionic eminence (MGE) of the embryonic mice. Then they transplanted the MGE cells into the animals' visual cortex at two different juvenile stages. The cells, targeted to the visual cortex, dispersed through the region, matured into GABAergic inhibitory neurons, and made widespread synaptic connections with excitatory neurons.



The scientists then carried out a process known as monocular visual deprivation, in which they blocked the visual signals to one eye in each of the animals for four days. When this process is carried out during the critical period, cells in the visual cortex quickly become less responsive to the eye deprived of sensory input, and become more responsive to the non-deprived eye, creating alterations in the neural circuitry. This phenomenon, known as ocular dominance plasticity, greatly diminishes as the brain matures past this critical postnatal developmental period.



The team wanted to see if the transplanted cells would affect the visual system's response to the visual deprivation after the critical period. They studied the cells' effects after allowing them to mature for varying lengths of time. When the cells were as young as 17 days old or as old as 43 days old, they had little impact on the neural circuitry of the region. However, when they were 33-39 days old, their impact was significant. During that time, monocular visual deprivation shifted the neural responses away from the deprived eye and toward the non-deprived eye, revealing the state of ocular dominance plasticity.
















Naturally occurring, or endogenous, inhibitory neurons are also around 33-39 days old when the normal critical period for plasticity occurs. Thus, the transplanted cells' impact occurred once they had reached the cellular age of inhibitory neurons during the normal critical period.



The finding, the team says, suggests that the normal critical period of plasticity in the visual cortex is regulated by a developmental program intrinsic to inhibitory neurons, and that embryonic inhibitory neuron precursors can retain and execute this program when transplanted into the postnatal cortex, thereby creating a new period of plasticity.



"The findings suggest it ultimately might be possible to use inhibitory neuron transplantation, or some factor that is produced by inhibitory neurons, to create a new period of plasticity of limited duration for repairing damaged brains," says author Sunil P. Gandhi, PhD, a postdoctoral fellow in the lab of Michael Stryker, PhD, professor of physiology and a member of the Keck Center for Integrative Neurosciences at UCSF. "It will be important to determine whether transplantation is equally effective in older animals."



Likewise, "the results raise a fundamental question: how do these cells, as they pass through a specific stage in their development, create these windows of plasticity?" says author Derek G. Southwell, PhD, a student in the lab of Arturo Alvarez-Buylla, PhD, Heather and Melanie Muss Professor of Neurological Surgery and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.



The findings could be relevant to understanding why learning certain behaviors, such as language, occurs with ease in young children but not in adults, says Alvarez-Buylla. "Grafted MGE cells may some day provide a way to induce cortical plasticity and learning later in life."



The findings also complement two other recent UCSF studies using MGE cells to modify neural circuits. In a collaborative study among the laboratories of Scott Baraban, PhD, professor of neurological surgery; John Rubenstein, MD, PhD, professor of psychiatry, and Alvarez-Buylla, the cells were grafted into the neocortex of juvenile rodents, where they reduced the intensity and frequency of epileptic seizures. (Proceedings of the National Academy of Science, vol. 106, no. 36, 2009). Other teams are exploring this tactic, as well.



In the other study (Cell Stem Cell, vol. 6, issue 3, 2010), UCSF scientists reported the first use of MGEs to treat motor symptoms in mice with a condition designed to mimick Parkinson's disease. The finding was reported by the lab of Arnold Kriegstein, MD, PhD, UCSF professor of neurology and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, in collaboration with Alvarez-Buylla and Krys Bankiewicz, MD, PhD, UCSF professor of neurological surgery.



Link to related article: https://pharma-lexicon/mladmin/previewarticle.php?newsid=183708



The other co-author of the plasticity study was Robert C. Froemke, PhD, a postdoctoral fellow in the lab of Christoph Schreiner, MD, PhD, professor and vice chair of otolaryngology.



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



Source:

Jennifer O'Brien


University of California - San Francisco

Springer Expands Life Science Program With In Vitro Journals

Springer has entered into a partnership with the Society for In Vitro Biology (SIVB) and the International Association for Plant Biotechnology (IAPB, formerly IAPTC&B) to publish their journals In Vitro Cellular and Developmental Biology - Animal and In Vitro Cellular and Developmental Biology - Plant. Springer will assume publication of these key journals in January 2007.



Founded in 1965, the In Vitro - Animal and In Vitro - Plant journals are the only ones on the market sponsored by professional societies devoted solely to the in vitro biology of animals and plants. The latest research, techniques and other developments related to the in vitro cultivation of cells, tissues, organs, or tumors from plants and animals, including humans are presented in the journals. With newly designed covers, In Vitro - Animal will be published ten times a year and In Vitro - Plant will appear bi-monthly.



Dr. Dieter Czeschlik, Editorial Director for Life Sciences at Springer, said, "We are proud that the SIVB and the IAPB have entrusted us with the publication of their journals. Previously published by two different companies, the journals will now benefit by having a single publisher. We will increase the journals' worldwide visibility as well as the international impact of the two societies. Of course, we are delighted to join forces with both societies to provide their members with highly professional and fast publication services."



Dr. Paul J. Price, President of SIVB, stated, "Our partnership with Springer guarantees the financial health of the journals, expands their visibility and access, and provides improved editorial support. This represents a major accomplishment for the Society. We now have increased marketing possibilities and the potential for broader circulation, allowing our publications to have a greater impact. Having both journals under the same roof enables other synergies to develop within the sections of our Society."



Dr. Roger N. Beachy, President of IAPB, said, "The recent change that results in publication of the SIVB journals by Springer provides a unique opportunity for the Society. I am particularly pleased that the newly renamed IAPB will communicate to its membership through this medium. Our goal is to further inform the membership of the outcomes of research in plant biology and biotechnology: The partnership with Springer will facilitate this effort."



In Vitro - Animal and In Vitro - Plant will be available online as well as in print. All articles will be published online via Online First™ before they appear in print, thereby ensuring the most rapid dissemination possible of research results. In addition, all authors, via the Springer Open Choice program, have the option of publishing their articles using the open access publishing model. Springer will digitize the back volumes of the journal, making them available to readers through the Springer Online Archives Collection.



About SIVB

With over 1,000 members, the SIVB was founded in 1946 as the Tissue Culture Association to foster exchange of knowledge of in vitro biology of cells, tissues and organs from both plant and animals, including humans. The focus is on biological research, development, and applications of significance to science and society. The mission is accomplished through the Society's publications; national and local conferences, meetings and workshops; and support of teaching initiatives in cooperation with educational institutions.



About IAPB

The forerunner organization to IAPB was founded in 1963 and has over 2,000 members in more than 85 countries. The organization was renamed IAPB in 2006 to more closely reflect the research of its members. Internationally oriented, it is the largest, oldest, and most comprehensive professional organization in its field. Its mission is to promote research in all aspects of basic and applied plant tissue culture and biotechnology through its publications and scientific conferences.



About Springer

Springer is the second-largest publisher worldwide in the science, technology, and medicine (STM) sector. It publishes on behalf of more than 300 academic associations and professional societies. Springer is part of Springer Science+Business Media, one of the world's leading suppliers of scientific and specialist literature. The group owns 70 publishing houses, together publishing a total of 1,450 journals and more than 5,000 new books a year. The group operates in over 20 countries in Europe, the USA, and Asia, and has some 5,000 employees. In 2005, it generated annual sales of around EUR 838 million.



Contact: Joan Robinson


Springer

Traces Of Nanobubbles Determine Nanoboiling - Could Have An Effect On Some Proposed Cancer Therapies

Using a microscope and some extreme "snapshot" photography with shutter speeds only a few nanoseconds long, researchers from the National Institute of Standards and Technology (NIST) and Cornell University have uncovered the traces of ephemeral "nanobubbles" formed in boiling water on a microheater. Their observations* suggest an added complexity to the everyday phenomenon of boiling, and may affect technologies as diverse as inkjet printers and some proposed cancer therapies.



You might think that the science of boiling had been worked out some time ago, but it still has some mysteries, particularly at the nanometer scale. As water and other fluids change from their liquid state to a vapor, bubbles of the vapor form. The bubbles usually form at "nucleation sites," which can be small surface irregularities on the container or tiny suspended particles in the fluid. The exact onset of boiling depends on the presence and nature of these sites.



To observe the process, the NIST/Cornell team used a unique ultrafast laser strobe microscopy technique with an effective shutter speed of eight nanoseconds to photograph bubbles growing on a microheater surface about 15 micrometers wide. At this scale, a voltage pulse of only five microseconds superheats the water to nearly 300 °C, creating a microbubble tens of microns in diameter. When the pulse ends, the microbubble collapses as the water cools. What the team found was that if a second voltage pulse follows closely enough, the second microbubble forms earlier during the pulse and at a lower temperature apparently, as conjectured by the team, because nanobubbles formed by the collapse of the first bubble become new nucleation sites for the growth of later bubbles. The nanobubbles themselves are too small to observe, but by changing the timing between voltage pulses and observing how long it takes the second microbubble to form, the researchers were able to estimate the lifetime of the nanobubbles-roughly 100 microseconds.



These experiments are believed to be the first evidence that nanoscale bubbles can form on hydrophilic surfaces (previous evidence of nanobubbles was found only for hydrophobic surfaces like oilcloth) and the method for measuring nanobubble lifetimes may improve models for optimal heat transfer design in nanostructures. The work has immediate implications for inkjet printing, in which a metal film is heated with a voltage pulse to create a bubble that is used to eject a droplet of ink through a nozzle. If inkjet printing is pushed to higher speeds (repetition rates above about 10 kilohertz), the work suggests, nanobubbles on the heater surface between pulses will make it difficult or impossible to control bubble formation properly.



The findings also may impact proposed thermal cancer therapies in which nanoscale objects are designed to accumulate in tumors and are subsequently heated remotely by infrared radiation or alternating magnetic fields. Each particle acts as a nanoscale heater, with nanobubbles being created if the applied radiation is sufficient. The bubbles may have a therapeutic effect through additional heat delivered and mechanical stresses they may impart to the surrounding tissue.







View video clips of microbubble formation here



* R. E. Cavicchi and C.T. Avedisian. Bubble nucleation and growth anomaly for a hydrophilic microheater attributed to metastable nanobubbles. Phys. Rev. Lett. 98, 124501 (2007).



Contact: Michael Baum

National Institute of Standards and Technology (NIST)

Pan-South American Biological Database Project Under Way

The project of creating a South American biological database - with the official name Patrimonio GenГіmico y Saberes Locales (PGSL) which roughly translates to "Genomic Heritage and Local Wisdom" - manifested itself with a recent inaugural meeting in Ecuador, where universities and government agencies from various South American countries, as well as bioinformatics solution providers CLC bio, participated and agreed to move to the next phase of the project.


Ecuador's Deputy Secretary of State, Dr. Gonzalo Salvador, stated at the inaugural meeting:


"It is a milestone for South America to start the PGSL project, in order to recognize and ensure the unique cultural and natural heritage of South America, through modern and highly advanced science."


The overall goal of the PGSL project is to harvest and preserve nucleotide sequence data from the vast biodiversity throughout the continent and make a database, much like DDBJ in Japan, EMBL in Europe, and GenBank in North America. In addition, the project will scientifically investigate and preserve the ancient and traditional therapeutic healthcare substances - knowledge protected for thousands of years by native civilizations in South America. Another important issue for PGSL is to minimize "bio-piracy" - the act of non-native scientists harvesting and using genetic materials from South America for copyrighted products.


Via live video conference from Denmark, CLC bio's Vice President, Jan Lomholdt, stated at the meeting:


"Creating a biological database in South America, based on the profound biodiversity throughout the region, is of utmost importance - not only to South America, but to the whole world. It is vital to gain a deeper understanding of the unique species in Amazonia, Patagonia, and the GalГЎpagos Islands, to name a few exceptional areas in the region. It is also essential to develop and maintain the scientific knowledge in South America, and to help increase the overall level of understanding of genetics and bioinformatics."


A fundamental part of the process is the education and training of leaders of the indigenous organizations, scientists, and postgraduate students, under the common agenda of PGSL. CLC bio will support this academic program with their new Educational Package (clceducation) as well as bioinformatics solutions, and consultancy services throughout the project.


The South American countries have started the project with Mr. Pablo Morales Males from Pontificia Universidad CatГіlica of Ecuador (PUCE) as the Project Director, and PUCE as the central coordinating hub for the project.


Founding partners of PGSL


-- Pontificia Universidad CatГіlica of Ecuador (PUCE)

-- Universidad PolitГ©cnica Salesiana, Ecuador

-- Instituto de Biomedicina of Universidad Central del Ecuador

-- Pontificia Universidad Javieriana, Colombia

-- Sociedad Peruana de Derecho Ambiental, Peru

-- Universidad CatГіlica Andres Bello, Venezuela

-- Universidad de Buenos Aires, Argentina

-- Ecuador's Foreign Trade Affairs and Integration Ministry

-- Ecuador's Intellectual Property Institute

-- Departamento Nacional de Recursos FitogenГ©ticos y BiotecnologГ­a, Ecuador

-- AsociaciГіn de Shamanes IndГ­genas del Napo-ASHIN, Ecuador

-- AsociaciГіn de Mujeres Parteras Kichwas del Napo - AMUPAKIN, Ecuador

-- CLC bio, Brazil and Denmark


About CLC bio


CLC bio is the world's leading bioinformatics solution provider, solely focusing on the development of bioinformatics: software, hardware, data analysis, and custom-designed bioinformatics algorithms. CLC bio is an Apple solution provider and value added reseller.


CLC bio's mission is to be among the most innovative bioinformatics companies in the 21st century. This is realized through:


-- Development of bioinformatics software and hardware based on the latest scientific findings

-- User-friendly, integrated and intuitive software solutions

-- Continuous focus on customer needs and superior customer service

-- Frequent product updates including the latest IT technologies and bioinformatics algorithms

-- A flexible IT architecture, enabling customers to buy or develop individualized solutions at a reasonable price


clcbio


Pontificia Universidad CatГіlica of Ecuador

20th Anniversary Of Theoretical And Computational Biophysics Group Marked By Symposium

In 1989, the National Center for Supercomputing Applications was barely three years old, its first massively parallel computer, Connection Machines' CM-2, was just being installed, and physics professor Klaus Schulten, newly arrived at the University of Illinois, launched the Theoretical Biophysics Group (TBG). His overarching vision was to use the analytical tools of physics and chemistry, coupled with the horsepower of increasingly robust and sophisticated computers, to elucidate the organization and functioning of biological systems.



The TBG, now the Theoretical and Computational Biophysics Group (TCBG), on September 21st, will celebrate its 20 years of achievements in characteristic Schulten fashion, by looking forward - not back.



"The idea that is important to convey," stresses Schulten, "is not how many atoms we've simulated or how many processors we've employed, but the discoveries we will now be able to make. I've worked for 20 years to get to this point - to have the potent tools capable of addressing fundamental questions of how proteins assemble themselves and work in concert with other proteins to create living systems. In 1989, we could barely model the structure of a single simple protein. Now we are beginning to be able to model how biological molecules arrange themselves into increasingly complex assemblies that can communicate with one another and function collectively as teams to move, to change, to adapt, to become alive."



"Computational Biology - The Next Decade," the TCBG's 20th anniversary symposium, will be far from a retrospective of past achievements. Instead, it will bring together more than 200 researchers from more than 30 institutions for three full days of talks, posters, and intense discussions about the future of their discipline. Topics will range from the treatment of slow and complex conformal transitions to the challenges of petascale computing.



ABOUT THE THEORETICAL AND COMPUTATIONAL BIOPHYSICS GROUP AT ILLINOIS



The TCBG, directed by Klaus Schulten and comprising faculty from physics, computer science, chemistry, pharmacology, and biophysics, combines world-class expertise in modeling and visualization with advanced computer engineering. Since 1990, the TCBG has hosted the National Institutes of Health Resource for Macromolecular Modeling and Bioinformatics, which develops algorithms and designs computational tools to unlock the secrets of living cells' molecular machines. The TCBG also nucleates the theory efforts of Illinois' new National Science Foundation-funded Center for the Physics of Living Cells, an NSF Physics Frontiers Center.



The mission of the TCBG is to develop new theoretical concepts and exploit the most advanced computational technologies to answer long-standing questions of biomedical relevance. Research activities focus on elucidating the structure and function of supramolecular machines in the living cell, while developing new algorithms and efficient computing tools for physical biology. Their success can be measured in a record number of citations of Schulten's work.
















In the last 20 years, the TCBG has made profound advances to the state of the art in computational biology, as Schulten has pushed the simulation of very large biopolymer systems. He and his group were the first to demonstrate that parallel computers could be practically employed to solve the classical many-body problem in biomolecular modeling, first building from scratch and programming a 60-processor forerunner to today's supercomputers and then using it for the first simulation to reproduce consistently the behavior of a biological membrane.



In 1995, the TCBG released VMD, a molecular visualization program that displayed, animated, and analyzed large biomolecular systems, using three-dimensional graphics and built-in scripting and running on a $150 game board available for PCs. VMD put powerful molecular modeling tools, which could formerly be done only on high-end workstations costing tens of thousands of dollars, into the hands of more than 100,000 registered users.



In 1998, they added NAMD, a scalable parallel molecular dynamics code that enabled interactive simulation of molecules by linking to VMD. Since then, the versatile software package has continued to evolve as more than 30,000 scientists worldwide have exploited its scalability and flexibility. Today, NAMD can simulate the behavior of complex proteins having millions of atoms, making it the world's fastest parallel molecular dynamics program, capable of running efficiently on several thousand processors.



The TCBG received the Gordon Bell Prize in 2002 for exemplary use of a large parallel computer with NAMD. This award is given annually to recognize outstanding achievement in high-performance computing.



All software developed by the TCBG, including VMD and NAMD, is distributed free of charge to researchers. It has been used by thousands of scientists in industry and academia around the world, quickening the pace of drug discovery and unraveling problems of urgent biomedical importance, such as this year's study of possible drug resistance in the A/H1N1 influenza virus.



The group achieved another important breakthrough in 2006, when Schulten and his students produced the first simulation of the atom-by-atom behavior of a complete life form, the satellite tobacco mosaic virus. By calculating the dynamic interactions of the million atoms comprising the virus and a surrounding saline solution, the group was able to show how the virus shell protects its genetic content.



"This is our ultimate goal," said Schulten, "to be able to understand how the inert substances that make up biological molecules organize and transform themselves into something alive. It's a bit like trying to look at the 300 million people who live in the United States, their individual behavior, to discover how they organize themselves into ever larger groups and function collectively to make our society work the way it does. We're not able to do that yet with the entire society of molecules forming themselves into a living cell, but each year, we are getting closer."



ABOUT KLAUS SCHULTEN



Klaus Schulten received his bachelor's degree in physics from the University of MГјnster, Germany, in 1969, and a doctorate in chemical physics from Harvard University in 1974. He was an assistant at the Max-Planck-Institut for Biophysical Chemistry from 1974 to 1980, and professor of theoretical physics at the Technical University of MГјnich from 1980 to 1988. In 1988, he joined the Department of Physics at the University of Illinois. He is the founder and director of both the TCBG and the NIH Resource for Macromolecular Modeling and Bioinformatics at Illinois, and he is co-director, with experimentalist Taekjip Ha, of the Center for the Physics of Living Cells. He has held a Swanlund Chair in Physics at Illinois since 1997.



Schulten's research applies theoretical concepts and methods from physics and chemistry to explain the "machinery" of living cells. Schulten has pioneered the development of tools and techniques that he has termed a "computational microscope." Just as optical microscopes use light to reveal cellular details too small for the human eye to see unaided, Schulten's experiments in silico reveal the physical structure of the molecular workings of cells. "We can now apply the laws of physics and our knowledge of chemistry to describe how these structures and materials evolve in biological functions," said Schulten.



Schulten received the 2008 International Society of Quantum Biology and Pharmacology Award for Computational Biology. He is a fellow of the American Physical Society.



To register for the symposium, please go to questionpro/akira/TakeSurvey?id=1268746



Source:
Celia Elliott


University of Illinois at Urbana-Champaign

Gene Detection May Be Revolutionized In A Single Cell By Nanotechnology Innovation

Scientists at Arizona State University's Biodesign Institute have developed the world's first gene detection platform made up entirely from self-assembled DNA nanostructures. The results, appearing in the January 11 issue of the journal Science, could have broad implications for gene chip technology and may also revolutionize the way in which gene expression is analyzed in a single cell.



"We are starting with the most well-known structure in biology, DNA, and applying it as a nano-scale building material, " said Hao Yan, a member of the institute's Center for Single Molecule Biophysics and an assistant professor of chemistry and biochemistry in the College of Liberal and Sciences.



Yan is a researcher in the fast-moving field known as structural DNA nanotechnology - that assembles the molecule of life into a variety of nanostructures with a broad range of applications from human health to nanoelectronics.



Yan led an interdisciplinary ASU team to develop a way to use structural DNA nanotechnology to target the chemical messengers of genes, called RNA.



The team included: lead author and chemistry and biochemistry graduate student Yonggang Ke; assistant professor of chemistry and biochemistry Yan Liu; Center for Single Molecule Biophysics director and physics professor Stuart Lindsay; and associate professor in the School of Life Sciences, Yung Chang.



"This is one of the first practical applications of a powerful technology, that, till now, has mainly been the subject of research demonstrations," said Lindsay. "The field of structural DNA nanotechnology has recently seen much exciting progress from constructing geometrical and topological nanostructures through tile based DNA self-assembly initially demonstrated by Ned Seeman, Erik Winfree and colleagues," said Yan.



A recent breakthrough of making spatially addressable DNA nanoarrays came from Paul Rothemund's work on scaffolded DNA origami, a method in which a long, single-stranded viral DNA scaffold can be folded and stapled by a large number of short synthetic "helper strands" into nanostructures that display complex patterns.



"But the potential of structural DNA nanotechnology in biological applications has been underestimated, and if we look at the process of DNA self-assembly, you will be amazed that trillions of DNA nanostructures can form simultaneously in a solution of few microliters, and very importantly, they are biocompatible and water soluble," said Yan.



DNA chip and microarray technology have become a multi-billion dollar industry as scientists use it to examine thousands of genes at the same time for mutations or uncovering clues to disease. However, because DNA probes are pinned to the solid surface of the microarray chips, it is relatively slow process for the targets to search and find the probes. Also, it is hard to control the distances between the probes with nanometer accuracy.



"In this work, we developed a water soluble nanoarray that can take advantage of the DNA self-assembling process and also have benefits that the macroscopic DNA microchip arrays do not have," said Yan. "The arrays themselves are reagents, instead of solid surface chips."
















To make the DNA origami RNA probes, Yan has taken advantage of the basic DNA pairing rules in the DNA chemical alphabet ("A" can only form a zipper-like chemical bond with "T" and "G" only pair with "C"). By controlling the exact position and location of the chemical bases within a synthetic replica of DNA, Yan programmed a single stranded genomic DNA, M13, into nanotiles to contain the probes for specific gene expression targets.



Yan refers to the self-assembled DNA nanoarrays as nucleic acid probe tiles, which look like a nanosized postage stamp. In a single step, the M13 scaffold system can churn out as many as 100 trillion of the tiles with close to 100 percent yield.



Yan's team designed three different DNA probe tiles to detect three different RNA genes along with a bar code index to tell the tiles apart from each other. "Each probe can be distinguished by its own bar code, so we mixed them together in one solution and we used this for multiplex detection," said Yan. The group uses a powerful instrument, atomic force microscopy (AFM), which allows the researchers to image the tiles at the single molecule level.



On the surface of each DNA probe tile is a dangling single stranded piece of DNA that can bind to the RNA target of interest. "Each probe actually contains two half probes, so when the target RNA comes in, it will hybridize to the half probes and turn the single stranded dangling probes into a stiff structure," said Yan. "When it is stiffened, it will be sensed by the atomic force microscope cantilever, and you can see a bright line, which is a height increase. The result is a mechanical, label-free detection."



The technology is able to detect minute quantities of RNA. "Since the DNA-RNA hybridization has such a strong affinity, in principle, a single molecule would be able to hybridize to the probe tile," said Yan.



Although there are still many technical hurdles yet to overcome, the group is excited about the potential applications of the technology. "What our approach provides is that the probe tiles are a water-soluble reagent, so the sample volume can potentially be shrunk down to the volume of a single cell level. Our ultimate goal is to detect RNA gene expression at the single cell level."







The research was performed in the Biodesign Institute's Center for Single Molecule Biophysics, Center for Infectious Diseases and Vaccinology, and ASU's Department of Chemistry and Biochemistry, Department of Physics and School of Life Sciences.



This research is partly supported by funding from NIH and from NSF, U.S. Air Force Office of Scientific Research, and Office of Naval Research.



About the Biodesign Institute at ASU



The Biodesign Institute at Arizona State University is focused on innovations that improve health care; provide renewable sources of energy and clean our environment; outpace the global threat of infectious disease; and enhance national security. Using a team approach that converges the biosciences with nanoscale engineering and advanced computing, the goal is to find solutions to complex global challenges and accelerate these discoveries to market. The institute also educates future scientists by providing hands-on laboratory research for more than 250 students per semester. For more information, visit biodesign.asu/



Source:



Hao Yan

Joe Caspermeyer


Arizona State University

Climate Changes Increase Risk Of Plague

Climate changes can lead to more cases of plague. Warmer springs and moister summers can create conditions that will increase the prevalence of the plague bacterium Yersina pestis in great gerbils in Central Asia. These are the facts of a scientific article published in this week's edition of the American scientific journal PNAS, by Nils C. Stenseth, Professor of Biology at the University of Oslo.


"A temperature increase of one degree Celsius in spring may lead to a 50 percent increase in the prevalence of the plague bacterium," he stated to Uniforum, the University of Oslo's own news bulletin.


Climate changes cannot lead to any new Black Death, but it is quite clear that a small increase in temperature may create more cases of bubonic plague than we have today," said Professor Stenseth, who heads the international top-notch Centre for Ecological and Evolutionary Synthesis (CEES) at the University of Oslo. Using field data from a national surveillance programme which monitored the stock of gerbils in Kazakhstan from 1949-1995, and using new statistical techniques, Stenseth and his team found a clear connection between the prevalence of the bacterium Yersina pestis in gerbils and climate variations.


"Samples from the annual rings of trees in Kazakhstan revealed that when the Black Death broke out there in the 14th century, the springs were warm and the summers were wet. Conditions were the same at the onset of the plague of the 1800's in the same region," he explained. Stenseth obtained these figures from the Swiss researcher Jan Esper, one of the co-authors of the article. He is pleased that the researchers were given access to data from the health authorities' surveillance programme in Kazakhstan.


After Kazakhstan initiated this surveillance programme in 1949, the cases of plague here decreased from over 100 cases a year to a few cases a year. In the past Stenseth and his colleagues have been close to finding out why the prevalence of the bacterium varies from year to year.


"In an article we wrote on this bacterium in Science in 2004, I had a feeling that there was a part of the variation which we couldn't explain adequately. But we could have explained it, had we included climate as a cause of variation in the prevalence of this bacteria," Stenseth said to Uniforum.


Hence, one of the candidates of co-author Noelle I. Samia from the University of Iowa was given the task of running all the data of the surveillance programme through an advanced statistical analysis.


"The results of this work enabled us to write this article and conclude that climate changes have affected the prevalence of the bacterium which causes plague," Stenseth said. He was not sure what the conclusions would be after the investigations were finished.


"In the US, researchers have studied infectious diseases that are passed on among humans, indicating a similar connection between the prevalence of bacteria and climate changes, but this is the first time anyone has found a clear connection between the prevalence of the plague bacteria carried by gerbils and climate change," he stated.


"It was precisely in this area that the genetic and climatic conditions which brought on the Black Death and the Asian flu, emerged", he said.


It is the prevalence of the bacterium Yersina pestis which has been the subject of study for Nils Chr. Stenseth and his colleagues from the Universities of Norway, Kazakhstan, Switzerland, Denmark, Belgium, UK and the US. This bacterium lives in gerbils in the semideserts and steppes of Central Asia, and it is passed from gerbils to other animals and humans through flea bites. The gerbils themselves are not infected by the plague bacterium, they merely serve as hosts.


"In central Asia people can also catch the plague through infected camel meat, as camels often lay in places with gerbil burrows," Stenseth explained.


RESEARCH COUNCIL OF NORWAY

P.O Box 2700

St.Hanshaugen

N-0131

Oslo


forskningsradet.no/

Bidirectional Sex Change In Mushroom Stony Corals

We describe for the first time sex change occurring in corals. This includes a novel mode of bidirectional (repetitive) sex change, which resembles that found in plants that display labile sexuality in response to environmental and/or energetic constraints.


We point out some intriguing analogies between the studied mushroom corals to plants and posit that the sex change in coral individuals enhances their reproductive success (fitness), stressing the important role of the wide plasticity in reproductive modes of stony corals in determining their evolutionary success.


Theories related to sex change in plants and animals have often progressed along disparate lines.


Our discovery of plant-like sex allocation in corals brings our understanding of the evolutionary significance of sex change in the plant and the animal kingdoms closer together.


Proceedings of the Royal Society B: Biological Sciences


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


Proceedings of the Royal Society B: Biological Sciences

Scientists Elucidate Structure Details Of Protein Sam68

Scientists of the Institute of Structural Biology of Helmholtz Zentrum Munchen and the Technische Universitat Munchen have succeeded in elucidating the structure of an important region of the Sam68 protein. The renowned Journal of Biological Chemistry has selected the report of these research findings as one of two "papers of the week" for its September 10, 2010 issue and has chosen the structural model as cover image.



Using NMR spectroscopy, Professor Michael Sattler and his team elucidated the spatial structure of the Qua1 region of Sam68, which is responsible for the dimerization of the protein. In collaboration with the research group of Professor Ruth Brack-Werner of the Institute of Virology, the authors showed that this region is essential for the biological function of Sam68. The image reveals an unusual spatial structure, in which two helices of respectively one Qua1 region (green and blue) interact with each other and mediate the dimerization of Qua1 and thus of Sam68.



Sam68 belongs to the family of STAR proteins which carry out important tasks in the signal-regulated processing of genetic information and its translation into protein. Among others, Sam68 regulates specific processes linked to the cell cycle and apoptosis and plays a key role in the pathogenesis of cancer.



Original publication:

Meyer, NH. et al.: Structural basis for homodimerization of the Src-associated during mitosis, 68 kD protein (Sam68) Qua1 domain. The Journal of Biological Chemistry, Vol. 285, Issue 37, 28893-28901, 10. September 2010.



Source:

Sven Winkler


Helmholtz Zentrum MГјnchen - German Research Center for Environmental Health

Agent Protects Cells From Lethal Effects Of Radiation Even If Given After Exposure

No drugs exist to protect the public from the high levels of radiation that could be released by a "dirty" bomb or nuclear explosion. Such excessive exposure typically causes death within weeks as the radiation kills blood cells vital to clotting and fighting infection, along with the stem cells needed to replenish their supply. But now researchers at Washington University School of Medicine in St. Louis report they have developed an agent that protects cells from the lethal effects of radiation, regardless of whether it is given before or after exposure.



Using this agent in mice, the investigators found that the treatment helped shield rapidly dividing cells that are most vulnerable to radiation-induced death, providing proof in principle that it is possible to fend off radiation damage, according to a study published in the April issue of Biochemical and Biophysical Research Communications.



Current treatments for severe radiation exposure, also called acute radiation syndrome, are limited to drugs that boost the production of blood cells and platelets, but this approach is futile if underlying stem cells are also killed off. Moreover, there are no available treatments that can be given after exposure to limit damage to cells.



"We are using an entirely different approach," says Clayton Hunt, Ph.D., of the Department of Radiation Oncology. "Rather than ramp up the production of blood cells, we are trying to prevent radiation-induced cell death from occurring in the first place."



The researchers developed the agent by attaching a portion of the Bcl-xL protein already known to block cell death - a snippet called BH4 - to the HIV protein TAT, which can deftly carry other molecules into cells. They gave the agent intravenously to mice exposed to 5 Grays of radiation. In humans, this level of exposure would cause a sharp drop in blood cells, leaving individuals with an increased risk of infection and bleeding.



They found the treatment helped protect rapidly dividing T cells and B cells in the spleen - immune system cells that are prone to radiation damage - whether it was given 30 minutes before radiation exposure or 30 minutes afterward.



As part of the research, the investigators monitored the levels at which old or damaged cells in the spleen were dying, a process called apoptosis. In a group of control mice that were not exposed to radiation, the researchers determined that 4.7 percent of T cells and 5.1 percent of B cells in the spleen were undergoing apoptosis. This level is considered normal as cells naturally die and are replaced by new ones. After the mice received 5 Grays of whole body radiation, apoptosis increased to 15.6 percent of T cells and 38.7 percent of B cells.



But when the researchers gave TAT-BH4 to the mice prior to whole body radiation, levels of apoptosis dropped significantly, to 8.6 percent of T cells and 16.9 percent of B cells. In mice given TAT-BH4 after radiation exposure, the proportion of cells undergoing apoptosis dropped even further, to 5.7 percent of T cells and 12.3 percent of B cells.
















The Washington University approach appears to halt apoptosis by targeting pathways within cells that are far removed, or downstream, from the initial radiation insult. In particular, BH4 is thought to block a release of the electrical charge across the membrane of mitochondria - the powerhouses of cells - a key event in initiating cellular self-destruction. "This gives us a window of opportunity to treat patients and still prevent cells from undergoing programmed cell death," said Richard Hotchkiss, M.D., professor of anesthesiology, medicine and surgery. "We have a lot more work to do, but we are encouraged by these early findings."



Follow-up data suggest that TAT-BH4 is still effective when it is given to irradiated mice one hour after exposure, and the researchers plan further studies to determine how long after exposure the agent can prevent radiation-induced apoptosis.



In the past several years, the federal government has devoted increasing resources to the development of countermeasures that protect the public from chemical, biological, radiological or nuclear attack. TAT-BH4 may one day be a viable candidate because theoretically it could be given after radiation exposure, administered in pill form, and synthesized and stored in large quantities - all properties that would be desirable for treating large groups of individuals exposed to high levels of radiation, Hotchkiss said.



The researchers contend that developing such a drug would be less challenging than finding a way to protect healthy cells from radiation therapy aimed at destroying cancer cells. "In radiation therapy, you want to give a dose of radiation to a tumor and reduce the exposure to surrounding, healthy tissues," Hunt said. "This is difficult because a drug has to distinguish between tumor and normal tissue. But with people exposed to a large dose of radiation over the entire body, you want to protect all the cells in the body. To me, that is an easier problem to solve."






McConnell KW, Muenzer JT, Chang KC, Davis CG, McDunn JE, Coopersmith CM, Hilliard CA, Hotchkiss RS, Grigsby PW, Hunt CR. Anti-apoptotic peptides protect against radiation-induced cell death. Biochemical and Biophysical Research Communications. 6 April 2007, p. 501-507.



Funding from the National Institutes of Health supported this research.



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



Contact: Caroline Arbanas


Washington University School of Medicine

Erwin Schrodinger Prize 2008 Goes To The Max DelbrГјck Center In Berlin - First Map Showing Human Protein Interactions

A Berlin research team led by Professor Erich E. Wanker of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, has been awarded this year's Erwin Schrodinger Prize for creating a unique "connection scheme" showing for the first time how thousands of human proteins - the building blocks and machines of life - interact with each other. The prize, endowed with 50 000 euros, will be awarded by the Helmholtz Association of German Research Centres, of which the MDC is a member, at its General Assembly on September 11, 2008. Along with Professor Wanker*, the prizewinners are Dr. Ulrich Stelzl (now at the Max Planck Institute of Molecular Genetics, Berlin), Christian Hänig, Dipl.-Ing. (MDC), Gautam Chaurasia, M.Sc. (Humboldt University Berlin and MDC), and Dr. Matthias Futschik (Charité - Universitätsmedizin Berlin). Interactions between proteins are of great interest for understanding disease mechanisms and for developing new drugs. Moreover, with their help, researchers can detect disease-relevant genes.


The researchers performed more than 25 million single experiments to see whether specific proteins work with each other. This way they succeeded in creating a map showing 3 200 protein interactions between 1 700 proteins. Furthermore, they were able to identify 195 proteins and their cooperation partners that have been linked to different diseases and to assign 342 not previously characterized proteins to already known signaling pathways.


The extensive studies on human protein interactions only became possible with a special technique which Professor Wanker, Dr. Stelzl and Christian Hänig developed six years ago. In this method, yeast cells are employed to identify the binding partners of the proteins.


"We have laid the foundation for a comprehensive connection scheme of the human body. The map helps us understand the functions of proteins and the complex processes in our cells," explained Professor Wanker, who directed the study. The researchers published their results in 2005 in the journal Cell (Vol. 122, No. 6, September 23, 2005, pp. 957-968). The scientists supplemented the robotics study with a large-scale database project on protein interactions.


The prize is named after the Austrian physicist and Nobel laureate Erwin Schrödinger (1887 Vienna - 1961 Vienna). The annual prize is conferred alternately by the Donors' Association for the Promotion of Sciences and Humanities in Germany and by the Helmholtz Association. The prize honors outstanding scientific research or innovative technological achievements.


Short Biographies:


Professor Erich E. Wanker (1965 in Klagenfurt, Austria), 1983 - 1992 degree in Biotechnology and PhD at the TU Graz (Austria); 1993 - 1995 postdoc at UCLA, Los Angeles, USA; 1995 - 2001 research group leader at the Max Planck Institute of Molecular Genetics, Berlin; since 2001 research group leader at MDC and C4 professor at the Charité Universitätsmedizin Berlin, Germany.















Dr. Ulrich Stelzl (1971 in Vienna, Austria), 1990 - 1996 degreen in Biochemistry at the TU Vienna; 1994 - 1995 studies and diploma thesis at the Swiss Federal Institute of Technology (ETH) Zurich, Switzerland; 1996 - 2000 PhD student and postdoc at the Max Planck Institute of Molecular Genetics, Berlin, Germany; 2000 - 2002 research fellow at the Memorial Sloan Kettering Cancer Center, New York, USA; 2002 - 2007 postdoc at MDC; since 2007 research group leader at the Max Planck Institute of Molecular Genetics, Berlin, Germany.


Christian Hänig, Dipl.-Ing. (1967 in Halle/Saale, Germany), 1989 - 1995 degree in Mechanical Engineering at the TU Dresden, Germany; 1992 - 1993 work in the development division of the Strömungsmaschinenwerk GmbH, Dresden; 1995 - 1998 post-graduate study of building services engineering, TU Dresden; until 2001 work for various engineering firms in Dresden and supplementary qualification in IT Engineering at the University of Applied Sciences Berlin, Germany; 2002-2004 programmer and IT manager at the Max Planck Institute of Molecular Genetics, Berlin; since 2004 engineer and programmer at MDC.


Gautam Chaurasia, M.Sc. (1977 in Kanpur, India) 1995 - 1998 Bachelor of Science (B.Sc.) in Biology, Kanpur University, India; 2000 - 2003 B.Sc. in Bioinformatics, Free University (FU) Berlin, Germany; 2003 - 2005 Master of Science (M.Sc.) in Bioinformatics at the University of the Saarland, SaarbrГјcken, Germany; since 2006 PhD student at Humboldt University Berlin and at MDC.


Dr. Matthias Futschik (1970 in Waiblingen, Germany), 1992 - 1997 degree in Physics and Philosophy at the University of TГјbingen, Germany; Brown University in Providence, Rhode Island, USA and Humboldt University Berlin, Germany; 1998 diploma in Physics, Humboldt University Berlin; 1999 - 2002 PhD in Information Sciences at the University of Otago in Dunedin, New Zealand; 2002 - 2003 senior bioinformatician at Pacific Edge Biotechnology, Dunedin, New Zealand; 2003 - 2004 research fellow at the Institute of Theoretical Biology of the CharitГ©, Germany; since 2004 assistant professor there; from September 2008 research group leader at the University of Algarve, Faro, Portugal.



Click here for further Information



Unique Map Created of Human Protein Interactions

ScienceDirect - Cell : A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome

mdc-berlin/neuroprot/database.htm

mdc-berlin/unihi

helmholtz/forschung/forschungspreise/erwin_schroedingerpreis

Max DelbrГјck Center for Molecular Medicine (MDC) Berlin-Buch

Reporting On Advances In Malaria Research

In a novel approach at disseminating scientific research, the Johns Hopkins Malaria Research Institute (JHMRI) held a web summit to release the latest breakthroughs in malaria research, including new approaches to boosting mosquito immunity to malaria, mapping mosquito migrations, and the promise of a rapid sputum test that could revolutionize the way malaria is tracked and tested for in rural areas, which are hotbeds for the disease.



Each year more than 300 million malaria cases occur worldwide. Nearly one million people die of malaria every year, most of them children. In Africa, malaria is responsible for one in five childhood deaths.



"Many young people today are passionate about global health issues. We want to engage them to pursue scientific careers in the battle against malaria," says Peter Agre, MD, Nobel Laureate, Director of the JHMRI, and current president of the American Association for the Advancement of Science (AAAS).



Mosquito Immunity to Malaria



George Dimopoulos, PhD, Associate Professor of Molecular Microbiology and Immunology at the JHMRI, will discuss new ways to make mosquitoes' immune systems resistant to the malaria-causing parasite, Plasmodium falciparum.



"The mosquito is the most dangerous organism in the world after humans. It has killed more than any other higher organism, which is why vector biology and vector research are incredibly important in controlling diseases in developing countries," says Dimopoulos.



Earlier this year, Dimopoulos' group identified a molecular pathway that triggers an immune response in multiple mosquito species capable of stopping the development of Plasmodium falciparum. By silencing the gene, caspar, the researchers were able to block the development of the parasite in Anopheles gambiae, A. stephensi and A. albimanus mosquitoes - three mosquito species that spread malaria in Africa, Asia and the Americas.



The process relied on a technique called transient gene silencing, which means that they didn't make lasting changes to the DNA of a mosquito. Now, Dimopoulos and his team are using genetic modification (GM) to permanently manipulate this particular molecular pathway so that mosquitoes' bodies will attack, rather than host, the malaria-causing parasite. So far they have successfully produced two lines of GM mosquitoes that work. In one line, the immune pathway gene was expressed in the mosquitoes' gut tissue (where the parasite enters). in the other line, it was expressed in the organ that functions like a liver, the 'fat body.' They now hope to create a strain of GM mosquitoes that will express the immune pathway gene in the gut and the fat body tissue simultaneously, and maximize the potency of this immune response.



"This kind of work is pioneering for malaria," says Dimopoulos. "These are the first genetically modified mosquitoes that are resistant to the Plasmodium parasite that causes human malaria because of a modification in their immune systems."
















Dimopoulos stresses that as promising as this line of research is, "We still need an arsenal of several control strategies to contain malaria because different tactics will work in different scenarios. In some places, a vaccine may work best, in more remote places, other low cost, low tech approaches will work better. You can't win a war with the Air Force alone - you need all the branches."



Marcelo Jacobs-Lorena, PhD, Professor of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health, is also working on modifying the mosquito in order to make it a poor vector for the parasite. His lab was the first to introduce genes into the mosquito genome which caused the mosquito to express a Plasmodium-repelling peptide. But spreading these genes into wild populations of mosquitoes has proven challenging. Even though several breeds of mosquitoes can transmit malaria, they don't cross-breed, so just because researchers can introduce a gene into one population of mosquitoes, it doesn't mean that another population in the same area will also get that gene.



Now, Jacobs-Lorena is taking a new approach to creating a malaria-resistant mosquito by tinkering with the bacteria that occur naturally in mosquitoes' guts.



"The idea we are now exploring is how to genetically modify this bacteria so it secretes a substance that is lethal to the Plasmodium parasite, but not to the mosquito," he explains.



The benefit of cultivating GM bacteria is that it's much easier to grow large amounts of bacteria than to grow large numbers of mosquitoes. Jacobs-Lorena is currently looking at ways to spread GM bacteria in the wild by creating artificial refuges for mosquitoes containing cotton balls impregnated with sugar and GM bacteria. The theory is that mosquitoes will be drawn to the dark, humid, artificial refuges and get a helping of Plasmodium-killing bacteria while they eat the sugar.



Development of a Non-Invasive Malaria Diagnostic



Sungano Mharakurwa, PhD, Scientific Director of the Malaria Institute at Macha (MIAM) in Zambia, a living laboratory for mosquito and human behavior in malaria-stricken areas, is developing a rapid saliva-based malaria diagnostic test that works without the need for specialized personnel or equipment, and can be used at a grass-roots level.



This new microfluidic device would be affordable to produce in large numbers and would act as a miniature laboratory that could analyze a small spit sample to quickly determine whether or not someone is infected with malaria.



"The safe, affordable, and non-invasive nature of the test would make it an ideal tool for community surveillance and elimination of malaria, especially in children, asymptomatic carriers and communities that have taboos about drawing of blood," says Mharakurwa.



Current diagnostic tests for malaria come with prohibitions. They require trained health workers to take blood samples, which can only be drawn so often, hindering researchers' ability to routinely monitor the efficacy of malarial drugs or vaccines.



"In areas like Southern Africa, we need a test that can cover all communities, particularly those regions where many people don't exhibit symptoms of malaria, even if they carry the disease. These segments can be an inadvertent reservoir for the parasite, and if malaria is pushed down, but not entirely eliminated, it can resurge worse than before," he says.



Phil Thuma, MD, Managing Director of the Malaria Institute at Macha, says that there has been a remarkable decrease in malaria case load in Macha since the research institute has been carrying out research studies. Thuma believes that credit goes to the remarkable local community cooperation with the research studies and ownership by the community and MIAM staff of the research programs, which has led to a wonderful research working environment. This, coupled with effective tools like insecticide treated bed nets and an effective anti-malarial combination drug based on artemisinin, has helped the fight.



"Malaria control and possible elimination in rural Africa seems very probable, but we need to continue working hard to get there and sustain it. That will take ongoing research studies to better understand the vector and the disease," says Thuma.



Mapping Mosquito Migrations



Gregory Glass, PhD, Professor of Molecular Microbiology and Immunology and Epidemiology with the Johns Hopkins Bloomberg School of Public Health, uses sophisticated satellite imaging to track populations of mosquitoes to help reduce malaria transmission in Africa.



"We study spatial patterns of malaria risk, using new technology like satellite images to target where the mosquitoes are living and breeding in order to get the biggest bang for the buck for our resources," says Glass.



He explains that people differ in their risk for contracting malaria based on their local environment - for example, how close they are to malaria breeding grounds. This is the kind of risk that Glass's group can show with satellite pictures.



In Europe and North America, public health officials control mosquito-borne diseases by carefully monitoring and controlling aquatic breeding sites for mosquitoes. But in sub-Saharan Africa, where there are three vector species and mosquitoes propagate in the likes of watery hoof prints of cattle, controlling mosquito breeding sites is much more difficult.



Satellite images can change this. In Zambia, remote sensing specialists look at satellite data to unearth information about the landscape, like soil moisture, or where water drains to, and bubbles up, in order to identify the most likely breeding places for mosquitoes.



"In Macha, we see some villages where most households are infected with malaria, but six miles away, no one is. Teasing apart this difference will help figure out exactly where to deliver bed nets, medicines and insecticide spray," says Glass.



Source: Carol Lin Vieira


Burness Communications


Tim Parsons


Johns Hopkins Malaria Research Institute