Vanderbilt University has been selected as one of 10 centers in the nation to participate in the Chemical Biology Consortium (CBC), a major new initiative to facilitate the discovery and development of new agents to treat cancer.
As one of four Chemical Diversity Centers, Vanderbilt's role in the consortium will be to synthesize and optimize new compounds as potential cancer therapeutics.
"This is a real tribute to our growth in cancer chemistry and the leverage between the Vanderbilt Institute of Chemical Biology (VICB) and the Vanderbilt-Ingram Cancer Center (VICC)," said Lawrence Marnett, Ph.D., the Mary Geddes Stahlman Professor of Cancer Research and director of the VICB.
Alex Waterson, Ph.D., research assistant professor of Pharmacology and director of the VICB's Chemical Synthesis Core, will lead efforts developing small molecule drug candidates. Gary Sulikowski, Ph.D., Stevenson Professor of Chemistry and a co-director of the core, will direct projects involving natural products.
Designed to accelerate the discovery and development of effective, first-in-class targeted therapies, the CBC will choose high-risk targets that are of low interest to the pharmaceutical industry. The CBC is a National Cancer Institute initiative administered by contractor SAIC-Frederick, Inc.
"It's exciting in the sense that, right off the bat, (the NCI) said that the goal of this program is to develop drugs for cancer treatment," said Sulikowski. "They're looking for unique targets, unique approaches, and they think that academia may offer that."
"Oftentimes pharmaceutical companies will not go after targets that are not expected to be huge blockbusters," said Waterson, who came to Vanderbilt in 2008 from GlaxoSmithKline where he had worked for seven years on oncology drug development projects. "So an effort like this can fill in a niche that industry is not taking on at the moment."
One particular area of interest is in screening and developing natural products as potential drug candidates.
This "is something that pharmaceutical industry has de-emphasized just because of the way things have evolved," said Sulikowski. "And that's one of our advantages, in that we have expertise in natural products as well as medicinal chemistry."
Cancer drug development poses many challenges - but also unique opportunities.
"There is a difficulty in that cancer is not a single disease; it's a family of loosely related diseases," said Waterson. "There's an opportunity for a whole myriad of different treatments that are pretty much only tailored to a small subset of people, where your treatment addresses their specific need."
A unique aspect of the CBC is the NCI's efforts to establish intellectual property rights for investigators and institutions that develop assays or drug candidates.
"The hope is that by recognizing establishment of intellectual property as one of the goals, they will attract people with the best ideas, things that really might be able to become a drug," said Waterson.
Vanderbilt's involvement with the CBC, along with the recent arrival of Stephen Fesik, Ph.D., who previously led cancer drug discovery efforts at Abbott Laboratories, will make Vanderbilt "one of the best academic institutions doing cancer drug discovery in the country," Marnett said.
Other Vanderbilt investigators involved in this effort include:
Brian Bachmann, Ph.D., assistant professor of Chemistry and Biochemistry
Jeffrey Johnston, Ph.D., professor of Chemistry
Jens Meiler, Ph.D., assistant professor of Chemistry, Pharmacology and Biomedical Informatics
Craig Lindsley, Ph.D., associate professor of Pharmacology and Chemistry, and director of Medicinal Chemistry
Other sites participating in the CBC are:
The Burnham Institute for Medical Research, in La Jolla, Calif.;
Southern Research Institute in Birmingham, Ala.;
University of North Carolina at Chapel Hill;
Georgetown University in Washington, D.C.;
University of Minnesota;
University of Pittsburgh;
University of Pittsburgh, Drug Discovery Institute;
University of California, San Francisco;
SRI International in Menlo Park, Calif.; and
Emory University in Atlanta
This project has been funded in whole or in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Source:
Melissa Marino
Vanderbilt University Medical Center
понедельник, 25 апреля 2011 г.
Hidden conversations within cells revealed, computer modeling
University of California, San Diego biochemists have developed a computer program that helps explain a long-standing mystery: how the same proteins can play different roles in a wide range of cellular processes, including those leading to immune responses and cancer.
Prior to the UCSD team's findings, which are published in the September 16 issue of the journal Science, many scientists expressed doubts that a computational approach could represent the intricate mechanisms through which cells respond to outside signals. However, the researchers report that their computer model accurately predicts particular behaviors of living cells. They also believe that the model has important practical applications, including guiding the design of better treatments for cancer and other diseases that involve failures in cell communication.
"Our computational approach revealed how the same set of proteins produce physiologically different outputs in response to only subtly different inputs," explained Alexander Hoffmann, an assistant professor of chemistry and biochemistry, who led the team. "This is the first step toward developing drugs that interfere with one of the pathological functions of the proteins, but leave the healthy functions intact. For example, many current cancer drugs dramatically reduce immune function. Computer modeling should make it possible to design anti-cancer drugs that do not weaken patients' immune systems."
The computer model comprises 70 equations to account for the behavior of five proteins and three RNA molecules in the "NF-kappaB signaling pathway," which regulates genes involved in cancer, inflammation, immune function and cell death. Each equation takes into account a different parameter, such as how quickly a protein is synthesized, or how quickly it is degraded.
The researchers chose the NF-kappaB proteins because there is a wide body of prior research that they were able to draw on to set the initial parameters in the model. As they were developing the model, they repeatedly tested and refined it by comparing the model's predictions with the results of experiments with living cells.
"The beauty of this kind of interdisciplinary work is the almost circular way the model's predictions drive the design of new experiments, and the how results of those experiments can be fed back into the model to improve it," said Shannon Werner, a graduate student in chemistry and biochemistry, who did the experimental work described in the paper.
Once the model consistently predicted the behavior of living cells in a variety of experimental conditions, the researchers used the model to infer what was going on inside cells in much greater detail than would be possible through laboratory experiments alone.
The model revealed why two natural chemicals have opposite physiological effects. When exposed to one of the chemicals, the proteins create positive feedback that lengthens the amount of time they are active. When exposed to the other chemical, they initiate negative feedback, which shuts them down rapidly.
"The prevailing view has been that proteins are either on or off like a light switch, but that didn't explain how activating the same proteins with different chemicals could have opposing effects on cells," explained Hoffmann. "Our model shows that, analogous to how a telephone transmits an infinite number of different signals along a single wire, it is the timing of the proteins' activity that allows them to exert intricate control over the behavior of a cell. The computer model reveals the hidden conversations in the cell's wiring."
The researchers attribute their success in developing the computer model, despite criticism that the computational approach would require too many simplifications to accurately model cell communication, to the diverse expertise they brought together.
"Developing a computer model is both science and art," said Derren Barken, a graduate student in bioinformatics and experienced software engineer, who programmed the model. "It requires intuition built up over time, but it also requires someone like Alex, who can critically evaluate the scientific literature to decide what parameters need to be included in the model, and someone like Shannon who can take the predictions of the model and design experiments to test them in the laboratory."
The study was supported by the National Institutes of Health, the National Science Foundation and the UC Academic Senate.
Sherry Seethaler
sseethalerucsd
858-534-4656
University of California - San Diego
ucsd
Prior to the UCSD team's findings, which are published in the September 16 issue of the journal Science, many scientists expressed doubts that a computational approach could represent the intricate mechanisms through which cells respond to outside signals. However, the researchers report that their computer model accurately predicts particular behaviors of living cells. They also believe that the model has important practical applications, including guiding the design of better treatments for cancer and other diseases that involve failures in cell communication.
"Our computational approach revealed how the same set of proteins produce physiologically different outputs in response to only subtly different inputs," explained Alexander Hoffmann, an assistant professor of chemistry and biochemistry, who led the team. "This is the first step toward developing drugs that interfere with one of the pathological functions of the proteins, but leave the healthy functions intact. For example, many current cancer drugs dramatically reduce immune function. Computer modeling should make it possible to design anti-cancer drugs that do not weaken patients' immune systems."
The computer model comprises 70 equations to account for the behavior of five proteins and three RNA molecules in the "NF-kappaB signaling pathway," which regulates genes involved in cancer, inflammation, immune function and cell death. Each equation takes into account a different parameter, such as how quickly a protein is synthesized, or how quickly it is degraded.
The researchers chose the NF-kappaB proteins because there is a wide body of prior research that they were able to draw on to set the initial parameters in the model. As they were developing the model, they repeatedly tested and refined it by comparing the model's predictions with the results of experiments with living cells.
"The beauty of this kind of interdisciplinary work is the almost circular way the model's predictions drive the design of new experiments, and the how results of those experiments can be fed back into the model to improve it," said Shannon Werner, a graduate student in chemistry and biochemistry, who did the experimental work described in the paper.
Once the model consistently predicted the behavior of living cells in a variety of experimental conditions, the researchers used the model to infer what was going on inside cells in much greater detail than would be possible through laboratory experiments alone.
The model revealed why two natural chemicals have opposite physiological effects. When exposed to one of the chemicals, the proteins create positive feedback that lengthens the amount of time they are active. When exposed to the other chemical, they initiate negative feedback, which shuts them down rapidly.
"The prevailing view has been that proteins are either on or off like a light switch, but that didn't explain how activating the same proteins with different chemicals could have opposing effects on cells," explained Hoffmann. "Our model shows that, analogous to how a telephone transmits an infinite number of different signals along a single wire, it is the timing of the proteins' activity that allows them to exert intricate control over the behavior of a cell. The computer model reveals the hidden conversations in the cell's wiring."
The researchers attribute their success in developing the computer model, despite criticism that the computational approach would require too many simplifications to accurately model cell communication, to the diverse expertise they brought together.
"Developing a computer model is both science and art," said Derren Barken, a graduate student in bioinformatics and experienced software engineer, who programmed the model. "It requires intuition built up over time, but it also requires someone like Alex, who can critically evaluate the scientific literature to decide what parameters need to be included in the model, and someone like Shannon who can take the predictions of the model and design experiments to test them in the laboratory."
The study was supported by the National Institutes of Health, the National Science Foundation and the UC Academic Senate.
Sherry Seethaler
sseethalerucsd
858-534-4656
University of California - San Diego
ucsd
Faster Protein Folding Achieved Through Nanosecond Pressure Jump
A new method to induce protein folding by taking the pressure off of proteins is up to 100 times faster than previous methods, and could help guide more accurate computer simulations for how complex proteins fold, according to research by a team of University of Illinois scientists accepted for publication in the journal Nature Methods and posted on the journal's Web site May 31.
Martin Gruebele, the James R. Eiszner Professor of Chemistry at the U. of I. and corresponding author of the paper, says that prodding proteins to fold by suddenly removing high pressure (a technique also known as "pressure jumping") through electrical bursting makes for a "kindler, gentler way" of inducing proteins to fold.
"When you're increasing the pressure on something, you're squeezing the atoms and making them come closer to one another," Gruebele said, "but you're not necessarily causing the very complicated changes to the microscopic motion that occur when you change the temperature. Pressure is a simpler variable than temperature."
In order to carry out their biomolecular functions, proteins fold from a chaotic, random coil that looks like spaghetti strands floating in boiling water to their native state as an orderly, well-defined but compact structure.
From the point-of-view of the protein, Gruebele said, pressurizing it to about 2,500 atmospheres is much less disruptive than, say, cranking up the temperature by 30 degrees.
"Temperature is a pretty complicated variable in that it involves random motion at a microscopic level," Gruebele said. "When you perturb a protein by raising its temperature, its chains completely unravel, and it might take longer for it to collapse back down to the folded structure."
To induce protein folding, a sample contained in a sapphire cube covered by a small steel diaphragm is pressurized to several thousand atmospheres, causing the biomolecules to unfold. A powerful electrical current then bursts the diaphragm, which releases the pressure and produces a sub-microsecond pressure drop. The proteins re-fold, and are monitored through laser-excited fluorescence.
Gruebele's electrical-bursting method also allowed for a miniaturization of the apparatus, which improved the speed and sample volume of the diaphragm design. That, in turn, allows for a better comparison between how proteins fold in vitro in the lab versus how a computer algorithm would predict how they would fold.
After the pressure is applied, the proteins were able to re-fold or "spring back" to their native-state structures "much more readily than if we had heated them and cooled them down," Gruebele said.
Applying pressure to induce protein folding is not a novel laboratory technique. According to Gruebele, previous methods using electrically controlled valves, piezoelectric constriction and burst diaphragms weren't fast enough or didn't produce enough pressure to generate viable data on the microsecond timescale.
To reach the realm of simulation-worthy data, "you need hundreds of nanoseconds to a few microseconds worth of data-capture time," Gruebele said. With the previous methods, "we weren't close to the timeframe where you could perform computer simulations, right now or in the near future."
Ultimately, being able to feed experiment-generated data into a computer simulation will lead to better computer forecasts about how proteins fold, Gruebele said.
"By putting experiments and computer simulations together, we're going to be able to predict how proteins fold much more quickly and reliably," he said.
Gruebele, who is also a researcher at the Beckman Institute, believes that scientists will eventually be able to perform computer simulations of protein folding that are accurate enough predictors of folding so that "if you had a protein involved in a disease and its structure wasn't known, you could go to the computer and model how it behaves."
For example, when certain proteins in the brain mutate, that can lead to Alzheimer's disease, Gruebele said.
"The structures of proteins are ultimately what's responsible for their function," he said. "Changes to their structure often cause abnormal functions. That's why we want to understand protein structures, and be able to model how they change."
Gruebele said that computer simulations already yield a pretty accurate picture of a given small organic molecule. But with this new method that breaks the microsecond barrier, "we've just opened up a whole new world of proteins for study," he said.
"There are only a handful of proteins that we know about that would fold by temperature jumps or other methods in a couple of microseconds," Gruebele said. "But there are many proteins that do it in hundreds of microseconds, and that could be sped up to a few microseconds by pressure jumps."
Gruebele said that if you want to improve computer simulations of protein folding so that they're 99.9 percent reliable - so reliable that a medical doctor could trust the results - you need many test cases. And if you need lots of test cases, you need to be able to run computer simulations quickly, Gruebele said.
"This experiment enables a greater number of proteins to be tested by simulations and experiments simultaneously, which will push forward the agenda of getting computer simulations that are more reliable and faster," Gruebele said.
Gruebele's co-authors of the paper are Charles Dumont and Tryggvi Emilsson.
Funding was provided by the National Science Foundation.
Source:
Phil Ciciora
University of Illinois at Urbana-Champaign
Martin Gruebele, the James R. Eiszner Professor of Chemistry at the U. of I. and corresponding author of the paper, says that prodding proteins to fold by suddenly removing high pressure (a technique also known as "pressure jumping") through electrical bursting makes for a "kindler, gentler way" of inducing proteins to fold.
"When you're increasing the pressure on something, you're squeezing the atoms and making them come closer to one another," Gruebele said, "but you're not necessarily causing the very complicated changes to the microscopic motion that occur when you change the temperature. Pressure is a simpler variable than temperature."
In order to carry out their biomolecular functions, proteins fold from a chaotic, random coil that looks like spaghetti strands floating in boiling water to their native state as an orderly, well-defined but compact structure.
From the point-of-view of the protein, Gruebele said, pressurizing it to about 2,500 atmospheres is much less disruptive than, say, cranking up the temperature by 30 degrees.
"Temperature is a pretty complicated variable in that it involves random motion at a microscopic level," Gruebele said. "When you perturb a protein by raising its temperature, its chains completely unravel, and it might take longer for it to collapse back down to the folded structure."
To induce protein folding, a sample contained in a sapphire cube covered by a small steel diaphragm is pressurized to several thousand atmospheres, causing the biomolecules to unfold. A powerful electrical current then bursts the diaphragm, which releases the pressure and produces a sub-microsecond pressure drop. The proteins re-fold, and are monitored through laser-excited fluorescence.
Gruebele's electrical-bursting method also allowed for a miniaturization of the apparatus, which improved the speed and sample volume of the diaphragm design. That, in turn, allows for a better comparison between how proteins fold in vitro in the lab versus how a computer algorithm would predict how they would fold.
After the pressure is applied, the proteins were able to re-fold or "spring back" to their native-state structures "much more readily than if we had heated them and cooled them down," Gruebele said.
Applying pressure to induce protein folding is not a novel laboratory technique. According to Gruebele, previous methods using electrically controlled valves, piezoelectric constriction and burst diaphragms weren't fast enough or didn't produce enough pressure to generate viable data on the microsecond timescale.
To reach the realm of simulation-worthy data, "you need hundreds of nanoseconds to a few microseconds worth of data-capture time," Gruebele said. With the previous methods, "we weren't close to the timeframe where you could perform computer simulations, right now or in the near future."
Ultimately, being able to feed experiment-generated data into a computer simulation will lead to better computer forecasts about how proteins fold, Gruebele said.
"By putting experiments and computer simulations together, we're going to be able to predict how proteins fold much more quickly and reliably," he said.
Gruebele, who is also a researcher at the Beckman Institute, believes that scientists will eventually be able to perform computer simulations of protein folding that are accurate enough predictors of folding so that "if you had a protein involved in a disease and its structure wasn't known, you could go to the computer and model how it behaves."
For example, when certain proteins in the brain mutate, that can lead to Alzheimer's disease, Gruebele said.
"The structures of proteins are ultimately what's responsible for their function," he said. "Changes to their structure often cause abnormal functions. That's why we want to understand protein structures, and be able to model how they change."
Gruebele said that computer simulations already yield a pretty accurate picture of a given small organic molecule. But with this new method that breaks the microsecond barrier, "we've just opened up a whole new world of proteins for study," he said.
"There are only a handful of proteins that we know about that would fold by temperature jumps or other methods in a couple of microseconds," Gruebele said. "But there are many proteins that do it in hundreds of microseconds, and that could be sped up to a few microseconds by pressure jumps."
Gruebele said that if you want to improve computer simulations of protein folding so that they're 99.9 percent reliable - so reliable that a medical doctor could trust the results - you need many test cases. And if you need lots of test cases, you need to be able to run computer simulations quickly, Gruebele said.
"This experiment enables a greater number of proteins to be tested by simulations and experiments simultaneously, which will push forward the agenda of getting computer simulations that are more reliable and faster," Gruebele said.
Gruebele's co-authors of the paper are Charles Dumont and Tryggvi Emilsson.
Funding was provided by the National Science Foundation.
Source:
Phil Ciciora
University of Illinois at Urbana-Champaign
Modelling The Effectiveness And Risks Of Vaccination Strategies To Control Classical Swine Fever Epidemics
In a recent update of the Dutch contingency plan for controlling outbreaks of Classical Swine Fever emergency vaccination is preferred to large-scale preemptive culling.
Our modelling study evaluates the implications of this policy change. We find that vaccination in a ring of 2-km radius around a detected infection source is as effective as ring culling in a 1-km radius.
Although vaccinated infected animals can escape detection during the epidemic, the risk posed by these animals is reduced sufficiently by targeting screening efforts on vaccinated farms.
These results suggest that emergency vaccination can be equally effective and safe as preemptive culling.
Journal of the Royal Society Interface
Journal of the Royal Society Interface is the Society's cross-disciplinary publication promoting research at the interface between the physical and life sciences. It offers rapidity, visibility and high-quality peer review and is ranked fifth in JCR's multidisciplinary category. The journal also incorporates Interface Focus, a peer-reviewed, themed supplement, each issue of which concentrates on a specific cross-disciplinary subject.
Journal of the Royal Society Interface
Our modelling study evaluates the implications of this policy change. We find that vaccination in a ring of 2-km radius around a detected infection source is as effective as ring culling in a 1-km radius.
Although vaccinated infected animals can escape detection during the epidemic, the risk posed by these animals is reduced sufficiently by targeting screening efforts on vaccinated farms.
These results suggest that emergency vaccination can be equally effective and safe as preemptive culling.
Journal of the Royal Society Interface
Journal of the Royal Society Interface is the Society's cross-disciplinary publication promoting research at the interface between the physical and life sciences. It offers rapidity, visibility and high-quality peer review and is ranked fifth in JCR's multidisciplinary category. The journal also incorporates Interface Focus, a peer-reviewed, themed supplement, each issue of which concentrates on a specific cross-disciplinary subject.
Journal of the Royal Society Interface
Changes In Gene Expression May Cause Tolerance To Inhalants
Changes in the expression of genes may be the reason why people who abuse inhalants, such as spray paint or glue, quickly develop a tolerance, biologists at The University of Texas at Austin have discovered.
The team, led by graduate student Yan Wang, used the fruit fly Drosophila melanogaster as a model system to determine how the nervous system becomes tolerant to sedation with organic solvent inhalants.
The team's work appears in the October 16 issue of Public Library of Science-Biology.
"Drug tolerance causes the user to consume more of the drug, speeding them down the path of addiction," said Nigel Atkinson, an associate professor of neurobiology who supervised the research.
This is the first study to show that a single drug experience alters the response of an animal to future doses by epigenetically modifying a single gene.
The research lays the groundwork for understanding mechanisms of inhalant addiction in humans, and it is hoped, developing methods of treatment and recovery. Because the effects of organic solvent inhalants and alcohol on animals are similar, this work may also be relevant to understanding the response of the brain to alcohol.
When fruit flies are sedated with an organic solvent, the expression of the slo K+ channel gene increases. Increased expression of the gene enables the fruit flies to recover faster from sedation. This gene is very similar to the human slo gene.
Wang and colleagues sedated fruit flies with the organic solvent benzyl alcohol, then documented changes in chromosomal structures called histones. Histones are positively charged protein structures that bind to negatively charged DNA. They organize and control access to the DNA.
Benzyl alcohol sedation made the charge of the histone more negative, "relaxing the grip" of the DNA to the histones in a part of the slo gene that controls its expression.
When the chromatin is in a relaxed state, gene transcription occurs more frequently.
The researchers predict that increased expression of the slo channels, through epigenetic modifications to the histones, helped neurons recover from sedation and resist the effects of the drug, increasing tolerance.
"While the fruit fly seems very different from us, the cells of its nervous system are remarkably similar to ours and can be used to understand how drugs change our brains," Atkinson said.
This work was funded by the National Institute on Drug Abuse.
Source: Nigel Atkinson
University of Texas at Austin
The team, led by graduate student Yan Wang, used the fruit fly Drosophila melanogaster as a model system to determine how the nervous system becomes tolerant to sedation with organic solvent inhalants.
The team's work appears in the October 16 issue of Public Library of Science-Biology.
"Drug tolerance causes the user to consume more of the drug, speeding them down the path of addiction," said Nigel Atkinson, an associate professor of neurobiology who supervised the research.
This is the first study to show that a single drug experience alters the response of an animal to future doses by epigenetically modifying a single gene.
The research lays the groundwork for understanding mechanisms of inhalant addiction in humans, and it is hoped, developing methods of treatment and recovery. Because the effects of organic solvent inhalants and alcohol on animals are similar, this work may also be relevant to understanding the response of the brain to alcohol.
When fruit flies are sedated with an organic solvent, the expression of the slo K+ channel gene increases. Increased expression of the gene enables the fruit flies to recover faster from sedation. This gene is very similar to the human slo gene.
Wang and colleagues sedated fruit flies with the organic solvent benzyl alcohol, then documented changes in chromosomal structures called histones. Histones are positively charged protein structures that bind to negatively charged DNA. They organize and control access to the DNA.
Benzyl alcohol sedation made the charge of the histone more negative, "relaxing the grip" of the DNA to the histones in a part of the slo gene that controls its expression.
When the chromatin is in a relaxed state, gene transcription occurs more frequently.
The researchers predict that increased expression of the slo channels, through epigenetic modifications to the histones, helped neurons recover from sedation and resist the effects of the drug, increasing tolerance.
"While the fruit fly seems very different from us, the cells of its nervous system are remarkably similar to ours and can be used to understand how drugs change our brains," Atkinson said.
This work was funded by the National Institute on Drug Abuse.
Source: Nigel Atkinson
University of Texas at Austin
Low-Carb Diets' Effects Linked To Rise In Newly Identified 'Starvation Hormone'
The benefits sometimes seen in those on a low-carbohydrate, high-fat diet may depend on increased levels of a newly identified "starvation hormone" produced by the liver, according to a report in the June issue of the journal Cell Metabolism, published by Cell Press. Two studies in the issue show that the hormone plays a critical role in the metabolic shift seen in animals after a period of fasting and in those fed an Atkins-like diet. That shift is characterized by an increased reliance on fat stores as an alternative source of fuel when glucose, the body's primary energy source, plummets.
A team led by Eleftheria Maratos-Flier of Harvard University reports evidence that increased blood levels of liver-derived "fibroblast growth factor 21" (FGF21) are required for fasted mice and mice on a carbohydrate-restricted diet to switch gears and begin burning fat. Likewise, an accompanying study led by Steven Kliewer of the University of Texas Southwestern Medical Center found that FGF21 mobilizes fat in food-restricted animals and those with chronically elevated concentrations of the liver hormone. Kliewer's team further showed that the hormone contributes to energy-conserving behavioral changes as animals ride out food shortages.
"What's really exciting is that mice with excess FGF21 - even when they are fed - look like they are fasted," Kliewer said. "It's startling that you can give one hormone and flip the whole metabolic profile."
"We think these findings would increase the desirability of a drug that [might work through this mechanism] to increase fat oxidation in the liver," added Maratos-Flier, noting that the rise in obesity has contributed to a growing epidemic of nonalcoholic fatty liver disease. Although the physiology remained uncertain, pharmacological studies of mice and diabetic monkeys had previously shown promise for FGF21 therapy as a means to lower blood sugar and lipids and stave off weight gain.
Mammals survive periods of nutrient deprivation by shifting from carbohydrates to so-called ketone bodies as a primary fuel source. Ketone bodies are produced from fatty acids transferred from storage in fat tissue to the liver when carbohydrates are scarce. During prolonged fasts, ketone bodies can provide nearly half of baseline energy requirements and up to 70% of the energy required by the brain.
Earlier studies also showed that feeding rodents a high-fat, low-carbohydrate ("ketogenic") diet induces lipid oxidation associated with weight loss, according to Maratos-Flier. Yet the underlying mechanism responsible for the profound physiological changes that the diets induced wasn't fully understood.
In the new study, Maratos-Flier's team examined changes in gene activity occurring in mice fed a high-fat, low-carb diet for 30 days. Their comprehensive genetic screen of the animals, which lost weight on the special diet, turned up FGF21.
"We saw a dramatic increase in FGF21 in the livers of the mice [on the diet]," she said. "We thought, 'Maybe there is something to this.'"
Through further experimentation, the researchers found that liver and circulating levels of FGF21 increase in mice in response to both a low-carb, high-fat diet and fasting. Moreover, the hormone declined rapidly when fasted animals were fed again. In mice unable to produce FGF21 in their livers, the special diet resulted only in fatty liver, high blood lipids, and reduced blood ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism.
Meanwhile, Kliewer's group identified the FGF21 endocrine hormone as a mediator of peroxisome proliferator-activated receptor " (PPAR"). Scientists have known that PPAR""controls fats' use as an energy source during starvation. In addition, some drugs that lower "bad" cholesterol work by targeting PPAR""
Kliewer's group showed that FGF21 is induced directly by PPAR" in liver in response to fasting in mice. FGF21 in turn stimulates lipid breakdown in white adipose tissue and ketone body production in the liver. They unexpectedly also found that FGF21 led the animals to reduce their physical activity and made them more sensitive to entering torpor, a short-term, hibernation-like state.
In addition to altering their fuel sources, many small mammals conserve energy when food is scarce by undergoing periodic bouts of torpor, Kliewer explained.
"When you step back, the whole thing makes sense," he said. "During fasting, the liver hormone communicates with adipose tissue to send fat to the liver. It turns on the metabolism of fat into ketone bodies - and at the same time, it sensitizes the animals to going into torpor to conserve energy. It's clear that FGF21 is a principal component of the fasting or starvation response."
The two studies together lead to an "obvious possibility that FGF21 accounts for the proposed positive effect of the Atkins diet - including weight loss and an increase in 'good' cholesterol," Kliewer continued.
The degree to which the physiological effects of a ketogenic diet in humans mimic those seen in mice remains to be determined, Maratos-Flier added. She intends to examine FGF21 levels in humans after a few days on the Atkins diet, she said.
Either way, such low-carb, high-fat diets aren't likely to work for everyone.
"It may be that some people are more likely to turn on FGF21 than others," Maratos-Flier said. In obese individuals, for example, high insulin levels may interfere with the liver hormone, she said.
Badman et al.: "Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States." Publishing in Cell Metabolism 5, 426-437, June 2007. DOI 10.1016/j.cmet.2007.05.002 cellmetabolism/
The researchers include Michael K. Badman, Pavlos Pissios, Adam R. Kennedy, Jeffrey S. Flier, and Eleftheria Maratos-Flier of Beth Israel Deaconess Medical Center in Boston, MA; George Koukos of Boston University School of Medicine in Boston, MA.
This work was supported by NIH grant 5P30DK46200-14 from the Boston Obesity Nutrition Research Center to M.K.B., NIH grant HL-48739 to G.K., and a grant from Takeda Pharmaceuticals to J.S.F. and E.M.-F.
Inagaki et al.: "Endocrine Regulation of the Fasting Response by PPARa-Mediated Induction of Fibroblast Growth Factor 21." Publishing in Cell Metabolism 5, 415-425, June 2007. DOI 10.1016/j.cmet.2007.05.003 cellmetabolism/
The researchers include Takeshi Inagaki, Paul Dutchak, Guixiang Zhao, Laurent Gautron, Vinay Parameswara, Victoria Esser, Joel K. Elmquist, Robert D. Gerard, Shawn C. Burgess, Robert E. Hammer, and Steven A. Kliewer of the University of Texas Southwestern Medical Center in Dallas, TX; Xunshan Ding and David J. Mangelsdorf of Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center in Dallas, TX; Yong Li of Van Andel Research Institute in Grand Rapids, MI; Regina Goetz and Moosa Mohammadi of New York University School of Medicine in New York, NY.
This work was funded by National Institutes of Health grants DK067158 (SAK), P20RR20691 (SAK and DJM), U19DK62434 (DJM), DK53301 (JKE), and DE13686 (MM), the Robert A. Welch Foundation (SAK and DJM), the Betty Van Andel Foundation (YL), the Smith Family Foundation Pinnacle Program Project Award from the American Diabetes Association (JKE) and the Howard Hughes Medical Institute (XD and DJM). DJM is an investigator of the Howard Hughes Medical Institute.
Contact: Erin Doonan
Cell Press
A team led by Eleftheria Maratos-Flier of Harvard University reports evidence that increased blood levels of liver-derived "fibroblast growth factor 21" (FGF21) are required for fasted mice and mice on a carbohydrate-restricted diet to switch gears and begin burning fat. Likewise, an accompanying study led by Steven Kliewer of the University of Texas Southwestern Medical Center found that FGF21 mobilizes fat in food-restricted animals and those with chronically elevated concentrations of the liver hormone. Kliewer's team further showed that the hormone contributes to energy-conserving behavioral changes as animals ride out food shortages.
"What's really exciting is that mice with excess FGF21 - even when they are fed - look like they are fasted," Kliewer said. "It's startling that you can give one hormone and flip the whole metabolic profile."
"We think these findings would increase the desirability of a drug that [might work through this mechanism] to increase fat oxidation in the liver," added Maratos-Flier, noting that the rise in obesity has contributed to a growing epidemic of nonalcoholic fatty liver disease. Although the physiology remained uncertain, pharmacological studies of mice and diabetic monkeys had previously shown promise for FGF21 therapy as a means to lower blood sugar and lipids and stave off weight gain.
Mammals survive periods of nutrient deprivation by shifting from carbohydrates to so-called ketone bodies as a primary fuel source. Ketone bodies are produced from fatty acids transferred from storage in fat tissue to the liver when carbohydrates are scarce. During prolonged fasts, ketone bodies can provide nearly half of baseline energy requirements and up to 70% of the energy required by the brain.
Earlier studies also showed that feeding rodents a high-fat, low-carbohydrate ("ketogenic") diet induces lipid oxidation associated with weight loss, according to Maratos-Flier. Yet the underlying mechanism responsible for the profound physiological changes that the diets induced wasn't fully understood.
In the new study, Maratos-Flier's team examined changes in gene activity occurring in mice fed a high-fat, low-carb diet for 30 days. Their comprehensive genetic screen of the animals, which lost weight on the special diet, turned up FGF21.
"We saw a dramatic increase in FGF21 in the livers of the mice [on the diet]," she said. "We thought, 'Maybe there is something to this.'"
Through further experimentation, the researchers found that liver and circulating levels of FGF21 increase in mice in response to both a low-carb, high-fat diet and fasting. Moreover, the hormone declined rapidly when fasted animals were fed again. In mice unable to produce FGF21 in their livers, the special diet resulted only in fatty liver, high blood lipids, and reduced blood ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism.
Meanwhile, Kliewer's group identified the FGF21 endocrine hormone as a mediator of peroxisome proliferator-activated receptor " (PPAR"). Scientists have known that PPAR""controls fats' use as an energy source during starvation. In addition, some drugs that lower "bad" cholesterol work by targeting PPAR""
Kliewer's group showed that FGF21 is induced directly by PPAR" in liver in response to fasting in mice. FGF21 in turn stimulates lipid breakdown in white adipose tissue and ketone body production in the liver. They unexpectedly also found that FGF21 led the animals to reduce their physical activity and made them more sensitive to entering torpor, a short-term, hibernation-like state.
In addition to altering their fuel sources, many small mammals conserve energy when food is scarce by undergoing periodic bouts of torpor, Kliewer explained.
"When you step back, the whole thing makes sense," he said. "During fasting, the liver hormone communicates with adipose tissue to send fat to the liver. It turns on the metabolism of fat into ketone bodies - and at the same time, it sensitizes the animals to going into torpor to conserve energy. It's clear that FGF21 is a principal component of the fasting or starvation response."
The two studies together lead to an "obvious possibility that FGF21 accounts for the proposed positive effect of the Atkins diet - including weight loss and an increase in 'good' cholesterol," Kliewer continued.
The degree to which the physiological effects of a ketogenic diet in humans mimic those seen in mice remains to be determined, Maratos-Flier added. She intends to examine FGF21 levels in humans after a few days on the Atkins diet, she said.
Either way, such low-carb, high-fat diets aren't likely to work for everyone.
"It may be that some people are more likely to turn on FGF21 than others," Maratos-Flier said. In obese individuals, for example, high insulin levels may interfere with the liver hormone, she said.
Badman et al.: "Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States." Publishing in Cell Metabolism 5, 426-437, June 2007. DOI 10.1016/j.cmet.2007.05.002 cellmetabolism/
The researchers include Michael K. Badman, Pavlos Pissios, Adam R. Kennedy, Jeffrey S. Flier, and Eleftheria Maratos-Flier of Beth Israel Deaconess Medical Center in Boston, MA; George Koukos of Boston University School of Medicine in Boston, MA.
This work was supported by NIH grant 5P30DK46200-14 from the Boston Obesity Nutrition Research Center to M.K.B., NIH grant HL-48739 to G.K., and a grant from Takeda Pharmaceuticals to J.S.F. and E.M.-F.
Inagaki et al.: "Endocrine Regulation of the Fasting Response by PPARa-Mediated Induction of Fibroblast Growth Factor 21." Publishing in Cell Metabolism 5, 415-425, June 2007. DOI 10.1016/j.cmet.2007.05.003 cellmetabolism/
The researchers include Takeshi Inagaki, Paul Dutchak, Guixiang Zhao, Laurent Gautron, Vinay Parameswara, Victoria Esser, Joel K. Elmquist, Robert D. Gerard, Shawn C. Burgess, Robert E. Hammer, and Steven A. Kliewer of the University of Texas Southwestern Medical Center in Dallas, TX; Xunshan Ding and David J. Mangelsdorf of Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center in Dallas, TX; Yong Li of Van Andel Research Institute in Grand Rapids, MI; Regina Goetz and Moosa Mohammadi of New York University School of Medicine in New York, NY.
This work was funded by National Institutes of Health grants DK067158 (SAK), P20RR20691 (SAK and DJM), U19DK62434 (DJM), DK53301 (JKE), and DE13686 (MM), the Robert A. Welch Foundation (SAK and DJM), the Betty Van Andel Foundation (YL), the Smith Family Foundation Pinnacle Program Project Award from the American Diabetes Association (JKE) and the Howard Hughes Medical Institute (XD and DJM). DJM is an investigator of the Howard Hughes Medical Institute.
Contact: Erin Doonan
Cell Press
Pitt Professor's Theory Of Evolution Gets Boost From Cell Research
An article by University of Pittsburgh Professor of Anthropology Jeffrey H. Schwartz and University of Salerno Professor of Biochemistry Bruno Maresca, published Jan. 30 in the New Anatomist journal, shows that the emerging understanding of cell structure lends strong support to Schwartz's theory of evolution, originally explained in his seminal work, Sudden Origins: Fossils, Genes, and the Emergence of Species (John Wiley & Sons, 2000).
In that book, Schwartz hearkens back to earlier theories that suggest that the Darwinian model of evolution as continual and gradual adaptation to the environment glosses over gaps in the fossil record by assuming the intervening fossils simply have not been found yet. Rather, Schwartz argues, they have not been found because they don't exist, since evolution is not necessarily gradual but often sudden, dramatic expressions of change that began on the cellular level because of radical environmental stressors--like extreme heat, cold, or crowding--years earlier.
Determining the mechanism that causes those delayed expressions of change is Schwartz's major contribution to the evolution of the theory of evolution. The mechanism, the authors explain, is this: Environmental upheaval causes genes to mutate, and those altered genes remain in a recessive state, spreading silently through the population until offspring appear with two copies of the new mutation and change suddenly, seemingly appearing out of thin air. Those changes may be significant and beneficial (like teeth or limbs) or, more likely, kill the organism.
Why does it take an environmental drama to cause mutations? Why don't cells subtly and constantly change in small ways over time, as Darwin suggests?
Cell biologists know the answer: Cells don't like to change and don't do so easily. As Schwartz and Maresca explain: Cells in their ordinary states have suites of molecules-- various kinds of proteins--whose jobs are to eliminate error that might get introduced and derail the functioning of their cell. For instance, some proteins work to keep the cell membrane intact. Other proteins act as chaperones, bringing molecules to their proper locations in the cell, and so on. In short, with that kind of protection from change, it is very difficult for mutations, of whatever kind, to gain a foothold. But extreme stress pushes cells beyond their capacity to produce protective proteins, and then mutation can occur.
This revelation has enormous implications for the notion that organisms routinely change to adapt to the environment. Actually, Schwartz argues, it is the environment that knocks them off their equilibrium and as likely ultimately kills them as changes them. And so they are being rocked by the environment, not adapting to it.
The article's conclusions also have important implications for the notion of "fixing" the environment to protect endangered species. While it is indeed the environment causing the mutation, the resulting organism is in an altogether different environment by the time the novelty finally escapes its recessive state and expresses itself.
"You just can't do a quick fix on the environment to prevent extinction because the cause of the mutation occurred some time in the past, and you don't know what the cause of the stress was at that time," Schwartz said.
"This new understanding of how organisms change provides us with an opportunity to forestall the damage we might cause by unthinking disruption of the environment," added Schwartz. "The Sudden Origins theory, buttressed by modern cell biology, underscores the need to preserve the environment--not only to enhance life today, but to protect life generations from now."
Schwartz, with his colleague Ian Tattersall, curator of anthropology at the American Museum of Natural History in New York, also authored the four-volume The Human Fossil Record (Wiley-Liss, 2002-05). Together, the volumes represent the first study of the entire human fossil record. Volume 1 was recognized by the Association of American Publishers with its Professional Scholarly Publishing Award. In 1987, Schwartz's The Red Ape: Orang-utans and Human Origin (Houghton Mifflin Company) was met with critical acclaim.
Schwartz, who also is a Pitt professor of the history and philosophy of science, was named a fellow in Pitt's Center for the Philosophy of Science and a fellow of the prestigious World Academy of Arts and Science.
The journal, The New Anatomist, is an invitation-only supplement to the Anatomical Record.
Click here for full article:
Click here for Full Article.
Patricia Lomando White
laerpitt
University of Pittsburgh
pitt
In that book, Schwartz hearkens back to earlier theories that suggest that the Darwinian model of evolution as continual and gradual adaptation to the environment glosses over gaps in the fossil record by assuming the intervening fossils simply have not been found yet. Rather, Schwartz argues, they have not been found because they don't exist, since evolution is not necessarily gradual but often sudden, dramatic expressions of change that began on the cellular level because of radical environmental stressors--like extreme heat, cold, or crowding--years earlier.
Determining the mechanism that causes those delayed expressions of change is Schwartz's major contribution to the evolution of the theory of evolution. The mechanism, the authors explain, is this: Environmental upheaval causes genes to mutate, and those altered genes remain in a recessive state, spreading silently through the population until offspring appear with two copies of the new mutation and change suddenly, seemingly appearing out of thin air. Those changes may be significant and beneficial (like teeth or limbs) or, more likely, kill the organism.
Why does it take an environmental drama to cause mutations? Why don't cells subtly and constantly change in small ways over time, as Darwin suggests?
Cell biologists know the answer: Cells don't like to change and don't do so easily. As Schwartz and Maresca explain: Cells in their ordinary states have suites of molecules-- various kinds of proteins--whose jobs are to eliminate error that might get introduced and derail the functioning of their cell. For instance, some proteins work to keep the cell membrane intact. Other proteins act as chaperones, bringing molecules to their proper locations in the cell, and so on. In short, with that kind of protection from change, it is very difficult for mutations, of whatever kind, to gain a foothold. But extreme stress pushes cells beyond their capacity to produce protective proteins, and then mutation can occur.
This revelation has enormous implications for the notion that organisms routinely change to adapt to the environment. Actually, Schwartz argues, it is the environment that knocks them off their equilibrium and as likely ultimately kills them as changes them. And so they are being rocked by the environment, not adapting to it.
The article's conclusions also have important implications for the notion of "fixing" the environment to protect endangered species. While it is indeed the environment causing the mutation, the resulting organism is in an altogether different environment by the time the novelty finally escapes its recessive state and expresses itself.
"You just can't do a quick fix on the environment to prevent extinction because the cause of the mutation occurred some time in the past, and you don't know what the cause of the stress was at that time," Schwartz said.
"This new understanding of how organisms change provides us with an opportunity to forestall the damage we might cause by unthinking disruption of the environment," added Schwartz. "The Sudden Origins theory, buttressed by modern cell biology, underscores the need to preserve the environment--not only to enhance life today, but to protect life generations from now."
Schwartz, with his colleague Ian Tattersall, curator of anthropology at the American Museum of Natural History in New York, also authored the four-volume The Human Fossil Record (Wiley-Liss, 2002-05). Together, the volumes represent the first study of the entire human fossil record. Volume 1 was recognized by the Association of American Publishers with its Professional Scholarly Publishing Award. In 1987, Schwartz's The Red Ape: Orang-utans and Human Origin (Houghton Mifflin Company) was met with critical acclaim.
Schwartz, who also is a Pitt professor of the history and philosophy of science, was named a fellow in Pitt's Center for the Philosophy of Science and a fellow of the prestigious World Academy of Arts and Science.
The journal, The New Anatomist, is an invitation-only supplement to the Anatomical Record.
Click here for full article:
Click here for Full Article.
Patricia Lomando White
laerpitt
University of Pittsburgh
pitt
New Jersey Institute Of Technology: Former NASA Astronaut Bonnie J. Dunbar To Speak At Biomedical Engineering Seminar
One of the first women astronauts, Bonnie J. Dunbar, now a flight museum president, will speak at New Jersey Institute of Technology on April 23, 2009. The public is invited to attend this exciting free event during which Dunbar will detail how she made it into the world of flight.
The event will be held at 11:30 a.m., on Thursday, April 23, 2009, in 118 Kupfrian Hall. Event sponsors include Purdue Pharma L.P. and Bristol-Myers Squibb Company.
Dr. Bonnie J. Dunbar is currently president and CEO of The Museum of Flight in Seattle,Washington. The "MOF" is the largest private air and space museum in the world, with an education program that provides for nearly 100,000 students per year and an aircraft restoration center. Dr. Dunbar recently retired from the NASA Johnson Space Center where she was Associate Director, Technology Integration and Risk Management for the Space Life Sciences Directorate (SLSD) of the NASA Johnson Space Center. SLSD is responsible for Astronaut Crew Health, Human Health Research for Space Exploration, Human Factor Design of Spacecraft, and Life Support Requirements.
A NASA Mission Specialist astronaut and veteran of 5 space flights, Dr. Dunbar has logged more than 50 days in space. She has served as the Payload Commander on two flights, including the first Space Shuttle docking mission to the Russian Space Station Mir.
Dr. Dunbar holds BS and MS degrees in ceramic engineering from the University of Washington, and a PhD in mechanical/biomedical engineering from the University of Houston. Prior to working for NASA, she was a senior research engineer with Rockwell International Space Division, where she helped to develop the equipment and processes for manufacturing the thermal protection system for the Space Shuttle. Dr. Dunbar is a member of the American Ceramic Society (Fellow), the National Institute of Ceramic Engineers, the Society of Women Engineers and the American Institute of Aeronautics and Astronautics (AIAA/Associate Fellow). She has been awarded the NASA Space Flight Medal, the NASA Exceptional Leadership Medal and the NASA Distinguished Service Medal. Dr. Dunbar is a registered Professional Engineer, a member of the Royal Society of Edinburgh, the Royal Aeronautical Society and in 2002 was elected to the National Academy of Engineers.
Source:
Sheryl Weinstein
New Jersey Institute of Technology
The event will be held at 11:30 a.m., on Thursday, April 23, 2009, in 118 Kupfrian Hall. Event sponsors include Purdue Pharma L.P. and Bristol-Myers Squibb Company.
Dr. Bonnie J. Dunbar is currently president and CEO of The Museum of Flight in Seattle,Washington. The "MOF" is the largest private air and space museum in the world, with an education program that provides for nearly 100,000 students per year and an aircraft restoration center. Dr. Dunbar recently retired from the NASA Johnson Space Center where she was Associate Director, Technology Integration and Risk Management for the Space Life Sciences Directorate (SLSD) of the NASA Johnson Space Center. SLSD is responsible for Astronaut Crew Health, Human Health Research for Space Exploration, Human Factor Design of Spacecraft, and Life Support Requirements.
A NASA Mission Specialist astronaut and veteran of 5 space flights, Dr. Dunbar has logged more than 50 days in space. She has served as the Payload Commander on two flights, including the first Space Shuttle docking mission to the Russian Space Station Mir.
Dr. Dunbar holds BS and MS degrees in ceramic engineering from the University of Washington, and a PhD in mechanical/biomedical engineering from the University of Houston. Prior to working for NASA, she was a senior research engineer with Rockwell International Space Division, where she helped to develop the equipment and processes for manufacturing the thermal protection system for the Space Shuttle. Dr. Dunbar is a member of the American Ceramic Society (Fellow), the National Institute of Ceramic Engineers, the Society of Women Engineers and the American Institute of Aeronautics and Astronautics (AIAA/Associate Fellow). She has been awarded the NASA Space Flight Medal, the NASA Exceptional Leadership Medal and the NASA Distinguished Service Medal. Dr. Dunbar is a registered Professional Engineer, a member of the Royal Society of Edinburgh, the Royal Aeronautical Society and in 2002 was elected to the National Academy of Engineers.
Source:
Sheryl Weinstein
New Jersey Institute of Technology
Mouse Mammary Tumor Virus Can Replicate In Human Cells
Mouse mammary tumor virus (MMTV) -- which causes mammary cancer in mice -- can replicate and spread in human cells, research published this week shows. The study, published in the online open access journal Retrovirology, adds weight to the theory that MMTV might be involved in causing human breast cancer.
The idea that MMTV is involved in human breast cancer has been around for over 50 years. In the 1990s, researchers detected MMTV in human breast tumors, but not in healthy breast tissue. The link between MMTV and human breast cancer was contentious though, as some scientists believed the presence of MMTV in tumors was caused by contamination rather than infection.
However, two years ago, researchers from the University of Veterinary Medicine, Austrianova Biotechnology and the Christian-Doppler Laboratory for Gene Therapeutic Vector Development, all based in Vienna, Austria, showed that MMTV does actually infect human cells.
Now, they have added to these findings with this latest study, which shows that MMTV can replicate in cultured human breast cells. The new virus particles produced by the infected cells enabled the virus to spread rapidly, leading to the infection of every cell in culture.
"It has recently been shown convincingly that MMTV can infect human cells. Often, however, viruses infect cells but cannot replicate further. If they can replicate, the chances that they cause disease may be increased," says Dr Stanislav Indik from the University of Veterinary Medicine, Vienna and one of the study's authors.
There are a number of questions still to be answered before a concrete role of MMTV in human breast cancer is established, including whether MMTV can infect primary cells -- those taken directly from the body, not from a cultured cell line. Also, researchers plan to investigate how the virus spreads from mice to humans, and to examine if one of the possible outcomes of human MMTV infection is breast cancer.
MMTV is a retrovirus, the same kind of virus as HIV. If MMTV is eventually found to play a role in human breast cancer, current treatments for HIV may also be effective against MMTV.
Article:
Rapid spread of mouse mammary tumor virus in cultured human breast cells.
Stanislav Indik, Walter H GГјnzburg, Pavel
Kulich, Brian Salmons and Francoise Rouault
Retrovirology (in press)
Click here for access to the article in Retrovirology. All articles are available free of charge, according to BioMed Central's Open Access policy.
Contact:
Susanne Bach (Press Office, Austrianova Biotechnology GmbH)
BioMed Central (biomedcentral/) is an independent online publishing house committed to providing open access to peer-reviewed biological and medical research. This commitment is based on the view that immediate free access to research and the ability to freely archive and reuse published information is essential to the rapid and efficient communication of science.
BioMed Central currently publishes over 180 journals across biology and medicine. In addition to open-access original research, BioMed Central also publishes reviews, commentaries and other non-original-research content. Depending on the policies of the individual journal, this content may be open access or provided only to subscribers.
Source: Charlotte Webber
BioMed Central
The idea that MMTV is involved in human breast cancer has been around for over 50 years. In the 1990s, researchers detected MMTV in human breast tumors, but not in healthy breast tissue. The link between MMTV and human breast cancer was contentious though, as some scientists believed the presence of MMTV in tumors was caused by contamination rather than infection.
However, two years ago, researchers from the University of Veterinary Medicine, Austrianova Biotechnology and the Christian-Doppler Laboratory for Gene Therapeutic Vector Development, all based in Vienna, Austria, showed that MMTV does actually infect human cells.
Now, they have added to these findings with this latest study, which shows that MMTV can replicate in cultured human breast cells. The new virus particles produced by the infected cells enabled the virus to spread rapidly, leading to the infection of every cell in culture.
"It has recently been shown convincingly that MMTV can infect human cells. Often, however, viruses infect cells but cannot replicate further. If they can replicate, the chances that they cause disease may be increased," says Dr Stanislav Indik from the University of Veterinary Medicine, Vienna and one of the study's authors.
There are a number of questions still to be answered before a concrete role of MMTV in human breast cancer is established, including whether MMTV can infect primary cells -- those taken directly from the body, not from a cultured cell line. Also, researchers plan to investigate how the virus spreads from mice to humans, and to examine if one of the possible outcomes of human MMTV infection is breast cancer.
MMTV is a retrovirus, the same kind of virus as HIV. If MMTV is eventually found to play a role in human breast cancer, current treatments for HIV may also be effective against MMTV.
Article:
Rapid spread of mouse mammary tumor virus in cultured human breast cells.
Stanislav Indik, Walter H GГјnzburg, Pavel
Kulich, Brian Salmons and Francoise Rouault
Retrovirology (in press)
Click here for access to the article in Retrovirology. All articles are available free of charge, according to BioMed Central's Open Access policy.
Contact:
Susanne Bach (Press Office, Austrianova Biotechnology GmbH)
BioMed Central (biomedcentral/) is an independent online publishing house committed to providing open access to peer-reviewed biological and medical research. This commitment is based on the view that immediate free access to research and the ability to freely archive and reuse published information is essential to the rapid and efficient communication of science.
BioMed Central currently publishes over 180 journals across biology and medicine. In addition to open-access original research, BioMed Central also publishes reviews, commentaries and other non-original-research content. Depending on the policies of the individual journal, this content may be open access or provided only to subscribers.
Source: Charlotte Webber
BioMed Central
Renowned Molecular Geneticist George Church To Present At Upcoming Next Generation Dx Summit In Washington, DC
Renowned molecular geneticist and Harvard Professor, George Church will speak at the Next Generation Dx Summit to take place in Washington, DC on August 24-26. Dr. Church will discuss how the evolution of next generation sequencing technology is significantly enhancing the diagnostic landscape for infectious disease, and will offer a perspective on the need to demonstrate clear clinical benefits to achieve more wide spread adoption by healthcare organizations and clinicians.
Church, who recently co-founded Pathogenica ™ with Adeyemi Adesokan, will use Pathogenica as a study in how next generation technologies such as his company's unique BioDetection (DxSeq) system are significantly faster and more affordable than the current standards, thereby facilitating more widespread adoption by healthcare providers.
Pathogenica's novel BioDetection ™ system utilizes next-generation DNA sequencing technology to provide high throughput, ultra-low cost assays with high sensitivity and specificity for rapid multiplex identification of pathogens, such as MRSA and human viruses. This unique multiplexing technology can target many pathogens simultaneously, greatly accelerating accurate diagnosis from the current 4-10 days by culture, to under 24 hours, and all at less than a dollar per pathogen. Low cost multiplexed diagnostic assays offer a convincing solution to questions over current healthcare reimbursement for nucleic acid tests, and can save millions of dollars of unnecessary single pathogen assays.
In his presentation, Church will outline Pathogenica's strategy toward Clinical Laboratory Improvement Amendments (CLIA) certification and FDA-approved diagnostic panels, present proof of concept application of Pathogenica's technology for detection of multiple pathogens in clinical samples, and discuss new approaches to diagnostic monitoring enabled by this low-cost technology.
Source: Pathogenica
Church, who recently co-founded Pathogenica ™ with Adeyemi Adesokan, will use Pathogenica as a study in how next generation technologies such as his company's unique BioDetection (DxSeq) system are significantly faster and more affordable than the current standards, thereby facilitating more widespread adoption by healthcare providers.
Pathogenica's novel BioDetection ™ system utilizes next-generation DNA sequencing technology to provide high throughput, ultra-low cost assays with high sensitivity and specificity for rapid multiplex identification of pathogens, such as MRSA and human viruses. This unique multiplexing technology can target many pathogens simultaneously, greatly accelerating accurate diagnosis from the current 4-10 days by culture, to under 24 hours, and all at less than a dollar per pathogen. Low cost multiplexed diagnostic assays offer a convincing solution to questions over current healthcare reimbursement for nucleic acid tests, and can save millions of dollars of unnecessary single pathogen assays.
In his presentation, Church will outline Pathogenica's strategy toward Clinical Laboratory Improvement Amendments (CLIA) certification and FDA-approved diagnostic panels, present proof of concept application of Pathogenica's technology for detection of multiple pathogens in clinical samples, and discuss new approaches to diagnostic monitoring enabled by this low-cost technology.
Source: Pathogenica
Potential New Drug Target For Chronic Leukemia Identified By UCSD Researchers
Researchers at the University of California, San Diego (UCSD) and the Moores UCSD Cancer Center have discovered what could be a novel drug target for an often difficult-to-treat form of leukemia. The investigators have identified a unique "signature" or pattern of a specific family of enzymes in patients with chronic lymphocytic leukemia (CLL), the most common form of adult leukemia.
Paul Insel, M.D., professor of pharmacology and medicine at the UC San Diego School of Medicine and his co-workers compared white blood cells in patients with CLL to those of healthy adults. They found that one form of the group of enzymes, collectively known as cyclic nucleotide phosphodiesterases, was 10 times higher in CLL patients than in normal individuals. The specific type of enzyme, phosphodiesterase 7B (PDE7B), controls the levels of cyclic AMP (cAMP), a molecule that can promote programmed cell death, a process that is defective in CLL. The team reports its findings this week in the Proceedings of the National Academy of Sciences.
Whereas most cancers have out-of-control cell growth, CLL is characterized by an overabundance of white blood cells that do not die when they should, Insel explained.
The scientists subsequently tested the effects of drugs that blocked PDE7B in CLL cells, and found that this raised cAMP levels and caused CLL cells to undergo cell death. He explained that since PDE7B degrades cAMP, blocking PDE7B in essence takes the clamp off of programmed cell death, enabling CLL cells to die.
"PDE7B is thus a new drug target for CLL," he said. "We have preliminary data from patient samples studied in the laboratory showing that we can increase the killing of CLL cells even more if we block PDE7B and also add other drugs used to treat CLL."
He noted that a test for PDE7B might also potentially be used as a way to detect CLL, though this has yet to be proven. CLL, which usually strikes adults over age 35, has two major forms. One form progresses slowly, with few symptoms for years, and can be difficult to detect. The other form is more aggressive and dangerous. No one knows what makes one form different from the other. Current therapies have limited effectiveness, especially once the disease is in its aggressive phase.
The researchers are planning to screen potential drugs to treat CLL based on the PDE7B-cAMP connection. They are also exploring other potential treatment strategies to increase cAMP or disrupt its breakdown.
"We think that CLL cells may have found ways to help keep themselves alive by preventing cAMP from increasing," Insel said. "This paper provides a validation of the importance of the cAMP pathway as a target for drugs that might be used to treat CLL."
The American Cancer Society estimates that, in 2008, there will be about 15,110 new cases of CLL in the United States. About 4,390 people in this country will die of CLL during 2008.
Other contributors to the work include Thomas Kipps, M.D., Ph.D., Lingzhi Zhang, Ph.D., Fiona Murray, Ph.D., Anja Zahno, Joan Kanter, Daisy Chou, Ryan Suda, Michael Fenlon, Laura Rassenti, Ph.D. and Howard Cottam, Ph.D.
The Moores UCSD Cancer Center is one of the nation's 41 National Cancer Institute-designated Comprehensive Cancer Centers, combining research, clinical care and community outreach to advance the prevention, treatment and cure of cancer.
Source: Steve Benowitz
University of California - San Diego
Paul Insel, M.D., professor of pharmacology and medicine at the UC San Diego School of Medicine and his co-workers compared white blood cells in patients with CLL to those of healthy adults. They found that one form of the group of enzymes, collectively known as cyclic nucleotide phosphodiesterases, was 10 times higher in CLL patients than in normal individuals. The specific type of enzyme, phosphodiesterase 7B (PDE7B), controls the levels of cyclic AMP (cAMP), a molecule that can promote programmed cell death, a process that is defective in CLL. The team reports its findings this week in the Proceedings of the National Academy of Sciences.
Whereas most cancers have out-of-control cell growth, CLL is characterized by an overabundance of white blood cells that do not die when they should, Insel explained.
The scientists subsequently tested the effects of drugs that blocked PDE7B in CLL cells, and found that this raised cAMP levels and caused CLL cells to undergo cell death. He explained that since PDE7B degrades cAMP, blocking PDE7B in essence takes the clamp off of programmed cell death, enabling CLL cells to die.
"PDE7B is thus a new drug target for CLL," he said. "We have preliminary data from patient samples studied in the laboratory showing that we can increase the killing of CLL cells even more if we block PDE7B and also add other drugs used to treat CLL."
He noted that a test for PDE7B might also potentially be used as a way to detect CLL, though this has yet to be proven. CLL, which usually strikes adults over age 35, has two major forms. One form progresses slowly, with few symptoms for years, and can be difficult to detect. The other form is more aggressive and dangerous. No one knows what makes one form different from the other. Current therapies have limited effectiveness, especially once the disease is in its aggressive phase.
The researchers are planning to screen potential drugs to treat CLL based on the PDE7B-cAMP connection. They are also exploring other potential treatment strategies to increase cAMP or disrupt its breakdown.
"We think that CLL cells may have found ways to help keep themselves alive by preventing cAMP from increasing," Insel said. "This paper provides a validation of the importance of the cAMP pathway as a target for drugs that might be used to treat CLL."
The American Cancer Society estimates that, in 2008, there will be about 15,110 new cases of CLL in the United States. About 4,390 people in this country will die of CLL during 2008.
Other contributors to the work include Thomas Kipps, M.D., Ph.D., Lingzhi Zhang, Ph.D., Fiona Murray, Ph.D., Anja Zahno, Joan Kanter, Daisy Chou, Ryan Suda, Michael Fenlon, Laura Rassenti, Ph.D. and Howard Cottam, Ph.D.
The Moores UCSD Cancer Center is one of the nation's 41 National Cancer Institute-designated Comprehensive Cancer Centers, combining research, clinical care and community outreach to advance the prevention, treatment and cure of cancer.
Source: Steve Benowitz
University of California - San Diego
Tiny Molecules May Tell Big Story About Cardiovascular Disease Risk
Tiny bits of molecular "trash" found in circulating blood appear to be good predictors of cardiovascular disease and untimely death, say researchers at Duke University Medical Center.
The discovery, published online in the April issue of the journal Circulation Genetics, comes from the largest study of its kind for cardiovascular disease, and is the first to identify specific metabolic profiles associated with coronary artery disease, heart attacks and death among patients who have undergone coronary catheterization.
The Duke study analyzed metabolites, the molecular debris left over after the body breaks food down into energy sources and building blocks of cells and tissues.
Scientists believe metabolites may be useful in diagnosing disease, said Svati Shah, M.D., M.H.S., a cardiologist in the Duke Heart Center, the Duke Center for Human Genetics and the lead author of the study. But the tiny molecules are notoriously hard to identify, quantify and characterize. Shah has been studying metabolic signatures in heart disease for several years and led earlier research showing that metabolic profiles associated with early-onset coronary artery disease can be inherited.
Shah and William Kraus, M.D., professor of medicine at Duke and the senior author of the study, wanted to know if they could isolate and identify particular metabolites associated with coronary artery disease. They began their investigation with information in Duke's CATHGEN biorepository which holds health records and blood samples from nearly 10,000 patients who had come to Duke over the past eight years for catheterization. Collaboration with Christopher B. Newgard, PhD., director of Duke's Sarah W. Stedman Center for Nutrition and Metabolism, allowed Shah, Kraus and others to accurately quantify and characterize the metabolites.
Researchers selected 174 patients who had experienced early-onset coronary artery disease (CAD) and compared them to 174 controls who had undergone catheterization but who were not found to have CAD. Using a panel of 69 metabolites previously identified as potentially involved in the development of CAD, they examined the metabolic profiles in both groups.
"We found two sets, or clusters of metabolites that seemed to differentiate between the two groups," says Shah.
Next, they tested the two sets of metabolites to see if they could differentiate between patients of any age who had CAD and those who did not. Again, the two sets of metabolites were able to discriminate between the two groups.
In order to evaluate the ability of the metabolites to predict risk of heart attack or death, the researchers also created an "event group" comprising 314 patients from all groups who suffered a heart attack or death during a follow-up period of almost three years. They compared metabolic profiles between those who suffered a heart attack or death with those who did not. Using multiple analytic and statistical methods, they found two factors that were clearly associated with coronary artery disease and one factor that predicted greater risk of heart attack or death among patients with coronary artery disease.
"When we added these biomarkers to traditional clinical risk models, we found that they increased the accuracy of projected risk," says Shah.
While earlier studies have suggested that certain metabolites are associated with the presence and severity of CAD, researchers have not been able to identify most of the individual molecules within those profiles, says Shah, "which in the end meant that these studies were not that clinically useful."
"Here, we specifically selected clusters of metabolites that we know are involved in multiple pathways of lipid, protein and glucose metabolism - pathways that are often disrupted in CAD -- and we showed that they are indeed associated with CAD and subsequent risk of cardiac events," says Kraus, "These metabolic profiles may be a way from routine clinical use, but we feel they are a good first step in that direction."
Colleagues from Duke who contributed to the study include James Bain, David Crosslin, Michael Muehlbauer, Robert Stevens, Carol Haynes, Jennifer Dungan, Kristin Newby, Elizabeth Hauser, Geoffrey Ginsburg and Christopher Newgard, director of the Sarah W. Stedman Nutrition & Metabolism Center.
Source:
Debbe Geiger
Duke University Medical Center
The discovery, published online in the April issue of the journal Circulation Genetics, comes from the largest study of its kind for cardiovascular disease, and is the first to identify specific metabolic profiles associated with coronary artery disease, heart attacks and death among patients who have undergone coronary catheterization.
The Duke study analyzed metabolites, the molecular debris left over after the body breaks food down into energy sources and building blocks of cells and tissues.
Scientists believe metabolites may be useful in diagnosing disease, said Svati Shah, M.D., M.H.S., a cardiologist in the Duke Heart Center, the Duke Center for Human Genetics and the lead author of the study. But the tiny molecules are notoriously hard to identify, quantify and characterize. Shah has been studying metabolic signatures in heart disease for several years and led earlier research showing that metabolic profiles associated with early-onset coronary artery disease can be inherited.
Shah and William Kraus, M.D., professor of medicine at Duke and the senior author of the study, wanted to know if they could isolate and identify particular metabolites associated with coronary artery disease. They began their investigation with information in Duke's CATHGEN biorepository which holds health records and blood samples from nearly 10,000 patients who had come to Duke over the past eight years for catheterization. Collaboration with Christopher B. Newgard, PhD., director of Duke's Sarah W. Stedman Center for Nutrition and Metabolism, allowed Shah, Kraus and others to accurately quantify and characterize the metabolites.
Researchers selected 174 patients who had experienced early-onset coronary artery disease (CAD) and compared them to 174 controls who had undergone catheterization but who were not found to have CAD. Using a panel of 69 metabolites previously identified as potentially involved in the development of CAD, they examined the metabolic profiles in both groups.
"We found two sets, or clusters of metabolites that seemed to differentiate between the two groups," says Shah.
Next, they tested the two sets of metabolites to see if they could differentiate between patients of any age who had CAD and those who did not. Again, the two sets of metabolites were able to discriminate between the two groups.
In order to evaluate the ability of the metabolites to predict risk of heart attack or death, the researchers also created an "event group" comprising 314 patients from all groups who suffered a heart attack or death during a follow-up period of almost three years. They compared metabolic profiles between those who suffered a heart attack or death with those who did not. Using multiple analytic and statistical methods, they found two factors that were clearly associated with coronary artery disease and one factor that predicted greater risk of heart attack or death among patients with coronary artery disease.
"When we added these biomarkers to traditional clinical risk models, we found that they increased the accuracy of projected risk," says Shah.
While earlier studies have suggested that certain metabolites are associated with the presence and severity of CAD, researchers have not been able to identify most of the individual molecules within those profiles, says Shah, "which in the end meant that these studies were not that clinically useful."
"Here, we specifically selected clusters of metabolites that we know are involved in multiple pathways of lipid, protein and glucose metabolism - pathways that are often disrupted in CAD -- and we showed that they are indeed associated with CAD and subsequent risk of cardiac events," says Kraus, "These metabolic profiles may be a way from routine clinical use, but we feel they are a good first step in that direction."
Colleagues from Duke who contributed to the study include James Bain, David Crosslin, Michael Muehlbauer, Robert Stevens, Carol Haynes, Jennifer Dungan, Kristin Newby, Elizabeth Hauser, Geoffrey Ginsburg and Christopher Newgard, director of the Sarah W. Stedman Nutrition & Metabolism Center.
Source:
Debbe Geiger
Duke University Medical Center
Nobel Scientists Craig Mello And John Mather To Speak On Origins Of Life And Universe
A free and public event, "On the origins of life and the universe: An afternoon with 2006 Nobel Laureates Craig Mello and John Mather," will be held at the Library of Congress on 26 July from 2:00 to 4:00 p.m., in Room 119 of the Thomas Jefferson Building, 10 First Street, S.E., Washington, D.C.
John Mather, 2006 Nobel Laureate in Physics, will present the talk "From the Big Bang to the Nobel Prize." He will discuss the history of the universe in a nutshell - how the universe began with a Big Bang, how it produced an Earth where sentient beings can live, and how those beings are discovering their history. Mather also will discuss NASA's plans for the next great telescope in space, the James Webb Space Telescope. Planned for launch in 2013, the new telescope will explore the first galaxies formed in the universe and investigate where stars and planets are being born today.
Craig Mello, 2006 Nobel Laureate in Physiology or Medicine, will give a presentation titled "Life on a Cosmic Scale: From the Primordial Soup to a Nobel Prize-Winning Worm." He will reveal what worms, petunias and humans have in common and what this means for the future prospects of life on Earth and beyond. Mello also will explain how RNA interference (RNAi) works and describe how, along with the human genome sequence, it promises to revolutionize medicine.
The event is sponsored by the Library of Congress John W. Kluge Center and Science, Business and Technology Division, and the American Association for the Advancement of Science (AAAS).
Speakers
John Mather, recently named Chief Scientist at NASA, is an astrophysicist in the Observational Cosmology Laboratory at Goddard Space Flight Center and leads the James Webb Space Telescope science team. He served as project scientist for NASA's Cosmic Background Explorer (COBE) satellite, which measured the spectrum of heat radiation from the Big Bang. As principal investigator for the Far Infrared Absolute Spectrophotometer on COBE, he showed that the cosmic microwave background radiation has a blackbody spectrum within 50 parts per million, confirming the Big Bang theory to extraordinary accuracy.
Craig Mello is the Blais Professor of Molecular Medicine and an Investigator with the Howard Hughes Medical Institute at the University of Massachusetts Medical School. His research is focused on gene regulation during development and the mechanism of RNA interference. Along with Andrew Fire and colleagues, Mello reported in 1998 that double-stranded RNA can induce sequence-specific gene silencing in animals. Along with researchers around the world, Mello and colleagues went on to show that the underlying mechanism is conserved in numerous other organisms, including humans, and is even essential for human life.
Sponsors
Through a generous endowment from John W. Kluge, the Library of Congress established the Kluge Center in 2000 to bring together the world's best thinkers to stimulate, energize and distill wisdom from the Library's rich resources and to interact with policymakers in Washington. For more information on fellowships, grants and programs offered by the Kluge Center, visit loc/kluge.
The Science, Technology and Business Division of the Library of Congress provides reference and bibliographic services and develops the Library's rich and vast collections in all areas of science (with the exception of clinical medicine and technical agriculture), technology, business, management, and economics. For more information, visit loc/rr/scitech and loc/rr/business.
The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society, and publisher of the journal, Science (sciencemag/). AAAS was founded in 1848, and has 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of 1 million. The non-profit AAAS (aaas/) is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy; international programs; science education; and more.
Contact: Tiffany Lohwater
American Association for the Advancement of Science
John Mather, 2006 Nobel Laureate in Physics, will present the talk "From the Big Bang to the Nobel Prize." He will discuss the history of the universe in a nutshell - how the universe began with a Big Bang, how it produced an Earth where sentient beings can live, and how those beings are discovering their history. Mather also will discuss NASA's plans for the next great telescope in space, the James Webb Space Telescope. Planned for launch in 2013, the new telescope will explore the first galaxies formed in the universe and investigate where stars and planets are being born today.
Craig Mello, 2006 Nobel Laureate in Physiology or Medicine, will give a presentation titled "Life on a Cosmic Scale: From the Primordial Soup to a Nobel Prize-Winning Worm." He will reveal what worms, petunias and humans have in common and what this means for the future prospects of life on Earth and beyond. Mello also will explain how RNA interference (RNAi) works and describe how, along with the human genome sequence, it promises to revolutionize medicine.
The event is sponsored by the Library of Congress John W. Kluge Center and Science, Business and Technology Division, and the American Association for the Advancement of Science (AAAS).
Speakers
John Mather, recently named Chief Scientist at NASA, is an astrophysicist in the Observational Cosmology Laboratory at Goddard Space Flight Center and leads the James Webb Space Telescope science team. He served as project scientist for NASA's Cosmic Background Explorer (COBE) satellite, which measured the spectrum of heat radiation from the Big Bang. As principal investigator for the Far Infrared Absolute Spectrophotometer on COBE, he showed that the cosmic microwave background radiation has a blackbody spectrum within 50 parts per million, confirming the Big Bang theory to extraordinary accuracy.
Craig Mello is the Blais Professor of Molecular Medicine and an Investigator with the Howard Hughes Medical Institute at the University of Massachusetts Medical School. His research is focused on gene regulation during development and the mechanism of RNA interference. Along with Andrew Fire and colleagues, Mello reported in 1998 that double-stranded RNA can induce sequence-specific gene silencing in animals. Along with researchers around the world, Mello and colleagues went on to show that the underlying mechanism is conserved in numerous other organisms, including humans, and is even essential for human life.
Sponsors
Through a generous endowment from John W. Kluge, the Library of Congress established the Kluge Center in 2000 to bring together the world's best thinkers to stimulate, energize and distill wisdom from the Library's rich resources and to interact with policymakers in Washington. For more information on fellowships, grants and programs offered by the Kluge Center, visit loc/kluge.
The Science, Technology and Business Division of the Library of Congress provides reference and bibliographic services and develops the Library's rich and vast collections in all areas of science (with the exception of clinical medicine and technical agriculture), technology, business, management, and economics. For more information, visit loc/rr/scitech and loc/rr/business.
The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society, and publisher of the journal, Science (sciencemag/). AAAS was founded in 1848, and has 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of 1 million. The non-profit AAAS (aaas/) is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy; international programs; science education; and more.
Contact: Tiffany Lohwater
American Association for the Advancement of Science
New Findings About Brain Proteins Suggest Possible Way To Fight Alzheimer's
The action of a small protein that is a major villain in Alzheimer's disease can be counterbalanced with another brain protein, researchers at UT Southwestern Medical Center have found in an animal study.
The findings, available online in the journal Proceedings of the National Academy of Sciences, suggest a promising new tactic against the devastating illness, the researchers said.
The harmful protein, called beta-amyloid, is found in the brain and, when functioning properly, suppresses nerve activity involved with memory and learning. Its normal function can be likened to a red traffic light, restraining nerve cells from getting overexcited when they receive stimulating signals from neighboring cells. People with Alzheimer's disease, however, accumulate too much beta-amyloid - the traffic light gets stuck on "red" and nerve cells become less responsive.
Another brain protein, called Reelin, acts as a "green light," stimulating nerve cells to respond more strongly to their neighbors' signals.
The new study shows that applying Reelin directly to brain slices from mice prevents excess beta-amyloid from completely silencing nerves.
"If we can identify a mechanism to keep the nerve cells functioning strongly, that might provide a way to fight Alzheimer's disease," said Dr. Joachim Herz, professor of molecular genetics and neuroscience at UT Southwestern and the study's senior author.
In the study, the researchers recorded electrical currents in the mouse hippocampus, an area of the brain associated with learning and memory. From their experiments they determined that Reelin and beta-amyloid interact with the same protein complex, called an NMDA receptor, which plays an important role in coordinating chemical signals between adjacent nerve cells.
They found that Reelin activates and strengthens the response of the NMDA receptor. In the presence of too much beta-amyloid, the receptor migrates into the cell, reducing the cell's sensitivity to incoming signals. By contrast, in strong concentrations of Reelin, the receptor remains active and the cell has the green light to continue receiving normally.
Dr. Herz said the study is especially important because this mechanism involves another protein involved in Alzheimer's called ApoE4, which is the primary risk factor for the most frequent late-onset form of the disease. The receptor that binds to ApeE molecules also binds to Reelin, and is part of the red-light/green-light complex that controls the sensitivity of the NMDA receptors.
"These results imply that Reelin, ApoE and beta-amyloid converge on the same molecular mechanism, which is critical in the Alzheimer's disease process, and Reelin may be a common factor to fight both beta-amyloid and mutated ApoE," Dr. Herz said. "This study establishes a rationale that ApoE receptors have an action that can keep the Alzheimer's disease process at bay by preventing damage in the first place."
The researchers are currently studying the role of ApoE4 in this mechanism. Mimicking or preserving normal Reelin function to stimulate the ApoE receptors might provide a path to stave off the disease, Dr. Herz said.
Other UT Southwestern authors included lead author Dr. Murat Durakoglugil, assistant instructor of molecular genetics; graduate student Ying Chen; Dr. Charles White, professor of pathology; and Dr. Ege Kavalali, associate professor of neuroscience.
The study was funded by the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation and the Humboldt Foundation.
Visit utsouthwestern/neurosciences to learn more about clinical services in the neurosciences at UT Southwestern, including Alzheimer's disease treatment.
Source:
Aline McKenzie
UT Southwestern Medical Center
The findings, available online in the journal Proceedings of the National Academy of Sciences, suggest a promising new tactic against the devastating illness, the researchers said.
The harmful protein, called beta-amyloid, is found in the brain and, when functioning properly, suppresses nerve activity involved with memory and learning. Its normal function can be likened to a red traffic light, restraining nerve cells from getting overexcited when they receive stimulating signals from neighboring cells. People with Alzheimer's disease, however, accumulate too much beta-amyloid - the traffic light gets stuck on "red" and nerve cells become less responsive.
Another brain protein, called Reelin, acts as a "green light," stimulating nerve cells to respond more strongly to their neighbors' signals.
The new study shows that applying Reelin directly to brain slices from mice prevents excess beta-amyloid from completely silencing nerves.
"If we can identify a mechanism to keep the nerve cells functioning strongly, that might provide a way to fight Alzheimer's disease," said Dr. Joachim Herz, professor of molecular genetics and neuroscience at UT Southwestern and the study's senior author.
In the study, the researchers recorded electrical currents in the mouse hippocampus, an area of the brain associated with learning and memory. From their experiments they determined that Reelin and beta-amyloid interact with the same protein complex, called an NMDA receptor, which plays an important role in coordinating chemical signals between adjacent nerve cells.
They found that Reelin activates and strengthens the response of the NMDA receptor. In the presence of too much beta-amyloid, the receptor migrates into the cell, reducing the cell's sensitivity to incoming signals. By contrast, in strong concentrations of Reelin, the receptor remains active and the cell has the green light to continue receiving normally.
Dr. Herz said the study is especially important because this mechanism involves another protein involved in Alzheimer's called ApoE4, which is the primary risk factor for the most frequent late-onset form of the disease. The receptor that binds to ApeE molecules also binds to Reelin, and is part of the red-light/green-light complex that controls the sensitivity of the NMDA receptors.
"These results imply that Reelin, ApoE and beta-amyloid converge on the same molecular mechanism, which is critical in the Alzheimer's disease process, and Reelin may be a common factor to fight both beta-amyloid and mutated ApoE," Dr. Herz said. "This study establishes a rationale that ApoE receptors have an action that can keep the Alzheimer's disease process at bay by preventing damage in the first place."
The researchers are currently studying the role of ApoE4 in this mechanism. Mimicking or preserving normal Reelin function to stimulate the ApoE receptors might provide a path to stave off the disease, Dr. Herz said.
Other UT Southwestern authors included lead author Dr. Murat Durakoglugil, assistant instructor of molecular genetics; graduate student Ying Chen; Dr. Charles White, professor of pathology; and Dr. Ege Kavalali, associate professor of neuroscience.
The study was funded by the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation and the Humboldt Foundation.
Visit utsouthwestern/neurosciences to learn more about clinical services in the neurosciences at UT Southwestern, including Alzheimer's disease treatment.
Source:
Aline McKenzie
UT Southwestern Medical Center
Research On Type B Flu Strain Could Yield Clues About Bird Flu
Scientists from Baylor College of Medicine (BCM) and Rice University have developed a three-dimensional, molecular map that could yield clues about the genetic mutations that will allow bird flu to spread among humans.
The research, which appears this week in the Proceedings of the National Academy of Science (PNAS) Online Early Edition, was conducted on a strain of the influenza B virus initially isolated from Hong Kong. Unlike strains of influenza A -- which include bird flu, swine flu and others -- influenza B affects only humans.
"The big question is, 'What would it take for the bird flu to change and start killing us?" said research co-author Jianpeng Ma, a structural biologist who holds joint appointments at both BCM and Rice. "Since flu B is a distant relative of flu A, the fewer common features among them would allow identifying the critical parts required for infecting humans."
The research is based on a more than six years of painstaking experiments by lead author Qinghua Wang, assistant professor of biochemistry and molecular biology at BCM. The experiments focused on a protein called hemagglutinin (HA), the chemical key that allows flu viruses to attach to target cells and infect them with viral DNA. There are 16 HA proteins, but only flu B and H1, H2 and H3 of flu A are found in human-transmissible strains. Scientists know H5, the HA key used by bird flu, is very similar to the chemical keys used by human strains of flu A. Like all proteins, the HA keys consist of a precise sequence of amino acids.
"In terms of sequence, there is only a 25 percent overlap between HA proteins for type A and type B," Ma said. "But in terms of function, the two are remarkably similar.
Wang said, "It would be better if there were more differences. The similarities suggest that only minor mutations are needed for bird flu to become transmissible to human."
Scientists know the precise 3D structure of several HA keys for flu A, but Wang and Ma's work represents the first mapping of an HA key for flu B. Currently, Ma and Wang are working out the precise molecular mutations that will be required for bird flu's HA to change into a human transmissible form.
The research is supported by the National Institutes of Health and the Welch Foundation.
Source: Jade Boyd
Rice University
The research, which appears this week in the Proceedings of the National Academy of Science (PNAS) Online Early Edition, was conducted on a strain of the influenza B virus initially isolated from Hong Kong. Unlike strains of influenza A -- which include bird flu, swine flu and others -- influenza B affects only humans.
"The big question is, 'What would it take for the bird flu to change and start killing us?" said research co-author Jianpeng Ma, a structural biologist who holds joint appointments at both BCM and Rice. "Since flu B is a distant relative of flu A, the fewer common features among them would allow identifying the critical parts required for infecting humans."
The research is based on a more than six years of painstaking experiments by lead author Qinghua Wang, assistant professor of biochemistry and molecular biology at BCM. The experiments focused on a protein called hemagglutinin (HA), the chemical key that allows flu viruses to attach to target cells and infect them with viral DNA. There are 16 HA proteins, but only flu B and H1, H2 and H3 of flu A are found in human-transmissible strains. Scientists know H5, the HA key used by bird flu, is very similar to the chemical keys used by human strains of flu A. Like all proteins, the HA keys consist of a precise sequence of amino acids.
"In terms of sequence, there is only a 25 percent overlap between HA proteins for type A and type B," Ma said. "But in terms of function, the two are remarkably similar.
Wang said, "It would be better if there were more differences. The similarities suggest that only minor mutations are needed for bird flu to become transmissible to human."
Scientists know the precise 3D structure of several HA keys for flu A, but Wang and Ma's work represents the first mapping of an HA key for flu B. Currently, Ma and Wang are working out the precise molecular mutations that will be required for bird flu's HA to change into a human transmissible form.
The research is supported by the National Institutes of Health and the Welch Foundation.
Source: Jade Boyd
Rice University
Researchers Develop Novel Method For Treatment Of Sickle Cell Disease
Virginia Commonwealth University researchers have developed a unique anti-sickling agent that may one day be effective in treating sickle cell disease, a painful and debilitating genetic blood disorder that affects approximately 80,000 Americans.
The research team led by Donald Abraham, Ph.D., of Biological and Medicinal Chemistry, in the Department of Medicinal Chemistry in VCU's School of Pharmacy, has shown that 5-HMF, a pure compound developed by the team, has a high affinity for sickle cell hemoglobin and holds promise for the treatment of sickle cell disease.
"Our findings suggest that this anti-sickling agent may lead to new drug treatments and may one day help those suffering with sickle cell disease. This molecule, 5-HMF, is the most promising molecule to treat sickle cell anemia to come from our research group in more than 30 years," said Abraham, who is also the director of the Institute of Structural Biology and Drug Discovery.
The United States Patent and Trademark Office recently issued VCU a Notice of Allowance for a patent relating to a method of treating sickle cell disease with 5-HMF compound. A Notice of Allowance is a written notification that a patent application has cleared an internal review and it has been approved for issuance.
Sickle cell disease is caused by an abnormality in the hemoglobin molecule. Normal red blood cells carrying hemoglobin are smooth, round and flexible and can travel easily throughout blood vessels. However, sickle cells are stiff, abnormally shaped, red blood cells that do not flow freely through blood vessels. The sickle cells also may clot together causing a blockage to form which results in pain and potentially dangerous complications that can compromise a patient's organs.
According to Abraham, the 5-membered, heterocyclic, anti-sickling agent binds to hemoglobin to increase the oxygen affinity of both normal and sickle hemoglobin. In a patient with sickle cell disease, the binding action of 5-HMF would allow sickle cells to move more smoothly throughout the blood vessels of the body and prevent blockages from forming.
Abraham is internationally known for his groundbreaking work discovering and developing drugs that interact with hemoglobin. His research focus is to develop targeted therapeutics in sickle cell anemia, cardiovascular disease, stroke, cancer, Alzheimer's disease and radiation oncology.
This research was supported in part by a grant from the National Institutes of Health.
Xechem International, Inc., a biopharmaceutical company headquartered in New Brunswick, N.J., has entered into a licensing agreement with VCU Technology Transfer and has the exclusive worldwide rights for the production, sales and marketing of 5-HMF for use to fight sickle cell disease.
A recent grant from the National Heart, Lung and Blood Institute, part of the National Institutes of Health, awarded to Xechem International Inc., will allow researchers to carry out toxicity studies on 5-HMF. The research team will include researchers from VCU and Children's Hospital of Philadelphia, University of Philadelphia.
Working with Abraham to develop the anti-sickling agent were: Martin K. Safo, Ph.D., Richmond Danso-Danquah, Ph.D., and Gajanan S. Joshi, Ph.D., all researchers in the VCU Department of Medicinal Chemistry.
About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 30,000 students in nearly 200 certificate and degree programs in the arts, sciences and humanities. Sixty-three of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see vcu/.
About Xechem: Xechem International is a development stage biopharmaceutical company working on Sickle Cell Disease (SCD), antimalarials, and antiviral (including AIDS), anticancer, antifungal and antibacterial products from natural sources, including microbial and marine organisms. Its focus is on the development of phyto-pharmaceuticals (Natural Herbal Drugs) and other proprietary technologies, including those used in the treatment of orphan diseases. Xechem's mission is to bring relief to the millions of people who suffer from these diseases. Its recent focus and resources have been directed primarily toward the development and launch of NICOSANTM (named HEMOXINTM in the US and Europe) for the prophylactic management of Sickle Cell Disease (SCD). With the recent Nigerian regulatory approval of NICOSANTM, Xechem is now scaling-up the commercialization of the drug in Nigeria and making preparations for the pursuit of US FDA and European regulatory approval.
Contact: Sathya Achia-Abraham
Virginia Commonwealth University
The research team led by Donald Abraham, Ph.D., of Biological and Medicinal Chemistry, in the Department of Medicinal Chemistry in VCU's School of Pharmacy, has shown that 5-HMF, a pure compound developed by the team, has a high affinity for sickle cell hemoglobin and holds promise for the treatment of sickle cell disease.
"Our findings suggest that this anti-sickling agent may lead to new drug treatments and may one day help those suffering with sickle cell disease. This molecule, 5-HMF, is the most promising molecule to treat sickle cell anemia to come from our research group in more than 30 years," said Abraham, who is also the director of the Institute of Structural Biology and Drug Discovery.
The United States Patent and Trademark Office recently issued VCU a Notice of Allowance for a patent relating to a method of treating sickle cell disease with 5-HMF compound. A Notice of Allowance is a written notification that a patent application has cleared an internal review and it has been approved for issuance.
Sickle cell disease is caused by an abnormality in the hemoglobin molecule. Normal red blood cells carrying hemoglobin are smooth, round and flexible and can travel easily throughout blood vessels. However, sickle cells are stiff, abnormally shaped, red blood cells that do not flow freely through blood vessels. The sickle cells also may clot together causing a blockage to form which results in pain and potentially dangerous complications that can compromise a patient's organs.
According to Abraham, the 5-membered, heterocyclic, anti-sickling agent binds to hemoglobin to increase the oxygen affinity of both normal and sickle hemoglobin. In a patient with sickle cell disease, the binding action of 5-HMF would allow sickle cells to move more smoothly throughout the blood vessels of the body and prevent blockages from forming.
Abraham is internationally known for his groundbreaking work discovering and developing drugs that interact with hemoglobin. His research focus is to develop targeted therapeutics in sickle cell anemia, cardiovascular disease, stroke, cancer, Alzheimer's disease and radiation oncology.
This research was supported in part by a grant from the National Institutes of Health.
Xechem International, Inc., a biopharmaceutical company headquartered in New Brunswick, N.J., has entered into a licensing agreement with VCU Technology Transfer and has the exclusive worldwide rights for the production, sales and marketing of 5-HMF for use to fight sickle cell disease.
A recent grant from the National Heart, Lung and Blood Institute, part of the National Institutes of Health, awarded to Xechem International Inc., will allow researchers to carry out toxicity studies on 5-HMF. The research team will include researchers from VCU and Children's Hospital of Philadelphia, University of Philadelphia.
Working with Abraham to develop the anti-sickling agent were: Martin K. Safo, Ph.D., Richmond Danso-Danquah, Ph.D., and Gajanan S. Joshi, Ph.D., all researchers in the VCU Department of Medicinal Chemistry.
About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 30,000 students in nearly 200 certificate and degree programs in the arts, sciences and humanities. Sixty-three of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see vcu/.
About Xechem: Xechem International is a development stage biopharmaceutical company working on Sickle Cell Disease (SCD), antimalarials, and antiviral (including AIDS), anticancer, antifungal and antibacterial products from natural sources, including microbial and marine organisms. Its focus is on the development of phyto-pharmaceuticals (Natural Herbal Drugs) and other proprietary technologies, including those used in the treatment of orphan diseases. Xechem's mission is to bring relief to the millions of people who suffer from these diseases. Its recent focus and resources have been directed primarily toward the development and launch of NICOSANTM (named HEMOXINTM in the US and Europe) for the prophylactic management of Sickle Cell Disease (SCD). With the recent Nigerian regulatory approval of NICOSANTM, Xechem is now scaling-up the commercialization of the drug in Nigeria and making preparations for the pursuit of US FDA and European regulatory approval.
Contact: Sathya Achia-Abraham
Virginia Commonwealth University
Nanoparticles In Ivy May Hold The Key To Making Sunscreen Safer And More Effective
When Mingjun Zhang was watching his son play in the yard, he was hit with a burning question: "What makes the ivy in his backyard cling to the fence so tightly?"
That simple question has led to a pioneering discovery that the tiny particles secreted from ivy rootlets can be used in many breakthrough applications in items such as military technologies, medical adhesives and drug delivery, and, most recently, sun-block.
Zhang, an associate professor of biomedical engineering at the University of Tennessee, Knoxville, along with his research team and collaborators, has found that ivy nanoparticles may protect skin from UV radiation at least four times better than the metal-based sunblocks found on store shelves today.
"The discovery of ivy nanoparticles' application to sunscreen was triggered by a real need. While hearing a talk at a conference about toxicity concerns in the use of metal-based nanoparticles in sunscreen, I was wondering, 'Why not try naturally occurring organic nanoparticles?'" Zhang said.
Zhang speculated the greenery's hidden power lay within a yellowish material secreted by the ivy for surface climbing. He placed this material onto a silicon wafer and examined it under an atomic force microscope and was surprised by what they found -- lots of nanoparticles, tiny particles 1,000 times thinner than the diameter of a human hair. The properties of these tiny bits create the ability for the vine leaves to hold almost 2 million more times than its weight. It also has the ability to soak up and disperse light which is integral to sunscreens.
"Nanoparticles exhibit unique physical and chemical properties due to large surface-to-volume ratio which allows them to absorb and scatter light," Zhang said. "Titanium dioxide and zinc oxide are currently used for sunscreen for the same reason, but the ivy nanoparticles are more uniform than the metal-based nanoparticles, and have unique material properties, which may help to enhance the absorption and scattering of light, and serve better as a sun-blocker."
The team's study indicates that ivy nanoparticles can improve the extinction of ultraviolet light at least four times better than its metal counterparts. Furthermore, the metal-based sunscreens used today can pose health hazards. Zhang notes some studies have shown that the small-scale metal oxides in sunscreen can wind up in organs such as the liver or brain.
Ivy nanoparticles, on the other hand, exhibit better biocompatibility with humans and the environment. The team's studies indicate that the ivy nanoparticles were less toxic to mammalian cells, have a limited potential to penetrate through human skin, and are easily biodegradable.
"In general, it is not a good idea to have more metal-based nanoparticles for cosmetic applications. They are a significant concern for the environment. Naturally occurring nanoparticles originated from plants seem to be a better choice, especially since they have been demonstrated to be less toxic and easily biodegradable," Zhang said.
Sunscreens made with ivy nanoparticles may not need to be reapplied after swimming. That's because the plant's nanoparticles are a bit more adhesive so sunscreens made with them may not wash off as easily as traditional sunscreens. And while sunscreens made with metal-based nanoparticles give the skin a white tinge, sunscreens made with ivy nanoparticles are virtually invisible when applied to the skin.
Zhang worked with assistant professor Zhili Zhang, graduate student Lijin Xia, and post-doctoral research associates Scott Lenaghan and Quanshui Li in the Department of Mechanical, Aerospace and Biomedical Engineering.
Source:
University of Tennessee at Knoxville
That simple question has led to a pioneering discovery that the tiny particles secreted from ivy rootlets can be used in many breakthrough applications in items such as military technologies, medical adhesives and drug delivery, and, most recently, sun-block.
Zhang, an associate professor of biomedical engineering at the University of Tennessee, Knoxville, along with his research team and collaborators, has found that ivy nanoparticles may protect skin from UV radiation at least four times better than the metal-based sunblocks found on store shelves today.
"The discovery of ivy nanoparticles' application to sunscreen was triggered by a real need. While hearing a talk at a conference about toxicity concerns in the use of metal-based nanoparticles in sunscreen, I was wondering, 'Why not try naturally occurring organic nanoparticles?'" Zhang said.
Zhang speculated the greenery's hidden power lay within a yellowish material secreted by the ivy for surface climbing. He placed this material onto a silicon wafer and examined it under an atomic force microscope and was surprised by what they found -- lots of nanoparticles, tiny particles 1,000 times thinner than the diameter of a human hair. The properties of these tiny bits create the ability for the vine leaves to hold almost 2 million more times than its weight. It also has the ability to soak up and disperse light which is integral to sunscreens.
"Nanoparticles exhibit unique physical and chemical properties due to large surface-to-volume ratio which allows them to absorb and scatter light," Zhang said. "Titanium dioxide and zinc oxide are currently used for sunscreen for the same reason, but the ivy nanoparticles are more uniform than the metal-based nanoparticles, and have unique material properties, which may help to enhance the absorption and scattering of light, and serve better as a sun-blocker."
The team's study indicates that ivy nanoparticles can improve the extinction of ultraviolet light at least four times better than its metal counterparts. Furthermore, the metal-based sunscreens used today can pose health hazards. Zhang notes some studies have shown that the small-scale metal oxides in sunscreen can wind up in organs such as the liver or brain.
Ivy nanoparticles, on the other hand, exhibit better biocompatibility with humans and the environment. The team's studies indicate that the ivy nanoparticles were less toxic to mammalian cells, have a limited potential to penetrate through human skin, and are easily biodegradable.
"In general, it is not a good idea to have more metal-based nanoparticles for cosmetic applications. They are a significant concern for the environment. Naturally occurring nanoparticles originated from plants seem to be a better choice, especially since they have been demonstrated to be less toxic and easily biodegradable," Zhang said.
Sunscreens made with ivy nanoparticles may not need to be reapplied after swimming. That's because the plant's nanoparticles are a bit more adhesive so sunscreens made with them may not wash off as easily as traditional sunscreens. And while sunscreens made with metal-based nanoparticles give the skin a white tinge, sunscreens made with ivy nanoparticles are virtually invisible when applied to the skin.
Zhang worked with assistant professor Zhili Zhang, graduate student Lijin Xia, and post-doctoral research associates Scott Lenaghan and Quanshui Li in the Department of Mechanical, Aerospace and Biomedical Engineering.
Source:
University of Tennessee at Knoxville
Putting Beta-Diversity On The Map: Broad-Scale Congruence And Coincidence In The Extremes
Beta-diversity, how species composition varies from place to place, is a
fundamental attribute of biodiversity. However, despite its recognized
importance, beta-diversity is rarely studied across large spatial scales.
Here, Meghan McKnight, Simon Stuart, and colleagues, published in the
open-access journal PLoS Biology, use a new method to compare amphibian,
bird,
and mammal beta-diversity across large regions within the Western
Hemisphere. They show that although the areas of low beta-diversity are
different
for the three groups, areas of high beta-diversity largely coincide.
Moreover, they find that the degree to which the groups exhibit similar
patterns
of beta-diversity depends on the geographic location and extent at which
it is measured. Beta-diversity is high where species are most susceptible
to
climate change, such as in areas with complex topography or high
environmental variation. Identifying where areas of high beta-diversity
coincide for
different species groups is essential to the design of effective protected
area networks.
Citation: McKnight MW, White PS,McDonald RI, Lamoreux JF, Sechrest W, et
al. (2007) Putting beta-diversity on themap: Broad-scale congruence and
coincidence in the extremes.
PLoS Biol 5(10): e272. doi:10.1371/journal.pbio.0050272
Please click here
plosbiology
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
fundamental attribute of biodiversity. However, despite its recognized
importance, beta-diversity is rarely studied across large spatial scales.
Here, Meghan McKnight, Simon Stuart, and colleagues, published in the
open-access journal PLoS Biology, use a new method to compare amphibian,
bird,
and mammal beta-diversity across large regions within the Western
Hemisphere. They show that although the areas of low beta-diversity are
different
for the three groups, areas of high beta-diversity largely coincide.
Moreover, they find that the degree to which the groups exhibit similar
patterns
of beta-diversity depends on the geographic location and extent at which
it is measured. Beta-diversity is high where species are most susceptible
to
climate change, such as in areas with complex topography or high
environmental variation. Identifying where areas of high beta-diversity
coincide for
different species groups is essential to the design of effective protected
area networks.
Citation: McKnight MW, White PS,McDonald RI, Lamoreux JF, Sechrest W, et
al. (2007) Putting beta-diversity on themap: Broad-scale congruence and
coincidence in the extremes.
PLoS Biol 5(10): e272. doi:10.1371/journal.pbio.0050272
Please click here
plosbiology
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
Key To Virulence Protein Entry Into Host Cells Discovered
Researchers from the Virginia Bioinformatics Institute (VBI) at Virginia Tech have identified the region of a large family of virulence proteins in oomycete plant pathogens that enables the proteins to enter the cells of their hosts. The protein region contains the amino acid sequence motifs RXLR and dEER and has the ability to carry the virulence proteins across the membrane surrounding plant cells without any additional machinery from the pathogen. Once inside the plant cell, the proteins suppress the immune system of the plant allowing the infection to progress. The work, which focused on the virulence protein Avr1b from the soybean plant pathogen Phytophthora sojae, is published in the advance online edition of The Plant Cell.*
Oomycetes are fungal-like organisms related to marine algae that cause tens of billions of dollars of losses to agriculture, forestry and natural ecosystems every year. The oomycete Phytophthora infestans caused the Irish potato famine in the nineteenth century. Another Phytophthora species, P. ramorum, is causing Sudden Oak Death disease in California's coastal forests. P. sojae results in $200-300 million in annual losses for commercial soybean farmers in the United States and estimated annual soybean losses of $1-2 billion worldwide. All of these oomycete species contain hundreds of genes that encode for virulence proteins that have the RXLR-dEER region.**
The virulence proteins, including Avr1b, enter the soybean host where they are capable of suppressing an important process in plant immunity called programmed cell death.*** Programmed cell death is an in-built suicide mechanism that kills infected plant tissue, filling it with toxins so the pathogen can no longer feed on it. By preventing this protective mechanism in the host, the virulence proteins ensure that the pathogen can establish an unassailable foothold in the plant tissue from which the pathogen can pursue its destructive path.
Postdoctoral fellow Dr. Daolong Dou, the lead author of the article, commented: "We have suspected for a long time that these virulence proteins had some way of slipping inside plant cells to suppress immunity. Our findings finally nail down that mechanism and enable us to focus on how to block the entry mechanism."
The researchers also demonstrated that the RXLR and dEER motifs could be replaced by similar targeting sequences found in effector proteins produced by the malarial parasite Plasmodium. This hints that the targets of the effectors in the soybean and human hosts may be very ancient.
VBI Professor Brett Tyler remarked: "The finding that virulence proteins from oomycetes and the malaria parasite Plasmodium use the same entry mechanism means that we may be able to use the same or similar drugs to block infection by both groups of pathogens. This type of approach may also be relevant to other groups of pathogens, such as fungi, which we also suspect of slipping virulence proteins into host cells."
The breakthrough was enabled by an ingenious device for introducing DNA into living tissues invented by a Virginia Tech undergraduate, Shiv Kale. Kale, who has subsequently joined Dr. Tyler's research team as a graduate student, remarked: "The double-barreled Gene Gun enabled us to make much more accurate measurements of the Avr1b protein than were previously possible, which made it practicable to measure the action of the RXLR and dEER motifs." Kale was co-lead author of the article.
The research was supported by funding from the National Research Initiative of the United States Department of Agriculture's Cooperative State Research, Education and Extension Service, the National Science Foundation, the Netherlands Genomics Initiative, and the Virginia Bioinformatics Institute.
* Daolong D, Kale SD, Wang X, Jiang RHY, Bruce NA, Arredondo FD, Zhang X, Tyler BM (2008) RXLR-mediated entry of Phytophthora sojae effector Avr1b into soybean cells does not require pathogen-encoded machinery. The Plant Cell Published on July 11, 2008; plantcell/cgi/doi/10.1105/tpc.107.056093. See also the following commentary: Govers F, Bouwmeester K (2008) Effector trafficking: RXLR-dEER as extra gear for delivery into plant cells. The Plant Cell 10.1105/tpc.108.062075
** Jiang, RHY, Tripathy S, Govers F, Tyler BM (2008) RXLR effector reservoir in two Phytophthora species is dominated by a single rapidly evolving super-family with more than 700 members. Proceedings of the National Academy of Sciences 105(12): 4874-4879.
*** Dou D, Kale SD, Wang X-L, Chen Y-B, Wang Q-Q, Wang X, Jiang RHY, Arredondo FD, Anderson RG, Thakur PB, McDowell JM, Wang YC, Tyler BM (2008) Conserved C-terminal motifs required for avirulence and suppression of cell death by Phytophthora sojae effector Avr1b. Plant Cell 20(4): 1118-1133.
Barry Whyte
Virginia Tech
Oomycetes are fungal-like organisms related to marine algae that cause tens of billions of dollars of losses to agriculture, forestry and natural ecosystems every year. The oomycete Phytophthora infestans caused the Irish potato famine in the nineteenth century. Another Phytophthora species, P. ramorum, is causing Sudden Oak Death disease in California's coastal forests. P. sojae results in $200-300 million in annual losses for commercial soybean farmers in the United States and estimated annual soybean losses of $1-2 billion worldwide. All of these oomycete species contain hundreds of genes that encode for virulence proteins that have the RXLR-dEER region.**
The virulence proteins, including Avr1b, enter the soybean host where they are capable of suppressing an important process in plant immunity called programmed cell death.*** Programmed cell death is an in-built suicide mechanism that kills infected plant tissue, filling it with toxins so the pathogen can no longer feed on it. By preventing this protective mechanism in the host, the virulence proteins ensure that the pathogen can establish an unassailable foothold in the plant tissue from which the pathogen can pursue its destructive path.
Postdoctoral fellow Dr. Daolong Dou, the lead author of the article, commented: "We have suspected for a long time that these virulence proteins had some way of slipping inside plant cells to suppress immunity. Our findings finally nail down that mechanism and enable us to focus on how to block the entry mechanism."
The researchers also demonstrated that the RXLR and dEER motifs could be replaced by similar targeting sequences found in effector proteins produced by the malarial parasite Plasmodium. This hints that the targets of the effectors in the soybean and human hosts may be very ancient.
VBI Professor Brett Tyler remarked: "The finding that virulence proteins from oomycetes and the malaria parasite Plasmodium use the same entry mechanism means that we may be able to use the same or similar drugs to block infection by both groups of pathogens. This type of approach may also be relevant to other groups of pathogens, such as fungi, which we also suspect of slipping virulence proteins into host cells."
The breakthrough was enabled by an ingenious device for introducing DNA into living tissues invented by a Virginia Tech undergraduate, Shiv Kale. Kale, who has subsequently joined Dr. Tyler's research team as a graduate student, remarked: "The double-barreled Gene Gun enabled us to make much more accurate measurements of the Avr1b protein than were previously possible, which made it practicable to measure the action of the RXLR and dEER motifs." Kale was co-lead author of the article.
The research was supported by funding from the National Research Initiative of the United States Department of Agriculture's Cooperative State Research, Education and Extension Service, the National Science Foundation, the Netherlands Genomics Initiative, and the Virginia Bioinformatics Institute.
* Daolong D, Kale SD, Wang X, Jiang RHY, Bruce NA, Arredondo FD, Zhang X, Tyler BM (2008) RXLR-mediated entry of Phytophthora sojae effector Avr1b into soybean cells does not require pathogen-encoded machinery. The Plant Cell Published on July 11, 2008; plantcell/cgi/doi/10.1105/tpc.107.056093. See also the following commentary: Govers F, Bouwmeester K (2008) Effector trafficking: RXLR-dEER as extra gear for delivery into plant cells. The Plant Cell 10.1105/tpc.108.062075
** Jiang, RHY, Tripathy S, Govers F, Tyler BM (2008) RXLR effector reservoir in two Phytophthora species is dominated by a single rapidly evolving super-family with more than 700 members. Proceedings of the National Academy of Sciences 105(12): 4874-4879.
*** Dou D, Kale SD, Wang X-L, Chen Y-B, Wang Q-Q, Wang X, Jiang RHY, Arredondo FD, Anderson RG, Thakur PB, McDowell JM, Wang YC, Tyler BM (2008) Conserved C-terminal motifs required for avirulence and suppression of cell death by Phytophthora sojae effector Avr1b. Plant Cell 20(4): 1118-1133.
Barry Whyte
Virginia Tech
Potential Role Of Fish-Based Fatty Acids In Resolving, Preventing Asthma
WHAT: In an ongoing effort to determine the anti-inflammatory value of diets rich in some types of fish, scientists studying asthma and allergic reactions have found that a molecule produced by the body from omega-3 fatty acids helps resolve and prevent respiratory distress in laboratory mice. The research, supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, was led by a research team at Brigham and Women's Hospital and Harvard Medical School.
Resolvin E1 (RvE1) is a metabolic product of an omega-3 fatty acid found in cold-water fish such as salmon, mackerel and anchovies. It is made by the body in response to the onset of inflammation. This study identified RvE1 as having a key role in both dampening the development of airway inflammation and promoting its resolution in mice, in part by dampening innate immune signals that trigger inflammation. Other studies have indicated that increased levels of omega-3 fatty acids are associated with lower asthma prevalence in people, but the mechanisms to support that observation are poorly understood. This study provides scientists an opportunity to focus on the role of RvE1 as a potential therapeutic candidate.
ARTICLE: O Haworth et al. Resolvin E1 regulates interleukin-23, interferon-y and lipoxin A4 to promote resolution of allergic airway inflammation. Nature Immunology DOI 10.1038/ni.1627
WHO: Alkis Togias, M.D., Chief of the Asthma and Inflammation Section, NIAID Allergy and Inflammation Branch, is available to comment on this article.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at niaid.nih/.
Source: NIAID Office of Communications
NIH/National Institute of Allergy and Infectious Diseases
Resolvin E1 (RvE1) is a metabolic product of an omega-3 fatty acid found in cold-water fish such as salmon, mackerel and anchovies. It is made by the body in response to the onset of inflammation. This study identified RvE1 as having a key role in both dampening the development of airway inflammation and promoting its resolution in mice, in part by dampening innate immune signals that trigger inflammation. Other studies have indicated that increased levels of omega-3 fatty acids are associated with lower asthma prevalence in people, but the mechanisms to support that observation are poorly understood. This study provides scientists an opportunity to focus on the role of RvE1 as a potential therapeutic candidate.
ARTICLE: O Haworth et al. Resolvin E1 regulates interleukin-23, interferon-y and lipoxin A4 to promote resolution of allergic airway inflammation. Nature Immunology DOI 10.1038/ni.1627
WHO: Alkis Togias, M.D., Chief of the Asthma and Inflammation Section, NIAID Allergy and Inflammation Branch, is available to comment on this article.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at niaid.nih/.
Source: NIAID Office of Communications
NIH/National Institute of Allergy and Infectious Diseases
New Clues To Cancer Provided By Algae
A microscopic green alga helped scientists at the Salk Institute for Biological Studies identify a novel function for the retinoblastoma protein (RB), which is known for its role as a tumor suppressor in mammalian cells. By coupling cell size with cell division, RB ensures that cells stay within an optimal size range.
Their findings, which will be published in the October 13 online edition of PLoS Genetics, show that RB blocks cells from dividing before they reach a minimum size and could provide new insights into the origins of cancer.
"Being the right size is very important for cells because their physiology changes quite dramatically when the surface-to-volume ratio changes," explains senior author James Umen, Ph.D., an assistant professor and Hearst Endowment Chair in Salk's Plant Biology Laboratory. "The human body is composed of trillions of cells, each of which must coordinate its growth and division in order to maintain size equilibrium," he adds.
This process is very tightly regulated and any given cell type will always stay within a very narrow size range, but the means by which cell size is determined remain mysterious. In proliferating cells, control mechanisms termed checkpoints are thought to prevent cells from dividing until they reach a specific size, but the nature of the checkpoints has proved difficult to dissect.
Understanding how cells balance the opposing processes of growth and division in order to achieve size control is more than just a fascinating intellectual pursuit for cell biologists: loss of size control is a hallmark of cancer cells, which exhibit severe defects in regulating growth and division.
"In mammalian cells it is very hard to separate size control from cell cycle control because it is very easy to mess up cell size as an indirect consequence of manipulating cell cycle rates," says Umen.
The tiny single-celled alga Chlamydomonas reinhardtii provided a model organism to study the link between cell size and growth. In nature, the organism is found in fresh and brackish water and in all kinds of soil. Its close relatives have adapted to the harsh conditions found in underwater thermal vents and even to life under the Antarctic ice shelf. In the lab, C. reinhardtii has been used to investigate agricultural, energy-related and medical questions.
Chlamydomonas is particularly well suited as an organism to dissect the control mechanisms behind cell size not only because of its simplicity but due to its peculiar cell cycle: during a prolonged growth phase cells enlarge to many times their original size and then suddenly divide several times in rapid succession. Despite this rapid-fire response, cell division is tightly controlled by a sizing mechanism that ensures daughter cells are never too large or too small.
In the course of earlier work, Umen identified an RB homolog encoded by the mat3 gene in C. reinhardtii and later discovered algal counterparts of other players in the RB pathway in humans and mice. To analyze their function in Chlamydomonas, the Salk team isolated cells with mutations in individual members of the RB signaling pathway - and things immediately started to go wrong.
Explains Umen, "Cells with mutations in the C. reinhardtii RB homolog start dividing prematurely, and continue dividing excessively, producing abnormally small daughter cells. Mutations in the algal versions of two key targets of the RB tumor suppressor have exactly the opposite effect of RB mutations, resulting in abnormally large cells that don't divide when they should." These findings demonstrate that once cells reach a critical size, they need those two RB target proteins to divide on schedule.
"The interesting thing for us is that the whole genetic module has been conserved from algae to plants to humans," says Umen. "It's been controlling cell division for well over a billion years. As multicellular organisms evolved, the RB pathway was co-opted to integrate growth factor signals, but its original purpose in single cells was more fundamental: to couple cell size to cell cycle progression," he adds.
Recently, evidence has emerged that animal cells also have size checkpoints whose nature is still unknown. "Our results open up the possibility that the ancient size control function for the RB pathway we discovered in Chlamydomonas may still be there in animal cells, but was integrated into a larger network that also responds to extracellular input from growth factors. It will be an interesting challenge now to dissect out that function for RB in animal cells," he says.
Researchers who contributed to this study include postdoctoral fellow and first author Su-Chiung Fang, Ph.D., and laboratory assistant Chris de los Reyes.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Contact: Gina Kirchweger
Salk Institute
Their findings, which will be published in the October 13 online edition of PLoS Genetics, show that RB blocks cells from dividing before they reach a minimum size and could provide new insights into the origins of cancer.
"Being the right size is very important for cells because their physiology changes quite dramatically when the surface-to-volume ratio changes," explains senior author James Umen, Ph.D., an assistant professor and Hearst Endowment Chair in Salk's Plant Biology Laboratory. "The human body is composed of trillions of cells, each of which must coordinate its growth and division in order to maintain size equilibrium," he adds.
This process is very tightly regulated and any given cell type will always stay within a very narrow size range, but the means by which cell size is determined remain mysterious. In proliferating cells, control mechanisms termed checkpoints are thought to prevent cells from dividing until they reach a specific size, but the nature of the checkpoints has proved difficult to dissect.
Understanding how cells balance the opposing processes of growth and division in order to achieve size control is more than just a fascinating intellectual pursuit for cell biologists: loss of size control is a hallmark of cancer cells, which exhibit severe defects in regulating growth and division.
"In mammalian cells it is very hard to separate size control from cell cycle control because it is very easy to mess up cell size as an indirect consequence of manipulating cell cycle rates," says Umen.
The tiny single-celled alga Chlamydomonas reinhardtii provided a model organism to study the link between cell size and growth. In nature, the organism is found in fresh and brackish water and in all kinds of soil. Its close relatives have adapted to the harsh conditions found in underwater thermal vents and even to life under the Antarctic ice shelf. In the lab, C. reinhardtii has been used to investigate agricultural, energy-related and medical questions.
Chlamydomonas is particularly well suited as an organism to dissect the control mechanisms behind cell size not only because of its simplicity but due to its peculiar cell cycle: during a prolonged growth phase cells enlarge to many times their original size and then suddenly divide several times in rapid succession. Despite this rapid-fire response, cell division is tightly controlled by a sizing mechanism that ensures daughter cells are never too large or too small.
In the course of earlier work, Umen identified an RB homolog encoded by the mat3 gene in C. reinhardtii and later discovered algal counterparts of other players in the RB pathway in humans and mice. To analyze their function in Chlamydomonas, the Salk team isolated cells with mutations in individual members of the RB signaling pathway - and things immediately started to go wrong.
Explains Umen, "Cells with mutations in the C. reinhardtii RB homolog start dividing prematurely, and continue dividing excessively, producing abnormally small daughter cells. Mutations in the algal versions of two key targets of the RB tumor suppressor have exactly the opposite effect of RB mutations, resulting in abnormally large cells that don't divide when they should." These findings demonstrate that once cells reach a critical size, they need those two RB target proteins to divide on schedule.
"The interesting thing for us is that the whole genetic module has been conserved from algae to plants to humans," says Umen. "It's been controlling cell division for well over a billion years. As multicellular organisms evolved, the RB pathway was co-opted to integrate growth factor signals, but its original purpose in single cells was more fundamental: to couple cell size to cell cycle progression," he adds.
Recently, evidence has emerged that animal cells also have size checkpoints whose nature is still unknown. "Our results open up the possibility that the ancient size control function for the RB pathway we discovered in Chlamydomonas may still be there in animal cells, but was integrated into a larger network that also responds to extracellular input from growth factors. It will be an interesting challenge now to dissect out that function for RB in animal cells," he says.
Researchers who contributed to this study include postdoctoral fellow and first author Su-Chiung Fang, Ph.D., and laboratory assistant Chris de los Reyes.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Contact: Gina Kirchweger
Salk Institute
Capping A Two-Faced Particle Gives Duke Engineers Complete Control
Scientists drew fittingly from Roman mythology when they named a unique class of miniscule particles after the god Janus, who is usually depicted as having two faces looking in opposite directions.
For years, scientists have been fascinated by the tantalizing possibilities of these particles for their potential applications in electronic display devices, sensors and many other devices. However, realizing these applications requires precise control over the positions and orientation of the particles, something which has until now eluded scientists.
Duke University engineers say they can for the first time control all the degrees of the particle's motion, opening up broad possibilities for nanotechnology and device applications. Their unique technology should make it more likely that Janus particles can be used as the building blocks for a myriad of applications, including such new technologies as electronic paper and self-propelling micromachines.
Typical Janus particles consist of miniscule spherical beads that have one hemisphere coated with a magnetic or metallic material. External magnetic or electric fields can then be used to control the orientation of the particles. However, this coating interferes with optical beams, or traps, another tool scientists use to control positioning.
The breakthrough of Duke engineers was to devise a fabrication strategy to coat the particle with a much smaller fraction of material. This discovery allows these particles to be compatible with optical traps and external magnetic fields, allowing for total control over the particles' positions and orientations.
"Past experiments have only been able to achieve four degrees of control using a combination of magnetic and optical techniques," said Nathan Jenness, a graduate student who completed his studies this year from Duke's Pratt School of Engineering. He and co-author Randall Erb, also a graduate student, were first authors of a paper appearing online in the journal Advanced Materials. "We have created a novel Janus particle that can be manipulated or constrained with six degrees of freedom."
The researchers have dubbed the unique particles they created "dot-Janus" particles.
Using optical traps on dot-Janus particles, researchers controlled three degrees of movement - up and down, left and right, forward and backward, while constraining one degree of rotation - side-to-side tilting. Using magnetic fields, they controlled the remaining two degrees of rotation - forward and backward tilting, and left and right turning.
"The solution was to create a particle with a small cap of cobalt that covers about a quarter of the particle," Erb said. He and Jenness conducted their research in the laboratory of Benjamin Yellen, Duke assistant professor of Mechanical Engineering and Materials Science. "This gave the particle just enough of a magnetic handle to allow it to be manipulated by magnetism without interfering with the optical tweezers."
The researchers said that the fabrication of these unique dot-Janus particles combined with the ability to control their orientation will have important ramifications in the burgeoning field of nanoengineering.
"Being able to more completely control these particles affords us a greater ability to measure the mechanical properties of biomolecules, including DNA," Yellen said. "It may also be possible to control the behavior of cells by manipulating dot-Janus particles attached to cell surfaces. These biological applications, as well as the ability to control the assembly of nanostructures, establish the broad scientific value of these findings."
The research was supported by the National Science Foundation and the Nanoscale Interdisciplinary Research Team. Robert Clark, former Duke dean of engineering and now in the same position at the University of Rochester, was also part of the research team.
Source:
Richard Merritt
Duke University
For years, scientists have been fascinated by the tantalizing possibilities of these particles for their potential applications in electronic display devices, sensors and many other devices. However, realizing these applications requires precise control over the positions and orientation of the particles, something which has until now eluded scientists.
Duke University engineers say they can for the first time control all the degrees of the particle's motion, opening up broad possibilities for nanotechnology and device applications. Their unique technology should make it more likely that Janus particles can be used as the building blocks for a myriad of applications, including such new technologies as electronic paper and self-propelling micromachines.
Typical Janus particles consist of miniscule spherical beads that have one hemisphere coated with a magnetic or metallic material. External magnetic or electric fields can then be used to control the orientation of the particles. However, this coating interferes with optical beams, or traps, another tool scientists use to control positioning.
The breakthrough of Duke engineers was to devise a fabrication strategy to coat the particle with a much smaller fraction of material. This discovery allows these particles to be compatible with optical traps and external magnetic fields, allowing for total control over the particles' positions and orientations.
"Past experiments have only been able to achieve four degrees of control using a combination of magnetic and optical techniques," said Nathan Jenness, a graduate student who completed his studies this year from Duke's Pratt School of Engineering. He and co-author Randall Erb, also a graduate student, were first authors of a paper appearing online in the journal Advanced Materials. "We have created a novel Janus particle that can be manipulated or constrained with six degrees of freedom."
The researchers have dubbed the unique particles they created "dot-Janus" particles.
Using optical traps on dot-Janus particles, researchers controlled three degrees of movement - up and down, left and right, forward and backward, while constraining one degree of rotation - side-to-side tilting. Using magnetic fields, they controlled the remaining two degrees of rotation - forward and backward tilting, and left and right turning.
"The solution was to create a particle with a small cap of cobalt that covers about a quarter of the particle," Erb said. He and Jenness conducted their research in the laboratory of Benjamin Yellen, Duke assistant professor of Mechanical Engineering and Materials Science. "This gave the particle just enough of a magnetic handle to allow it to be manipulated by magnetism without interfering with the optical tweezers."
The researchers said that the fabrication of these unique dot-Janus particles combined with the ability to control their orientation will have important ramifications in the burgeoning field of nanoengineering.
"Being able to more completely control these particles affords us a greater ability to measure the mechanical properties of biomolecules, including DNA," Yellen said. "It may also be possible to control the behavior of cells by manipulating dot-Janus particles attached to cell surfaces. These biological applications, as well as the ability to control the assembly of nanostructures, establish the broad scientific value of these findings."
The research was supported by the National Science Foundation and the Nanoscale Interdisciplinary Research Team. Robert Clark, former Duke dean of engineering and now in the same position at the University of Rochester, was also part of the research team.
Source:
Richard Merritt
Duke University
MCP3 Entices Monocytes To Leave The Bone Marrow
Immune cells known as monocytes are recruited to sites of inflammation, such as sites where microbes have invaded the body. Recruitment is mediated by soluble factors known as chemokines, but the precise identity of the chemokines that mediate the movement of monocytes from the bone marrow to the blood and then from the blood to the site of inflammation have not been well defined.
In a study that appears online in advance of publication in the April print issue of the Journal of Clinical Investigation, Israel Charo and colleagues from the Gladstone Institute of Cardiovascular Disease in San Francisco show that the chemokines MCP1 and MCP3 are crucial for monocyte movement from the bone marrow to the blood. Compared with normal mice, mice lacking either MCP1 or MCP3 had reduced numbers of monocytes in their blood and increased numbers of monocytes in their bone marrow. Similar observations were made in mice lacking the protein CCR2, which is the receptor to which MCP1 and MCP3 bind. The interaction of MCP1 and MCP3 with CCR2 was also shown to be required for the early recruitment of monocytes from the blood to sites of inflammation. This study indicates that MCP1/MCP3 and CCR2 are essential for the maintenance of a normal number of monocytes in the blood and for the early recruitment of monocytes from the blood to sites of inflammation.
TITLE: Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites
AUTHOR CONTACT:
Israel F. Charo
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
JCI table of contents: March 15, 2007
Contact: Karen Honey
Journal of Clinical Investigation
In a study that appears online in advance of publication in the April print issue of the Journal of Clinical Investigation, Israel Charo and colleagues from the Gladstone Institute of Cardiovascular Disease in San Francisco show that the chemokines MCP1 and MCP3 are crucial for monocyte movement from the bone marrow to the blood. Compared with normal mice, mice lacking either MCP1 or MCP3 had reduced numbers of monocytes in their blood and increased numbers of monocytes in their bone marrow. Similar observations were made in mice lacking the protein CCR2, which is the receptor to which MCP1 and MCP3 bind. The interaction of MCP1 and MCP3 with CCR2 was also shown to be required for the early recruitment of monocytes from the blood to sites of inflammation. This study indicates that MCP1/MCP3 and CCR2 are essential for the maintenance of a normal number of monocytes in the blood and for the early recruitment of monocytes from the blood to sites of inflammation.
TITLE: Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites
AUTHOR CONTACT:
Israel F. Charo
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
JCI table of contents: March 15, 2007
Contact: Karen Honey
Journal of Clinical Investigation
Scientists Identify Possible Therapy Target For Aggressive Cancer
UT Southwestern Medical Center researchers have found that a naturally occurring protein -- transforming growth factor beta1 (TGF-Гџ1) -- which normally suppresses the growth of cancer cells, causes a rebound effect after a prolonged exposure. Cancer cells go into overdrive and become even more aggressive and likely to spread, the researchers report.
The mechanism for this reversal is unknown, but UT Southwestern researchers and their colleagues in Indiana suspect that cancerous cells activate a defense mechanism in response to the lethal protein. This mechanism turns on a cascade of cancer-promoting genes.
But clinicians may be able to exploit this rebound for better treatments, said Dr. David Boothman, co-senior author of the study, available online today and appearing in the January issue of The Journal of Clinical Investigation.
"These genetic changes would start prior to metastases, so if we detect them early, we might be able to tailor treatment in anticipation of a more aggressive cancer," said Dr. Boothman, a professor of radiation oncology and pharmacology and associate director of translational research in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He also holds the Robert B. and Virginia Payne Professorship in Oncology.
The study was conducted on cells from mice and in samples from women with metastatic breast cancer.
TGF-Гџ1 controls many cellular functions, including cell growth, cell proliferation and natural cell death. It also can act to suppress tumors and prevent cancers from spreading.
The researchers, including co-senior collaborator Dr. Lindsey Mayo from the Indiana University School of Medicine, examined a cascade of biochemical reactions in cells exposed to TGF-Гџ1. They suspected that prolonged exposure would turn on a particular cancer-causing gene, which in turn, activates other cancer-supporting reactions.
In tissue from women with metastatic breast cancer, 60 percent of the patients showed both TGF-Гџ1 action and high levels of the cancer-causing gene.
The team also looked at nutlin3, a protein that blocks the action of the cancer-causing gene. They found that nutlin3 blocks the cancer-boosting effects of long-term TGF-Гџ1 exposure, preventing metastasis and killing cancer cells. Further research will be needed to determine whether nutlin3 might be worth developing further as an anti-cancer drug, Dr. Boothman said.
In other studies, UT Southwestern researchers found similar effects in cells from colon and non-small cell lung cancers.
Other UT Southwestern researchers involved in the study included Dr. Shinako Araki, postdoctoral fellow in the Simmons Comprehensive Cancer Center; Dr. Xian-Jin Xie, associate professor of clinical sciences and in the Simmons Comprehensive Cancer Center.
The study was supported by grants from the Department of Energy and the National Cancer Institute.
Source: UT Southwestern Medical Center
The mechanism for this reversal is unknown, but UT Southwestern researchers and their colleagues in Indiana suspect that cancerous cells activate a defense mechanism in response to the lethal protein. This mechanism turns on a cascade of cancer-promoting genes.
But clinicians may be able to exploit this rebound for better treatments, said Dr. David Boothman, co-senior author of the study, available online today and appearing in the January issue of The Journal of Clinical Investigation.
"These genetic changes would start prior to metastases, so if we detect them early, we might be able to tailor treatment in anticipation of a more aggressive cancer," said Dr. Boothman, a professor of radiation oncology and pharmacology and associate director of translational research in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He also holds the Robert B. and Virginia Payne Professorship in Oncology.
The study was conducted on cells from mice and in samples from women with metastatic breast cancer.
TGF-Гџ1 controls many cellular functions, including cell growth, cell proliferation and natural cell death. It also can act to suppress tumors and prevent cancers from spreading.
The researchers, including co-senior collaborator Dr. Lindsey Mayo from the Indiana University School of Medicine, examined a cascade of biochemical reactions in cells exposed to TGF-Гџ1. They suspected that prolonged exposure would turn on a particular cancer-causing gene, which in turn, activates other cancer-supporting reactions.
In tissue from women with metastatic breast cancer, 60 percent of the patients showed both TGF-Гџ1 action and high levels of the cancer-causing gene.
The team also looked at nutlin3, a protein that blocks the action of the cancer-causing gene. They found that nutlin3 blocks the cancer-boosting effects of long-term TGF-Гџ1 exposure, preventing metastasis and killing cancer cells. Further research will be needed to determine whether nutlin3 might be worth developing further as an anti-cancer drug, Dr. Boothman said.
In other studies, UT Southwestern researchers found similar effects in cells from colon and non-small cell lung cancers.
Other UT Southwestern researchers involved in the study included Dr. Shinako Araki, postdoctoral fellow in the Simmons Comprehensive Cancer Center; Dr. Xian-Jin Xie, associate professor of clinical sciences and in the Simmons Comprehensive Cancer Center.
The study was supported by grants from the Department of Energy and the National Cancer Institute.
Source: UT Southwestern Medical Center
First Individual Genome Sequence Published Sequence Reveals That Human-To-Human Variation Is Substantially Greater Than Earlier Estimates
Independent sequence and assembly of the six billion base pairs from the
genome of one person ushers in the era of individualized genomics.
Researchers at the J. Craig Venter Institute (JCVI), along with
collaborators at The Hospital for Sick Children in Toronto and the
University of
California San Diego (UCSD), have published a genome sequence of an
individual, Craig Venter, that covers both sets of chromosomes that were
inherited
from each parent.
Two other versions of the human genome currently exist-one published in
2001 by J. Craig Venter, Ph.D., and colleagues at Celera Genomics, and
another at the same time by a consortium of government-funded researchers.
These genomes were not of any single individual, but, rather, were a
melding of DNA from various people. In the case of Celera, it was a
consensus assembly from five individuals, while the government-funded
version was
a haploid genome based on sequencing from a limited number of individuals.
Both versions greatly underestimated human genetic diversity.
This new genome, known as the "HuRef" version, represents the first time a
true diploid genome from one individual - Dr. Venter- has been
published. The research is available in the latest issue of the
open-access journal PLoS Biology.
Researchers at the JCVI have been sequencing and analyzing this version of
Dr. Venter's genome since 2003. Building on reanalyzed data from Dr.
Venter's genome that constituted 60% of the previously published Celera
genome, the team had the goal of constructing a true reference human
genome
based on one individual. Using whole genome shotgun sequencing and highly
accurate long reads from Sanger dideoxy automated DNA sequencing, the team
produced additional data making the final 32 million sequences.
From the combined data set of more than 20 billion base pairs, the
researchers were able to assemble the human genome with an overall length
of 2.810
billion base pairs. The genome was covered 7.5 times, ensuring that each
set of contributing chromosomes was covered over 3.2 times for greater
than
96% coverage of the two parental genomes. The team at JCVI compared and
contrasted the new HuRef diploid genome sequence to earlier versions of
published human genomes and found that the HuRef version improved upon
both these early versions by providing more and correctly oriented base
pairs.
Since the HuRef genome is diploid, each of the parental chromosomes could
be directly compared to each other. One of the most surprising and
important
findings from this research was the high degree of genetic variation that
was found between two chromosomes within a single individual.
"Each time we peer into the human genome, we uncover more valuable insight
into our intricate biology," said Dr. Venter. "With this publication,
we have shown that human-to-human variation is more than seven-fold
greater than earlier estimates, proving that we are in fact very unique
individuals at the genetic level." He added, "It is clear, however, that
we are still at the earliest stages of discovery about ourselves, and
only with continued sequencing of more individual genomes will we be able
to garner a full understanding of how our genes influence our lives."
Within the human genome, there are different kinds of DNA variants. The
most studied type is single nucleotide polymorphisms, or SNPs. These have
long
been thought to be the most prevalent and perhaps the most important type
of variant implicated in human traits and disease susceptibility. However,
in this analysis of Dr. Venter's genome, the team found a surprising
number of other important variants. A total of 4.1 million variants
covering
12.3 million base pairs of DNA were uncovered with more than 1.2 million
new variants discovered.
Of the 4.1 million variations between chromosome sets, 3.2 million were
SNPs, while nearly one million were other kinds of variants, such as
insertion/deletions ("indels"), copy number variants, block substitutions,
and segmental duplications. While the SNPs outnumbered the non-SNP
types of variants, the non-SNP variants involved a larger portion of the
genome. This suggests that human-to-human variation is much greater than
previously thought. The researchers suggest that much more research needs
to be done on these non-SNP variants to better understand their role in
individual genomics.
According to Sam Levy, Ph.D., lead author and senior scientist at JCVI,
"The ability to use unbiased, high throughput sequencing methods, coupled
with advance computational analytic methods, enables us to characterize
more comprehensively the wide variety of individual genetic variation.
This
offers us an unprecedented opportunity to study the prevalence and impact
of these DNA variants on traits and diseases in human populations."
Another important feature that is made possible by having an individual,
diploid genome is the ability to begin to do better and more informed
haplotype assemblies. Haplotypes are groups of linked variants. Through
the government-sponsored HapMap project, many common haplotypes have been
identified; however, these are based on averages of large ethnogeographic
populations rather than individuals. Having individual haplotypes would
enable researchers to understand and find more rare or individual variants
that would explain and help predict diseases in that particular person-a
truly personalized, individualized genomics paradigm. In the HuRef
analysis, the team used the 4.1 million variant set and new algorithms to
build
haplotype assemblies that, when compared to the HapMap project,
represented longer and more complete linkages. The JCVI researchers expect
this number
to improve significantly as additional sequence coverage is added to HuRef
using a variety of new sequencing technologies.
Long-range haplotype linkages will enable much more complete analysis of
human variation and the genetic association with complex human traits,
behaviors, and diseases. In the near future, the scientists believe that
it will be possible to know from which parent various traits were
inherited.
Already in this analysis, the JCVI team has found more than 300 disease
genes and 4,000 genes overall that exhibit different protein forms. This
will
be an important area for further study and analysis to determine how these
altered proteins affect Dr. Venter's health status.
Citation: Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, et al. (2007) The
diploid genome sequence of an individual human. PLoS Biol 5(10): e254.
doi:10.1371/journal.pbio.0050254.
Please click here
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185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
genome of one person ushers in the era of individualized genomics.
Researchers at the J. Craig Venter Institute (JCVI), along with
collaborators at The Hospital for Sick Children in Toronto and the
University of
California San Diego (UCSD), have published a genome sequence of an
individual, Craig Venter, that covers both sets of chromosomes that were
inherited
from each parent.
Two other versions of the human genome currently exist-one published in
2001 by J. Craig Venter, Ph.D., and colleagues at Celera Genomics, and
another at the same time by a consortium of government-funded researchers.
These genomes were not of any single individual, but, rather, were a
melding of DNA from various people. In the case of Celera, it was a
consensus assembly from five individuals, while the government-funded
version was
a haploid genome based on sequencing from a limited number of individuals.
Both versions greatly underestimated human genetic diversity.
This new genome, known as the "HuRef" version, represents the first time a
true diploid genome from one individual - Dr. Venter- has been
published. The research is available in the latest issue of the
open-access journal PLoS Biology.
Researchers at the JCVI have been sequencing and analyzing this version of
Dr. Venter's genome since 2003. Building on reanalyzed data from Dr.
Venter's genome that constituted 60% of the previously published Celera
genome, the team had the goal of constructing a true reference human
genome
based on one individual. Using whole genome shotgun sequencing and highly
accurate long reads from Sanger dideoxy automated DNA sequencing, the team
produced additional data making the final 32 million sequences.
From the combined data set of more than 20 billion base pairs, the
researchers were able to assemble the human genome with an overall length
of 2.810
billion base pairs. The genome was covered 7.5 times, ensuring that each
set of contributing chromosomes was covered over 3.2 times for greater
than
96% coverage of the two parental genomes. The team at JCVI compared and
contrasted the new HuRef diploid genome sequence to earlier versions of
published human genomes and found that the HuRef version improved upon
both these early versions by providing more and correctly oriented base
pairs.
Since the HuRef genome is diploid, each of the parental chromosomes could
be directly compared to each other. One of the most surprising and
important
findings from this research was the high degree of genetic variation that
was found between two chromosomes within a single individual.
"Each time we peer into the human genome, we uncover more valuable insight
into our intricate biology," said Dr. Venter. "With this publication,
we have shown that human-to-human variation is more than seven-fold
greater than earlier estimates, proving that we are in fact very unique
individuals at the genetic level." He added, "It is clear, however, that
we are still at the earliest stages of discovery about ourselves, and
only with continued sequencing of more individual genomes will we be able
to garner a full understanding of how our genes influence our lives."
Within the human genome, there are different kinds of DNA variants. The
most studied type is single nucleotide polymorphisms, or SNPs. These have
long
been thought to be the most prevalent and perhaps the most important type
of variant implicated in human traits and disease susceptibility. However,
in this analysis of Dr. Venter's genome, the team found a surprising
number of other important variants. A total of 4.1 million variants
covering
12.3 million base pairs of DNA were uncovered with more than 1.2 million
new variants discovered.
Of the 4.1 million variations between chromosome sets, 3.2 million were
SNPs, while nearly one million were other kinds of variants, such as
insertion/deletions ("indels"), copy number variants, block substitutions,
and segmental duplications. While the SNPs outnumbered the non-SNP
types of variants, the non-SNP variants involved a larger portion of the
genome. This suggests that human-to-human variation is much greater than
previously thought. The researchers suggest that much more research needs
to be done on these non-SNP variants to better understand their role in
individual genomics.
According to Sam Levy, Ph.D., lead author and senior scientist at JCVI,
"The ability to use unbiased, high throughput sequencing methods, coupled
with advance computational analytic methods, enables us to characterize
more comprehensively the wide variety of individual genetic variation.
This
offers us an unprecedented opportunity to study the prevalence and impact
of these DNA variants on traits and diseases in human populations."
Another important feature that is made possible by having an individual,
diploid genome is the ability to begin to do better and more informed
haplotype assemblies. Haplotypes are groups of linked variants. Through
the government-sponsored HapMap project, many common haplotypes have been
identified; however, these are based on averages of large ethnogeographic
populations rather than individuals. Having individual haplotypes would
enable researchers to understand and find more rare or individual variants
that would explain and help predict diseases in that particular person-a
truly personalized, individualized genomics paradigm. In the HuRef
analysis, the team used the 4.1 million variant set and new algorithms to
build
haplotype assemblies that, when compared to the HapMap project,
represented longer and more complete linkages. The JCVI researchers expect
this number
to improve significantly as additional sequence coverage is added to HuRef
using a variety of new sequencing technologies.
Long-range haplotype linkages will enable much more complete analysis of
human variation and the genetic association with complex human traits,
behaviors, and diseases. In the near future, the scientists believe that
it will be possible to know from which parent various traits were
inherited.
Already in this analysis, the JCVI team has found more than 300 disease
genes and 4,000 genes overall that exhibit different protein forms. This
will
be an important area for further study and analysis to determine how these
altered proteins affect Dr. Venter's health status.
Citation: Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, et al. (2007) The
diploid genome sequence of an individual human. PLoS Biol 5(10): e254.
doi:10.1371/journal.pbio.0050254.
Please click here
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
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