A team of Rutgers University scientists led by Richard H. Ebright and Eddy Arnold has identified a new antibiotic target and a new antibiotic mechanism that may enable the development of broad-spectrum antibacterial agents effective against bacterial pathogens resistant to current antibiotics. In particular, the results could lead the way to new treatments for tuberculosis (TB) that involve shorter courses of therapy and are effective against drug-resistant TB.
The researchers showed how three antibiotics - myxopyronin, corallopyronin and ripostatin - block the action of bacterial RNA polymerase (RNAP). RNAP is the enzyme that transcribes genetic information from DNA into RNA, which, in turn, directs the assembly of proteins, the building blocks of all biological systems. Blocking bacterial RNAP kills bacterial cells.
The research findings are reported in the journal Cell, published online Oct. 16 and in the Oct. 17 print issue of the journal.
The shape of the RNAP molecule is key to the action of the three antibiotics, Ebright explained. "RNAP has a shape reminiscent of a crab claw, with two prominent pincer-like projections," he said. "Just as with a real crab claw, one pincer stays fixed and one pincer moves - opening to allow DNA into the enzyme and closing to keep DNA in the enzyme. The pincer that moves does so by rotating about a hinge, termed the 'switch region,' located at its base."
The studies showed that the three antibiotics bind to this hinge and, further, that by jamming the hinge, they prevent the pincer from opening to let DNA into the enzyme, Ebright said.
Once the target and mechanism of the three antibiotics were elucidated, the researchers proceeded to determine the structure of RNAP bound to one of the three antibiotics. "This has allowed us to define how the enzyme and the antibiotic interact and to characterize how the enzyme changes shape in response to the antibiotic," Arnold said. "Perhaps more important, this has allowed us to explore ways to change the chemical structure of the antibiotic to make tighter interactions with the enzyme for higher potency."
The three antibiotics exhibit potent activity against a broad spectrum of bacterial species, including the bacterium that causes TB, and exhibit no cross resistance with current antibacterial agents.
"The three antibiotics are attractive candidates for development as broad spectrum antibacterial agents," Ebright said, "and their target within RNAP - the hinge or 'switch region' - is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents."
Arnold points out that the binding site for the three antibiotics has attractive features for design of new agents. "The target site is a pocket that accommodates a variety of chemical types. The nature of the binding site and mechanism of inhibition are analogous to those of the HIV-1 reverse transcriptase non-nucleoside inhibitors, which include four FDA-approved drugs for treating HIV-1 infections. The parallels are encouraging and suggest that multiple classes of agents can be developed to target the new site."
Ebright, a Howard Hughes Medical Institute investigator, is a professor in the Department of Chemistry and Chemical Biology and a member of the Waksman Institute of Microbiology at Rutgers, The State University of New Jersey. Arnold, also a professor of chemistry and chemical biology, is a member of the Center for Advanced Biotechnology and Medicine (CABM), jointly operated by Rutgers and the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.
Jayanta Mukhopadhyay from Ebright's laboratory and Kalyan Das from Arnold's laboratory carried out much of the work.
The research team also included Rolf Jansen and Herbert Irschik of the Helmholtz Center for Infection Research in Braunschweig, Germany.
Most antibacterial compounds are able to kill actively growing TB bacteria but are unable to kill resting, dormant TB bacteria. As a result, most antibacterial compounds can rapidly reduce populations of TB bacteria in infected patients to low numbers but cannot rapidly reduce these numbers to zero. Antibacterial compounds that target RNAP, however, are able to kill both active and dormant TB bacteria since RNAP plays essential roles in, and is required for survival of, both active and dormant TB bacteria.
A class of antibacterial compounds known as rifamycins, which target RNAP, are current first-line treatment of TB and are the sole current treatments that can relatively rapidly reduce populations of TB bacteria to zero. Unfortunately, rifamycins are too toxic to administer at doses that most rapidly clear infection. Also, resistance to rifamycins occurs frequently, due to mutations that alter their binding site on RNAP.
The three antibiotics studied by Ebright and co-workers also target RNAP; however, they target a new site on RNAP, different from the site on RNAP targeted by rifamycins. "A key point about these antibiotics is that their binding site on RNAP is different from, and does not overlap with, the binding site for rifamycins," Ebright said. "As a result, these antibiotics can function simultaneously with rifamycins and can be co-administered with rifamycins for more rapid clearance of infection. As a further result, these antibiotics do not exhibit cross-resistance with rifamycins. Mutations that alter the binding site for rifamycins on RNAP and confer resistance to rifamycins do not confer resistance to these antibiotics.
The standard course of therapy for most bacterial infections is about two weeks, but TB is different. The shortest course of therapy for TB is six to nine months. "That is, if you can use rifamycins," Ebright notes. "If you have a patient who cannot tolerate rifamycins, or if you have a patient whose infection is resistant to rifamycins, that patient is looking at 18 to 24 months of therapy."
"The Holy Grail in TB therapy is to reduce the course of therapy from six months to two weeks - to make treatment of TB like treatment of other bacterial infections," Ebright said. "If you could develop a two-week therapy for TB, you could eradicate TB. With a six-month course of therapy for a disease that is largely centered in the third world, the logistical problems of administering therapy over space and time make eradication a nonstarter. But if there were a two-week course of therapy, the logistics would be manageable, and the disease would be eradicated."
The hope is that the new findings will bring that goal closer.
Source: Joseph Blumberg
Rutgers University
четверг, 26 мая 2011 г.
Prenatal Drinking, Environmental Enrichment: Effects On Neurotrophins Are Independent Of Each Other
Prenatal alcohol exposure may be particularly destructive for neurotrophins, a family of peptides that influence the growth, development and functional plasticity of the fetal brain. A new rodent study of alcohol's effects on three key neurotrophins has found that, even though environmental enrichment may be able to improve some fetal-alcohol effects, those benefits do not appear to be mediated by neurotrophins.
Results will be published in the October issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"Neurotrophins are produced in the nervous system and are critical for normal development of the brain," explained Robert F. Berman, a professor in the department of neurological surgery and at the Center for Neuroscience at the University of California - Davis, as well as corresponding author for the study.
"Neurotrophins also play important roles in learning and memory, and contribute to the repair of the brain following injury or stress. We chose to examine three - nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) - because previous research had shown that prenatal alcohol exposure alters their levels in the brain, and that treatment of other types of brain injury with NGF or BDNF can be beneficial."
Researchers divided 22 pregnant Sprague-Dawley rats into four groups: Zero (receiving 0 g of alcohol), Low (4 g/kg/day), High (6 g/kg/day) and NaГЇve (untreated pregnant rats). The two alcohol groups were given alcohol on gestational days eight to 20. After weaning on postnatal day 21, the 228 offspring were housed for six weeks in one of three conditions: Isolated, Social or Enriched. Levels of NGF, NT-3 and BDNF were then measured in the offsprings' frontal cortex, occipital cortex, hippocampus, and cerebellar vermis.
"We found that prenatal alcohol exposure generally increased brain neurotrophin levels in adult rats," said Berman. "This suggests that neurotrophin levels increased as compensation for damage to the developing brain from prenatal alcohol exposure. Results also demonstrated that the effects of prenatal alcohol exposure can be enduring and last into adulthood."
Previous rodent research conducted by Berman had shown that rearing rats in an enriched environment following prenatal alcohol exposure improved their motor function as well as learning and memory. "In this study, we found that being raised in an enriched environment, with ample opportunities for motor and sensory stimulation, and social interactions, unexpectedly resulted in reduced levels of neurotrophins in some areas of the cortex, but not in other areas which are well known to be affected by prenatal alcohol exposure," he said.
When both sets of findings are considered together, he added, they indicate that the effects of prenatal alcohol exposure and environmental rearing conditions on neurotrophin levels are largely independent, with little evidence that one directly influenced the other's effects on neurotrophin levels. "In other words," he said, "our results did not support our hypothesis that the beneficial effects of early environmental enrichment in rats exposed prenatally to alcohol were mediated directly by the three neurotrophins we examined in four specific brain areas."
This means that the molecular and cellular mechanisms underlying environmental enrichment effects after prenatal alcohol exposure are still not understood, said Berman. "While the importance of the postnatal rearing environment for brain development is clear, we need additional research to aid in devising rational treatment strategies for Fetal Alcohol Spectrum Disorders, including fetal alcohol syndrome," he said.
Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Environmental Enrichment Alters Neurotrophin Levels after Fetal Alcohol Exposure in Rats," were: Elizabeth A. Parks of the Neuroscience Program and Department of Neurological Surgery at the University of California - Davis; and Andrew P. McMechan and John H. Hannigan of the Department of Obstetrics & Gynecology and the C.S. Mott Center for Human Growth and Development in the School of Medicine, and the Department of Psychology at Wayne State University. The study was funded by the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism.
Additional contact:
John H. Hannigan, Ph.D.
Wayne State University
Source: Robert F. Berman, Ph.D.
University of California - Davis
Alcoholism: Clinical & Experimental Research
Results will be published in the October issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"Neurotrophins are produced in the nervous system and are critical for normal development of the brain," explained Robert F. Berman, a professor in the department of neurological surgery and at the Center for Neuroscience at the University of California - Davis, as well as corresponding author for the study.
"Neurotrophins also play important roles in learning and memory, and contribute to the repair of the brain following injury or stress. We chose to examine three - nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) - because previous research had shown that prenatal alcohol exposure alters their levels in the brain, and that treatment of other types of brain injury with NGF or BDNF can be beneficial."
Researchers divided 22 pregnant Sprague-Dawley rats into four groups: Zero (receiving 0 g of alcohol), Low (4 g/kg/day), High (6 g/kg/day) and NaГЇve (untreated pregnant rats). The two alcohol groups were given alcohol on gestational days eight to 20. After weaning on postnatal day 21, the 228 offspring were housed for six weeks in one of three conditions: Isolated, Social or Enriched. Levels of NGF, NT-3 and BDNF were then measured in the offsprings' frontal cortex, occipital cortex, hippocampus, and cerebellar vermis.
"We found that prenatal alcohol exposure generally increased brain neurotrophin levels in adult rats," said Berman. "This suggests that neurotrophin levels increased as compensation for damage to the developing brain from prenatal alcohol exposure. Results also demonstrated that the effects of prenatal alcohol exposure can be enduring and last into adulthood."
Previous rodent research conducted by Berman had shown that rearing rats in an enriched environment following prenatal alcohol exposure improved their motor function as well as learning and memory. "In this study, we found that being raised in an enriched environment, with ample opportunities for motor and sensory stimulation, and social interactions, unexpectedly resulted in reduced levels of neurotrophins in some areas of the cortex, but not in other areas which are well known to be affected by prenatal alcohol exposure," he said.
When both sets of findings are considered together, he added, they indicate that the effects of prenatal alcohol exposure and environmental rearing conditions on neurotrophin levels are largely independent, with little evidence that one directly influenced the other's effects on neurotrophin levels. "In other words," he said, "our results did not support our hypothesis that the beneficial effects of early environmental enrichment in rats exposed prenatally to alcohol were mediated directly by the three neurotrophins we examined in four specific brain areas."
This means that the molecular and cellular mechanisms underlying environmental enrichment effects after prenatal alcohol exposure are still not understood, said Berman. "While the importance of the postnatal rearing environment for brain development is clear, we need additional research to aid in devising rational treatment strategies for Fetal Alcohol Spectrum Disorders, including fetal alcohol syndrome," he said.
Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Environmental Enrichment Alters Neurotrophin Levels after Fetal Alcohol Exposure in Rats," were: Elizabeth A. Parks of the Neuroscience Program and Department of Neurological Surgery at the University of California - Davis; and Andrew P. McMechan and John H. Hannigan of the Department of Obstetrics & Gynecology and the C.S. Mott Center for Human Growth and Development in the School of Medicine, and the Department of Psychology at Wayne State University. The study was funded by the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism.
Additional contact:
John H. Hannigan, Ph.D.
Wayne State University
Source: Robert F. Berman, Ph.D.
University of California - Davis
Alcoholism: Clinical & Experimental Research
How Enzymes Break Down Cellulose; Study By Iowa State Researcher
Peter Reilly pointed to the framed journal covers decorating his office.
Each of the six showed the swirling, twisting, complicated structure of an enzyme. Those bright and colorful illustrations are the work of his lab. And they're part of Reilly's work to understand how the structure of an enzyme influences its mechanism and its activity.
In other words, he's trying to figure out "how is it that these things work," said Reilly, a professor of chemical and biological engineering and an Anson Marston Distinguished Professor of Engineering at Iowa State University.
That's important because enzymes do a lot for all of us.
Enzymes are proteins produced by living organisms that accelerate chemical reactions. They, for example, work inside the human digestive system to break starch or protein molecules into smaller pieces that can be absorbed by the intestines. Enzymes are also used to produce bread, they're added to detergents to clean stains and they're used to treat leather. And because enzymes break down cellulose into simple sugars that can be fermented into alcohol, they're a big part of producing ethanol from cellulose.
Reilly is particularly interested in the enzymes that work on cellulose. He has a three-year, $306,000 grant from the U.S. Department of Agriculture to develop a basic understanding of how they work.
Those enzymes are known as cellulases. They're commonly produced by fungi and bacteria. And they've got a very hard job.
Cellulose is tough stuff. It's in the cell walls of plants. It's what gives a plant its structure.
"It's why trees stand up," Reilly said.
He also said, "Nature has done its best to break down cellulose."
So different enzymes have developed different ways of attacking cellulose.
One enzyme Reilly has studied and illustrated - a cellobiohydrolase enzyme - has an extension that works like a little plow. It rips up one cellulose chain from a cellulose crystal and feeds it into a tunnel on the main enzyme surface so that it can be chopped up.
Reilly, who can't resist a lesson in biochemistry, likes to explain how enzymes attack and break chemical bonds. He'll display diagrams on his office computer that show the bonds in cellulose molecules. He'll point out where enzymes attack some of those bonds. He'll say the chemical reactions create high-energy transition states that scientists are working hard to understand. And he'll get back to the bottom line.
"These different enzymes all do the same thing," Reilly said. "They all break down bonds between the sugars that make up cellulose."
And, he said, "For something that's not alive, enzymes are awfully sophisticated."
Reilly's students use a lot of computing power to figure out how enzymes are put together. They routinely work with CyBlue, Iowa State's supercomputer capable of 5.7 trillion calculations per second, and Lightning, an Iowa State high-performance computer capable of 1.8 trillion calculations per second.
By adding to the basic understanding of enzymes, Reilly is opening doors for new and better applications of enzymes. Better enzymes, for example, could be the key to making the production of cellulosic ethanol more efficient and more economical.
There's still a lot for chemical engineers to learn about the specialized proteins.
After all, Reilly said, "Nature has tried over and over to find ways to break down cellulose."
Source: Peter Reilly
Iowa State University
Each of the six showed the swirling, twisting, complicated structure of an enzyme. Those bright and colorful illustrations are the work of his lab. And they're part of Reilly's work to understand how the structure of an enzyme influences its mechanism and its activity.
In other words, he's trying to figure out "how is it that these things work," said Reilly, a professor of chemical and biological engineering and an Anson Marston Distinguished Professor of Engineering at Iowa State University.
That's important because enzymes do a lot for all of us.
Enzymes are proteins produced by living organisms that accelerate chemical reactions. They, for example, work inside the human digestive system to break starch or protein molecules into smaller pieces that can be absorbed by the intestines. Enzymes are also used to produce bread, they're added to detergents to clean stains and they're used to treat leather. And because enzymes break down cellulose into simple sugars that can be fermented into alcohol, they're a big part of producing ethanol from cellulose.
Reilly is particularly interested in the enzymes that work on cellulose. He has a three-year, $306,000 grant from the U.S. Department of Agriculture to develop a basic understanding of how they work.
Those enzymes are known as cellulases. They're commonly produced by fungi and bacteria. And they've got a very hard job.
Cellulose is tough stuff. It's in the cell walls of plants. It's what gives a plant its structure.
"It's why trees stand up," Reilly said.
He also said, "Nature has done its best to break down cellulose."
So different enzymes have developed different ways of attacking cellulose.
One enzyme Reilly has studied and illustrated - a cellobiohydrolase enzyme - has an extension that works like a little plow. It rips up one cellulose chain from a cellulose crystal and feeds it into a tunnel on the main enzyme surface so that it can be chopped up.
Reilly, who can't resist a lesson in biochemistry, likes to explain how enzymes attack and break chemical bonds. He'll display diagrams on his office computer that show the bonds in cellulose molecules. He'll point out where enzymes attack some of those bonds. He'll say the chemical reactions create high-energy transition states that scientists are working hard to understand. And he'll get back to the bottom line.
"These different enzymes all do the same thing," Reilly said. "They all break down bonds between the sugars that make up cellulose."
And, he said, "For something that's not alive, enzymes are awfully sophisticated."
Reilly's students use a lot of computing power to figure out how enzymes are put together. They routinely work with CyBlue, Iowa State's supercomputer capable of 5.7 trillion calculations per second, and Lightning, an Iowa State high-performance computer capable of 1.8 trillion calculations per second.
By adding to the basic understanding of enzymes, Reilly is opening doors for new and better applications of enzymes. Better enzymes, for example, could be the key to making the production of cellulosic ethanol more efficient and more economical.
There's still a lot for chemical engineers to learn about the specialized proteins.
After all, Reilly said, "Nature has tried over and over to find ways to break down cellulose."
Source: Peter Reilly
Iowa State University
Data Acquisition And Coordination Key To Human Microbiome Project
At birth, your body was 100-percent human in terms of cells. At death, about 10-percent of the cells in your body will be human and the remaining 90-percent will be microorganisms. That makes you a "supraorganism," and it is the interactions between your human and microbial cells that go a long way towards determining your health and physical well-being, especially your resistance to infectious diseases.
To learn more about the community of symbiotic microbes that outnumber our own somatic and germ cells by a 10:1 ratio, the National Institutes of Health (NIH) in 2008 launched the Human Microbiome Project (HMP) - a microbiome is the full complement of microorganisms populating a supraorganism. The goal of the HMP is to sequence the genomes of 1,000 or more of these microbial species and assemble the information in a "project catalog" as a reference for future investigations. The project catalog is housed at the HMP Data Acquisition and Coordination Center (DACC), which was created and is maintained by researchers with the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab).
"The HMP project catalog is a unique worldwide resource," says molecular biologist Nikos Kyrpides of Berkeley Lab's Genomics Division, who heads the Genome Biology and Metagenomics Programs for the Joint Genome Institute (JGI) and is the co-principal investigator of the DACC. "It has a central role in the HMP, not only in maintaining the list and status of over 1,400 individual human microbiome projects, but also as a data managements system for the metadata associated with these projects, such as information on the microbial isolation sites and the sites in the human body where these microbes can be found, and information on the phenotypic properties of these microbes."
At JGI, Kyrpides oversees projects such as GenePRIMP, a highly rated quality control program for genome sequencing, and GOLD, the Genomes On-Line Database. GenePRIMP stands for "Gene PRediction IMprovement Pipeline, and it consists of a series of computational units that can be used to significantly improve the overall quality of the predicted genes in any sequenced genome. The results identify gene-calling errors such as potentially incorrect gene start and end positions, large overlaps between genes, and fragmented or missed genes. GOLD provides comprehensive information on genome sequencing projects, including metagenomes and metadata from around the world. The HMP project catalog is powered by the GOLD database and provides a specialized user interface by which the data stored in GOLD can be read.
The other co-principal investigator of the DACC is Victor Markowitz who heads Berkeley Lab's Biological Data Management and Technology Center in the Computational Research Division, and also serves as the Chief Informatics Officer and Associate Director at JGI. Markowitz oversees the development and maintenance of the Integrated Microbial Genomics with Microbiome samples (IMG/M) system, which provides comparative analysis tools for the study of metagenomes вЂ" the collective genetic material of a given microbiome. First released in 2006, IMG/M contains millions of annotated microbial gene sequences, recovered from wild varieties of microbial communities. IMG/M is now being applied to the HMP.
"Resources such as GenePRIMP, GOLD and IMG/M are among the best in the world when it comes to providing comparative analysis tools for microbial genomes and metagenomes," Markowitz says. "As the HMP moves forward, these resources will provide support for the annotation and analysis of HMP datasets, in particular via the metagenome annotation pipeline at JGI and a HMP specific version of the IMG/M system."
The first 178 reference microbial genomes have now been analyzed and catalogued by the HMP. The results were published in the journal Science in a paper titled, "A Catalog of Reference Genomes from the Human Microbiome."
In this paper, HMP researchers report comparing data from the sequenced reference genomes to human metagenomic data in the public domain to identify proteins, determine gene functionality and link metagenomic data to individual microbial species. From an analysis of 547,968 predicted proteins, the HMP researchers report 29,987 unique proteins, which suggests a far greater diversity in the human microbiome than previously suspected.
"The Science paper is a milestone in the human microbiome research with the release to the public of 178 finished or high quality draft genomes from organisms isolated from various sites in the human body," says Kyrpides. "It signals the beginning of a much larger effort that aims to provide a more comprehensive genetic catalog of the microbes living in the human body. The impact of understanding what is the normal microbial flora, what is its core genetic content, and how perturbations of the normal microbial flora of the human body can shift from protecting our bodies into causing diseases will eventually be enormous."
Kyrpides, Markowitz and their colleagues at the DACC are playing a critical role in fulfilling an NIH call for development of common sequencing and annotation standards that have not existed before. Lack of common language and a clearing house for genome data have been among the most daunting problems in genomics research.
Says Markowitz, "The greatest challenge ahead will be handling hundred of metagenomic datasets generated as part of the HMP, which will represent several orders of magnitude more data than the datasets presented in the current paper. We need to develop novel analysis and visualization methods to handle this massive increase in data."
Adds Kyrpides, "New sequencing technologies and our ability to generate orders of magnitude more data compared to only a year or two ago are changing the field entirely, and are mandating a social shift among the scientists involved to a more collaborative rather than competitive spirit. None of us can provide solutions alone any more, and joint efforts such as the HMP are the only way we'll succeed."
Other Berkeley Lab/JGI researchers with prominent roles in the HMP include Gary Andersen, Todd DeSantis, Amy Chen, Konstantinos Liolios, Amrita Pati and Konstantinos Mavrommatis.
Berkeley Lab is a U.S. Department of Energy (DOE) national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California for the DOE Office of Science.
Source:
Lynn Yarris
DOE/Lawrence Berkeley National Laboratory
To learn more about the community of symbiotic microbes that outnumber our own somatic and germ cells by a 10:1 ratio, the National Institutes of Health (NIH) in 2008 launched the Human Microbiome Project (HMP) - a microbiome is the full complement of microorganisms populating a supraorganism. The goal of the HMP is to sequence the genomes of 1,000 or more of these microbial species and assemble the information in a "project catalog" as a reference for future investigations. The project catalog is housed at the HMP Data Acquisition and Coordination Center (DACC), which was created and is maintained by researchers with the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab).
"The HMP project catalog is a unique worldwide resource," says molecular biologist Nikos Kyrpides of Berkeley Lab's Genomics Division, who heads the Genome Biology and Metagenomics Programs for the Joint Genome Institute (JGI) and is the co-principal investigator of the DACC. "It has a central role in the HMP, not only in maintaining the list and status of over 1,400 individual human microbiome projects, but also as a data managements system for the metadata associated with these projects, such as information on the microbial isolation sites and the sites in the human body where these microbes can be found, and information on the phenotypic properties of these microbes."
At JGI, Kyrpides oversees projects such as GenePRIMP, a highly rated quality control program for genome sequencing, and GOLD, the Genomes On-Line Database. GenePRIMP stands for "Gene PRediction IMprovement Pipeline, and it consists of a series of computational units that can be used to significantly improve the overall quality of the predicted genes in any sequenced genome. The results identify gene-calling errors such as potentially incorrect gene start and end positions, large overlaps between genes, and fragmented or missed genes. GOLD provides comprehensive information on genome sequencing projects, including metagenomes and metadata from around the world. The HMP project catalog is powered by the GOLD database and provides a specialized user interface by which the data stored in GOLD can be read.
The other co-principal investigator of the DACC is Victor Markowitz who heads Berkeley Lab's Biological Data Management and Technology Center in the Computational Research Division, and also serves as the Chief Informatics Officer and Associate Director at JGI. Markowitz oversees the development and maintenance of the Integrated Microbial Genomics with Microbiome samples (IMG/M) system, which provides comparative analysis tools for the study of metagenomes вЂ" the collective genetic material of a given microbiome. First released in 2006, IMG/M contains millions of annotated microbial gene sequences, recovered from wild varieties of microbial communities. IMG/M is now being applied to the HMP.
"Resources such as GenePRIMP, GOLD and IMG/M are among the best in the world when it comes to providing comparative analysis tools for microbial genomes and metagenomes," Markowitz says. "As the HMP moves forward, these resources will provide support for the annotation and analysis of HMP datasets, in particular via the metagenome annotation pipeline at JGI and a HMP specific version of the IMG/M system."
The first 178 reference microbial genomes have now been analyzed and catalogued by the HMP. The results were published in the journal Science in a paper titled, "A Catalog of Reference Genomes from the Human Microbiome."
In this paper, HMP researchers report comparing data from the sequenced reference genomes to human metagenomic data in the public domain to identify proteins, determine gene functionality and link metagenomic data to individual microbial species. From an analysis of 547,968 predicted proteins, the HMP researchers report 29,987 unique proteins, which suggests a far greater diversity in the human microbiome than previously suspected.
"The Science paper is a milestone in the human microbiome research with the release to the public of 178 finished or high quality draft genomes from organisms isolated from various sites in the human body," says Kyrpides. "It signals the beginning of a much larger effort that aims to provide a more comprehensive genetic catalog of the microbes living in the human body. The impact of understanding what is the normal microbial flora, what is its core genetic content, and how perturbations of the normal microbial flora of the human body can shift from protecting our bodies into causing diseases will eventually be enormous."
Kyrpides, Markowitz and their colleagues at the DACC are playing a critical role in fulfilling an NIH call for development of common sequencing and annotation standards that have not existed before. Lack of common language and a clearing house for genome data have been among the most daunting problems in genomics research.
Says Markowitz, "The greatest challenge ahead will be handling hundred of metagenomic datasets generated as part of the HMP, which will represent several orders of magnitude more data than the datasets presented in the current paper. We need to develop novel analysis and visualization methods to handle this massive increase in data."
Adds Kyrpides, "New sequencing technologies and our ability to generate orders of magnitude more data compared to only a year or two ago are changing the field entirely, and are mandating a social shift among the scientists involved to a more collaborative rather than competitive spirit. None of us can provide solutions alone any more, and joint efforts such as the HMP are the only way we'll succeed."
Other Berkeley Lab/JGI researchers with prominent roles in the HMP include Gary Andersen, Todd DeSantis, Amy Chen, Konstantinos Liolios, Amrita Pati and Konstantinos Mavrommatis.
Berkeley Lab is a U.S. Department of Energy (DOE) national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California for the DOE Office of Science.
Source:
Lynn Yarris
DOE/Lawrence Berkeley National Laboratory
Advances In Proteomics Bring Scientists Closer To Infertility Cures
Proteins found in sperm are central to understanding male infertility and could be used to determine new diagnostic methods and fertility treatments according to a paper published by the journal Molecular and Cellular Proteomics (MCP). The article demonstrates how proteomics, a relatively new field focusing on the function of proteins in a cell, can be successfully applied to infertility, helping identify which proteins in sperm cells are dysfunctional.
"Up to 50 percent of male-factor infertility cases in the clinic have no known cause, and therefore no direct treatment. In-depth study of the molecular basis of infertility has great potential to inform the development of sensitive diagnostic tools and effective therapies," write co-authors Diana Chu, assistant professor of biology at San Francisco State University and Tammy Wu, post-doctoral fellow at SF State. The study is included in a special Oct. 10 issue of MCP dedicated to the clinical application of proteomics.
"We suggest how the study of proteins is useful in the clinic, to help people move from infertile to fertile and ultimately to help couples have a baby," Chu said. "The ultimate goal is that a doctor could be able to say to a patient, 'this is the protein that is misregulated in your sperm and this is the drug that corrects it or decreases the level of that protein.' Understanding sperm proteins also means that a doctor could be able to inform patients of the likely success rates of different fertility therapies, an important factor given the high cost of fertility treatments."
More than 2 million couples in the U.S. are facing infertility. While many scientific studies examine the supply of sperm, its mobility and its ability to fertilize, Chu argues that a wider array of sensitive tests - including studies of cell proteins - are needed to determine the root causes of male infertility.
Proteins found in sperm cells are unique. This means therapies can be developed that target only these proteins and do not produce side effects in the patient or defects in the resulting offspring.
Chu's paper highlights a selection of recent advances in the study of proteins in sperm cells, citing studies that have identified specific proteins that correlate with infertility.
Chu argues that further large-scale clinical studies are needed to identify patterns in the proteins found in the sperm of infertile patients. This would help scientists to better understand which proteins to focus on, since each sperm cell contains more than 2,000 proteins and each patient's sperm varies slightly in its protein content.
Understanding the function of individual proteins in sperm cells may not only aid scientists' understanding of fertility, but can also explain the causes of miscarriages, 50 percent of which have unexplained causes. Chu also suggests that further studies of the proteins found in sperm cells will have a significant impact on our understanding of the paternal protein contribution that can have long lasting effects on future generations.
Diana Chu is assistant professor of biology at San Francisco State University where she uses proteomic approaches to research the function of proteins associated to sperm chromatin. San Francisco State University's biology department is the largest in the California State University system. SF State ranks second among all U.S. comprehensive universities whose graduates successfully enroll in Ph.D. programs.
Source: Diana Chu
San Francisco State University
"Up to 50 percent of male-factor infertility cases in the clinic have no known cause, and therefore no direct treatment. In-depth study of the molecular basis of infertility has great potential to inform the development of sensitive diagnostic tools and effective therapies," write co-authors Diana Chu, assistant professor of biology at San Francisco State University and Tammy Wu, post-doctoral fellow at SF State. The study is included in a special Oct. 10 issue of MCP dedicated to the clinical application of proteomics.
"We suggest how the study of proteins is useful in the clinic, to help people move from infertile to fertile and ultimately to help couples have a baby," Chu said. "The ultimate goal is that a doctor could be able to say to a patient, 'this is the protein that is misregulated in your sperm and this is the drug that corrects it or decreases the level of that protein.' Understanding sperm proteins also means that a doctor could be able to inform patients of the likely success rates of different fertility therapies, an important factor given the high cost of fertility treatments."
More than 2 million couples in the U.S. are facing infertility. While many scientific studies examine the supply of sperm, its mobility and its ability to fertilize, Chu argues that a wider array of sensitive tests - including studies of cell proteins - are needed to determine the root causes of male infertility.
Proteins found in sperm cells are unique. This means therapies can be developed that target only these proteins and do not produce side effects in the patient or defects in the resulting offspring.
Chu's paper highlights a selection of recent advances in the study of proteins in sperm cells, citing studies that have identified specific proteins that correlate with infertility.
Chu argues that further large-scale clinical studies are needed to identify patterns in the proteins found in the sperm of infertile patients. This would help scientists to better understand which proteins to focus on, since each sperm cell contains more than 2,000 proteins and each patient's sperm varies slightly in its protein content.
Understanding the function of individual proteins in sperm cells may not only aid scientists' understanding of fertility, but can also explain the causes of miscarriages, 50 percent of which have unexplained causes. Chu also suggests that further studies of the proteins found in sperm cells will have a significant impact on our understanding of the paternal protein contribution that can have long lasting effects on future generations.
Diana Chu is assistant professor of biology at San Francisco State University where she uses proteomic approaches to research the function of proteins associated to sperm chromatin. San Francisco State University's biology department is the largest in the California State University system. SF State ranks second among all U.S. comprehensive universities whose graduates successfully enroll in Ph.D. programs.
Source: Diana Chu
San Francisco State University
Failing Mouse Hearts Safely Regenerated With Programmed Embryonic Stem Cells
Mayo Clinic researchers have safely transplanted cardiac preprogrammed embryonic stem cells into diseased hearts of mice successfully regenerating infarcted heart muscle without precipitating the growth of a cancerous tumor -- which, so far, has impeded successful translation into practice of embryonic stem cell research.
The Mayo study is the first known report establishing a successful, tumor-resistant approach to growing new heart tissue from an embryonic stem cell source. The study is published in the February issue of the Journal of Experimental Medicine.
Embryonic stem cells have the potential to become any cell type in the body. But directing the stem cells to regenerate targeted tissue is a process that hasn't yet been perfected. Scientists continue to closely scrutinize stem cell strategies to establish even safer and more effective treatments for disease.
"Embryonic stem cells are like a stealth fighter jet that flies virtually undetectable by radar," says the study's first author, Atta Behfar, M.D., Ph.D., a clinician-investigator fellow in the Mayo Graduate School of Medicine. "The host body doesn't recognize embryonic stem cells, which it allows to multiply freely in an unimpeded fashion."
The Mayo study is the first known report of a successful strategy for programming embryonic stem cells to suppress cancer genes, to mature into heart cells (also known as cardiomyocytes) and to successfully fix injured hearts without causing tumors to develop. The study removes a critical obstacle towards translation of regenerative technology into developing new therapies for people with heart disease.
"Embryonic stem cells have an unequaled potential for repair, yet it has been uncertain whether we can drive them to safely regenerate the tissue we would like to replace," says Andre Terzic, M.D., Ph.D., a stem cell specialist and lead investigator of the study. "Our objective was to repair heart muscle by avoiding the limitations intrinsic to embryonic stem cells, i.e., potential tumor growth."
"In this study, we have successfully programmed embryonic stem cells to safely generate new cardiac muscle tissue, leading potentially to new therapy," Dr. Terzic says.
The Study
Researchers transplanted mouse embryonic stem cells into infarcted hearts of mice. Consistent with the risk for uncontrolled growth, a significant number of recipient mouse hearts developed tumors. To avoid tumor formation, researchers secured guided differentiation of stem cells to produce cardiopoietic cells, or cardiac specified cell precursors rather than any cell type. Treatment with cardiopoietic cells proved to have no tendency to develop into cancer. Tumor-free heart repair occurred in all treated mice. Two months after cardiopoietic stem cell transplantation, scientists reported a 35 percent improved output in treated hearts.
The threat of tumor growth associated with embryonic stem cell transplants was eliminated by restricting expression of oncogenes and pluripotency genes through transgenic manipulation of tumor necrosis factor alpha (TNFa), a genome reprogramming protein. Researchers found that over-expressed TNFa promoted guided control of cardiac embryonic stem cells to drive the cardiogenesis process.
Researchers discovered approximately 15 proteins whose production was dramatically increased after TNFa stimulation. These proteins, when combined into a 'cocktail,' secured guided differentiation of embryonic stem cells, producing cardiac progenitors called cardiopoietic cells. Such guided heart precursor cells did not form tumors, even though they were transplanted at doses that would otherwise carry a high risk for tumorigenesis with embryonic stem cells.
"Our goal is to apply these findings to adult stem cells, and in our next step create the first human cardioprogenitor stem cells as a tool for therapies in the future," Dr. Terzic says.
The study was funded by the National Institutes of Health, American Heart Association, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, Heart and Stroke Foundation of Canada, and Asper Foundation. Dr. Behfar is supported by the Clinician-Investigator Program at Mayo Clinic.
The Mayo study was a multidisciplinary effort with investigators from the Mayo Clinic Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Physical Medicine and Rehabilitation. Other investigators include: Carmen Terzic, M.D., Ph.D.; Randolph Faustino, Ph.D.; D. Kent Arrell, Ph.D.; Denice Hodgson, Satsuki Yamada, M.D., Ph.D., Michel Puceat, Nicolas Niederl'nder, Ph.D.; Alexey Alekseev, Ph.D.; and Leonid Zingman, M.D.
Contact: Amy Reyes
Mayo Clinic
The Mayo study is the first known report establishing a successful, tumor-resistant approach to growing new heart tissue from an embryonic stem cell source. The study is published in the February issue of the Journal of Experimental Medicine.
Embryonic stem cells have the potential to become any cell type in the body. But directing the stem cells to regenerate targeted tissue is a process that hasn't yet been perfected. Scientists continue to closely scrutinize stem cell strategies to establish even safer and more effective treatments for disease.
"Embryonic stem cells are like a stealth fighter jet that flies virtually undetectable by radar," says the study's first author, Atta Behfar, M.D., Ph.D., a clinician-investigator fellow in the Mayo Graduate School of Medicine. "The host body doesn't recognize embryonic stem cells, which it allows to multiply freely in an unimpeded fashion."
The Mayo study is the first known report of a successful strategy for programming embryonic stem cells to suppress cancer genes, to mature into heart cells (also known as cardiomyocytes) and to successfully fix injured hearts without causing tumors to develop. The study removes a critical obstacle towards translation of regenerative technology into developing new therapies for people with heart disease.
"Embryonic stem cells have an unequaled potential for repair, yet it has been uncertain whether we can drive them to safely regenerate the tissue we would like to replace," says Andre Terzic, M.D., Ph.D., a stem cell specialist and lead investigator of the study. "Our objective was to repair heart muscle by avoiding the limitations intrinsic to embryonic stem cells, i.e., potential tumor growth."
"In this study, we have successfully programmed embryonic stem cells to safely generate new cardiac muscle tissue, leading potentially to new therapy," Dr. Terzic says.
The Study
Researchers transplanted mouse embryonic stem cells into infarcted hearts of mice. Consistent with the risk for uncontrolled growth, a significant number of recipient mouse hearts developed tumors. To avoid tumor formation, researchers secured guided differentiation of stem cells to produce cardiopoietic cells, or cardiac specified cell precursors rather than any cell type. Treatment with cardiopoietic cells proved to have no tendency to develop into cancer. Tumor-free heart repair occurred in all treated mice. Two months after cardiopoietic stem cell transplantation, scientists reported a 35 percent improved output in treated hearts.
The threat of tumor growth associated with embryonic stem cell transplants was eliminated by restricting expression of oncogenes and pluripotency genes through transgenic manipulation of tumor necrosis factor alpha (TNFa), a genome reprogramming protein. Researchers found that over-expressed TNFa promoted guided control of cardiac embryonic stem cells to drive the cardiogenesis process.
Researchers discovered approximately 15 proteins whose production was dramatically increased after TNFa stimulation. These proteins, when combined into a 'cocktail,' secured guided differentiation of embryonic stem cells, producing cardiac progenitors called cardiopoietic cells. Such guided heart precursor cells did not form tumors, even though they were transplanted at doses that would otherwise carry a high risk for tumorigenesis with embryonic stem cells.
"Our goal is to apply these findings to adult stem cells, and in our next step create the first human cardioprogenitor stem cells as a tool for therapies in the future," Dr. Terzic says.
The study was funded by the National Institutes of Health, American Heart Association, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, Heart and Stroke Foundation of Canada, and Asper Foundation. Dr. Behfar is supported by the Clinician-Investigator Program at Mayo Clinic.
The Mayo study was a multidisciplinary effort with investigators from the Mayo Clinic Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Physical Medicine and Rehabilitation. Other investigators include: Carmen Terzic, M.D., Ph.D.; Randolph Faustino, Ph.D.; D. Kent Arrell, Ph.D.; Denice Hodgson, Satsuki Yamada, M.D., Ph.D., Michel Puceat, Nicolas Niederl'nder, Ph.D.; Alexey Alekseev, Ph.D.; and Leonid Zingman, M.D.
Contact: Amy Reyes
Mayo Clinic
Scientists Identify A Molecule That Coordinates The Movement Of Cells
Even cells commute. To get from their birthplace to their work site, they sequentially attach to and detach from an elaborate track of exceptionally strong proteins known as the extracellular matrix. Now, in research to appear in the October 3 issue of Cell, scientists at the Howard Hughes Medical Institute and Rockefeller University show that a molecule, called ACF7, helps regulate and power this movement from the inside - findings that could have implications for understanding how cancer cells metastasize.
"The most dangerous part of cancer is that cancer cells migrate from their primary location and invade other parts of the body," says first author Xiaoyang Wu, a postdoc in Elaine Fuchs's Laboratory of Mammalian Cell Biology and Development. "ACF7 facilitates cell movement, so it's possible that the less ACF7 a cell has, the less malignant it would become. It's a really exciting question in cancer biology now."
To travel along the extracellular matrix, cells must stick to and unstick from it via focal adhesions, structures composed of molecules that connect the inside to the outside of the cell. (While some molecules connect to the matrix, others connect to a scaffold inside the cell called the cytoskeleton.) As these structures collectively assemble and disassemble, the cell walks forward. Fuchs and Wu show that ACF7 can not only access energy stores to power this movement from within but also coordinate it by linking two fiber-like proteins called f-actin and microtubules, which together form the cytoskeleton and help give cells their shape.
"Inside the cell, actin cables converge at focal adhesions at the cell's leading edge," Fuchs explains. "We found that ACF7 guides microtubules along a roadway of actin cables and leads them toward the focal adhesions at the cell's periphery. Among the cargo transported along microtubules are factors that disassemble focal adhesions. Hence by coupling microtubule, actin and focal adhesion dynamics within the cell, ACF7 becomes an orchestrator of directed cellular movement."
In particular, Wu and Fuchs, who is also a Howard Hughes Medical Institute investigator and Rebecca C. Lancefield Professor at Rockefeller, found that without ACF7, microtubules were no longer guided toward the focal adhesions in a directed manner. They also noticed that cellular movement slowed, suggesting that the sticky adhesive sites were no longer assembling and disassembling efficiently.
To figure out why, Fuchs and Wu studied how quickly wounds heal in mice. "During injury, stem cells proliferate and migrate to the affected site and replenish lost cells," explains Wu. "We saw that the cells without ACF7 proliferated normally, but they moved very, very slowly compared to normal skin cells. So the problem wasn't with abnormal proliferation but with cell migration." When the researchers mutated ACF7 so it couldn't release stored energy in cells, ACF7 linked f-actin and microtubules but the cells were also sluggish in their movement.
In previous work, the Fuchs team had already showed that ACF7 appeared side by side with focal adhesion molecules, but they never knew, until now, that ACF7 guides microtubules along actin cables to these sites. "Now, we have a better idea of why it's important for ACF7 to be there," says Fuchs. "In order to make the adhesive sites dynamically stick and unstick, assembly and disassembly factors need to be recruited there. The intracellular roadway governed by ACF7 makes that possible."
In the future, this information could be relevant in developing cancer therapeutics. "A major goal in the clinical arena is to halt cancer cells from migrating, a process important in metastasis," says Fuchs. By suppressing ACF7's function in cancer cells, it might be possible to slow metastasis.
This research was supported by the National Institutes of Health.
Source: Thania Benios
Rockefeller University
"The most dangerous part of cancer is that cancer cells migrate from their primary location and invade other parts of the body," says first author Xiaoyang Wu, a postdoc in Elaine Fuchs's Laboratory of Mammalian Cell Biology and Development. "ACF7 facilitates cell movement, so it's possible that the less ACF7 a cell has, the less malignant it would become. It's a really exciting question in cancer biology now."
To travel along the extracellular matrix, cells must stick to and unstick from it via focal adhesions, structures composed of molecules that connect the inside to the outside of the cell. (While some molecules connect to the matrix, others connect to a scaffold inside the cell called the cytoskeleton.) As these structures collectively assemble and disassemble, the cell walks forward. Fuchs and Wu show that ACF7 can not only access energy stores to power this movement from within but also coordinate it by linking two fiber-like proteins called f-actin and microtubules, which together form the cytoskeleton and help give cells their shape.
"Inside the cell, actin cables converge at focal adhesions at the cell's leading edge," Fuchs explains. "We found that ACF7 guides microtubules along a roadway of actin cables and leads them toward the focal adhesions at the cell's periphery. Among the cargo transported along microtubules are factors that disassemble focal adhesions. Hence by coupling microtubule, actin and focal adhesion dynamics within the cell, ACF7 becomes an orchestrator of directed cellular movement."
In particular, Wu and Fuchs, who is also a Howard Hughes Medical Institute investigator and Rebecca C. Lancefield Professor at Rockefeller, found that without ACF7, microtubules were no longer guided toward the focal adhesions in a directed manner. They also noticed that cellular movement slowed, suggesting that the sticky adhesive sites were no longer assembling and disassembling efficiently.
To figure out why, Fuchs and Wu studied how quickly wounds heal in mice. "During injury, stem cells proliferate and migrate to the affected site and replenish lost cells," explains Wu. "We saw that the cells without ACF7 proliferated normally, but they moved very, very slowly compared to normal skin cells. So the problem wasn't with abnormal proliferation but with cell migration." When the researchers mutated ACF7 so it couldn't release stored energy in cells, ACF7 linked f-actin and microtubules but the cells were also sluggish in their movement.
In previous work, the Fuchs team had already showed that ACF7 appeared side by side with focal adhesion molecules, but they never knew, until now, that ACF7 guides microtubules along actin cables to these sites. "Now, we have a better idea of why it's important for ACF7 to be there," says Fuchs. "In order to make the adhesive sites dynamically stick and unstick, assembly and disassembly factors need to be recruited there. The intracellular roadway governed by ACF7 makes that possible."
In the future, this information could be relevant in developing cancer therapeutics. "A major goal in the clinical arena is to halt cancer cells from migrating, a process important in metastasis," says Fuchs. By suppressing ACF7's function in cancer cells, it might be possible to slow metastasis.
This research was supported by the National Institutes of Health.
Source: Thania Benios
Rockefeller University
Effects Of Low Dose Arsenic On Development Shown By Dartmouth Researchers
A team of Dartmouth Medical School (DMS) researchers has determined that low doses of arsenic disrupt the activity of a hormone critical in development. The finding is further evidence that arsenic at low doses (at levels found in U.S. drinking water in some areas) can be harmful. The study appeared in the online edition of the journal Environmental Health Perspectives (EHP), and it will be published in a forthcoming issue of the journal.
"Arsenic is a natural, yet pervasive, chemical in the environment; we can't seem to escape it," says Joshua Hamilton, one of the authors on this study and the director of the Center for Environmental Health Sciences at Dartmouth and Dartmouth's Superfund Basic Research Program on Toxic Metals. "By learning how it adversely affects biological processes and at what levels we should be concerned, we will hopefully someday be able to mitigate its impact on human health." Hamilton is also a professor of pharmacology and toxicology at DMS.
Hamilton and his team, in previous work, have learned that arsenic at low doses appears to suppress the ability of all critical steroid receptors, including those for estrogen and testosterone, to respond to their normal hormone signals. Chemicals that disrupt steroid hormone receptor signaling are called endocrine disruptors. Arsenic can disrupt these hormone pathways at extremely low doses equivalent to what many people in the U.S. have in their drinking water.
This study set out to see whether arsenic can also disrupt the activity of two hormone receptors that are involved in normal development - the retinoic acid receptor and the thyroid hormone receptor, two important members of the larger nuclear hormone receptor family. While the researchers studied the impact on frog development, these two hormone receptors are also vital to human development.
"I believe this is the first demonstration in an animal model that arsenic actually disrupts a developmental process that is regulated by hormones, and it does this at extremely low doses that are directly relevant to human exposures of concern," says Hamilton.
The work is funded by grants to Dartmouth from the National Institute of Environmental Health Sciences, a component of the National Institutes of Health. Other researchers on the paper include Jennifer C. Davey, Athena P. Nomikos, Manida Wungjiranirun, Jenna R. Sherman, Liam Ingram, Cavus Batki, and Jean P. Lariviere, all with, or formerly with, the Department of Pharmacology and Toxicology at DMS.
Source: Sue Knapp
Dartmouth College
"Arsenic is a natural, yet pervasive, chemical in the environment; we can't seem to escape it," says Joshua Hamilton, one of the authors on this study and the director of the Center for Environmental Health Sciences at Dartmouth and Dartmouth's Superfund Basic Research Program on Toxic Metals. "By learning how it adversely affects biological processes and at what levels we should be concerned, we will hopefully someday be able to mitigate its impact on human health." Hamilton is also a professor of pharmacology and toxicology at DMS.
Hamilton and his team, in previous work, have learned that arsenic at low doses appears to suppress the ability of all critical steroid receptors, including those for estrogen and testosterone, to respond to their normal hormone signals. Chemicals that disrupt steroid hormone receptor signaling are called endocrine disruptors. Arsenic can disrupt these hormone pathways at extremely low doses equivalent to what many people in the U.S. have in their drinking water.
This study set out to see whether arsenic can also disrupt the activity of two hormone receptors that are involved in normal development - the retinoic acid receptor and the thyroid hormone receptor, two important members of the larger nuclear hormone receptor family. While the researchers studied the impact on frog development, these two hormone receptors are also vital to human development.
"I believe this is the first demonstration in an animal model that arsenic actually disrupts a developmental process that is regulated by hormones, and it does this at extremely low doses that are directly relevant to human exposures of concern," says Hamilton.
The work is funded by grants to Dartmouth from the National Institute of Environmental Health Sciences, a component of the National Institutes of Health. Other researchers on the paper include Jennifer C. Davey, Athena P. Nomikos, Manida Wungjiranirun, Jenna R. Sherman, Liam Ingram, Cavus Batki, and Jean P. Lariviere, all with, or formerly with, the Department of Pharmacology and Toxicology at DMS.
Source: Sue Knapp
Dartmouth College
Treating Epilepsy With An Atkins-Like Diet: Leptin Attenuates Rodent Seizure Severity
Not all individuals who have epilepsy respond to traditional treatments and these individuals are said to have medically refractory epilepsy. Strict use of a ketogenic diet high in fats and extremely low in carbohydrates is sometimes used for treatment of refractory epilepsy, and is effective about half of the time. However, the mechanisms whereby ketogenic diets suppress epileptic symptoms have long been a mystery. New data generated by Kelvin Yamada and colleagues at the Washington University School of Medicine, St. Louis, has revealed that intranasal delivery of leptin, a hormone important in feeding and energy metabolism, delayed the onset of convulsions in a rodent model of seizures. As indicated by Tamas Horvath and Sabrina Diano in an accompanying commentary, these data suggest that leptin-triggered signaling may be a key to how a ketogenic diet combats epilepsy.
In the study, when focal seizures were induced by injection of the chemical 4AP into rat brains, co-injection of leptin reduced both the length and the frequency of these seizures. Intranasal administration permitted leptin to cross the blood-brain barrier and delay the onset of chemical-induced generalized seizures in mice. Additional experiments revealed that leptin may assert these antiseizure effects via interaction with the JAK2/PI3K signaling pathway. The authors concluded that successful epilepsy treatments may include dietary changes to increase leptin levels, intranasal administration of the compound, and pharmacological targeting of JAK2/PI3K signaling pathways.
Title: Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents
Author Contact:
Kelvin A. Yamada
Washington University School of Medicine, St. Louis, Missouri, USA.
Accompanying Commentary Title:
Anticonvulsant effects of leptin in epilepsy
Author Contact:
Tamas L. Horvath
Yale School of Medicine, New Haven, Connecticut, USA.
Source: Karen Honey
Journal of Clinical Investigation
In the study, when focal seizures were induced by injection of the chemical 4AP into rat brains, co-injection of leptin reduced both the length and the frequency of these seizures. Intranasal administration permitted leptin to cross the blood-brain barrier and delay the onset of chemical-induced generalized seizures in mice. Additional experiments revealed that leptin may assert these antiseizure effects via interaction with the JAK2/PI3K signaling pathway. The authors concluded that successful epilepsy treatments may include dietary changes to increase leptin levels, intranasal administration of the compound, and pharmacological targeting of JAK2/PI3K signaling pathways.
Title: Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents
Author Contact:
Kelvin A. Yamada
Washington University School of Medicine, St. Louis, Missouri, USA.
Accompanying Commentary Title:
Anticonvulsant effects of leptin in epilepsy
Author Contact:
Tamas L. Horvath
Yale School of Medicine, New Haven, Connecticut, USA.
Source: Karen Honey
Journal of Clinical Investigation
Academic Science: Basic Research Robust In Face Of More University Patenting
As universities continue transforming scientific discoveries into potentially lucrative patents, many wonder how this might be transforming academic science itself. Some critics contend that commercial interests are changing university research from a publicly funded enterprise performed for the social good into one pursued for private purposes and monetary gain.
A University of Wisconsin-Madison study of more than 1,800 U.S. life scientists now indicates this may not be true. Despite an explosion in academic patenting in recent years, most life science professors still do research the "old-fashioned" way, say agricultural and applied economic professors Brad Barham and Jeremy Foltz: by winning federal grants, publishing results in scientific journals, and graduating Ph.D. students.
"Change isn't the story," says Barham. "Resilience is the story."
In an online survey of agricultural, medical, and other life scientists at the nation's top 125 universities for biological research, the economists found that 90 percent of researchers held one or fewer patents, and just 8 percent had received patent revenues. Moreover, federal funds from agencies such as the National Institutes of Health (NIH) made up 67 percent of the group's total research budget, while industry funding contributed just 5 percent.
In fact, 53 percent of scientists reported no commercial ties whatsoever, such as invention disclosures or company board memberships. In short, says Foltz, "the connection to commercialization appears to be marginal in terms of funding the overall research enterprise."
The findings should reassure those concerned with preserving the country's longstanding model of basic, publicly supported and openly shared research. But they also come amid flattening budgets at NIH and other funding agencies, a trend that has some officials -- including the U.S. presidential science advisor -- suggesting that scientists must learn to rely more on industry and other nonfederal sources to support their work.
Universities may be unwittingly encouraging this thinking when they trumpet the possible monetary returns of academic research, caution Foltz and Barham.
"Our study suggests that commercialization really means relatively little in terms of resource flow to life science research at U.S. universities, and yet there's a big push being made for commercialization of life science," says Barham. "If this gets in the way of public support for research, then we're in trouble."
When the 1980 Bayh-Dole Act gave U.S. universities the right to patent inventions made with federal dollars and license them to companies for profit, university patenting began to soar. Since then, the number of patents issued annually has grown from roughly 40 to nearly 800 in the life sciences alone, and with them other commercial endeavors, including licensing arrangements and faculty spin-off companies.
Curious as to how these activities might be reshaping the mission of universities, Foltz and Barham conducted a survey in 2005 of 1,822 professors randomly selected across a wide range of life science disciplines. As the largest general survey of biological scientists in more than a decade, the study stands in contrast to other, similar investigations, which have focused on individual departments or institutions, or certain groups, such as medical scientists.
One major question the economists aimed to address is whether research productivity -- measured as number of journal articles -- suffers when scientists get involved in commercial ventures like patenting. "Do articles and patents go together?" says Foltz. "Or are there tradeoffs, because if you're working on one, you're not working on the other?"
What they found is that the two indeed complement one another, suggesting that important discoveries can serve both research and commercial purposes without much cost. "It seems that coming up with a good idea is the main cost," says Barham, "not the extra effort needed to produce the patent or the article."
The economists also found that higher percentages of industry funding neither hurt nor helped research productivity. Instead, federal funding was the driving force, with scientists who had greater percentages of federal support consistently publishing larger numbers of papers.
Some of the most interesting findings came from an examination of patent revenues. Not only had just 8 percent of scientists received them, but the money was highly concentrated as well. One researcher in the sample reported $24 million, two others got $1 million each, and the rest split another $1 million, for a median gain of $5,000 each, or two percent of their research budgets.
In other words, patenting is like a lottery that mostly yields nothing, sometimes pays a little, and once in a great while hits big, says Foltz. "Put a patent in -- that's your scientific lottery ticket," he says. "But you can't run a lab on a lottery."
This doesn't mean patenting and licensing aren't worthwhile, the economists emphasize, just that so far patent revenues haven't been able to support a wide range of research. That's why universities should make sure that citizens and policy makers understand the other benefits, such as economic development and products that enhance human welfare, says Barham.
"Our concern is that since federal money really is the mainstay of university research funding, universities need to make the point that the public commitment is still huge," he says. "Otherwise, people are likely to say, 'We don't need to commit more money to research, because commercial money will come in. Universities are making a big push there, so we don't need to worry.'"
Source: Brad Barham
University of Wisconsin-Madison
A University of Wisconsin-Madison study of more than 1,800 U.S. life scientists now indicates this may not be true. Despite an explosion in academic patenting in recent years, most life science professors still do research the "old-fashioned" way, say agricultural and applied economic professors Brad Barham and Jeremy Foltz: by winning federal grants, publishing results in scientific journals, and graduating Ph.D. students.
"Change isn't the story," says Barham. "Resilience is the story."
In an online survey of agricultural, medical, and other life scientists at the nation's top 125 universities for biological research, the economists found that 90 percent of researchers held one or fewer patents, and just 8 percent had received patent revenues. Moreover, federal funds from agencies such as the National Institutes of Health (NIH) made up 67 percent of the group's total research budget, while industry funding contributed just 5 percent.
In fact, 53 percent of scientists reported no commercial ties whatsoever, such as invention disclosures or company board memberships. In short, says Foltz, "the connection to commercialization appears to be marginal in terms of funding the overall research enterprise."
The findings should reassure those concerned with preserving the country's longstanding model of basic, publicly supported and openly shared research. But they also come amid flattening budgets at NIH and other funding agencies, a trend that has some officials -- including the U.S. presidential science advisor -- suggesting that scientists must learn to rely more on industry and other nonfederal sources to support their work.
Universities may be unwittingly encouraging this thinking when they trumpet the possible monetary returns of academic research, caution Foltz and Barham.
"Our study suggests that commercialization really means relatively little in terms of resource flow to life science research at U.S. universities, and yet there's a big push being made for commercialization of life science," says Barham. "If this gets in the way of public support for research, then we're in trouble."
When the 1980 Bayh-Dole Act gave U.S. universities the right to patent inventions made with federal dollars and license them to companies for profit, university patenting began to soar. Since then, the number of patents issued annually has grown from roughly 40 to nearly 800 in the life sciences alone, and with them other commercial endeavors, including licensing arrangements and faculty spin-off companies.
Curious as to how these activities might be reshaping the mission of universities, Foltz and Barham conducted a survey in 2005 of 1,822 professors randomly selected across a wide range of life science disciplines. As the largest general survey of biological scientists in more than a decade, the study stands in contrast to other, similar investigations, which have focused on individual departments or institutions, or certain groups, such as medical scientists.
One major question the economists aimed to address is whether research productivity -- measured as number of journal articles -- suffers when scientists get involved in commercial ventures like patenting. "Do articles and patents go together?" says Foltz. "Or are there tradeoffs, because if you're working on one, you're not working on the other?"
What they found is that the two indeed complement one another, suggesting that important discoveries can serve both research and commercial purposes without much cost. "It seems that coming up with a good idea is the main cost," says Barham, "not the extra effort needed to produce the patent or the article."
The economists also found that higher percentages of industry funding neither hurt nor helped research productivity. Instead, federal funding was the driving force, with scientists who had greater percentages of federal support consistently publishing larger numbers of papers.
Some of the most interesting findings came from an examination of patent revenues. Not only had just 8 percent of scientists received them, but the money was highly concentrated as well. One researcher in the sample reported $24 million, two others got $1 million each, and the rest split another $1 million, for a median gain of $5,000 each, or two percent of their research budgets.
In other words, patenting is like a lottery that mostly yields nothing, sometimes pays a little, and once in a great while hits big, says Foltz. "Put a patent in -- that's your scientific lottery ticket," he says. "But you can't run a lab on a lottery."
This doesn't mean patenting and licensing aren't worthwhile, the economists emphasize, just that so far patent revenues haven't been able to support a wide range of research. That's why universities should make sure that citizens and policy makers understand the other benefits, such as economic development and products that enhance human welfare, says Barham.
"Our concern is that since federal money really is the mainstay of university research funding, universities need to make the point that the public commitment is still huge," he says. "Otherwise, people are likely to say, 'We don't need to commit more money to research, because commercial money will come in. Universities are making a big push there, so we don't need to worry.'"
Source: Brad Barham
University of Wisconsin-Madison
Finding Better Ways To Diagnose Pancreatic Cancer And Chronic Pancreatitis
In the August issue of Molecular & Cellular Proteomics (mcponline), scientists provide the first large scale identification of proteins that are overexpressed in chronic pancreatitis, an inflammatory condition of the pancreas that shares many features with pancreatic cancer. The information will help diagnose the early stages of both diseases.
Many of the proteins that are overexpressed in pancreatic cancer are also overexpressed in chronic pancreatitis, so when these proteins are detected in a patient, doctors cannot easily tell whether the patient is developing pancreatic cancer or chronic pancreatitis. To solve this problem, scientists are trying to identify the proteins that are overexpressed in one of the diseases but not the other.
Ru Chen and colleagues identified proteins specifically expressed in chronic pancreatitis and compared them with those identified in pancreatic cancer in a previous study. They found that two proteins called annexin A2 and IGFBP-2 were overexpressed in cancer but not in chronic pancreatitis, and showed that three proteins cathepsin D, integrin beta-1, and plasminogen that are currently known to be overexpressed in pancreatic cancer are actually overexpressed in both diseases. This latter result indicates that such proteins are probably not as reliable as previously assumed for the diagnosis of pancreatic cancer.
These proteins are part of a total of 116 identified proteins, 60 of which had not been reported in prior studies and could provide new ways of diagnosing pancreatitis and understanding how it develops.
American Society for Biochemistry and Molecular Biology (ASBMB)
9650 Rockville Pike
Bethesda, MD 20814-3996
United States
asbmb
Many of the proteins that are overexpressed in pancreatic cancer are also overexpressed in chronic pancreatitis, so when these proteins are detected in a patient, doctors cannot easily tell whether the patient is developing pancreatic cancer or chronic pancreatitis. To solve this problem, scientists are trying to identify the proteins that are overexpressed in one of the diseases but not the other.
Ru Chen and colleagues identified proteins specifically expressed in chronic pancreatitis and compared them with those identified in pancreatic cancer in a previous study. They found that two proteins called annexin A2 and IGFBP-2 were overexpressed in cancer but not in chronic pancreatitis, and showed that three proteins cathepsin D, integrin beta-1, and plasminogen that are currently known to be overexpressed in pancreatic cancer are actually overexpressed in both diseases. This latter result indicates that such proteins are probably not as reliable as previously assumed for the diagnosis of pancreatic cancer.
These proteins are part of a total of 116 identified proteins, 60 of which had not been reported in prior studies and could provide new ways of diagnosing pancreatitis and understanding how it develops.
American Society for Biochemistry and Molecular Biology (ASBMB)
9650 Rockville Pike
Bethesda, MD 20814-3996
United States
asbmb
Lengthening Drug Residence Time May Lead To Improving Diagnostics, Therapy
Research conducted at the Stony Brook University Institute for Chemical Biology & Drug Discovery that enhances the time a drug remains bound to its target, or residence time, may prove to be an important step in developing better diagnostic and therapeutic agents based partly on longer drug residence time. Led by Stony Brook University Professor of Chemistry Peter J. Tonge, Ph.D., the research results will be presented at the American Society for Biochemistry and Molecular Biology (ASBMB) Annual Meeting in Anaheim, Calif., on April 24.
"Our research team believes that many drugs are effective because they have long residence times on their target," says Dr. Tonge, Director of Infectious Disease Research at the Institute for Chemical Biology & Drug Discovery. "This concept has largely been ignored by investigators, and residence time is not usually incorporated into the drug discovery process."
Dr. Tonge explains that most drug discovery efforts obtain only data on the thermodynamic affinity of the drug for its target, measurements that are made at constant drug concentration. However, the SBU-led research factors in residence time, which he emphasizes is critical for activity in vivo where drug concentrations fluctuate with time.
"The central component of our work is that the length of time a drug remains bound to a target is very important for the activity of the compound in vivo," he adds.
Dr. Tonge, together with collaborators at Colorado State University and the University of WГјrzburg in Germany, have developed a series of compounds that inhibit an enzyme target from Francisella tularensis where the in vivo antibacterial activity of the compounds correlate with their residence time on the target and not with their thermodynamic affinity for the target. This resulted in a direct correlation between residence time and in vivo activity against an infectious agent.
The research team has also developed a long residence time inhibitor of an enzyme drug target in Mycobacterium tuberculosis and demonstrated that this compound has antibacterial activity in an animal model of tuberculosis.
Because compounds with long residence times should accumulate in bacteria, Dr. Tonge explains that the research may lead to the development of agents to image bacterial populations in vivo using positron emission tomography. He says that researchers could then further the concept and develop a method for non-invasive imaging of bacterial populations in humans for both diagnostic purposes and also to monitor bacterial load during drug therapy, thereby helping to chart a drug's effectiveness against bacterial infection.
Titled "Slow Onset Inhibitors of Bacterial Fatty Acid Biosynthesis: Residence Time, In Vivo Activity and In Vivo Imaging," Dr. Tonge's presentation at the ASBMB meeting will highlight his team's research results.
Source: Stony Brook University Medical Center
"Our research team believes that many drugs are effective because they have long residence times on their target," says Dr. Tonge, Director of Infectious Disease Research at the Institute for Chemical Biology & Drug Discovery. "This concept has largely been ignored by investigators, and residence time is not usually incorporated into the drug discovery process."
Dr. Tonge explains that most drug discovery efforts obtain only data on the thermodynamic affinity of the drug for its target, measurements that are made at constant drug concentration. However, the SBU-led research factors in residence time, which he emphasizes is critical for activity in vivo where drug concentrations fluctuate with time.
"The central component of our work is that the length of time a drug remains bound to a target is very important for the activity of the compound in vivo," he adds.
Dr. Tonge, together with collaborators at Colorado State University and the University of WГјrzburg in Germany, have developed a series of compounds that inhibit an enzyme target from Francisella tularensis where the in vivo antibacterial activity of the compounds correlate with their residence time on the target and not with their thermodynamic affinity for the target. This resulted in a direct correlation between residence time and in vivo activity against an infectious agent.
The research team has also developed a long residence time inhibitor of an enzyme drug target in Mycobacterium tuberculosis and demonstrated that this compound has antibacterial activity in an animal model of tuberculosis.
Because compounds with long residence times should accumulate in bacteria, Dr. Tonge explains that the research may lead to the development of agents to image bacterial populations in vivo using positron emission tomography. He says that researchers could then further the concept and develop a method for non-invasive imaging of bacterial populations in humans for both diagnostic purposes and also to monitor bacterial load during drug therapy, thereby helping to chart a drug's effectiveness against bacterial infection.
Titled "Slow Onset Inhibitors of Bacterial Fatty Acid Biosynthesis: Residence Time, In Vivo Activity and In Vivo Imaging," Dr. Tonge's presentation at the ASBMB meeting will highlight his team's research results.
Source: Stony Brook University Medical Center
In Pre-Clinical Work A Missing Enzyme Conveys Major Heart Protection
Mice born without a certain enzyme can resist the normal effects of a heart attack and retain nearly normal function in the heart's ventricles and still-oxygenated heart tissue, according to a study by researchers at Duke University Medical Center.
The findings raise the possibility of a therapy that could stimulate the growth of blood vessels and limit damage from a heart attack as well as prevent an attack from occurring at all, the scientists said.
Normal mice that went through the same experiment had full heart attacks, suffering damage to their heart pumps and a lack of oxygen in their heart tissues, which are typical effects of a heart attack.
The scientists found that in mice lacking the enzyme GNSOR (or S-nitrosoglutathione reductase) the blood was able to get around the blockage point that normally would cut off blood to the heart because of remarkable capillary growth in these animals.
"There were blood vessels everywhere in these mice born without the enzyme," said Jonathan Stamler, M.D., a Duke professor of medicine and biochemistry and author of the study published in the Proceedings of the National Academy of Sciences online on March 27. "The hope is that this discovery someday could result in a therapy for new blood vessel growth that could be a sort of natural bypass in humans. Perhaps it could also benefit patients with peripheral artery disease, who cannot walk, for example, but who might be able to grow new blood vessels in their legs."
Stamler said his research group might look into the question of improving peripheral artery disease.
"Normally if you block the major artery to a heart, oxygen tension drops in the tissues - you can't get oxygen to the tissues and they die," Stamler said. "This appears to be a major step forward in the science of stimulating blood vessel growth around the heart, which many people have been trying to do."
"The remarkable aspect of this study is that we show that under conditions of elevated levels of nitric oxide, the heart can grow new blood vessels in the absence of chronic ischemia (inadequate circulation)," said Howard Rockman, M.D., Duke professor of medicine, chief of cardiology at Duke Heart Center and senior author of the study. Chronic ischemia usually occurs in people with severe coronary blockages, and who are at risk for heart attacks, he said.
"A therapy that can increase blood vessel growth in a person with only mild coronary artery narrowing would potentially decrease the amount of heart damage if a heart attack were ever to occur," Rockman said.
Stamler is an expert in nitric oxide (NO) chemistry and S-nitrosylation, a reaction perhaps as common in all cells as phosphorylation, a process that turns on enzymes for biological activity. Stamler's lab has been studying a class of compounds called S-nitrosothiols (SNOs) that regulate S-nitrosylation, and the most prevalent of these is GSNO (S-nitrosoglutathione). Rockman's group has been studying ways to protect the heart from failing, which has lead to a natural collaboration by these two investigators to study the role in S-nitrosylation in cardiac protection.
"We knew that NO had benefits in the heart and helped blood flow and blood vessel growth (angiogenesis), but we didn't know why, so that is what Dr. Rockman and I were exploring in this study," Stamler said.
The scientists also had discovered the enzyme in question, GSNOR, which breaks down GSNO and turns off the S-nitrosylation reactions in cells. Accumulating evidence suggests that the SNOs play various key roles in human health and disease.
"We wondered what the consequences would be if an animal did not have the GSNOR enzyme, so we created mice without the enzyme and studied heart function," Stamler said. "Lo and behold, there were clearly advantages to the animals, but there were no changes in their big blood vessels, no malformations. The answer was that small blood vessels - the capillaries - grew like crazy and established new pathways for blood flow." This was the case in six of the experimental animals studied compared with six normal mice.
Stamler said that the questions to ponder now are how long it takes to grow new blood vessels, and are there are dangerous or undesirable effects anywhere else in the animals?
Potentially, he foresees a day when people whose arteries are in the early stages of blockage could be treated so they can grow new blood vessels to preserve their heart function.
Notes:
The work was supported by an NIH grant. Other authors included Brian Lima, Nestor Villamizar, Jeffrey Nienaber, Emily Messina, and Dawn Bowles of the Duke Department of Surgery; Gregory Lamb, Liang Xie, Diana L. Diesen, and Christopher D. Kontos of the Duke Department of Medicine; and Joshua M. Hare of the Division of Cardiology of the University of Miami Miller School of Medicine.
Source:
Mary Jane Gore
Duke University Medical Center
The findings raise the possibility of a therapy that could stimulate the growth of blood vessels and limit damage from a heart attack as well as prevent an attack from occurring at all, the scientists said.
Normal mice that went through the same experiment had full heart attacks, suffering damage to their heart pumps and a lack of oxygen in their heart tissues, which are typical effects of a heart attack.
The scientists found that in mice lacking the enzyme GNSOR (or S-nitrosoglutathione reductase) the blood was able to get around the blockage point that normally would cut off blood to the heart because of remarkable capillary growth in these animals.
"There were blood vessels everywhere in these mice born without the enzyme," said Jonathan Stamler, M.D., a Duke professor of medicine and biochemistry and author of the study published in the Proceedings of the National Academy of Sciences online on March 27. "The hope is that this discovery someday could result in a therapy for new blood vessel growth that could be a sort of natural bypass in humans. Perhaps it could also benefit patients with peripheral artery disease, who cannot walk, for example, but who might be able to grow new blood vessels in their legs."
Stamler said his research group might look into the question of improving peripheral artery disease.
"Normally if you block the major artery to a heart, oxygen tension drops in the tissues - you can't get oxygen to the tissues and they die," Stamler said. "This appears to be a major step forward in the science of stimulating blood vessel growth around the heart, which many people have been trying to do."
"The remarkable aspect of this study is that we show that under conditions of elevated levels of nitric oxide, the heart can grow new blood vessels in the absence of chronic ischemia (inadequate circulation)," said Howard Rockman, M.D., Duke professor of medicine, chief of cardiology at Duke Heart Center and senior author of the study. Chronic ischemia usually occurs in people with severe coronary blockages, and who are at risk for heart attacks, he said.
"A therapy that can increase blood vessel growth in a person with only mild coronary artery narrowing would potentially decrease the amount of heart damage if a heart attack were ever to occur," Rockman said.
Stamler is an expert in nitric oxide (NO) chemistry and S-nitrosylation, a reaction perhaps as common in all cells as phosphorylation, a process that turns on enzymes for biological activity. Stamler's lab has been studying a class of compounds called S-nitrosothiols (SNOs) that regulate S-nitrosylation, and the most prevalent of these is GSNO (S-nitrosoglutathione). Rockman's group has been studying ways to protect the heart from failing, which has lead to a natural collaboration by these two investigators to study the role in S-nitrosylation in cardiac protection.
"We knew that NO had benefits in the heart and helped blood flow and blood vessel growth (angiogenesis), but we didn't know why, so that is what Dr. Rockman and I were exploring in this study," Stamler said.
The scientists also had discovered the enzyme in question, GSNOR, which breaks down GSNO and turns off the S-nitrosylation reactions in cells. Accumulating evidence suggests that the SNOs play various key roles in human health and disease.
"We wondered what the consequences would be if an animal did not have the GSNOR enzyme, so we created mice without the enzyme and studied heart function," Stamler said. "Lo and behold, there were clearly advantages to the animals, but there were no changes in their big blood vessels, no malformations. The answer was that small blood vessels - the capillaries - grew like crazy and established new pathways for blood flow." This was the case in six of the experimental animals studied compared with six normal mice.
Stamler said that the questions to ponder now are how long it takes to grow new blood vessels, and are there are dangerous or undesirable effects anywhere else in the animals?
Potentially, he foresees a day when people whose arteries are in the early stages of blockage could be treated so they can grow new blood vessels to preserve their heart function.
Notes:
The work was supported by an NIH grant. Other authors included Brian Lima, Nestor Villamizar, Jeffrey Nienaber, Emily Messina, and Dawn Bowles of the Duke Department of Surgery; Gregory Lamb, Liang Xie, Diana L. Diesen, and Christopher D. Kontos of the Duke Department of Medicine; and Joshua M. Hare of the Division of Cardiology of the University of Miami Miller School of Medicine.
Source:
Mary Jane Gore
Duke University Medical Center
Genetically Altered Mice Stay Lean With High-Carb Diet
Researchers at the University of California, Berkeley, have identified a gene that plays a critical regulatory role in the process of converting dietary carbohydrates to fat. In a new study, they disabled this gene in mice, which consequently had lower levels of body fat than their normal counterparts, despite being fed the equivalent of an all-you-can-eat pasta buffet.
The authors of the study, to be published in the March 20 issue of the journal Cell, say the gene, called DNA-PK, could potentially play a role in the prevention of obesity related to the over-consumption of high-carbohydrate foods, such as pasta, rice, soda and sugary snacks.
DNA-PK, which stands for DNA-dependent protein kinase, has already been the subject of much research because it helps repair breaks in the DNA. Suppression of DNA-PK has been used as a technique by researchers to enhance the ability of cancer treatments to kill tumor cells. Its role in fat synthesis, then, came as a surprise to the UC Berkeley researchers.
"It turns out that DNA-PK is critical to a metabolic process we have been trying to understand for 20 years," said Hei Sook Sul, a professor in UC Berkeley's Department of Nutritional Science & Toxicology and head of the research team behind these new findings. "For the first time, we have connected DNA-PK to the signaling pathway involved in the formation of fat from carbohydrates in the liver. Identifying this signaling pathway involving DNA-PK brings us one step forward in understanding obesity resulting from a diet high in carbohydrates, and could possibly serve as a potential pharmacological target for obesity prevention."
After a meal of pizza and soda, it is known that levels of blood glucose - the digested form of carbohydrates - go up. That rise in blood glucose triggers the secretion of the hormone insulin, which helps different cells in the body use glucose for energy. Glucose in the liver that isn't burned for energy turns into fatty acids, which then circulate to other parts of the body, primarily to fat tissue.
This conversion of excess glucose into fatty acids occurs in the liver, but the exact molecular pathway involved has not been fully understood until now. Researchers have known that insulin binds to receptors on the liver cells, which activates protein phosphatase-1 (PP1), the first molecule of the insulin-signaling pathway inside the liver cell. Sul's lab had previously shown that upstream stimulatory factor (USF) is needed to activate certain genes, such as fatty acid synthase (FAS), which converts glucose to fatty acids.
The link between PP1 and USF was still a mystery until Roger H. F. Wong, a UC Berkeley graduate student in comparative biochemistry in Sul's lab, finally connected the dots through proteomic sequencing. He found that DNA-PK, which is regulated by PP1, controls the activation of USF and the subsequent conversion of glucose to fatty acids.
"The missing link was DNA-PK," said Wong. "We determined that DNA-PK acts as a signaling molecule in the chain reaction that begins when insulin binds to receptors on liver cells. This helps explain why untreated Type 1 diabetics, who cannot produce insulin, may experience significant weight loss. Without treatment, they basically have trouble making enough fat."
"This insulin-signaling pathway is also disrupted in Type 2 diabetes, in which the body still produces insulin, but the cells become resistant to its effects," said Wong.
After identifying DNA-PK, the researchers put the gene to the test in mice fed a diet containing 70 percent carbohydrates, but no fat. A typical lab mouse diet is made up of both fat and carbohydrates. Half the mice had the DNA-PK gene disabled, and the other half comprised a control group of normal mice.
"The DNA-PK disabled mice were leaner and had 40 percent less body fat compared with a control group of normal mice because of their deficiency in turning carbs into fat," said Wong. "The knockout mice were resistant to high carbohydrate-induced obesity and had lower plasma lipids, which can reduce the risk of cardiovascular disease. With all of these health benefits, this gene can serve as a potential pharmacological target for obesity prevention."
The researchers noted that although interest in low-carb diets persists, there are many sources of carbohydrates, including fruits and vegetables, legumes and whole grain breads and pastas, that have important nutritional benefits.
"The best way to control your body weight is to eat a well-balanced diet and limit your caloric intake," said Wong. "We hope that this research will one day help people eat bread, pasta and rice and not worry about getting fat."
Notes:
This study is part of the larger research effort by the Sul lab to understand the molecular mechanisms underlying the synthesis of fatty acids, creation of fat cells and how fat is stored in the body. Recently, the lab published a study in the journal Cell Metabolism describing how a molecule called Pref-1 blocks the creation of fat cells. Two months ago, the discovery by Sul's lab of an enzyme called AdPLA critical to the breakdown of fat cells, was published in the journal Nature Medicine. This latest paper in Cell details the very first step of fat synthesis - making fat from carbohydrate.
Other co-authors of this study are members of Sul's lab and include several undergraduate students in the Department of Nutritional Science & Toxicology.
The National Institutes of Health helped support this study in Cell.
Source: Sarah Yang
University of California - Berkeley
The authors of the study, to be published in the March 20 issue of the journal Cell, say the gene, called DNA-PK, could potentially play a role in the prevention of obesity related to the over-consumption of high-carbohydrate foods, such as pasta, rice, soda and sugary snacks.
DNA-PK, which stands for DNA-dependent protein kinase, has already been the subject of much research because it helps repair breaks in the DNA. Suppression of DNA-PK has been used as a technique by researchers to enhance the ability of cancer treatments to kill tumor cells. Its role in fat synthesis, then, came as a surprise to the UC Berkeley researchers.
"It turns out that DNA-PK is critical to a metabolic process we have been trying to understand for 20 years," said Hei Sook Sul, a professor in UC Berkeley's Department of Nutritional Science & Toxicology and head of the research team behind these new findings. "For the first time, we have connected DNA-PK to the signaling pathway involved in the formation of fat from carbohydrates in the liver. Identifying this signaling pathway involving DNA-PK brings us one step forward in understanding obesity resulting from a diet high in carbohydrates, and could possibly serve as a potential pharmacological target for obesity prevention."
After a meal of pizza and soda, it is known that levels of blood glucose - the digested form of carbohydrates - go up. That rise in blood glucose triggers the secretion of the hormone insulin, which helps different cells in the body use glucose for energy. Glucose in the liver that isn't burned for energy turns into fatty acids, which then circulate to other parts of the body, primarily to fat tissue.
This conversion of excess glucose into fatty acids occurs in the liver, but the exact molecular pathway involved has not been fully understood until now. Researchers have known that insulin binds to receptors on the liver cells, which activates protein phosphatase-1 (PP1), the first molecule of the insulin-signaling pathway inside the liver cell. Sul's lab had previously shown that upstream stimulatory factor (USF) is needed to activate certain genes, such as fatty acid synthase (FAS), which converts glucose to fatty acids.
The link between PP1 and USF was still a mystery until Roger H. F. Wong, a UC Berkeley graduate student in comparative biochemistry in Sul's lab, finally connected the dots through proteomic sequencing. He found that DNA-PK, which is regulated by PP1, controls the activation of USF and the subsequent conversion of glucose to fatty acids.
"The missing link was DNA-PK," said Wong. "We determined that DNA-PK acts as a signaling molecule in the chain reaction that begins when insulin binds to receptors on liver cells. This helps explain why untreated Type 1 diabetics, who cannot produce insulin, may experience significant weight loss. Without treatment, they basically have trouble making enough fat."
"This insulin-signaling pathway is also disrupted in Type 2 diabetes, in which the body still produces insulin, but the cells become resistant to its effects," said Wong.
After identifying DNA-PK, the researchers put the gene to the test in mice fed a diet containing 70 percent carbohydrates, but no fat. A typical lab mouse diet is made up of both fat and carbohydrates. Half the mice had the DNA-PK gene disabled, and the other half comprised a control group of normal mice.
"The DNA-PK disabled mice were leaner and had 40 percent less body fat compared with a control group of normal mice because of their deficiency in turning carbs into fat," said Wong. "The knockout mice were resistant to high carbohydrate-induced obesity and had lower plasma lipids, which can reduce the risk of cardiovascular disease. With all of these health benefits, this gene can serve as a potential pharmacological target for obesity prevention."
The researchers noted that although interest in low-carb diets persists, there are many sources of carbohydrates, including fruits and vegetables, legumes and whole grain breads and pastas, that have important nutritional benefits.
"The best way to control your body weight is to eat a well-balanced diet and limit your caloric intake," said Wong. "We hope that this research will one day help people eat bread, pasta and rice and not worry about getting fat."
Notes:
This study is part of the larger research effort by the Sul lab to understand the molecular mechanisms underlying the synthesis of fatty acids, creation of fat cells and how fat is stored in the body. Recently, the lab published a study in the journal Cell Metabolism describing how a molecule called Pref-1 blocks the creation of fat cells. Two months ago, the discovery by Sul's lab of an enzyme called AdPLA critical to the breakdown of fat cells, was published in the journal Nature Medicine. This latest paper in Cell details the very first step of fat synthesis - making fat from carbohydrate.
Other co-authors of this study are members of Sul's lab and include several undergraduate students in the Department of Nutritional Science & Toxicology.
The National Institutes of Health helped support this study in Cell.
Source: Sarah Yang
University of California - Berkeley
Fish Evolve A Longer Lifespan By Evolving A Longer Reproductive Period, Researchers Find
A UC Riverside-led research team has found that as some populations of an organism evolve a longer lifespan, they do so by increasing only that segment of the lifespan that contributes to "fitness" - the relative ability of an individual to contribute offspring to the next generation.
Focusing on guppies, small fresh-water fish biologists have studied for long, the researchers found that guppies living in environments with a large number of predators have adapted to reproduce earlier in life than guppies from low-predation localities. Moreover, when reproduction ceases, guppies from high-predation localities are far older, on average, than guppies from low-predation localities, indicating that high-predation guppies enjoy a long "reproductive period" - the time between first and last reproduction.
"In earlier work, we showed that guppies from high predation environments have longer lifespans," said David Reznick, professor of biology. "Our new study explores how and why this happens. We found that fish from populations enjoying longer lifespans live longer because there is a selective increase in their reproductive lifespan. Indeed, theory predicts this result because only reproductive lifespan determines fitness."
Study results appear Dec. 27 in the online edition of the Public Library of Science - Biology.
The study supports the controversial hypothesis that natural selection - the process in nature by which only organisms best adapted to their environment tend to survive and pass on their genetic characters in increasing numbers to succeeding generations - introduces changes in only a specific segment of an organism's lifespan.
The researchers conducted their experiments by comparing life-history traits in 240 guppies they retrieved from high- and low-predation streams in mountains in Trinidad. In their analysis, they divided the life history into three non-overlapping segments: the age at maturity (birth to first reproduction), the reproductive lifespan (first to last reproduction) and the post-reproductive lifespan (last reproduction to death). They also devised a statistical criterion for evaluating whether or not guppies had a post-reproductive lifespan, that is, did guppies live significantly past the end of their capacity to reproduce?
"We were exploring whether or not fish have the equivalent of mammalian menopause," Reznick said. "We found that 60 percent of the fish had a significant post-reproductive lifespan, indicating that, yes, fish do have menopause. Indeed, their patterns of growing old are similar to those of mammals."
The researchers' statistical analysis also showed that regardless of which environments the guppies lived in, there were no differences among their populations in the probability of having a post-reproductive lifespan or in its duration.
"This is just what one might predict because these fish provide no care for their young," explained Reznick. "The older fish, after they stop reproducing, do not contribute to the fitness of young fish. As a result, the post-reproductive period is not influenced by natural selection. This result could be of interest to those who study menopause in humans and who have argued that post-reproductive humans can increase their own fitness by contributing to the fitness of their grandchildren and that the prolonged post-reproductive lifespan of humans is, therefore, the product of natural selection.
"But such arguments are difficult to prove by working on a single population or species. Nevertheless, our results show how it would be possible to evaluate whether or not menopause in humans has been shaped by natural selection. Appropriate comparisons, such as those between humans and apes, would help."
Reznick was assisted in the study by Michael Bryant of the California Institute of the Arts and Donna Holmes of the University of Idaho. The Population Biology Division of the National Research Foundation provided support.
Iqbal Pittalwala
iqbalucr
University of California - Riverside
ucr
Focusing on guppies, small fresh-water fish biologists have studied for long, the researchers found that guppies living in environments with a large number of predators have adapted to reproduce earlier in life than guppies from low-predation localities. Moreover, when reproduction ceases, guppies from high-predation localities are far older, on average, than guppies from low-predation localities, indicating that high-predation guppies enjoy a long "reproductive period" - the time between first and last reproduction.
"In earlier work, we showed that guppies from high predation environments have longer lifespans," said David Reznick, professor of biology. "Our new study explores how and why this happens. We found that fish from populations enjoying longer lifespans live longer because there is a selective increase in their reproductive lifespan. Indeed, theory predicts this result because only reproductive lifespan determines fitness."
Study results appear Dec. 27 in the online edition of the Public Library of Science - Biology.
The study supports the controversial hypothesis that natural selection - the process in nature by which only organisms best adapted to their environment tend to survive and pass on their genetic characters in increasing numbers to succeeding generations - introduces changes in only a specific segment of an organism's lifespan.
The researchers conducted their experiments by comparing life-history traits in 240 guppies they retrieved from high- and low-predation streams in mountains in Trinidad. In their analysis, they divided the life history into three non-overlapping segments: the age at maturity (birth to first reproduction), the reproductive lifespan (first to last reproduction) and the post-reproductive lifespan (last reproduction to death). They also devised a statistical criterion for evaluating whether or not guppies had a post-reproductive lifespan, that is, did guppies live significantly past the end of their capacity to reproduce?
"We were exploring whether or not fish have the equivalent of mammalian menopause," Reznick said. "We found that 60 percent of the fish had a significant post-reproductive lifespan, indicating that, yes, fish do have menopause. Indeed, their patterns of growing old are similar to those of mammals."
The researchers' statistical analysis also showed that regardless of which environments the guppies lived in, there were no differences among their populations in the probability of having a post-reproductive lifespan or in its duration.
"This is just what one might predict because these fish provide no care for their young," explained Reznick. "The older fish, after they stop reproducing, do not contribute to the fitness of young fish. As a result, the post-reproductive period is not influenced by natural selection. This result could be of interest to those who study menopause in humans and who have argued that post-reproductive humans can increase their own fitness by contributing to the fitness of their grandchildren and that the prolonged post-reproductive lifespan of humans is, therefore, the product of natural selection.
"But such arguments are difficult to prove by working on a single population or species. Nevertheless, our results show how it would be possible to evaluate whether or not menopause in humans has been shaped by natural selection. Appropriate comparisons, such as those between humans and apes, would help."
Reznick was assisted in the study by Michael Bryant of the California Institute of the Arts and Donna Holmes of the University of Idaho. The Population Biology Division of the National Research Foundation provided support.
Iqbal Pittalwala
iqbalucr
University of California - Riverside
ucr
Major Proteomics Initiative Project A Hope For The Future
Biologists still have no clear idea how many active genes there are coding for proteins in humans and other organisms, even though for some species the genomes have been completely sequenced. This is because many of the genes and their protein products have only been predicted by computer algorithms that are at this time imperfect.
The field of proteomics aims to discover all the proteins produced by a given organism. Such a proteome map would bring the possibility of deducing the precise number, and location in the genome, of the genes coding for proteins. This is much more complex than simply mapping the genome from end to end because it involves detecting all proteins even though some are present only in very small amounts, while some are confined to specific organs and/or are only synthesised at certain times or stages of an organism's life.
However a recent workshop supported by the European Science Foundation (ESF) concluded that it is now feasible to map at least nearly the whole proteome (the sum total of all proteins) of an organism. Such an extensive map will be an essential base for the development and eventually the widespread application of a new generation of proteomics technologies that are faster, more sensitive and more reliable than the present methods.
These technologies, in turn, thanks to their improved performance could greatly improve understanding of many diseases and lead to new therapies, according to the ESF workshop's coordinator Professor Rudolf Aebersold from Institute of Molecular Systems Biology in Switerzland. Most diseases, including cancer and many pathogenic infections, involve disruption to regulatory processes in cells or tissues with associated changes in the abundance of proteins and their interactions, Aebersold pointed out. "The idea would be that if we could map out the whole proteome, we could develop a toolbox structure enabling assays (for detecting proteins) to be done faster and more cheaply." It would then be possible to identify proteins implicated in a particular disease more readily, helping both with research into underlying causes, and ultimately in diagnosis.
Mapping the proteome will also help resolve one of biology's more recent puzzles, which is why all organisms, from the simplest to the most complex, contain a significantly higher number of predicted protein coding genes than experimentally detected proteins. The shortfall is significant -- in almost all organisms there are only about 65 per cent as many proteins as had been predicted through analysis of the genome. This is a surprise because each gene had been understood to code for a protein on a one-to-one basis. As Aebersold pointed out, there are several possible explanations for this apparent anomaly. The simplest explanation is simply a lack of sensitivity of proteomics methods, which may as a result have failed so far to identify specific classes of proteins. However given the increasing sensitivity of proteomics methods, this explanation is increasingly unlikely.
Another possibility is that there are not as many coding genes as had been thought. The number has not yet been reliably counted, and is currently estimated by computer predictions based on knowledge of the sequence structure of genes already known. Another possibility is that there are as many genes as had been thought, but either that a substantial number code for proteins that are only very rarely or under specific conditions expressed in cells or tissues, or that the mRNA, which is the intermediate product between the DNA of the genome and the proteins, is not translated into the final protein product.
Aebersold hopes that the workshop will lead to a major EU-funded project to map complete proteomes, answer some of these questions, and arrive at a more accurate count of how many genes there are in humans and other organisms. "If something can be identified as a protein, that's the most direct evidence we can have that a gene really exists," said Aebersold. It will though be hard to tell when the job is done, because the proteome, unlike the genome, is not a stable, defined physical entity. While the genome comprises the famous double helix of DNA that can be physically sequenced on an end-to-end basis, the proteome is simply the total of all proteins, and so by definition you can never be absolutely sure the last one has been found, given that some are present intermittently or in small amounts and can easily be missed during analysis. Mass spectrometry is used to perform this analysis and identify proteins in complex samples, after applying some technique such as chromatography to separate out the individual proteins. The amino acid sequence of each protein can be determined after separation, from the relationship between electric charge and mass.
As Aebersold noted, the biggest prize of proteomics will be a much simpler and efficient technique for identifying individual proteins within samples, which could eventually have huge diagnostic power as well as application in research and across the whole field of biotechnology and pharmacology. The ESF workshop has prepared the ground by helping establish the collaborative framework for Europe to participate fully in the great proteomics initiative, and now it is up to the EU to provide the funding.
The workshop Model Organism Proteomics, which was one of the series of events organised by the ESF Exploratory Workshops, was held 11-13 April 2007, in Zurich, Switzerland. Delegates were given a thorough overview of the state of the field and Europe's place in it, with details of various successful collaborations. Following the workshop, Europe is much better placed to harness its resources in the field effectively.
Each year, ESF supports approximately 50 Exploratory Workshops across all scientific domains. These small, interactive group sessions are aimed at opening up new directions in research to explore new fields with a potential impact on developments in science
Source: Rudolf Aebersold
European Science Foundation
The field of proteomics aims to discover all the proteins produced by a given organism. Such a proteome map would bring the possibility of deducing the precise number, and location in the genome, of the genes coding for proteins. This is much more complex than simply mapping the genome from end to end because it involves detecting all proteins even though some are present only in very small amounts, while some are confined to specific organs and/or are only synthesised at certain times or stages of an organism's life.
However a recent workshop supported by the European Science Foundation (ESF) concluded that it is now feasible to map at least nearly the whole proteome (the sum total of all proteins) of an organism. Such an extensive map will be an essential base for the development and eventually the widespread application of a new generation of proteomics technologies that are faster, more sensitive and more reliable than the present methods.
These technologies, in turn, thanks to their improved performance could greatly improve understanding of many diseases and lead to new therapies, according to the ESF workshop's coordinator Professor Rudolf Aebersold from Institute of Molecular Systems Biology in Switerzland. Most diseases, including cancer and many pathogenic infections, involve disruption to regulatory processes in cells or tissues with associated changes in the abundance of proteins and their interactions, Aebersold pointed out. "The idea would be that if we could map out the whole proteome, we could develop a toolbox structure enabling assays (for detecting proteins) to be done faster and more cheaply." It would then be possible to identify proteins implicated in a particular disease more readily, helping both with research into underlying causes, and ultimately in diagnosis.
Mapping the proteome will also help resolve one of biology's more recent puzzles, which is why all organisms, from the simplest to the most complex, contain a significantly higher number of predicted protein coding genes than experimentally detected proteins. The shortfall is significant -- in almost all organisms there are only about 65 per cent as many proteins as had been predicted through analysis of the genome. This is a surprise because each gene had been understood to code for a protein on a one-to-one basis. As Aebersold pointed out, there are several possible explanations for this apparent anomaly. The simplest explanation is simply a lack of sensitivity of proteomics methods, which may as a result have failed so far to identify specific classes of proteins. However given the increasing sensitivity of proteomics methods, this explanation is increasingly unlikely.
Another possibility is that there are not as many coding genes as had been thought. The number has not yet been reliably counted, and is currently estimated by computer predictions based on knowledge of the sequence structure of genes already known. Another possibility is that there are as many genes as had been thought, but either that a substantial number code for proteins that are only very rarely or under specific conditions expressed in cells or tissues, or that the mRNA, which is the intermediate product between the DNA of the genome and the proteins, is not translated into the final protein product.
Aebersold hopes that the workshop will lead to a major EU-funded project to map complete proteomes, answer some of these questions, and arrive at a more accurate count of how many genes there are in humans and other organisms. "If something can be identified as a protein, that's the most direct evidence we can have that a gene really exists," said Aebersold. It will though be hard to tell when the job is done, because the proteome, unlike the genome, is not a stable, defined physical entity. While the genome comprises the famous double helix of DNA that can be physically sequenced on an end-to-end basis, the proteome is simply the total of all proteins, and so by definition you can never be absolutely sure the last one has been found, given that some are present intermittently or in small amounts and can easily be missed during analysis. Mass spectrometry is used to perform this analysis and identify proteins in complex samples, after applying some technique such as chromatography to separate out the individual proteins. The amino acid sequence of each protein can be determined after separation, from the relationship between electric charge and mass.
As Aebersold noted, the biggest prize of proteomics will be a much simpler and efficient technique for identifying individual proteins within samples, which could eventually have huge diagnostic power as well as application in research and across the whole field of biotechnology and pharmacology. The ESF workshop has prepared the ground by helping establish the collaborative framework for Europe to participate fully in the great proteomics initiative, and now it is up to the EU to provide the funding.
The workshop Model Organism Proteomics, which was one of the series of events organised by the ESF Exploratory Workshops, was held 11-13 April 2007, in Zurich, Switzerland. Delegates were given a thorough overview of the state of the field and Europe's place in it, with details of various successful collaborations. Following the workshop, Europe is much better placed to harness its resources in the field effectively.
Each year, ESF supports approximately 50 Exploratory Workshops across all scientific domains. These small, interactive group sessions are aimed at opening up new directions in research to explore new fields with a potential impact on developments in science
Source: Rudolf Aebersold
European Science Foundation
Journal Of Clinical Investigation Table Of Contents: March 23, 2009
Licorice extract blocks colorectal cancer in mice
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and drugs that selectively target a protein known as COX-2 prevent the development of intestinal polyps, the precursors of colorectal cancer. However, these drugs have severe side effects that preclude their routine use in the prevention of colorectal cancer. But now, a team of researchers, at Vanderbilt University School of Medicine, Nashville, has found that inhibiting an enzyme known as 11-beta-HSD2 (both genetically and using an extract from licorice) blocks COX-2 activity in human and mouse colorectal tumor cells, inhibiting their growth and metastasis in experimental models of colorectal cancer. Importantly, long-term inhibition of 11-beta-HSD2 did not have side effects on the heart and blood vessels of mice, as long-term treatment with selective COX-2 inhibitors does. The authors therefore suggest that inhibiting 11-beta-HSD2 might provide a new approach to preventing colorectal cancer.
In an accompanying commentary, Paul Stewart and Stephen Prescott, highlight the importance of these data for the development of a potential new therapeutic option in colorectal cancer.
TITLE: Inhibition of 11-beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans
AUTHOR CONTACT:
Ming-Zhi Zhang
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Raymond C. Harris
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
View the PDF of this article at: https://the-jci/article.php?id=37398
ACCOMPANYING COMMENTARY
TITLE: Can licorice lick colon cancer?
AUTHOR CONTACT:
Paul M. Stewart
University of Birmingham, Birmingham, United Kingdom
Stephen M. Prescott
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
View the PDF of this article at: https://the-jci/article.php?id=38936
Approach to treat bone loss might increase bone cancer risk
One approach being considered as a new way to treat osteoporosis is the development of molecules that block the action of proteins that inhibit the Wnt signaling pathway. However, dysregulated Wnt signaling is associated with several cancers. Further, David Thomas and colleagues, at Peter MacCallum Cancer Centre, Australia, have now shown that the gene responsible for making the Wnt signaling pathway inhibitor WIF1 is silenced in human osteosarcomas (the most common form of bone cancer) and that its absence in mice accelerated the development of radiation-induced osteosarcomas. The authors therefore conclude that targeting Wnt signaling pathway inhibitors is likely to increase susceptibility to osteosarcomas. Thus, both the authors and, in an accompany commentary, Greg Enders, at Fox Chase Cancer Center, Philadelphia, note that caution is needed before this approach is used in clinical trials to treat patients with bone loss disorders such as osteoporosis.
TITLE: Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
AUTHOR CONTACT:
David M. Thomas
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
View the PDF of this article at: https://the-jci/article.php?id=37175
ACCOMPANYING COMMENTARY
TITLE: Wnt therapy for bone loss: golden goose or Trojan horse?
AUTHOR CONTACT:
Greg H. Enders
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
View the PDF of this article at: https://the-jci/article.php?id=38973
GENE THERAPY: Making gene therapy safer using self-inactivating LTRs
Several patients in gene therapy clinical trials have developed leukemia as a result of their treatment. The underlying cause of leukemia is thought to be that the viral vectors used to carry the therapeutic gene into cells (gamma-RVs) integrate into the genome of the cells disrupting the natural control of cancer-associated genes (a process known as insertional mutagenesis). By analyzing specific elements of gamma-RVs and another type of viral vector, LVs, in a tumor-prone mouse model, a team of researchers, at San Raffaele-Telethon Institute for Gene Therapy, Italy, has now provided evidence that LVs are substantially less likely to cause insertional mutagenesis and tumors than gamma-RVs. Further, they found that modifying an element (known as the LTR) of both LVs and gamma-RVs such that it is self-inactivating (SIN) further improved safety. The authors therefore conclude that SIN viral vectors should be the preferred choice in future gene therapy trials.
In an accompanying commentary, Ute Modlich and Christopher Baum, at Hannover Medical School, Germany, discuss the clinical importance of these data and the numerous questions that they pose for future research.
TITLE: The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy
AUTHOR CONTACT:
Eugenio Montini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
Luigi Naldini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
View the PDF of this article at: https://the-jci/article.php?id=37630
ACCOMPANYING COMMENTARY
TITLE: Preventing and exploiting the oncogenic potential of integrating gene vectors
AUTHOR CONTACT:
Christopher Baum
Hannover Medical School, Hannover, Germany.
View the PDF of this article at: https://the-jci/article.php?id=38831
ONCOLOGY: Too much oxygen not a good thing for tumors
As tumors grow, some regions lack a blood supply adequate to maintain good levels of oxygen, that is some regions become hypoxic. This is a hallmark of malignant tumors and has been suggested, but not experimentally proven, to promote tumor progression. However, Paolo Michieli and colleagues, at the University of Turin Medical School, Italy, have now developed xenograft models to examine how human lung tumors without regions of hypoxia develop and found that tumors rely on hypoxia to promote their own expansion.
In the study, human lung cancer cells were engineered to express the protein myoglobin, which specializes in oxygen transport, storage, and buffering. When these cells were injected into mice, the tumors that developed exhibited no regions of hypoxia, and this was associated with both markedly reduced tumor growth and an inability to metastasize to secondary locations. Further analysis confirmed that the effects were mainly a result of decreased tumor hypoxia, leading the authors to conclude that hypoxia seems to be a key factor driving tumor progression.
In an accompanying commentary, Ulrich Flögel and Chi Dang, highlight the importance of these data and discus other ways in which myoglobin might affect tumor progression.
TITLE: Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis
AUTHOR CONTACT:
Paolo Michieli
University of Turin Medical School, Turin, Italy.
View the PDF of this article at: https://the-jci/article.php?id=36579
ACCOMPANYING COMMENTARY
TITLE: Myoglobin tames tumor growth and spread
AUTHOR CONTACT:
Ulrich Flögel,
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Chi Dang
Johns Hopkins Medicine, Baltimore, Maryland, USA.
View the PDF of this article at: https://the-jci/article.php?id=38796
NEPHROLOGY: New gene linked to low levels of magnesium
A small number of individuals have genetic mutations that cause them to have very low levels of magnesium (Mg2+), which can cause altered heart beats, seizures, and involuntary muscle contraction. Study of these patients has provided a lot of our information about how Mg2+ levels are normally controlled, which is of clinical importance as it has been estimated that up to 60% of critically ill patients have low Mg2+ levels, and this is associated with increased mortality. RenГ© Bindels and colleagues, at Radboud University Nijmegen Medical Centre, The Netherlands, have now identified a new gene mutation in a family with hypomagnesemia, providing new insight into the mechanisms that regulate Mg2+ levels.
In the study, a mutation in the KCNA1 gene, which makes a protein known as Kv1.1, was found to cause hypomagnesemia in a large family with many individuals suffering from the disease. Detailed analysis revealed that the mutation generated a nonfunctional Kv1.1 protein and that it affected Mg2+ reabsorption by the protein TRPM6 in a region of the kidney known as the distal convoluted tubule. In an accompanying commentary, David Ellison, at Oregon Health & Science University, Portland, discusses the importance of the data and suggests how they might explain some of the clinical situations in which critically ill patients have low Mg2+ levels.
TITLE: A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
AUTHOR CONTACT:
RenГ© J. Bindels
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
View the PDF of this article at: https://the-jci/article.php?id=36948
ACCOMPANYING COMMENTARY
TITLE: The voltage-gated K+ channel subunit, Kv1.1, links kidney and brain
AUTHOR CONTACT:
David H. Ellison
Oregon Health & Science University, Portland, Oregon, USA.
View the PDF of this article at: https://the-jci/article.php?id=38835
NEPHROLOGY: Protective role for kallikrein proteins in kidney disease
A team of researchers, at the University of Texas Southwestern Medical Center, Dallas, and Uppsala University, Sweden, has shed new light on several forms of the kidney disease known as nephritis. Specifically, the data indicate a protective role for kallikrein proteins in anti-GBM antibody-induced nephritis (a mouse model of Goodpasture syndrome) and spontaneous lupus nephritis in mice and humans.
In the study, which was led by Chandra Mohan, Edward Wakeland, and Marta AlarcГіn-Riquelme, kallikrein genes were found to be underexpressed in the kidneys of mouse strains sensitive to anti-GBM antibody-induced nephritis. Conversely, mouse strains that upregulated kallikreins in the kidneys showed fewer signs of disease. Consistent with this, antagonizing the kallikrein pathway enhanced disease and agonists dampened disease severity. As both human systemic lupus erythematosus and spontaneous lupus nephritis were found to be associated with kallikrein genes, the authors conclude that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus. In an accompanying commentary, Claudio Ponticelli and Pier Luigi Meroni, at IRCCS Istituto Clinico Humanitas, Italy, discuss this possibility and suggest alternative roles for kallikreins in lupus nephritis.
TITLE: Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans
AUTHOR CONTACT:
Chandra Mohan
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Edward Wakeland
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Marta AlarcГіn-Riquelme
Uppsala University, Uppsala, Sweden.
View the PDF of this article at: https://the-jci/article.php?id=36728
ACCOMPANYING COMMENTARY
TITLE: Kallikreins and lupus nephritis
AUTHOR CONTACT:
Claudio Ponticelli
IRCCS Istituto Clinico Humanitas, Milano, Italy.
View the PDF of this article at: https://the-jci/article.php?id=38786
DERMATOLOGY: The protein SRF keeps the skin healthy
Sabine Werner and colleagues, at the Institute of Cell Biology, ETH ZГјrich, Switzerland, have determined a role for the protein SRF in the skin and found that its expression is markedly decreased in the diseased areas of skin of individuals with psoriasis.
In the study, human skin cells known as keratinocytes were found to express high levels of SRF when healthy but only low levels when psoriatic and when wounded. Mice lacking SRF in keratinocytes during embryonic development died in utero, whereas mice in which SRF was absent in keratinocytes only after birth developed psoriasis-like skin lesions. Further analysis characterized the lesions and led the authors to suggest that SRF is critical for normal maintenance of healthy skin and that it may have a role in the development of skin diseases such as psoriasis.
TITLE: Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice
AUTHOR CONTACT:
Sabine Werner
Institute of Cell Biology, ETH ZГјrich, ZГјrich, Switzerland.
View the PDF of this article at: https://the-jci/article.php?id=37771
Source: Karen Honey
Journal of Clinical Investigation
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and drugs that selectively target a protein known as COX-2 prevent the development of intestinal polyps, the precursors of colorectal cancer. However, these drugs have severe side effects that preclude their routine use in the prevention of colorectal cancer. But now, a team of researchers, at Vanderbilt University School of Medicine, Nashville, has found that inhibiting an enzyme known as 11-beta-HSD2 (both genetically and using an extract from licorice) blocks COX-2 activity in human and mouse colorectal tumor cells, inhibiting their growth and metastasis in experimental models of colorectal cancer. Importantly, long-term inhibition of 11-beta-HSD2 did not have side effects on the heart and blood vessels of mice, as long-term treatment with selective COX-2 inhibitors does. The authors therefore suggest that inhibiting 11-beta-HSD2 might provide a new approach to preventing colorectal cancer.
In an accompanying commentary, Paul Stewart and Stephen Prescott, highlight the importance of these data for the development of a potential new therapeutic option in colorectal cancer.
TITLE: Inhibition of 11-beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans
AUTHOR CONTACT:
Ming-Zhi Zhang
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Raymond C. Harris
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
View the PDF of this article at: https://the-jci/article.php?id=37398
ACCOMPANYING COMMENTARY
TITLE: Can licorice lick colon cancer?
AUTHOR CONTACT:
Paul M. Stewart
University of Birmingham, Birmingham, United Kingdom
Stephen M. Prescott
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
View the PDF of this article at: https://the-jci/article.php?id=38936
Approach to treat bone loss might increase bone cancer risk
One approach being considered as a new way to treat osteoporosis is the development of molecules that block the action of proteins that inhibit the Wnt signaling pathway. However, dysregulated Wnt signaling is associated with several cancers. Further, David Thomas and colleagues, at Peter MacCallum Cancer Centre, Australia, have now shown that the gene responsible for making the Wnt signaling pathway inhibitor WIF1 is silenced in human osteosarcomas (the most common form of bone cancer) and that its absence in mice accelerated the development of radiation-induced osteosarcomas. The authors therefore conclude that targeting Wnt signaling pathway inhibitors is likely to increase susceptibility to osteosarcomas. Thus, both the authors and, in an accompany commentary, Greg Enders, at Fox Chase Cancer Center, Philadelphia, note that caution is needed before this approach is used in clinical trials to treat patients with bone loss disorders such as osteoporosis.
TITLE: Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice
AUTHOR CONTACT:
David M. Thomas
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
View the PDF of this article at: https://the-jci/article.php?id=37175
ACCOMPANYING COMMENTARY
TITLE: Wnt therapy for bone loss: golden goose or Trojan horse?
AUTHOR CONTACT:
Greg H. Enders
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
View the PDF of this article at: https://the-jci/article.php?id=38973
GENE THERAPY: Making gene therapy safer using self-inactivating LTRs
Several patients in gene therapy clinical trials have developed leukemia as a result of their treatment. The underlying cause of leukemia is thought to be that the viral vectors used to carry the therapeutic gene into cells (gamma-RVs) integrate into the genome of the cells disrupting the natural control of cancer-associated genes (a process known as insertional mutagenesis). By analyzing specific elements of gamma-RVs and another type of viral vector, LVs, in a tumor-prone mouse model, a team of researchers, at San Raffaele-Telethon Institute for Gene Therapy, Italy, has now provided evidence that LVs are substantially less likely to cause insertional mutagenesis and tumors than gamma-RVs. Further, they found that modifying an element (known as the LTR) of both LVs and gamma-RVs such that it is self-inactivating (SIN) further improved safety. The authors therefore conclude that SIN viral vectors should be the preferred choice in future gene therapy trials.
In an accompanying commentary, Ute Modlich and Christopher Baum, at Hannover Medical School, Germany, discuss the clinical importance of these data and the numerous questions that they pose for future research.
TITLE: The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy
AUTHOR CONTACT:
Eugenio Montini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
Luigi Naldini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
View the PDF of this article at: https://the-jci/article.php?id=37630
ACCOMPANYING COMMENTARY
TITLE: Preventing and exploiting the oncogenic potential of integrating gene vectors
AUTHOR CONTACT:
Christopher Baum
Hannover Medical School, Hannover, Germany.
View the PDF of this article at: https://the-jci/article.php?id=38831
ONCOLOGY: Too much oxygen not a good thing for tumors
As tumors grow, some regions lack a blood supply adequate to maintain good levels of oxygen, that is some regions become hypoxic. This is a hallmark of malignant tumors and has been suggested, but not experimentally proven, to promote tumor progression. However, Paolo Michieli and colleagues, at the University of Turin Medical School, Italy, have now developed xenograft models to examine how human lung tumors without regions of hypoxia develop and found that tumors rely on hypoxia to promote their own expansion.
In the study, human lung cancer cells were engineered to express the protein myoglobin, which specializes in oxygen transport, storage, and buffering. When these cells were injected into mice, the tumors that developed exhibited no regions of hypoxia, and this was associated with both markedly reduced tumor growth and an inability to metastasize to secondary locations. Further analysis confirmed that the effects were mainly a result of decreased tumor hypoxia, leading the authors to conclude that hypoxia seems to be a key factor driving tumor progression.
In an accompanying commentary, Ulrich Flögel and Chi Dang, highlight the importance of these data and discus other ways in which myoglobin might affect tumor progression.
TITLE: Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis
AUTHOR CONTACT:
Paolo Michieli
University of Turin Medical School, Turin, Italy.
View the PDF of this article at: https://the-jci/article.php?id=36579
ACCOMPANYING COMMENTARY
TITLE: Myoglobin tames tumor growth and spread
AUTHOR CONTACT:
Ulrich Flögel,
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Chi Dang
Johns Hopkins Medicine, Baltimore, Maryland, USA.
View the PDF of this article at: https://the-jci/article.php?id=38796
NEPHROLOGY: New gene linked to low levels of magnesium
A small number of individuals have genetic mutations that cause them to have very low levels of magnesium (Mg2+), which can cause altered heart beats, seizures, and involuntary muscle contraction. Study of these patients has provided a lot of our information about how Mg2+ levels are normally controlled, which is of clinical importance as it has been estimated that up to 60% of critically ill patients have low Mg2+ levels, and this is associated with increased mortality. RenГ© Bindels and colleagues, at Radboud University Nijmegen Medical Centre, The Netherlands, have now identified a new gene mutation in a family with hypomagnesemia, providing new insight into the mechanisms that regulate Mg2+ levels.
In the study, a mutation in the KCNA1 gene, which makes a protein known as Kv1.1, was found to cause hypomagnesemia in a large family with many individuals suffering from the disease. Detailed analysis revealed that the mutation generated a nonfunctional Kv1.1 protein and that it affected Mg2+ reabsorption by the protein TRPM6 in a region of the kidney known as the distal convoluted tubule. In an accompanying commentary, David Ellison, at Oregon Health & Science University, Portland, discusses the importance of the data and suggests how they might explain some of the clinical situations in which critically ill patients have low Mg2+ levels.
TITLE: A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
AUTHOR CONTACT:
RenГ© J. Bindels
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
View the PDF of this article at: https://the-jci/article.php?id=36948
ACCOMPANYING COMMENTARY
TITLE: The voltage-gated K+ channel subunit, Kv1.1, links kidney and brain
AUTHOR CONTACT:
David H. Ellison
Oregon Health & Science University, Portland, Oregon, USA.
View the PDF of this article at: https://the-jci/article.php?id=38835
NEPHROLOGY: Protective role for kallikrein proteins in kidney disease
A team of researchers, at the University of Texas Southwestern Medical Center, Dallas, and Uppsala University, Sweden, has shed new light on several forms of the kidney disease known as nephritis. Specifically, the data indicate a protective role for kallikrein proteins in anti-GBM antibody-induced nephritis (a mouse model of Goodpasture syndrome) and spontaneous lupus nephritis in mice and humans.
In the study, which was led by Chandra Mohan, Edward Wakeland, and Marta AlarcГіn-Riquelme, kallikrein genes were found to be underexpressed in the kidneys of mouse strains sensitive to anti-GBM antibody-induced nephritis. Conversely, mouse strains that upregulated kallikreins in the kidneys showed fewer signs of disease. Consistent with this, antagonizing the kallikrein pathway enhanced disease and agonists dampened disease severity. As both human systemic lupus erythematosus and spontaneous lupus nephritis were found to be associated with kallikrein genes, the authors conclude that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus. In an accompanying commentary, Claudio Ponticelli and Pier Luigi Meroni, at IRCCS Istituto Clinico Humanitas, Italy, discuss this possibility and suggest alternative roles for kallikreins in lupus nephritis.
TITLE: Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans
AUTHOR CONTACT:
Chandra Mohan
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Edward Wakeland
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Marta AlarcГіn-Riquelme
Uppsala University, Uppsala, Sweden.
View the PDF of this article at: https://the-jci/article.php?id=36728
ACCOMPANYING COMMENTARY
TITLE: Kallikreins and lupus nephritis
AUTHOR CONTACT:
Claudio Ponticelli
IRCCS Istituto Clinico Humanitas, Milano, Italy.
View the PDF of this article at: https://the-jci/article.php?id=38786
DERMATOLOGY: The protein SRF keeps the skin healthy
Sabine Werner and colleagues, at the Institute of Cell Biology, ETH ZГјrich, Switzerland, have determined a role for the protein SRF in the skin and found that its expression is markedly decreased in the diseased areas of skin of individuals with psoriasis.
In the study, human skin cells known as keratinocytes were found to express high levels of SRF when healthy but only low levels when psoriatic and when wounded. Mice lacking SRF in keratinocytes during embryonic development died in utero, whereas mice in which SRF was absent in keratinocytes only after birth developed psoriasis-like skin lesions. Further analysis characterized the lesions and led the authors to suggest that SRF is critical for normal maintenance of healthy skin and that it may have a role in the development of skin diseases such as psoriasis.
TITLE: Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice
AUTHOR CONTACT:
Sabine Werner
Institute of Cell Biology, ETH ZГјrich, ZГјrich, Switzerland.
View the PDF of this article at: https://the-jci/article.php?id=37771
Source: Karen Honey
Journal of Clinical Investigation
Transglutaminase 2 Undergoes A Large Conformational Change Upon Activation
The transglutaminase family of enzymes is best known for crosslinking
proteins to form networks that strengthen tissues. Although this enzyme
family
has been extensively studied, a detailed understanding of the catalytic
mechanism has been hampered by the lack of a structure in which the enzyme
is
active.
This week in the open-access journal PLoS Biology, Daniel Pinkas,
Chaitan Khosla, and colleagues show how they have solved, at atomic
resolution, the structure of transglutaminase 2 (TG2) in complex with a
molecule that mimics a natural substrate. The structure exposes the active
site, giving direct insights into the catalytic mechanism. Unexpectedly,
they observed a very large conformational change with respect to previous
transglutaminase structures. Very few proteins have been observed to
undergo this type of large-scale transformation.
They propose a role for
this
structural rearrangement in the early stages of celiac disease, an
autoimmune disorder in which TG2 is the principal auto-antigen. Besides
the
fundamental implications, these results should allow for the rational
design of better inhibitors of TG2 for pharmacological and therapeutic
purposes.
Citation: Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase
2 undergoes a large conformational change upon activation. PLoS Biol
5(12):
e327. doi:10.1371/journal.pbio.0050327
Please click here
plosbiology
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
proteins to form networks that strengthen tissues. Although this enzyme
family
has been extensively studied, a detailed understanding of the catalytic
mechanism has been hampered by the lack of a structure in which the enzyme
is
active.
This week in the open-access journal PLoS Biology, Daniel Pinkas,
Chaitan Khosla, and colleagues show how they have solved, at atomic
resolution, the structure of transglutaminase 2 (TG2) in complex with a
molecule that mimics a natural substrate. The structure exposes the active
site, giving direct insights into the catalytic mechanism. Unexpectedly,
they observed a very large conformational change with respect to previous
transglutaminase structures. Very few proteins have been observed to
undergo this type of large-scale transformation.
They propose a role for
this
structural rearrangement in the early stages of celiac disease, an
autoimmune disorder in which TG2 is the principal auto-antigen. Besides
the
fundamental implications, these results should allow for the rational
design of better inhibitors of TG2 for pharmacological and therapeutic
purposes.
Citation: Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase
2 undergoes a large conformational change upon activation. PLoS Biol
5(12):
e327. doi:10.1371/journal.pbio.0050327
Please click here
plosbiology
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
New Location Found For Regulation Of RNA Fate
Thousands of scientists and hundreds of software programmers studying the process by which RNA inside cells normally degrades may soon broaden their focus significantly.
That's because University of Wisconsin-Madison researchers have discovered that the RNA degradation, which, when improperly regulated can lead to cancer and other diseases, can be launched in an unexpected location.
"We've been seeing only half the picture," says Vladimir Spiegelman, lead author on the new study and associate professor of dermatology at the UW-Madison School of Medicine and Public Health.
The Wisconsin team also found that CRD-BP, a protein activated in colorectal and other cancers, can prevent RNA from degrading in the newly identified spot.
The finding may have broad implications for cancer research as well as biology in general.
"The finding is important for the proto-oncogenes, or precursor cancer genes, we study, but it may be even more important for the thousands of other genes and proteins that are regulated in a similar way," says Spiegelman.
The study appears in the July 31 issue of Molecular Cell.
Spiegelman and his team study proto-oncogenes and other potential "cancer-causers" normally found in cells, analyzing them as they are "converted" from DNA into RNA and ultimately active proteins that can lead to cancer.
It's the same multistep process all genes in a cell - including "cancer-preventers" such as tumor suppressors, anti-inflammatory factors and cell death promoters - go through.
Controls at each step usually keep the process working smoothly, but if a control fails at any number of places along the way, a cancer-promoting gene can tilt the delicately balanced scale toward malignancy.
In their previous work, the Wisconsin researchers found that regulation of some proto-oncogenes occurs after CRD-BP binds to messenger RNA (mRNA). During this intermediary step, mRNA is typically either degraded or goes on unharmed to the next step of translation. The Wisconsin team showed that the mRNA bound by CRD-BP was not degraded, and thus became an active protein - in this case, a full-fledged cancer-causing oncogene.
Until the Spiegelman group's latest study appeared, scientists assumed that the regulation of mRNA fate took place exclusively in an area of the RNA strand called the 3 prime untranslated region, where small regulatory RNAs called microRNAs (miRNA) bind and inhibit mRNAs.
But the Wisconsin team found degradation can also be initiated in an area on the mRNA strand called the coding region.
"This changes the paradigm," says Spiegelman. "Now we can examine this important activity in two places."
The researchers demonstrated that degradation occurs here using a human mRNA, and described the mechanism by which CRD-BP stabilizes the mRNA and prevents it from degrading and expressing more protein.
"This may be the first example of a negative regulator of an miRNA-dependent RNA-degrading mechanism," Spiegelman says.
The mechanism is relevant to many proteins, he says.
"Understanding this mechanism should also help us in studying cell signaling pathways related to pro-inflammatory and cell death factors that contribute to tumor development," he says.
Source:
Dian Land
University of Wisconsin-Madison
That's because University of Wisconsin-Madison researchers have discovered that the RNA degradation, which, when improperly regulated can lead to cancer and other diseases, can be launched in an unexpected location.
"We've been seeing only half the picture," says Vladimir Spiegelman, lead author on the new study and associate professor of dermatology at the UW-Madison School of Medicine and Public Health.
The Wisconsin team also found that CRD-BP, a protein activated in colorectal and other cancers, can prevent RNA from degrading in the newly identified spot.
The finding may have broad implications for cancer research as well as biology in general.
"The finding is important for the proto-oncogenes, or precursor cancer genes, we study, but it may be even more important for the thousands of other genes and proteins that are regulated in a similar way," says Spiegelman.
The study appears in the July 31 issue of Molecular Cell.
Spiegelman and his team study proto-oncogenes and other potential "cancer-causers" normally found in cells, analyzing them as they are "converted" from DNA into RNA and ultimately active proteins that can lead to cancer.
It's the same multistep process all genes in a cell - including "cancer-preventers" such as tumor suppressors, anti-inflammatory factors and cell death promoters - go through.
Controls at each step usually keep the process working smoothly, but if a control fails at any number of places along the way, a cancer-promoting gene can tilt the delicately balanced scale toward malignancy.
In their previous work, the Wisconsin researchers found that regulation of some proto-oncogenes occurs after CRD-BP binds to messenger RNA (mRNA). During this intermediary step, mRNA is typically either degraded or goes on unharmed to the next step of translation. The Wisconsin team showed that the mRNA bound by CRD-BP was not degraded, and thus became an active protein - in this case, a full-fledged cancer-causing oncogene.
Until the Spiegelman group's latest study appeared, scientists assumed that the regulation of mRNA fate took place exclusively in an area of the RNA strand called the 3 prime untranslated region, where small regulatory RNAs called microRNAs (miRNA) bind and inhibit mRNAs.
But the Wisconsin team found degradation can also be initiated in an area on the mRNA strand called the coding region.
"This changes the paradigm," says Spiegelman. "Now we can examine this important activity in two places."
The researchers demonstrated that degradation occurs here using a human mRNA, and described the mechanism by which CRD-BP stabilizes the mRNA and prevents it from degrading and expressing more protein.
"This may be the first example of a negative regulator of an miRNA-dependent RNA-degrading mechanism," Spiegelman says.
The mechanism is relevant to many proteins, he says.
"Understanding this mechanism should also help us in studying cell signaling pathways related to pro-inflammatory and cell death factors that contribute to tumor development," he says.
Source:
Dian Land
University of Wisconsin-Madison
Human Kin Recognition Is Self- Rather Than Family-Referential
We feel more altruistic toward people who resemble us; this tendency probably evolved because it stimulated our ancestors to help their kin.
There were no mirrors then, so people could learn what kin looked like only by inspecting the faces of household members; these, however, may or may not be family. Hence, evolution might have favored a rewritable kin-image, where information about household members is replaced by any newly available information about the self.
Supporting this hypothesis, we found that even identical twins preferred helping strangers whose faces had been covertly manipulated to resemble their own rather than their co-twin's.
Royal Society Journal Biology Letters
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of the journal is diverse and is especially strong in organismal biology.
rspb.royalsocietypublishing
There were no mirrors then, so people could learn what kin looked like only by inspecting the faces of household members; these, however, may or may not be family. Hence, evolution might have favored a rewritable kin-image, where information about household members is replaced by any newly available information about the self.
Supporting this hypothesis, we found that even identical twins preferred helping strangers whose faces had been covertly manipulated to resemble their own rather than their co-twin's.
Royal Society Journal Biology Letters
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of the journal is diverse and is especially strong in organismal biology.
rspb.royalsocietypublishing
Breakthrough In The Understanding Of Cell Development
How do plants and animals end up with right number of cells in all the right places?
For the first time, scientists have gained an insight into how this process is co-ordinated in plants. An international team, including Cardiff University's School of Biosciences and Duke University in the USA, have linked the process of cell division with the way cells acquire their different characteristics.
A protein called Short-root, already known to play a part in determining what cells will become, was also found to control cell division.
The researchers report their findings on July 1 in the journal Nature. The discovery may have implications for animals and improve our understanding of what happens when organs are deformed.
The research team had already studied the molecular-level events that determine how particular cells in plants develop into different types. These events involve Short-root and another protein, Scarecrow.
Researchers also had a good understanding of the factors which allow cells to go through their cycle and divide into two daughter cells. "What was missing was a connection between the two," according to Dr Rosangela Sozzani, a postdoctoral researcher at the Duke Institute for Genome Sciences and Policy, North Carolina, who was lead author of the new study.
The research team combined a number of experimental techniques and technologies to produce a dynamic view of the genetic events that Short-root and its partner Scarecrow set into motion within a single type of cell in Arabidopsis plants. They found that at the very same time that cells divide, Short-root and Scarecrow switch on the gene cyclin D6. Cyclin D6 is one of a family of genes that govern cell growth and division.
Professor Jim Murray, who led the Cardiff University involvement in the discovery, said: "Not only does this finding have practical significance to our understanding of how plants develop, this may also be a fundamental process which is relevant to animals as well. For example, we already know that cyclin D6 is present in humans. We also know that disruption of this process can lead to tumours or badly-formed organs, so it is vital that we know more about it."
Source:
Stephen Rouse
Cardiff University
For the first time, scientists have gained an insight into how this process is co-ordinated in plants. An international team, including Cardiff University's School of Biosciences and Duke University in the USA, have linked the process of cell division with the way cells acquire their different characteristics.
A protein called Short-root, already known to play a part in determining what cells will become, was also found to control cell division.
The researchers report their findings on July 1 in the journal Nature. The discovery may have implications for animals and improve our understanding of what happens when organs are deformed.
The research team had already studied the molecular-level events that determine how particular cells in plants develop into different types. These events involve Short-root and another protein, Scarecrow.
Researchers also had a good understanding of the factors which allow cells to go through their cycle and divide into two daughter cells. "What was missing was a connection between the two," according to Dr Rosangela Sozzani, a postdoctoral researcher at the Duke Institute for Genome Sciences and Policy, North Carolina, who was lead author of the new study.
The research team combined a number of experimental techniques and technologies to produce a dynamic view of the genetic events that Short-root and its partner Scarecrow set into motion within a single type of cell in Arabidopsis plants. They found that at the very same time that cells divide, Short-root and Scarecrow switch on the gene cyclin D6. Cyclin D6 is one of a family of genes that govern cell growth and division.
Professor Jim Murray, who led the Cardiff University involvement in the discovery, said: "Not only does this finding have practical significance to our understanding of how plants develop, this may also be a fundamental process which is relevant to animals as well. For example, we already know that cyclin D6 is present in humans. We also know that disruption of this process can lead to tumours or badly-formed organs, so it is vital that we know more about it."
Source:
Stephen Rouse
Cardiff University
Dr. William Degrado Honored With The Ralph F. Hirschmann Award In Peptide Chemistry
Dr. William DeGrado, the scientific
founder of PolyMedix, Inc. (OTC BB: PYMX, polymedix), was
named the 2008 recipient of the prestigious Ralph F. Hirschmann Award
in Peptide Chemistry. The award recognizes a person who has made
outstanding contributions in the chemistry, biochemistry, or
biophysics of peptides.
Dr. DeGrado is the scientific founder of and Chief Scientific Advisor
for PolyMedix, an emerging biotechnology company developing new
therapeutic drugs for serious, life-threatening acute cardiovascular
and infectious disease. He is a Professor of Biochemistry and
Biophysics at the University of Pennsylvania School of Medicine in
Philadelphia, PA, and a member of the National Academy of Sciences.
He is a former President of the Protein Society, has over twenty
issued U.S. patents, and has over two hundred publications to his name.
Dr. DeGrado's work laid the foundations for PolyMedix's core lead
drug development programs and product candidates. Both PMX-30063
antibiotic, the world's first small molecule mimetic of host defense
proteins intended for systemic use, and PMX-60056 heptagonist, a new
reversing agent for heparin and Low Molecular Weight Heparins, are
based on pioneering discoveries originally made by Dr. DeGrado.
The Ralph F. Hirschmann Award was established by The Merck Research
Laboratories in 1988. This award, administered by the American
Chemical Society (ACS) was presented to Dr. DeGrado at the awards
ceremony on Tuesday, April 8, 2008, in conjunction with the 235th ACS
national meeting in New Orleans, LA.
"It is a great privilege and honor to work with such a renowned
scientist as Dr. DeGrado. PolyMedix has been able to achieve great
things because we have had the good fortune of building on the
pioneering breakthroughs of Dr. DeGrado. We look forward to
continuing to work together with him in the development of important
new medicines," commented Nicholas Landekic, President & Chief
Executive Officer of PolyMedix.
About PolyMedix, Inc
PolyMedix is a publicly traded biotechnology company focused on the
development of novel drugs and biomaterials for the treatment of
infectious diseases and acute cardiovascular disorders. PolyMedix's
compounds are based on biomimetics: non-peptide small molecule drugs
that mimic the activity of proteins. The Company's antibiotic
compounds - small molecule mimetics of human host-defense proteins -
are believed to have a completely different mechanism of action from
all current antibiotic drugs, a mechanism which is intended to make
bacterial resistance unlikely to develop. These compounds are being
developed as rapidly acting antibiotics for serious systemic and
local infections. The Company is also developing polymeric
formulations as antimicrobial biomaterials, which can be used as
additives to paints, plastics, and textiles to create self-
sterilizing products and surfaces. The Company's heptagonist
compounds reverse the activity of both heparin and low molecular
weight heparins, in keeping with our goal of developing an antagonist
drug that is safer and easier to use than currently approved therapy.
PolyMedix plans to shortly file regulatory applications in
anticipation of commencing human clinical trials for both its
antibiotic and heptagonist compounds. For more information, please
visit PolyMedix on its website at polymedix.
This press release contains forward-looking statements made pursuant
to the safe harbor provisions of the Private Securities Litigation
Reform Act of 1995 that involve risks and that could cause
PolyMedix's actual results and experience to differ materially from
anticipated results and expectations expressed in these forward
looking statements. PolyMedix has tried, wherever possible, to
identify these forward-looking statements by using words such as
"anticipates," "believes," "hopes," "estimates," "looks," "expects,"
"plans," "intends" and similar expressions. Among other things, there
can be no assurance that PolyMedix's compounds will enter or
successfully complete clinical testing or be granted regulatory
approval to be sold and marketed in the Unites States or elsewhere. A
more complete description of these risks, uncertainties and
assumptions is included in PolyMedix's filings with the Securities
and Exchange Commission. You should not place undue reliance on any
forward-looking statements. PolyMedix undertakes no obligation to
release publicly the results of any revisions to any such forward-
looking statements that may be made to reflect events or
circumstances after the date of this press release or to reflect the
occurrence of unanticipated events.
polymedix
founder of PolyMedix, Inc. (OTC BB: PYMX, polymedix), was
named the 2008 recipient of the prestigious Ralph F. Hirschmann Award
in Peptide Chemistry. The award recognizes a person who has made
outstanding contributions in the chemistry, biochemistry, or
biophysics of peptides.
Dr. DeGrado is the scientific founder of and Chief Scientific Advisor
for PolyMedix, an emerging biotechnology company developing new
therapeutic drugs for serious, life-threatening acute cardiovascular
and infectious disease. He is a Professor of Biochemistry and
Biophysics at the University of Pennsylvania School of Medicine in
Philadelphia, PA, and a member of the National Academy of Sciences.
He is a former President of the Protein Society, has over twenty
issued U.S. patents, and has over two hundred publications to his name.
Dr. DeGrado's work laid the foundations for PolyMedix's core lead
drug development programs and product candidates. Both PMX-30063
antibiotic, the world's first small molecule mimetic of host defense
proteins intended for systemic use, and PMX-60056 heptagonist, a new
reversing agent for heparin and Low Molecular Weight Heparins, are
based on pioneering discoveries originally made by Dr. DeGrado.
The Ralph F. Hirschmann Award was established by The Merck Research
Laboratories in 1988. This award, administered by the American
Chemical Society (ACS) was presented to Dr. DeGrado at the awards
ceremony on Tuesday, April 8, 2008, in conjunction with the 235th ACS
national meeting in New Orleans, LA.
"It is a great privilege and honor to work with such a renowned
scientist as Dr. DeGrado. PolyMedix has been able to achieve great
things because we have had the good fortune of building on the
pioneering breakthroughs of Dr. DeGrado. We look forward to
continuing to work together with him in the development of important
new medicines," commented Nicholas Landekic, President & Chief
Executive Officer of PolyMedix.
About PolyMedix, Inc
PolyMedix is a publicly traded biotechnology company focused on the
development of novel drugs and biomaterials for the treatment of
infectious diseases and acute cardiovascular disorders. PolyMedix's
compounds are based on biomimetics: non-peptide small molecule drugs
that mimic the activity of proteins. The Company's antibiotic
compounds - small molecule mimetics of human host-defense proteins -
are believed to have a completely different mechanism of action from
all current antibiotic drugs, a mechanism which is intended to make
bacterial resistance unlikely to develop. These compounds are being
developed as rapidly acting antibiotics for serious systemic and
local infections. The Company is also developing polymeric
formulations as antimicrobial biomaterials, which can be used as
additives to paints, plastics, and textiles to create self-
sterilizing products and surfaces. The Company's heptagonist
compounds reverse the activity of both heparin and low molecular
weight heparins, in keeping with our goal of developing an antagonist
drug that is safer and easier to use than currently approved therapy.
PolyMedix plans to shortly file regulatory applications in
anticipation of commencing human clinical trials for both its
antibiotic and heptagonist compounds. For more information, please
visit PolyMedix on its website at polymedix.
This press release contains forward-looking statements made pursuant
to the safe harbor provisions of the Private Securities Litigation
Reform Act of 1995 that involve risks and that could cause
PolyMedix's actual results and experience to differ materially from
anticipated results and expectations expressed in these forward
looking statements. PolyMedix has tried, wherever possible, to
identify these forward-looking statements by using words such as
"anticipates," "believes," "hopes," "estimates," "looks," "expects,"
"plans," "intends" and similar expressions. Among other things, there
can be no assurance that PolyMedix's compounds will enter or
successfully complete clinical testing or be granted regulatory
approval to be sold and marketed in the Unites States or elsewhere. A
more complete description of these risks, uncertainties and
assumptions is included in PolyMedix's filings with the Securities
and Exchange Commission. You should not place undue reliance on any
forward-looking statements. PolyMedix undertakes no obligation to
release publicly the results of any revisions to any such forward-
looking statements that may be made to reflect events or
circumstances after the date of this press release or to reflect the
occurrence of unanticipated events.
polymedix
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