Researchers at Boston University School of Medicine (BUSM) recently achieved first signal on the Cryogenic Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Mass Spectrometry (MALDI-FTMS) being developed at the school's Cardiovascular Proteomics Center (CPC). The Fourier transform mass spectrometer is the highest performance instrumentation currently available to those interested in structural characterization of proteins and other biomolecules.
"When working to its full capacity, the Cryogenic MALDI-FTMS will greatly enhance how we study and understand disease," says Peter B. O'Connor, PhD, research associate professor in the Department of Biochemistry at BUSM and assistant director of the BUSM Mass Spectrometry Resource. "This technology will give us an unbiased view of a disease by identifying proteins by comparing their peptides to those predicted from a DNA database, which helps identify biomarkers for disease." O'Connor goes on to add that this new technology will also allow researchers to identify which proteins are where during certain stages of disease progression, enabling them to more positively identify disease and decide upon treatment options.
The Cryogenic MALDI-FTMS is a major advance in Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometry design. It enables MALDI-FTMS at extremely low temperatures and involves close construction and integration of an FTICR instrument with a modern cryogenic superconducting magnet design.
This configuration provides three major advantages. First, the magnet bore and FTICR cell chamber become very cold, which cryopumps the chamber and decreases the base pressure. Second, because of the cryopumping, the bore tube diameter can be much smaller, allowing high homogeneity and high magnetic fields to be generated at greatly reduced cost. Third, the cold surfaces can be used to cool a preamplifier for improved signal-to-noise ratio.
The BUSM prototype instrument is designed with a 14 Tesla magnet at ~10 ppm homogeneity over the 2x2 cylindrical ICR cell. When fully tuned, this instrument will provide performance several orders of magnitude better than existing instruments, using parts that cost about half as much and a magnet costing about four times less.
This instrument is funded by the National Institutes of Health, National Heart Lung and Blood Institute and the National Center for Research Resources.
Contact: Gina DiGravio
Boston University
воскресенье, 31 июля 2011 г.
четверг, 28 июля 2011 г.
Estrogen Therapy Gives Aging Brain Cells A Boost
Cyclical, long-term estrogen injections protected brain cells from age-related deterioration, according to a new study conducted at Mount Sinai School of Medicine. The study suggests that age is a factor in estrogen treatment and sheds light on the intricate relationship between mind, age, and hormones. The study is published in the online edition of Proceedings of the National Academy of Sciences.
In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, Assistant Professor of Neuroscience, and senior co-author John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biological Sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, Interim Chair of the Department of Neuroscience and Associate Professor of Neuroscience, and Geriatrics and Adult Development, led the behavioral phase of the study. Partrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.
Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.
Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause - before the onset of full menopause - and began treatment within months of ovariectomy.
Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex - a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys - the older estrogen-treated animals showed a greater density of synaptic spines - tentacle-like structures that link brain cells to one another and aid in brain cell communication - while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.
The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. "There's been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful."
Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.
"We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline," Dr. Morrison explains. "Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything."
"The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity," says Dr. Morrison. "Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories."
The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, "but what's happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit."
Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit.
"'It's possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all," Dr. Morrison explains, "so this window of opportunity may be fairly narrow - we just don't know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it's too late, we may possibly prevent memory loss." What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.
Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center. Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.
Contact: Mount Sinai Press Office
The Mount Sinai Hospital / Mount Sinai School of Medicine
View drug information on Estradiol Transdermal System.
In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, Assistant Professor of Neuroscience, and senior co-author John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biological Sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, Interim Chair of the Department of Neuroscience and Associate Professor of Neuroscience, and Geriatrics and Adult Development, led the behavioral phase of the study. Partrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.
Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.
Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause - before the onset of full menopause - and began treatment within months of ovariectomy.
Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex - a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys - the older estrogen-treated animals showed a greater density of synaptic spines - tentacle-like structures that link brain cells to one another and aid in brain cell communication - while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.
The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. "There's been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful."
Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.
"We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline," Dr. Morrison explains. "Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything."
"The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity," says Dr. Morrison. "Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories."
The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, "but what's happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit."
Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit.
"'It's possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all," Dr. Morrison explains, "so this window of opportunity may be fairly narrow - we just don't know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it's too late, we may possibly prevent memory loss." What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.
Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center. Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.
Contact: Mount Sinai Press Office
The Mount Sinai Hospital / Mount Sinai School of Medicine
View drug information on Estradiol Transdermal System.
понедельник, 25 июля 2011 г.
New Chemistry Approach Promises Less Expensive Drugs
With a newly discovered method of assembling organic molecules, a team of Princeton University chemists may have found a way to sidestep many of the expensive and hazardous barriers that stand in the way of drug development.
The new approach allows scientists to synthesize molecules without employing toxic catalysts, and it also does not generate alternate versions of drug molecules that can damage the body, two perennial issues that plague the manufacturing process. David MacMillan, one of the researchers on the team, said the discovery is important not only for its industrial applications, but also because of the new research possibilities it opens up.
"This is a new type of chemistry that could expand the way people think about making biologically active molecules," said MacMillan, who holds Princeton's A. Barton Hepburn Chair of Chemistry and directs the chemistry department's Merck Center for Catalysis. "We've found more than a new chemical reaction. It's a common mode of molecule activation that allows a whole group of reactions to take place."
Broadly stated, the discovery will open up new possibilities for working with ketones and aldehydes, two chemical groups that are found on a large percentage of the substances in which organic chemists are interested. "They form a big region of the reaction landscape," MacMillan said.
The paper, which MacMillan cowrote with first author Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong and Kate Ashton, all members of his research group, appears in the March 29 issue of the journal Science. John Schwab, a chemist at the National Institutes of Health (NIH), applauded the work for the new possibilities it could provide.
"One sometimes hears that organic chemistry is a mature field, but MacMillan's work shows that there still are rich veins waiting to be mined," said Schwab, also a program director at the NIH's National Institute of General Medical Sciences, which supported the work. "What's particularly exciting to me is the depth and rigor of the analysis that enabled this very creative breakthrough. Equally important, MacMillan has discovered new reactions that will streamline the synthesis of compounds that are relevant to human health."
Most drug molecules that pharmaceutical companies produce can exist in two different forms, which are mirror images of one another. Though both forms of an organic molecule -- known in the chemistry world as "enantiomers" -- have the same chemical formula, their effect on the body can differ dramatically.
"The two enantiomers are like keys with the same number of teeth, but which have different orientation," MacMillan said. "One key fits in with our biology very well, opening the correct doors in our body and helping us to heal. But the other key doesn't fit the same doors because its teeth are in opposing locations."
The two forms are indistinguishable by most modern lab tests, yet our bodies can tell the difference. Where one enantiomer might be the basis for a helpful drug, its mirror image might do nothing for the body, or even damage it.
"This was the problem in the 1960s with the drug phthalidomide," MacMillan said. "One of its enantiomers helped pregnant women overcome morning sickness. Its mirror image, however, caused birth defects."
In the vast majority of cases, the Food and Drug Administration now requires that drug companies create only the beneficial enantiomer during the manufacturing process. While this requirement keeps any of these helpful molecules' "evil twins" from reaching our systems, it also places heavy demands on the drug companies.
Building large quantities of a drug molecule often requires a catalyst, a substance that permits a chemical reaction to take place without itself being affected. Until recently, however most catalysts would create both enantiomers simultaneously, MacMillan said. In cases where the catalyst can create only the helpful enantiomer -- a process called asymmetric catalysis -- they are often expensive, capricious and difficult to work with.
"That is one reason why for several years our lab has been looking for catalysts based on organic molecules rather than metals," MacMillan said. "Organic catalysts are generally inexpensive, robust to water and air and environmentally friendly. Organic catalysts, it turns out, are proving more capable than most people expected."
Since the year 2000, MacMillan's work has enabled the discovery of a new family of organic catalysts, which can be used to produce only beneficial enantiomers. These catalysts have proven desirable because they are based on organic substances, and are therefore not harmful either to patients or to the environment. But his team's latest paper does more than offer chemists a new set of organic catalysts with which to work.
"This discovery does not yield merely more organic catalysts, but makes a whole new type of chemical reactions available to us," MacMillan said. "It's almost like a new airport hub that allows you to extend the range of your air travel. You can reach destinations that were not open to you before."
Gregory Fu of the Massachusetts Institute of Technology said that these destinations would likely prove important to the pharmaceutical industry.
"This work adds an important new dimension to efforts to achieve asymmetric catalysis," said Fu, a professor of chemistry. "It will no doubt have a substantial impact on the discovery of new bioactive compounds for the benefit of society."
MacMillan said he hopes the findings would eventually make drugs both more useful and widely available.
"The big payoff here is that the discovery will allow new chemical reactions to be developed that are powerful yet unprecedented in the field of chemistry," MacMillan said. "They will allow access to single enantiomers, and they will do it using cheap, environmentally friendly small organic molecules as catalysts. It's a double whammy."
Abstract
Enantioselective Organocatalysis using SOMO Activation
Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong, Kate Ashton and David MacMillan
The invention of new modes of catalytic activation is essential for the continued development of the field of asymmetric catalysis. Here, a unique mode of organocatalytic activation is presented wherein a chiral amine catalyst reacts with an aldehyde to transiently generate an enamine that in turn undergoes a single-electron oxidation to yield a Singly Occupied Molecular Orbital (SOMO) radical cation that is subject to enantiofacial discrimination. While the parent enamine reacts only with electrophiles, the radical cation combines with SOMO nucleophiles at the same reaction site, thereby enabling a diverse range of previously unknown asymmetric transformations. As a first example, the direct and enantioselective alpha-allylation of aldehydes is reported.
Contact: Chad Boutin
Princeton University
The new approach allows scientists to synthesize molecules without employing toxic catalysts, and it also does not generate alternate versions of drug molecules that can damage the body, two perennial issues that plague the manufacturing process. David MacMillan, one of the researchers on the team, said the discovery is important not only for its industrial applications, but also because of the new research possibilities it opens up.
"This is a new type of chemistry that could expand the way people think about making biologically active molecules," said MacMillan, who holds Princeton's A. Barton Hepburn Chair of Chemistry and directs the chemistry department's Merck Center for Catalysis. "We've found more than a new chemical reaction. It's a common mode of molecule activation that allows a whole group of reactions to take place."
Broadly stated, the discovery will open up new possibilities for working with ketones and aldehydes, two chemical groups that are found on a large percentage of the substances in which organic chemists are interested. "They form a big region of the reaction landscape," MacMillan said.
The paper, which MacMillan cowrote with first author Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong and Kate Ashton, all members of his research group, appears in the March 29 issue of the journal Science. John Schwab, a chemist at the National Institutes of Health (NIH), applauded the work for the new possibilities it could provide.
"One sometimes hears that organic chemistry is a mature field, but MacMillan's work shows that there still are rich veins waiting to be mined," said Schwab, also a program director at the NIH's National Institute of General Medical Sciences, which supported the work. "What's particularly exciting to me is the depth and rigor of the analysis that enabled this very creative breakthrough. Equally important, MacMillan has discovered new reactions that will streamline the synthesis of compounds that are relevant to human health."
Most drug molecules that pharmaceutical companies produce can exist in two different forms, which are mirror images of one another. Though both forms of an organic molecule -- known in the chemistry world as "enantiomers" -- have the same chemical formula, their effect on the body can differ dramatically.
"The two enantiomers are like keys with the same number of teeth, but which have different orientation," MacMillan said. "One key fits in with our biology very well, opening the correct doors in our body and helping us to heal. But the other key doesn't fit the same doors because its teeth are in opposing locations."
The two forms are indistinguishable by most modern lab tests, yet our bodies can tell the difference. Where one enantiomer might be the basis for a helpful drug, its mirror image might do nothing for the body, or even damage it.
"This was the problem in the 1960s with the drug phthalidomide," MacMillan said. "One of its enantiomers helped pregnant women overcome morning sickness. Its mirror image, however, caused birth defects."
In the vast majority of cases, the Food and Drug Administration now requires that drug companies create only the beneficial enantiomer during the manufacturing process. While this requirement keeps any of these helpful molecules' "evil twins" from reaching our systems, it also places heavy demands on the drug companies.
Building large quantities of a drug molecule often requires a catalyst, a substance that permits a chemical reaction to take place without itself being affected. Until recently, however most catalysts would create both enantiomers simultaneously, MacMillan said. In cases where the catalyst can create only the helpful enantiomer -- a process called asymmetric catalysis -- they are often expensive, capricious and difficult to work with.
"That is one reason why for several years our lab has been looking for catalysts based on organic molecules rather than metals," MacMillan said. "Organic catalysts are generally inexpensive, robust to water and air and environmentally friendly. Organic catalysts, it turns out, are proving more capable than most people expected."
Since the year 2000, MacMillan's work has enabled the discovery of a new family of organic catalysts, which can be used to produce only beneficial enantiomers. These catalysts have proven desirable because they are based on organic substances, and are therefore not harmful either to patients or to the environment. But his team's latest paper does more than offer chemists a new set of organic catalysts with which to work.
"This discovery does not yield merely more organic catalysts, but makes a whole new type of chemical reactions available to us," MacMillan said. "It's almost like a new airport hub that allows you to extend the range of your air travel. You can reach destinations that were not open to you before."
Gregory Fu of the Massachusetts Institute of Technology said that these destinations would likely prove important to the pharmaceutical industry.
"This work adds an important new dimension to efforts to achieve asymmetric catalysis," said Fu, a professor of chemistry. "It will no doubt have a substantial impact on the discovery of new bioactive compounds for the benefit of society."
MacMillan said he hopes the findings would eventually make drugs both more useful and widely available.
"The big payoff here is that the discovery will allow new chemical reactions to be developed that are powerful yet unprecedented in the field of chemistry," MacMillan said. "They will allow access to single enantiomers, and they will do it using cheap, environmentally friendly small organic molecules as catalysts. It's a double whammy."
Abstract
Enantioselective Organocatalysis using SOMO Activation
Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong, Kate Ashton and David MacMillan
The invention of new modes of catalytic activation is essential for the continued development of the field of asymmetric catalysis. Here, a unique mode of organocatalytic activation is presented wherein a chiral amine catalyst reacts with an aldehyde to transiently generate an enamine that in turn undergoes a single-electron oxidation to yield a Singly Occupied Molecular Orbital (SOMO) radical cation that is subject to enantiofacial discrimination. While the parent enamine reacts only with electrophiles, the radical cation combines with SOMO nucleophiles at the same reaction site, thereby enabling a diverse range of previously unknown asymmetric transformations. As a first example, the direct and enantioselective alpha-allylation of aldehydes is reported.
Contact: Chad Boutin
Princeton University
пятница, 22 июля 2011 г.
New Breakthrough On Link Between Neuronal Activity And Networking Anatomy
A direct link between activity in the brain's cortex and the
microscopic structure of the neuronal network has been shown and
published in the open access journal PLoS ONE on
May 14, 2008.
Building on an existing body of research, Roberto FernГЎndez
GalГЎn, Ph.D., an assistant professor of neurosciences at Case Western
Reserve University (CWRU) School of Medicine, investigated the small
neuronal networks in the cortex. He found that the spontaneous activity
in which they engage is not just random "noise," but rather highly
structured patterns of signals. This illuminates previous speculations,
proving that these patterns are clearly shaped by network connectivity.
"The activity patterns can be used to inform researchers about the
anatomy of the underlying neuronal network," he explains.
"Reciprocally, the connections in the network determine the patterns of
spontaneous neuronal activity and their complexity."
GalГЎn added, indicating that there could be a relatively clearly
interpreted system interlaced: "The calculations and the computer model
showed that these structured
patterns can function as an 'alphabet' of the neural code, since the
network
activity consists of combinations of these patterns, similarly to a
printed text that consists of combinations of letters." He added,
noting on the importance of these findings, that they "are useful in
determining how much information a neuronal network in the brain can
process."
This research is a major step in the understanding of neuroscience on a
systems level -- that is, how neurons behave when they are connected to
form networks. In the end, how the brain processes and stores sensory
information is important to understand why alterations between these
connections can lead to pathologies, such as epilepsy.
Dr. GalГЎn entered the faculty at CWRU's School of Medicine in February
2008 after completing postdoctoral work at Carnegie Mellon University
and the Center for Neural Basis of Cognition in Pittsburgh. Shortly
after this, he was awarded as a scholar in the Mount Sinai Health Care
Foundation Scholars program, and he is the twelfth faculty member to
receive this honor since the program's inception in 1998. "Roberto
FernГЎndez GalГЎn has made an outstanding addition to the Case
Western Reserve University School of Medicine," commented Dean Pamela
B.
Davis, M.D., Ph.D. "We are excited about the impact of this paper in
the field of
neurosciences and are looking forward to his continued contributions to
the top-tier research conducted by our faculty."
The above research was supported by the Mount Sinai Foundation, one of
the leading health philanthropies in Greater Cleveland.
About PLoS ONE
All works published in PLoS
ONE
are open-access. Everything is immediately available - to read, download,
redistribute, include in databases and otherwise use - without cost to
anyone, anywhere, subject only to the condition that the original
authorship and source are properly attributed. Copyright is retained by
the authors. The Public Library of Science uses the Creative Commons
Attribution License.
PLoS ONE is
the first journal of primary research from all areas of science to
employ both pre- and post-publication peer review to maximize the
impact of every report it publishes. PLoS ONE
is published by the Public Library of Science (PLoS), the Open-access
publisher whose goal is to make the world's scientific and medical
literature a public resource.
On How Network Architecture Determines the Dominant Patterns
of Spontaneous Neural Activity.
GalГЎn RF (2008)
PLoS ONE 3(5): e2148.
doi:10.1371/journal.pone.0002148
Click
Here For Full Length Article
Written by Anna Sophia McKenney
microscopic structure of the neuronal network has been shown and
published in the open access journal PLoS ONE on
May 14, 2008.
Building on an existing body of research, Roberto FernГЎndez
GalГЎn, Ph.D., an assistant professor of neurosciences at Case Western
Reserve University (CWRU) School of Medicine, investigated the small
neuronal networks in the cortex. He found that the spontaneous activity
in which they engage is not just random "noise," but rather highly
structured patterns of signals. This illuminates previous speculations,
proving that these patterns are clearly shaped by network connectivity.
"The activity patterns can be used to inform researchers about the
anatomy of the underlying neuronal network," he explains.
"Reciprocally, the connections in the network determine the patterns of
spontaneous neuronal activity and their complexity."
GalГЎn added, indicating that there could be a relatively clearly
interpreted system interlaced: "The calculations and the computer model
showed that these structured
patterns can function as an 'alphabet' of the neural code, since the
network
activity consists of combinations of these patterns, similarly to a
printed text that consists of combinations of letters." He added,
noting on the importance of these findings, that they "are useful in
determining how much information a neuronal network in the brain can
process."
This research is a major step in the understanding of neuroscience on a
systems level -- that is, how neurons behave when they are connected to
form networks. In the end, how the brain processes and stores sensory
information is important to understand why alterations between these
connections can lead to pathologies, such as epilepsy.
Dr. GalГЎn entered the faculty at CWRU's School of Medicine in February
2008 after completing postdoctoral work at Carnegie Mellon University
and the Center for Neural Basis of Cognition in Pittsburgh. Shortly
after this, he was awarded as a scholar in the Mount Sinai Health Care
Foundation Scholars program, and he is the twelfth faculty member to
receive this honor since the program's inception in 1998. "Roberto
FernГЎndez GalГЎn has made an outstanding addition to the Case
Western Reserve University School of Medicine," commented Dean Pamela
B.
Davis, M.D., Ph.D. "We are excited about the impact of this paper in
the field of
neurosciences and are looking forward to his continued contributions to
the top-tier research conducted by our faculty."
The above research was supported by the Mount Sinai Foundation, one of
the leading health philanthropies in Greater Cleveland.
About PLoS ONE
All works published in PLoS
ONE
are open-access. Everything is immediately available - to read, download,
redistribute, include in databases and otherwise use - without cost to
anyone, anywhere, subject only to the condition that the original
authorship and source are properly attributed. Copyright is retained by
the authors. The Public Library of Science uses the Creative Commons
Attribution License.
PLoS ONE is
the first journal of primary research from all areas of science to
employ both pre- and post-publication peer review to maximize the
impact of every report it publishes. PLoS ONE
is published by the Public Library of Science (PLoS), the Open-access
publisher whose goal is to make the world's scientific and medical
literature a public resource.
On How Network Architecture Determines the Dominant Patterns
of Spontaneous Neural Activity.
GalГЎn RF (2008)
PLoS ONE 3(5): e2148.
doi:10.1371/journal.pone.0002148
Click
Here For Full Length Article
Written by Anna Sophia McKenney
вторник, 19 июля 2011 г.
Insight Into Alzheimer's Disease Provided By Engineered Mice
One factor that determines how at risk an individual is of developing late-onset Alzheimer disease (AD) is the version of the APOE gene that they carry - those carrying the gene that enables them to make the apoE4 form of the apoE protein are at increased risk and those carrying the gene that enables them to make the apoE2 form are at decreased risk. It has been hypothesized that increasing the amount of lipid (fat) associated with apoE by overexpressing the protein ABCA1 might decrease amyloid deposition in the brain, the hallmark of AD. Evidence to support this hypothesis has now been generated in mice by David Holtzman and colleagues at Washington University School of Medicine, St Louis.
In this study, mice that provide a model of AD (PDAPP mice) were engineered to overexpress the protein ABCA1 in the brain. These mice had characteristics almost identical to PDAPP mice lacking apoE - they had decreased amyloid deposition in the brain compared with normal PDAPP mice. As the PDAPP mice overexpressing ABCA1 in the brain were shown to have increased amounts of lipid associated with apoE, the authors concluded the hypothesis that an ABCA1-mediated increase in the amount of lipid associated with apoE would decrease amyloid deposition in the brain was correct. Furthermore, they suggested that approaches to increase the function of ABCA1 in the brain might be of benefit to individuals with, or at risk of developing, AD.
Title: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Author: David M. Holtzman
Washington University School of Medicine, St Louis, Missouri, USA.
Source: Karen Honey
Journal of Clinical Investigation
In this study, mice that provide a model of AD (PDAPP mice) were engineered to overexpress the protein ABCA1 in the brain. These mice had characteristics almost identical to PDAPP mice lacking apoE - they had decreased amyloid deposition in the brain compared with normal PDAPP mice. As the PDAPP mice overexpressing ABCA1 in the brain were shown to have increased amounts of lipid associated with apoE, the authors concluded the hypothesis that an ABCA1-mediated increase in the amount of lipid associated with apoE would decrease amyloid deposition in the brain was correct. Furthermore, they suggested that approaches to increase the function of ABCA1 in the brain might be of benefit to individuals with, or at risk of developing, AD.
Title: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Author: David M. Holtzman
Washington University School of Medicine, St Louis, Missouri, USA.
Source: Karen Honey
Journal of Clinical Investigation
суббота, 16 июля 2011 г.
Developing Methods To Separate The Brain's Good And Bad Iron To Combat Parkinson's And Alzheimer's
Duke University chemists are developing ways to bind up iron in the brain to combat the neurological devastation of Parkinson's and Alzheimer's diseases. The key is to weed out potentially destructive forms of iron that generate harmful free radicals while leaving benign forms of iron alone to carry out vital functions in the body.
"Using existing chelating (metal-binding) molecules to target iron in the brain can be tricky," said Katherine Franz, an assistant chemistry professor at Duke, because iron is essential to the body. "We want to go after only the iron that is causing the damage. We don't want to pull the iron out of healthy sites."
During the American Chemical Society's August 2007 national meeting in Boston, Franz described her work with graduate student Louise Charkoudian to formulate sensitive chemical sentinels they call "pro-chelators." Those are metal-binding agents wrapped in chemical "cages" so they can enter the brain and wait in reserve until they encounter a site of potential damage.
Such a site contains both iron and the molecule hydrogen peroxide. The reaction between these two players -- known as a "Fenton reaction" -- can lead to the production of a highly reactive oxygen-containing chemical group called a hydroxyl radical, Franz said.
These toxic chemical radicals can cause oxidative stress in brain cells that has been associated with Parkinson's and Alzheimer's as well as other age-related maladies such as macular degeneration in the eyes, she said.
The pro-chelators that Franz described at the ACS meeting contain phenols that wear chemical "masks" around themselves to keep them from binding with benign forms of iron or other metals, such as those found in some essential enzymes. But the presence of excessive amounts of hydrogen peroxide will trigger an unmasking, allowing the phenols to sop up and inactivate the bad iron, she said.
Franz and Charkoudian described their first formula for a pro-chelator in a report printed in the Sept. 27, 2006, issue of the Journal of the American Chemical Society. The work is being supported by the Parkinson's Disease Foundation and Duke University.
Franz's talk at the society's latest national meeting concentrated on a second generation of pro-chelator compounds that are better tailored in both sensitivity and response time to the brain's chemical environment, she said.
A report on those newer compounds is also pending in the journal Dalton Transactions and includes contributions by post-doctoral associate David Pham and Duke undergraduate students Ashley Kwon and Abbey Vangeloff.
While their previous experiments have been in laboratory glassware, the Duke pair has now begun working with living cells.
"That work looks promising," Franz said. "It looks like we're seeing iron binding only when we increase the levels of hydrogen peroxide. This level of peroxide normally kills cells, but we are seeing cell survival with the pro-chelators, so we're very excited."
Source: Monte Basgall
Duke University
"Using existing chelating (metal-binding) molecules to target iron in the brain can be tricky," said Katherine Franz, an assistant chemistry professor at Duke, because iron is essential to the body. "We want to go after only the iron that is causing the damage. We don't want to pull the iron out of healthy sites."
During the American Chemical Society's August 2007 national meeting in Boston, Franz described her work with graduate student Louise Charkoudian to formulate sensitive chemical sentinels they call "pro-chelators." Those are metal-binding agents wrapped in chemical "cages" so they can enter the brain and wait in reserve until they encounter a site of potential damage.
Such a site contains both iron and the molecule hydrogen peroxide. The reaction between these two players -- known as a "Fenton reaction" -- can lead to the production of a highly reactive oxygen-containing chemical group called a hydroxyl radical, Franz said.
These toxic chemical radicals can cause oxidative stress in brain cells that has been associated with Parkinson's and Alzheimer's as well as other age-related maladies such as macular degeneration in the eyes, she said.
The pro-chelators that Franz described at the ACS meeting contain phenols that wear chemical "masks" around themselves to keep them from binding with benign forms of iron or other metals, such as those found in some essential enzymes. But the presence of excessive amounts of hydrogen peroxide will trigger an unmasking, allowing the phenols to sop up and inactivate the bad iron, she said.
Franz and Charkoudian described their first formula for a pro-chelator in a report printed in the Sept. 27, 2006, issue of the Journal of the American Chemical Society. The work is being supported by the Parkinson's Disease Foundation and Duke University.
Franz's talk at the society's latest national meeting concentrated on a second generation of pro-chelator compounds that are better tailored in both sensitivity and response time to the brain's chemical environment, she said.
A report on those newer compounds is also pending in the journal Dalton Transactions and includes contributions by post-doctoral associate David Pham and Duke undergraduate students Ashley Kwon and Abbey Vangeloff.
While their previous experiments have been in laboratory glassware, the Duke pair has now begun working with living cells.
"That work looks promising," Franz said. "It looks like we're seeing iron binding only when we increase the levels of hydrogen peroxide. This level of peroxide normally kills cells, but we are seeing cell survival with the pro-chelators, so we're very excited."
Source: Monte Basgall
Duke University
среда, 13 июля 2011 г.
Unfolding The Genetic Code
It turns out that sequencing the human genome - determining the order of DNA building blocks -- has not completely cracked the code of how DNA directs various cellular processes. In addition to the sequence of the base pairs, the instructions are in the packaging - how DNA is folded within a cell.
Virginia Tech researchers used novel methodology and the university's System X supercomputer to carry out what is probably the first simulation that explores full range of motions of a DNA strand of 147 base pairs, the length that is required to form the fundamental unit of DNA packing in the living cells -- the nucleosome. Contrary to a long-held belief that DNA is hard to bend, the simulation shows in crisp atomic detail that DNA is considerably more flexible than commonly thought.
The research is published in the December issue of the Biophysical Journal, in the article "A Computational Study of Nucleosomal DNA Flexibility," by Jory Zmuda Ruscio of Leesburg, Va., a Ph.D. student in the Genetics, Bioinformatics and Computational Biology Program at Virginia Tech, and Alexey Onufriev of Blacksburg, assistant professor of computer sciences and physics at Virginia Tech. They have been invited to do a platform presentation at the 51st Biophysical Society Annual Meeting in Baltimore in March.
There is about 12 feet of DNA in a human cell but it is packaged into nucleosomes - lengths of 147 base pairs each wrapped around eight special proteins. A nucleosome looks kind of like the lumpy beginning of a rubber-band ball. Or maybe more like a lumpy worm coil. Uncoiled, the worm wiggles, flexes, and even kinks, according to a simulation performed on System X.
As we know from watching forensic detective shows on TV, the DNA in all of an individual's cells is identical. The DNA in fingernail cells is exactly the same as in muscle. Yet the cells are different. "This is because, roughly speaking, the DNA in different cell types is packed differently and the complexes it forms with the surrounding proteins are in different positions, so only the relevant part of the code can be read at a time," said Onufriev. "Although nobody knows exactly how it happens, you can imagine reading only what you can see on a part of a crumpled newspaper."
The traditional view is that DNA is relatively rigid and that considerable energy is required when it needs to be bent to form protein-DNA complexes. However, recent experiments (Nature, Aug. 17, 2006) have begun to challenge that view. "The famous double-helix may be much more flexible than previously thought," said Onufriev.
The Virginia Tech research responded to this debate. Using 128 of System X's 1,100 processors, the research resulted in a System X movie revealing DNA wiggling like a worm, showing greater flexibility than expected from the traditional view. The DNA packing in the nucleosome is also found to be surprisingly loose. "The implication is that it may not cost much energy to bend the DNA - even to bend sharply," said Onufriev.
The methodology that is making it possible is based on the so-called "implicit solvent" approach being developed by Onufriev. "Biology does not happen in a vacuum," he said. "We are 75 percent water, and the effect of the water environment must be taken into account when studying biomolecules."
Previous simulations were often slowed because they accounted for the water that is present in living systems. For instance, in early studies of protein folding, only a few percent of the computing effort was being spent on the activity of the protein while the rest accounted for the activity of the surrounding fluids. The "implicit solvent" approach accounts for the role of water on average, but the movements of individual water molecules are not predicted, freeing computation capacity for simulation of whatever protein is being studied.
"Experiment cannot always probe atomic detail of living molecules because they are too small and often move too fast, said Onufriev. "But we can combine computational power with good algorithms to simulate these motions at high (atom-scale) resolution.
"It is an exciting time to do molecular modeling," he said. "The computing power and the methodology have come to the point that we can begin to fully probe biology on timescales very relevant to living things - such as DNA packing."
Virginia Tech's System X supercomputer was critical to this research, he said. "It was the combination of its sheer compute power with the algorithmic advantages that made it possible to run molecular simulations on that scale."
So far, the Virginia Tech research team addressed the question of how flexible the DNA is, which is only a small piece of the "second part of the genetic code" puzzle, Onufriev said. "However, this small piece should pave the way to addressing bigger questions, such as 'Exactly how is the tightly packed genetic content read by cellular machines"'"
"Atomic level simulations can complement experimentation and narrow competing theories," said Onufriev. "For systems as large as the nucleosome, simulations using virtual water may be the only practical way to estimate the stability of various confirmations," he said.
How DNA bends and flexes is critical for many cellular processes including cell differentiation and DNA replication. Although also observed in recent experiments, this unusual DNA flexibility is still unexplained. "Now seeing that DNA is not as hard to bend may lead to radical changes in our perspective," said Onufriev. "We are using these detailed pictures to see exactly how DNA bends and to understand the details of the mechanism behind it, something that is very hard or impossible to do experimentally."
Onufriev and his group of biochemistry, physics, biology, and other computer science researchers received a $1.1 million grant from the National Institutes of Health to develop high performance computing methodology to create molecular models and to probe in atomic detail the mechanisms of biology.
The purpose of the NIH award is to develop the methodology for computer simulations of complex biological processes and address the question of the atomic mechanism of DNA flexibility, Onufriev said. "This research may not only provide fundamental insights into how life works at the molecular level, but also has applications in drug discovery and in particular for rational drug design, which is an important consideration for the NIH."
Contact: Susan Trulove
Virginia Tech
Virginia Tech researchers used novel methodology and the university's System X supercomputer to carry out what is probably the first simulation that explores full range of motions of a DNA strand of 147 base pairs, the length that is required to form the fundamental unit of DNA packing in the living cells -- the nucleosome. Contrary to a long-held belief that DNA is hard to bend, the simulation shows in crisp atomic detail that DNA is considerably more flexible than commonly thought.
The research is published in the December issue of the Biophysical Journal, in the article "A Computational Study of Nucleosomal DNA Flexibility," by Jory Zmuda Ruscio of Leesburg, Va., a Ph.D. student in the Genetics, Bioinformatics and Computational Biology Program at Virginia Tech, and Alexey Onufriev of Blacksburg, assistant professor of computer sciences and physics at Virginia Tech. They have been invited to do a platform presentation at the 51st Biophysical Society Annual Meeting in Baltimore in March.
There is about 12 feet of DNA in a human cell but it is packaged into nucleosomes - lengths of 147 base pairs each wrapped around eight special proteins. A nucleosome looks kind of like the lumpy beginning of a rubber-band ball. Or maybe more like a lumpy worm coil. Uncoiled, the worm wiggles, flexes, and even kinks, according to a simulation performed on System X.
As we know from watching forensic detective shows on TV, the DNA in all of an individual's cells is identical. The DNA in fingernail cells is exactly the same as in muscle. Yet the cells are different. "This is because, roughly speaking, the DNA in different cell types is packed differently and the complexes it forms with the surrounding proteins are in different positions, so only the relevant part of the code can be read at a time," said Onufriev. "Although nobody knows exactly how it happens, you can imagine reading only what you can see on a part of a crumpled newspaper."
The traditional view is that DNA is relatively rigid and that considerable energy is required when it needs to be bent to form protein-DNA complexes. However, recent experiments (Nature, Aug. 17, 2006) have begun to challenge that view. "The famous double-helix may be much more flexible than previously thought," said Onufriev.
The Virginia Tech research responded to this debate. Using 128 of System X's 1,100 processors, the research resulted in a System X movie revealing DNA wiggling like a worm, showing greater flexibility than expected from the traditional view. The DNA packing in the nucleosome is also found to be surprisingly loose. "The implication is that it may not cost much energy to bend the DNA - even to bend sharply," said Onufriev.
The methodology that is making it possible is based on the so-called "implicit solvent" approach being developed by Onufriev. "Biology does not happen in a vacuum," he said. "We are 75 percent water, and the effect of the water environment must be taken into account when studying biomolecules."
Previous simulations were often slowed because they accounted for the water that is present in living systems. For instance, in early studies of protein folding, only a few percent of the computing effort was being spent on the activity of the protein while the rest accounted for the activity of the surrounding fluids. The "implicit solvent" approach accounts for the role of water on average, but the movements of individual water molecules are not predicted, freeing computation capacity for simulation of whatever protein is being studied.
"Experiment cannot always probe atomic detail of living molecules because they are too small and often move too fast, said Onufriev. "But we can combine computational power with good algorithms to simulate these motions at high (atom-scale) resolution.
"It is an exciting time to do molecular modeling," he said. "The computing power and the methodology have come to the point that we can begin to fully probe biology on timescales very relevant to living things - such as DNA packing."
Virginia Tech's System X supercomputer was critical to this research, he said. "It was the combination of its sheer compute power with the algorithmic advantages that made it possible to run molecular simulations on that scale."
So far, the Virginia Tech research team addressed the question of how flexible the DNA is, which is only a small piece of the "second part of the genetic code" puzzle, Onufriev said. "However, this small piece should pave the way to addressing bigger questions, such as 'Exactly how is the tightly packed genetic content read by cellular machines"'"
"Atomic level simulations can complement experimentation and narrow competing theories," said Onufriev. "For systems as large as the nucleosome, simulations using virtual water may be the only practical way to estimate the stability of various confirmations," he said.
How DNA bends and flexes is critical for many cellular processes including cell differentiation and DNA replication. Although also observed in recent experiments, this unusual DNA flexibility is still unexplained. "Now seeing that DNA is not as hard to bend may lead to radical changes in our perspective," said Onufriev. "We are using these detailed pictures to see exactly how DNA bends and to understand the details of the mechanism behind it, something that is very hard or impossible to do experimentally."
Onufriev and his group of biochemistry, physics, biology, and other computer science researchers received a $1.1 million grant from the National Institutes of Health to develop high performance computing methodology to create molecular models and to probe in atomic detail the mechanisms of biology.
The purpose of the NIH award is to develop the methodology for computer simulations of complex biological processes and address the question of the atomic mechanism of DNA flexibility, Onufriev said. "This research may not only provide fundamental insights into how life works at the molecular level, but also has applications in drug discovery and in particular for rational drug design, which is an important consideration for the NIH."
Contact: Susan Trulove
Virginia Tech
воскресенье, 10 июля 2011 г.
European Network Of Biological Samples Key To Develop New Cures For Complex Diseases
A seminar to explore the challenges and requirements to create a European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) will take place at the EU Parliament on 28 May 2008.
Medical and health research have evolved very quickly in the last decades based on path-breaking advances and discoveries in genomics and molecular biology. Those developments have been proved especially useful in the prevention, diagnose and treatment of complex diseases that arise from a vast array of interacting effects. In this context, human samples such as blood, tissues, cells, DNA and other body fluids are the basic materials that researchers study to uncover the molecular and environmental factors that underlie disease.
Understanding those interactions will depend critically on the study of large sets of samples linked with accurate and up-to-date clinical, biological and molecular information. Europe is without a doubt in a very advantageous position to play a global leading role due to the existence of a long tradition of excellent health systems that have vast collections of samples and data. However, while these important collections already exist in hospital archives, biobanks, and biological resources centres across the EU member states, there is little collaboration and exchange between them. This fragmentation and the limited access by investigators are the main bottleneck impeding progress to the benefit of medical research, European health care, and ultimately, the citizens of the European Union.
This seminar will discuss the importance and the future plans to develop a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI). Members of the main European research centres and institutes, universities, industry and government representatives will participate in the session to determine the necessary steps to set up an unprecedented network that will enable researchers to interact better, to access larger collections of biological samples and data, and thus to translate already existing potentials into new opportunities. Some of the urgent actions in the agenda are the preparation of an inventory of existing resources, the search for common standards and access rules, the establishment of a data protection system and the definition of the legal, ethical, social and financial governance framework for this initiative.
The planning consortium compromises 51 participants from 21 member states and more than 150 associated organizations. The successful implementation of a pan-European BBMRI will result into increased quality and reduced costs of research, more effective drug discoveries, improved health care and secure industrial competitiveness for the EU.
For a complete program of the seminar please go to bioresource-med/ and check the Forthcoming Events section.
For a complete program of the seminar please go to bioresource-med/ and check the Forthcoming Events section.
bioresource-med/
Medical and health research have evolved very quickly in the last decades based on path-breaking advances and discoveries in genomics and molecular biology. Those developments have been proved especially useful in the prevention, diagnose and treatment of complex diseases that arise from a vast array of interacting effects. In this context, human samples such as blood, tissues, cells, DNA and other body fluids are the basic materials that researchers study to uncover the molecular and environmental factors that underlie disease.
Understanding those interactions will depend critically on the study of large sets of samples linked with accurate and up-to-date clinical, biological and molecular information. Europe is without a doubt in a very advantageous position to play a global leading role due to the existence of a long tradition of excellent health systems that have vast collections of samples and data. However, while these important collections already exist in hospital archives, biobanks, and biological resources centres across the EU member states, there is little collaboration and exchange between them. This fragmentation and the limited access by investigators are the main bottleneck impeding progress to the benefit of medical research, European health care, and ultimately, the citizens of the European Union.
This seminar will discuss the importance and the future plans to develop a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI). Members of the main European research centres and institutes, universities, industry and government representatives will participate in the session to determine the necessary steps to set up an unprecedented network that will enable researchers to interact better, to access larger collections of biological samples and data, and thus to translate already existing potentials into new opportunities. Some of the urgent actions in the agenda are the preparation of an inventory of existing resources, the search for common standards and access rules, the establishment of a data protection system and the definition of the legal, ethical, social and financial governance framework for this initiative.
The planning consortium compromises 51 participants from 21 member states and more than 150 associated organizations. The successful implementation of a pan-European BBMRI will result into increased quality and reduced costs of research, more effective drug discoveries, improved health care and secure industrial competitiveness for the EU.
For a complete program of the seminar please go to bioresource-med/ and check the Forthcoming Events section.
For a complete program of the seminar please go to bioresource-med/ and check the Forthcoming Events section.
bioresource-med/
четверг, 7 июля 2011 г.
In Vitro And In Vivo Data Show Alfacell's ONCONASE(R) Is Active Against Naive And Chemoresistant Neuroblastoma Cells
Alfacell
Corporation (Nasdaq: ACEL) today announced that new data show ONCONASE, the
company's lead drug candidate, is active against naive and chemoresistant
neuroblastoma cells.
The pre-clinical in vitro and in vivo data published in Cancer Letters
(2007; Vol. 250, Issue 1: 107-116) through a collaboration between Alfacell
and Martin Michaelis, M.D., Ph.D., at the Institute of Medicinal Virology
at Johann Wolfgang University of Frankfurt, were also recently presented in
Germany.
Conclusions from the studies presented indicate that ONCONASE inhibits
neuroblastoma cell growth and induces caspase-independent cell death in
neuroblastoma cells independently of P-gp expression or p53 status, which
has been shown to contribute to multi-drug resistance in neuroblastoma as
well as most other human cancers. Transmission electronic microscope
investigations suggest that ONCONASE induces a process in neuroblastoma
cells called autophagy (the digestion of cellular constituents by enzymes
of the same cell), which leads to apoptosis (programmed cell death).
Anti-tumor activity of ONCONASE against drug-sensitive and chemoresistant
neuroblastoma xenografts was confirmed in animals.
"The data speak to the broad potential application for ONCONASE in
various types of cancer other than the gateway indication for
mesothelioma," said Kuslima Shogen, Alfacell's chairman and chief executive
officer. "We now have an even better understanding of the mechanism of
action that ONCONASE utilizes in overcoming multiple drug resistance in
various tumor types."
Neuroblastoma is a cancer that forms in the nerve tissue. It is the
most common cancer in infants, and the fourth most common type of cancer in
children. Neurons (nerve cells) are the main components of the brain and
spinal cord and of the nerves that connect them to the rest of the body.
Approximately one in 100,000 children develops neuroblastoma in the United
States.
About ONCONASE(R)
ONCONASE is a first-in-class therapeutic product candidate based on
Alfacell's proprietary ribonuclease (RNase) technology. A natural protein
isolated from the leopard frog, ONCONASE has been shown in the laboratory
and clinic to target cancer cells while sparing normal cells. ONCONASE
triggers apoptosis, the natural death of cells, via multiple molecular
mechanisms of action.
About Alfacell Corporation
Alfacell Corporation is the first company to advance a
biopharmaceutical product candidate that works in a manner similar to RNA
interference (RNAi) through late-stage clinical trials. The product
candidate, ONCONASE, is an RNase that overcomes the challenges of targeting
RNA for therapeutic purposes while enabling the development of a new class
of targeted therapies for cancer and other life-threatening diseases. In
addition to an ongoing Phase IIIb study in malignant mesothelioma, Alfacell
is conducting a Phase I/II trial of ONCONASE in non-small cell lung cancer
(NSCLC) and other solid tumors. For more information, visit
alfacell.
Safe Harbor
This press release includes statements that may constitute "forward-
looking" statements, usually containing the words "believe," "estimate,"
"project," "expect" or similar expressions. Forward-looking statements
involve risks and uncertainties that could cause actual results to differ
materially from the forward-looking statements. Factors that would cause or
contribute to such differences include, but are not limited to,
uncertainties involved in transitioning from concept to product,
uncertainties involving the ability of the company to finance research and
development activities, potential challenges to or violations of patents,
uncertainties regarding the outcome of clinical trials, the company's
ability to secure necessary approvals from regulatory agencies, dependence
upon third-party vendors, and other risks discussed in the company's
periodic filings with the Securities and Exchange Commission. By making
these forward-looking statements, the company undertakes no obligation to
update these statements for revisions or changes after the date of this
release.
Alfacell Corporation
alfacell
Corporation (Nasdaq: ACEL) today announced that new data show ONCONASE, the
company's lead drug candidate, is active against naive and chemoresistant
neuroblastoma cells.
The pre-clinical in vitro and in vivo data published in Cancer Letters
(2007; Vol. 250, Issue 1: 107-116) through a collaboration between Alfacell
and Martin Michaelis, M.D., Ph.D., at the Institute of Medicinal Virology
at Johann Wolfgang University of Frankfurt, were also recently presented in
Germany.
Conclusions from the studies presented indicate that ONCONASE inhibits
neuroblastoma cell growth and induces caspase-independent cell death in
neuroblastoma cells independently of P-gp expression or p53 status, which
has been shown to contribute to multi-drug resistance in neuroblastoma as
well as most other human cancers. Transmission electronic microscope
investigations suggest that ONCONASE induces a process in neuroblastoma
cells called autophagy (the digestion of cellular constituents by enzymes
of the same cell), which leads to apoptosis (programmed cell death).
Anti-tumor activity of ONCONASE against drug-sensitive and chemoresistant
neuroblastoma xenografts was confirmed in animals.
"The data speak to the broad potential application for ONCONASE in
various types of cancer other than the gateway indication for
mesothelioma," said Kuslima Shogen, Alfacell's chairman and chief executive
officer. "We now have an even better understanding of the mechanism of
action that ONCONASE utilizes in overcoming multiple drug resistance in
various tumor types."
Neuroblastoma is a cancer that forms in the nerve tissue. It is the
most common cancer in infants, and the fourth most common type of cancer in
children. Neurons (nerve cells) are the main components of the brain and
spinal cord and of the nerves that connect them to the rest of the body.
Approximately one in 100,000 children develops neuroblastoma in the United
States.
About ONCONASE(R)
ONCONASE is a first-in-class therapeutic product candidate based on
Alfacell's proprietary ribonuclease (RNase) technology. A natural protein
isolated from the leopard frog, ONCONASE has been shown in the laboratory
and clinic to target cancer cells while sparing normal cells. ONCONASE
triggers apoptosis, the natural death of cells, via multiple molecular
mechanisms of action.
About Alfacell Corporation
Alfacell Corporation is the first company to advance a
biopharmaceutical product candidate that works in a manner similar to RNA
interference (RNAi) through late-stage clinical trials. The product
candidate, ONCONASE, is an RNase that overcomes the challenges of targeting
RNA for therapeutic purposes while enabling the development of a new class
of targeted therapies for cancer and other life-threatening diseases. In
addition to an ongoing Phase IIIb study in malignant mesothelioma, Alfacell
is conducting a Phase I/II trial of ONCONASE in non-small cell lung cancer
(NSCLC) and other solid tumors. For more information, visit
alfacell.
Safe Harbor
This press release includes statements that may constitute "forward-
looking" statements, usually containing the words "believe," "estimate,"
"project," "expect" or similar expressions. Forward-looking statements
involve risks and uncertainties that could cause actual results to differ
materially from the forward-looking statements. Factors that would cause or
contribute to such differences include, but are not limited to,
uncertainties involved in transitioning from concept to product,
uncertainties involving the ability of the company to finance research and
development activities, potential challenges to or violations of patents,
uncertainties regarding the outcome of clinical trials, the company's
ability to secure necessary approvals from regulatory agencies, dependence
upon third-party vendors, and other risks discussed in the company's
periodic filings with the Securities and Exchange Commission. By making
these forward-looking statements, the company undertakes no obligation to
update these statements for revisions or changes after the date of this
release.
Alfacell Corporation
alfacell
понедельник, 4 июля 2011 г.
Researchers Enlist DNA To Bring Carbon Nanotubes' Promise Closer To Reality
A team of researchers from DuPont and Lehigh University has reported a breakthrough in the quest to produce carbon nanotubes (CNTs) that are suitable for use in electronics, medicine and other applications.
In an article published in the July 9 issue of Nature, the group says it has developed a DNA-based method that sorts and separates specific types of CNTs from a mixture.
CNTs are long, narrow cylinders of graphite with a broad range of electronic, thermal and structural properties that vary according to the tubes' shape and structure. This versatility gives CNTs great promise in electronics, lasers, sensors and biomedicine, and as strengthening elements in composite materials.
Current methods of producing CNTs yield mixtures of tubes with different diameters and symmetry, or "chirality." Before the tubes can be used, however, they must be disentangled from a mixture and "purified" into separate species of CNTs of the same electronic type.
"A systematic method of purifying every single-chirality species of the same electronic type from a synthetic mixture of single-walled nanotubes is highly desirable," the DuPont-Lehigh group wrote in Nature, "but the task has proven to be insurmountable to date."
The Nature article is titled "DNA sequence motifs for structure-specific recognition and separation of carbon nanotubes." Its authors are Ming Zheng, Xiaomin Tu, Anand Jagota and Suresh Manohar. Zheng and Tu are scientists with DuPont Central Research and Development. Jagota is a professor of chemical engineering at Lehigh. Manohar is a graduate student in chemical engineering at Lehigh.
In 2003, a team of scientists from DuPont, MIT and the University of Illinois at Urbana-Champaign developed a new method of separating metallic CNTs from semiconducting CNTs using single-stranded DNA and anion-exchange chromatography. The scientists reported their discovery in Science. The team was led by Zheng and Jagota, who was then a research scientist with DuPont.
The new results improve on the 2003 results by identifying more than 20 DNA short sequences that can recognize individual types, or species, of carbon nanotubes and purify them from a mixture.
The new method utilizes tailored DNA sequences and "allows the purification of all 12 major single-chirality semiconducting species from a synthetic mixture, with sufficient yield for both fundamental studies and application development."
The current experiments were conducted at DuPont by Tu and Zheng, while Manohar and Jagota developed structural models using molecular simulations.
"The interesting discovery made by Tu and Zheng," says Jagota, "is that if you choose the DNA sequence correctly, it recognizes a particular type of CNT and enables us to sort that variety cleanly. This kind of practical improvement brings us closer to manufacturing possibility."
How does DNA recognize and sort types of CNTs? The DuPont-Lehigh team says this could be related to DNA's ability to form a structure different from its usual double helix by wrapping around the CNTs.
An alpha helix, like scotch tape wrapped around a pencil to form a tube, is a common shape seen in proteins, one of the main classes of biological molecules. Another common structure seen in proteins is the beta sheet. If you take a long strand in your palm, stretch it out to the tip of your index finger, loop it to your middle finger, then back to your palm, then out to your ring finger, back to your palm and out to your little finger, you form a type of beta sheet.
"Such a structure is not known for DNA," says Jagota, "but we've shown that it is possible as long as you allow the DNA to adsorb on a surface. If the surface is cylindrical, like a CNT, you get a variant called the beta-barrel."
While the researchers do not have absolute proof, they say circumstantial evidence strongly supports their hypothesis that the DNA is forming this well-organized structure and that it recognizes a specific CNT in the same way that biological molecules recognize each other by structure.
Jagota, who directs Lehigh's bioengineering program, says the biomedical ramifications of the researchers' discovery are particularly exciting. One potential application for CNTs, for example, is to place them on substrates that can be delivered to cells in the body.
"We are very interested in the biomedical applications of this work," says Jagota. "What does this say about how DNA interacts with nanomaterials? Will they be harmful inside the body? Can we take advantage of the interaction for therapeutic applications? It's a big open field."
Source:
Kurt Pfitzer
Lehigh University
In an article published in the July 9 issue of Nature, the group says it has developed a DNA-based method that sorts and separates specific types of CNTs from a mixture.
CNTs are long, narrow cylinders of graphite with a broad range of electronic, thermal and structural properties that vary according to the tubes' shape and structure. This versatility gives CNTs great promise in electronics, lasers, sensors and biomedicine, and as strengthening elements in composite materials.
Current methods of producing CNTs yield mixtures of tubes with different diameters and symmetry, or "chirality." Before the tubes can be used, however, they must be disentangled from a mixture and "purified" into separate species of CNTs of the same electronic type.
"A systematic method of purifying every single-chirality species of the same electronic type from a synthetic mixture of single-walled nanotubes is highly desirable," the DuPont-Lehigh group wrote in Nature, "but the task has proven to be insurmountable to date."
The Nature article is titled "DNA sequence motifs for structure-specific recognition and separation of carbon nanotubes." Its authors are Ming Zheng, Xiaomin Tu, Anand Jagota and Suresh Manohar. Zheng and Tu are scientists with DuPont Central Research and Development. Jagota is a professor of chemical engineering at Lehigh. Manohar is a graduate student in chemical engineering at Lehigh.
In 2003, a team of scientists from DuPont, MIT and the University of Illinois at Urbana-Champaign developed a new method of separating metallic CNTs from semiconducting CNTs using single-stranded DNA and anion-exchange chromatography. The scientists reported their discovery in Science. The team was led by Zheng and Jagota, who was then a research scientist with DuPont.
The new results improve on the 2003 results by identifying more than 20 DNA short sequences that can recognize individual types, or species, of carbon nanotubes and purify them from a mixture.
The new method utilizes tailored DNA sequences and "allows the purification of all 12 major single-chirality semiconducting species from a synthetic mixture, with sufficient yield for both fundamental studies and application development."
The current experiments were conducted at DuPont by Tu and Zheng, while Manohar and Jagota developed structural models using molecular simulations.
"The interesting discovery made by Tu and Zheng," says Jagota, "is that if you choose the DNA sequence correctly, it recognizes a particular type of CNT and enables us to sort that variety cleanly. This kind of practical improvement brings us closer to manufacturing possibility."
How does DNA recognize and sort types of CNTs? The DuPont-Lehigh team says this could be related to DNA's ability to form a structure different from its usual double helix by wrapping around the CNTs.
An alpha helix, like scotch tape wrapped around a pencil to form a tube, is a common shape seen in proteins, one of the main classes of biological molecules. Another common structure seen in proteins is the beta sheet. If you take a long strand in your palm, stretch it out to the tip of your index finger, loop it to your middle finger, then back to your palm, then out to your ring finger, back to your palm and out to your little finger, you form a type of beta sheet.
"Such a structure is not known for DNA," says Jagota, "but we've shown that it is possible as long as you allow the DNA to adsorb on a surface. If the surface is cylindrical, like a CNT, you get a variant called the beta-barrel."
While the researchers do not have absolute proof, they say circumstantial evidence strongly supports their hypothesis that the DNA is forming this well-organized structure and that it recognizes a specific CNT in the same way that biological molecules recognize each other by structure.
Jagota, who directs Lehigh's bioengineering program, says the biomedical ramifications of the researchers' discovery are particularly exciting. One potential application for CNTs, for example, is to place them on substrates that can be delivered to cells in the body.
"We are very interested in the biomedical applications of this work," says Jagota. "What does this say about how DNA interacts with nanomaterials? Will they be harmful inside the body? Can we take advantage of the interaction for therapeutic applications? It's a big open field."
Source:
Kurt Pfitzer
Lehigh University
пятница, 1 июля 2011 г.
Miniature Smart Pump
An innovative micro-pump makes it possible for tiny quantities of liquid - such as medicines - to be dosed accurately and flexibly. Active composites and an electronic control mechanism ensure that the low-maintenance pump works accurately - both forwards and backwards.
Medicines sometimes have to be administered in extremely small quantities. Just a few tenths of a milliliter may be sufficient to give the patient the ideal treatment. Micro-pumps greatly facilitate the dosage of minute quantities. Pumps like these have been built and constantly optimized for over 25 years. They find application in numerous areas - from medical engineering to microproduction technology - wherever tiny volumes have to be variably dosed with extreme accuracy.
However, these micro-pump systems are usually not as flexible as desired: They often work in only one direction, bubbles in the liquid impair their operation, they do not tolerate bothersome particles, they have a fixed pump output and they contain expendable parts such as valves or cogwheels. Together with partners from research institutes and industry, researchers at the Fraunhofer Institute for Mechanics of Materials IWM in Freiburg have developed an innovative pump system that solves all these problems: a controllable peristaltic micro-pump. "The peristaltic pump is a highly complex system," explains IWM project manager Dr. Bärbel Thielicke. "It contracts in waves in a similar way to the human esophagus, and thus propels the liquid along - it changes shape of its own accord. To achieve this, we had to use a whole range of different materials and special material composites." The researchers use lead-zirconate-titanate (PZT) films that are joined in a suitable way with bending elements made of carbon-fiber-reinforced plastic and a flexible tube. "PZT materials change their shape as soon as you apply an electric field to them. This makes it possible to control the pump system electronically," says Thielicke. Special adhesives additionally hold the various components of the pump system together. Thanks to the special control electronics, tiny quantities can be pumped accurately through the system.
The peristaltic pump system has already passed its first functional tests. Now the researchers are working to adapt the peristaltic micro-pump to the various different applications. "We work with special simulation models to do this," says Thielicke. "We calculate in advance how the structure of the pump needs to be modified in order to administer other dosages or other liquids. This helps us save time and money during the development phase."
Source: Baerbel Thielicke
Fraunhofer-Gesellschaft
Medicines sometimes have to be administered in extremely small quantities. Just a few tenths of a milliliter may be sufficient to give the patient the ideal treatment. Micro-pumps greatly facilitate the dosage of minute quantities. Pumps like these have been built and constantly optimized for over 25 years. They find application in numerous areas - from medical engineering to microproduction technology - wherever tiny volumes have to be variably dosed with extreme accuracy.
However, these micro-pump systems are usually not as flexible as desired: They often work in only one direction, bubbles in the liquid impair their operation, they do not tolerate bothersome particles, they have a fixed pump output and they contain expendable parts such as valves or cogwheels. Together with partners from research institutes and industry, researchers at the Fraunhofer Institute for Mechanics of Materials IWM in Freiburg have developed an innovative pump system that solves all these problems: a controllable peristaltic micro-pump. "The peristaltic pump is a highly complex system," explains IWM project manager Dr. Bärbel Thielicke. "It contracts in waves in a similar way to the human esophagus, and thus propels the liquid along - it changes shape of its own accord. To achieve this, we had to use a whole range of different materials and special material composites." The researchers use lead-zirconate-titanate (PZT) films that are joined in a suitable way with bending elements made of carbon-fiber-reinforced plastic and a flexible tube. "PZT materials change their shape as soon as you apply an electric field to them. This makes it possible to control the pump system electronically," says Thielicke. Special adhesives additionally hold the various components of the pump system together. Thanks to the special control electronics, tiny quantities can be pumped accurately through the system.
The peristaltic pump system has already passed its first functional tests. Now the researchers are working to adapt the peristaltic micro-pump to the various different applications. "We work with special simulation models to do this," says Thielicke. "We calculate in advance how the structure of the pump needs to be modified in order to administer other dosages or other liquids. This helps us save time and money during the development phase."
Source: Baerbel Thielicke
Fraunhofer-Gesellschaft
Подписаться на:
Комментарии (Atom)