Two groups of lowly marine worms are related to complex species including vertebrates (such as humans) and starfish, according to new research. Previously thought to be an evolutionary link between simple animals such as jellyfish and the rest of animal life - the worms' surprising promotion implies that they have not always been as simple as they now appear.
Although the marine worms Xenoturbella and Acoelomorpha are very simple animals - they lack a developed nervous system or gut -they have been a source of much debate among zoologists. Acoelomorphs were reclassified in the1990's as an early branch of evolution - the crucial link between the very simplest animals such as sponges and jellyfish and the rest of the animal kingdom including humans, starfish, insects and molluscs.
Now, in research published online in Nature, an international team lead by scientists from UCL (University College London) and the UniversitГ© de MontrГ©al have shown that neither type of worm is an early branch of evolution. They show that both groups descended from the same ancestor that gave rise to the complex groups of animals that includes vertebrates and starfish. This implies that the worms have in effect 'evolved backwards' into much simpler looking organisms.
Specimens of Xenoturbella were collected from the mud at the bottom of a Swedish fjord where it eats bivalve molluscs; the acoelomorphs are found in various marine environments - one called Meara stichopi even makes its home in the throat of a sea cucumber. Scientists compared hundreds of genes from both Xenoturbella and the Acoelomorpha with their counterparts from a whole range of animal species to determine their evolutionary relationships.
The results show that the two groups constitute a newly classified phylum (a major division of life), which the authors name the 'Xenacoelomorpha'. The xenacoelomorph phylum joins the three known phyla of deuterostomes: vertebrates (including humans), echinoderms (e.g. starfish) and hemichordates (acorn worms).
Professor Max Telford, from the UCL Department of Genetics, Evolution and Environment, and joint leader of the research said: "Because the simple Xenacoelomorpha are descended from the same ancestor that gave rise to complex groups such as vertebrates, echinoderms and hemichordates, these simple worms must have lost a lot of the complexity that they originally possessed."
Professor Telford said: "We can no longer consider the acoelomorphs as an intermediate between simple groups such as jelly fish and the rest of the animals. This means that we have no living representative of this stage of evolution: the missing link has gone missing!"
Professor HervГ© Philippe from the UniversitГ© de MontrГ©al said: "This is the happy result of a more than ten year struggle with these highly unusual organisms that have proved very difficult to locate on the tree of life. Improvements in DNA sequencing technology and in mathematical methods to infer evolutionary history were key to solving the conundrum of Xenoturbella and the acoelomorphs"
Notes:
'Acoelomorph flatworms are deuterostomes related to Xenoturbella' is published in online in Nature.
The research was funded by the Biotechnology and Biological Sciences Research Council SYNTAX scheme, the National Science Foundation, NASA, a Wellcome Trust core award, the Max-Planck Society for the Advancement of Sciences, Inez Johanssons Stiftelse and Stiftelsen Lars Hiertas Minne.
Source:
Clare Ryan
University College London
понедельник, 30 мая 2011 г.
Research Into Mouse Vision Improves Understanding Of The Physiological Importance Of Circadian Clocks
In the eyes of mammals, visual information is processed on a daily schedule set within the eyes themselves -- not one dictated by the brain, according to a new report in the journal Cell, a publication of Cell Press. The researchers found in mice that the eyes' normal rhythmic response to light requires only that a molecular "clock" inside the retina go on ticking. The retina is a layer of nerve tissue covering the back of the eyeball, which is often likened to the film in a camera; without it, images can't be captured.
The results offer the first glimpse into the physiological importance of circadian clocks found in organs throughout the body, said Charles Weitz of Harvard Medical School. The retina's apparent independence when it comes to keeping itself on time further challenges the notion that the circadian rhythms of the body--which drive regular patterns of physiology and behavior--strictly follow orders handed down from a "master clock" in the brain, the researchers said.
"We're moving from a dictatorial model of the circadian system to a federal model," Weitz said. He added, however, that the brain's master clock isn't "completely off its pedestal" yet as it might still play a lead role in synchronizing the clocks found in other organs.
It has long been known that the roughly 24 hour circadian clock controlling behavior in mammals is located in the brain's suprachiasmatic nucleus (SCN), Weitz explained. Even when animals are placed under conditions of constant darkness, that daily rhythm marches on.
More recently, researchers have discovered that circadian clocks are also distributed in other mammalian tissues, including the retina, multiple brain regions, and many peripheral tissues such as the liver and kidneys. But while scientists had suspected physiological functions for those many timepieces, few studies had addressed the issue.
In the new study, the researchers found that retinas of mice that completely lack a critical component of the clock -- a gene known as Bmal1 -- showed abnormal gene activity in hundreds of retinal genes and defective electrical responses in inner retinal cells critical for image processing. The animals' photoreceptors still sensed light normally and, upon close examination, their eyes appeared normal.
Mice deficient for the Bmal1clock gene only in their retinas had defects of vision essentially identical to those of mice lacking the gene in all tissues, evidence that the clock's function in the eye itself is the key. By contrast, the retinas of mice with brain lesions that disabled the SCN maintained normal visual responses and the regular ebb and flow of retinal gene activity.
"Circadian clocks in mammals are widely distributed, but except for the SCN clock known to regulate behavior, their physiological functions in vivo have largely been mysterious," Weitz concluded. "The studies described here indicate that an intrinsic retinal circadian clock regulates visual processing in vivo and that it does so autonomously, with no detectable contribution from the SCN or other clocks."
Whether the retina's ability to keep time on its own is the exception, "we don't know," Weitz said. Unlike other tissues, the eye's role as a light sensor does provide its component structures a unique ability to track the environment on their own authority, he noted.
Nonetheless, he said, "our work provides evidence that circadian clocks outside the SCN contribute important physiological functions in mammals. Over evolutionary time, different cell types have likely recruited the circadian clock mechanism inherited from a single-celled ancestor for control of specialized tissue-specific processes," he suggested.
The researchers include Kai-Florian Storch and Carlos Paz of the Department of Neurobiology, Harvard Medical School in Boston; James Signorovitch of the Department of Biostatistics, Harvard School of Public Health in Boston; Elio Raviola of the Department of Neurobiology, Harvard Medical School in Boston; Basil Pawlyk and Tiansen Li of Massachusetts Eye & Ear Infirmary, Berman-Gund Laboratory, Department of Ophthalmology, Harvard Medical School in Boston; and Charles J. Weitz of the Department of Neurobiology, Harvard Medical School in Boston. This work was supported by grants from the National Institutes of Health to C.J.W. (NS055831), E.R. (EY001344), and T.L. (EY10309).
Storch et al.: "Intrinsic Circadian Clock of the Mammalian Retina: Importance for Retinal Processing of Visual Information." Publishing in Cell 130, 730-741, August 24, 2007. DOI 10.1016/j.cell.2007.06.045 cell/
Source: Nancy Wampler
Cell Press
The results offer the first glimpse into the physiological importance of circadian clocks found in organs throughout the body, said Charles Weitz of Harvard Medical School. The retina's apparent independence when it comes to keeping itself on time further challenges the notion that the circadian rhythms of the body--which drive regular patterns of physiology and behavior--strictly follow orders handed down from a "master clock" in the brain, the researchers said.
"We're moving from a dictatorial model of the circadian system to a federal model," Weitz said. He added, however, that the brain's master clock isn't "completely off its pedestal" yet as it might still play a lead role in synchronizing the clocks found in other organs.
It has long been known that the roughly 24 hour circadian clock controlling behavior in mammals is located in the brain's suprachiasmatic nucleus (SCN), Weitz explained. Even when animals are placed under conditions of constant darkness, that daily rhythm marches on.
More recently, researchers have discovered that circadian clocks are also distributed in other mammalian tissues, including the retina, multiple brain regions, and many peripheral tissues such as the liver and kidneys. But while scientists had suspected physiological functions for those many timepieces, few studies had addressed the issue.
In the new study, the researchers found that retinas of mice that completely lack a critical component of the clock -- a gene known as Bmal1 -- showed abnormal gene activity in hundreds of retinal genes and defective electrical responses in inner retinal cells critical for image processing. The animals' photoreceptors still sensed light normally and, upon close examination, their eyes appeared normal.
Mice deficient for the Bmal1clock gene only in their retinas had defects of vision essentially identical to those of mice lacking the gene in all tissues, evidence that the clock's function in the eye itself is the key. By contrast, the retinas of mice with brain lesions that disabled the SCN maintained normal visual responses and the regular ebb and flow of retinal gene activity.
"Circadian clocks in mammals are widely distributed, but except for the SCN clock known to regulate behavior, their physiological functions in vivo have largely been mysterious," Weitz concluded. "The studies described here indicate that an intrinsic retinal circadian clock regulates visual processing in vivo and that it does so autonomously, with no detectable contribution from the SCN or other clocks."
Whether the retina's ability to keep time on its own is the exception, "we don't know," Weitz said. Unlike other tissues, the eye's role as a light sensor does provide its component structures a unique ability to track the environment on their own authority, he noted.
Nonetheless, he said, "our work provides evidence that circadian clocks outside the SCN contribute important physiological functions in mammals. Over evolutionary time, different cell types have likely recruited the circadian clock mechanism inherited from a single-celled ancestor for control of specialized tissue-specific processes," he suggested.
The researchers include Kai-Florian Storch and Carlos Paz of the Department of Neurobiology, Harvard Medical School in Boston; James Signorovitch of the Department of Biostatistics, Harvard School of Public Health in Boston; Elio Raviola of the Department of Neurobiology, Harvard Medical School in Boston; Basil Pawlyk and Tiansen Li of Massachusetts Eye & Ear Infirmary, Berman-Gund Laboratory, Department of Ophthalmology, Harvard Medical School in Boston; and Charles J. Weitz of the Department of Neurobiology, Harvard Medical School in Boston. This work was supported by grants from the National Institutes of Health to C.J.W. (NS055831), E.R. (EY001344), and T.L. (EY10309).
Storch et al.: "Intrinsic Circadian Clock of the Mammalian Retina: Importance for Retinal Processing of Visual Information." Publishing in Cell 130, 730-741, August 24, 2007. DOI 10.1016/j.cell.2007.06.045 cell/
Source: Nancy Wampler
Cell Press
Burroughs Wellcome Fund Awards $14M To Support Physician-Scientists
One of the strengths of the foundation world is its ability to be flexible; to have the ability to take an objective look at its funding capabilities and make a change even when it may not be an easy decision.
The Career Awards at the Biomedical Sciences (CABS) was the Burroughs Wellcome Fund's signature program since BWF became an independent and private foundation in 1994. Until 2006, 241 awards were given to young scientists at the postdoctoral level who were poised to go on to promising academic careers as independent researchers. BWF invested more than $100 million into the award program.
The program was so successful that it caught the attention of Nobel laureate Thomas Cech, who, in a report to the NIH by the National Academies, urged the federal government to model an award mechanism based on CABS. In January 2006, the NIH announced its Pathway to Independence awards (K99/R00), of which they would offer 175-200 a year, roughly five times the amount BWF would be able to make.
BWF prides itself on supporting underfunded areas of science. The shouldering of the career development awards by the government meant that this area had significant support. Despite its tradition of success, it was time to make a shift.
In May 2006, the BWF Board of Directors approved an award program designed to increase the number of physician-scientists into the biomedical research enterprise by providing career development funding. The newly minted Career Awards for Medical Scientists was influenced by several studies on physician-scientists, one of which went so far as to call the researchers "endangered species."
"We had an idea that this was certainly an area where there was a need for funding," said BWF President Dr. Queta Bond. "But the quality and quantity of the applications exceeded our expectations."
The program drew more than 150 applications. In the end, 20 physician-scientists received the inaugural Career Awards for Medical Scientist, including a dentist and a dermatologist, firsts for BWF.
"This was a historic move and will make a tremendous difference in medicine," Dr. George Miller, a BWF board member, remarked after the board moved to approve the awardees. "This is a pool of very good people doing incredible things."
The 2008 Career Awards for Medical Scientists are:
*
Jonathan Paul Alexander, M.D., Ph.D.
University of California-San Francisco
Isolation of a putative alveolar stem cell population and analysis of its role in development, maintenance, and repair of the lung epithelium
*
Robert Baloh, M.D., Ph.D.
Washington University
Mechanism of peripheral neuropathy from Mitofusin 2 mutations
*
James Elliott Bradner, M.D.
Harvard University
Design and characterization of highly potent inhibitors of HDAC6
*
Clark C. Chen, M.D., Ph.D.
Harvard Medical School
The molecular basis and therapeutic implications of genome instability during brain tumor progression
*
Arlene Dent, M.D., Ph.D.
Case Western Reserve University
Acquisition of immunity to blood stage Falciparum malaria in infants
*
Mahalia Sabrina Desruisseaux, M.D.
Albert Einstein College of Medicine of Yeshiva University
Neuroparasitology: neurological complications of cerebral malaria
*
Benjamin Levine Ebert, M.D., Ph.D.
Harvard Medical School
Genomic approaches to disorders of erythroid differentiation
*
Brian Todd Edelson, M.D., Ph.D.
Washington University
Macrophage and dendritic cell development
*
Rene L. Galindo, M.D., Ph.D.
University of Texas Southwestern Medical Center-Dallas
Genetic dissection of the Rhabdomyosarcoma initiator PAX-FKHR and PAX-related signaling in skeletal muscle development
*
Darnell Kaigler, D.D.S., Ph.D.
University of Michigan-Ann Arbor
Cell therapy for the treatment of alveolar bone defects
*
Michael Z. Lin, M.D., Ph.D.
University of California-San Diego
Elucidating mechanisms of synaptic plasticity and learning by visualizing and controlling local protein turnover
*
Roger Lo, M.D., Ph.D.
University of California-Los Angeles
Melanoma in the skin: initiation, progression, and crosstalk with dermal fibroblasts
*
Emanual Maverakis, M.D.
University of California-Davis
gC399tr an inhibitor of autoimmunity
*
Eric Matthew Morrow, M.D., Ph.D.
Harvard Medical School
Identification of autism genes in special founder populations using high-density SNP microarrays
*
Christopher Newton-Cheh, M.D.
Harvard Medical School
Genomic dissection of QT interval duration and sudden death
*
Dao Nguyen, M.D.
University of Washington
The stringent response in Pseudomonas aeruginosa biofilm formation and antibiotic tolerance
*
Anil Potti, M.D.
Duke University
Gene expression patterns coupled with signatures of oncogenic pathway deregulation provide a novel approach to targeted therapeutics in non-small cell lung carcinoma
*
Alice Shaw, M.D., Ph.D.
Massachusetts Institute of Technology
Novel biomarkers and targeted therapies for human lung cancer: translation from a mouse model
*
Joseph C. Wu, M.D., Ph.D.
Stanford University
Molecular and cellular mechanisms of cardiac regeneration
*
Mark Nan Wu, M.D., Ph.D.
University of Pennsylvania
Identification of novel genes that regulate sleep in Drosophila melanogaster
ABOUT THE FUND
The Burroughs Wellcome Fund is an independent, private foundation dedicated to advancing the medical sciences by supporting research and other scientific and educational activities. A majority of its grantmaking is made through competitive programs designed to support the career development of young scientists and to build capacity in undervalued research areas.
Contact: Russ Campbell
Burroughs Wellcome Fund
The Career Awards at the Biomedical Sciences (CABS) was the Burroughs Wellcome Fund's signature program since BWF became an independent and private foundation in 1994. Until 2006, 241 awards were given to young scientists at the postdoctoral level who were poised to go on to promising academic careers as independent researchers. BWF invested more than $100 million into the award program.
The program was so successful that it caught the attention of Nobel laureate Thomas Cech, who, in a report to the NIH by the National Academies, urged the federal government to model an award mechanism based on CABS. In January 2006, the NIH announced its Pathway to Independence awards (K99/R00), of which they would offer 175-200 a year, roughly five times the amount BWF would be able to make.
BWF prides itself on supporting underfunded areas of science. The shouldering of the career development awards by the government meant that this area had significant support. Despite its tradition of success, it was time to make a shift.
In May 2006, the BWF Board of Directors approved an award program designed to increase the number of physician-scientists into the biomedical research enterprise by providing career development funding. The newly minted Career Awards for Medical Scientists was influenced by several studies on physician-scientists, one of which went so far as to call the researchers "endangered species."
"We had an idea that this was certainly an area where there was a need for funding," said BWF President Dr. Queta Bond. "But the quality and quantity of the applications exceeded our expectations."
The program drew more than 150 applications. In the end, 20 physician-scientists received the inaugural Career Awards for Medical Scientist, including a dentist and a dermatologist, firsts for BWF.
"This was a historic move and will make a tremendous difference in medicine," Dr. George Miller, a BWF board member, remarked after the board moved to approve the awardees. "This is a pool of very good people doing incredible things."
The 2008 Career Awards for Medical Scientists are:
*
Jonathan Paul Alexander, M.D., Ph.D.
University of California-San Francisco
Isolation of a putative alveolar stem cell population and analysis of its role in development, maintenance, and repair of the lung epithelium
*
Robert Baloh, M.D., Ph.D.
Washington University
Mechanism of peripheral neuropathy from Mitofusin 2 mutations
*
James Elliott Bradner, M.D.
Harvard University
Design and characterization of highly potent inhibitors of HDAC6
*
Clark C. Chen, M.D., Ph.D.
Harvard Medical School
The molecular basis and therapeutic implications of genome instability during brain tumor progression
*
Arlene Dent, M.D., Ph.D.
Case Western Reserve University
Acquisition of immunity to blood stage Falciparum malaria in infants
*
Mahalia Sabrina Desruisseaux, M.D.
Albert Einstein College of Medicine of Yeshiva University
Neuroparasitology: neurological complications of cerebral malaria
*
Benjamin Levine Ebert, M.D., Ph.D.
Harvard Medical School
Genomic approaches to disorders of erythroid differentiation
*
Brian Todd Edelson, M.D., Ph.D.
Washington University
Macrophage and dendritic cell development
*
Rene L. Galindo, M.D., Ph.D.
University of Texas Southwestern Medical Center-Dallas
Genetic dissection of the Rhabdomyosarcoma initiator PAX-FKHR and PAX-related signaling in skeletal muscle development
*
Darnell Kaigler, D.D.S., Ph.D.
University of Michigan-Ann Arbor
Cell therapy for the treatment of alveolar bone defects
*
Michael Z. Lin, M.D., Ph.D.
University of California-San Diego
Elucidating mechanisms of synaptic plasticity and learning by visualizing and controlling local protein turnover
*
Roger Lo, M.D., Ph.D.
University of California-Los Angeles
Melanoma in the skin: initiation, progression, and crosstalk with dermal fibroblasts
*
Emanual Maverakis, M.D.
University of California-Davis
gC399tr an inhibitor of autoimmunity
*
Eric Matthew Morrow, M.D., Ph.D.
Harvard Medical School
Identification of autism genes in special founder populations using high-density SNP microarrays
*
Christopher Newton-Cheh, M.D.
Harvard Medical School
Genomic dissection of QT interval duration and sudden death
*
Dao Nguyen, M.D.
University of Washington
The stringent response in Pseudomonas aeruginosa biofilm formation and antibiotic tolerance
*
Anil Potti, M.D.
Duke University
Gene expression patterns coupled with signatures of oncogenic pathway deregulation provide a novel approach to targeted therapeutics in non-small cell lung carcinoma
*
Alice Shaw, M.D., Ph.D.
Massachusetts Institute of Technology
Novel biomarkers and targeted therapies for human lung cancer: translation from a mouse model
*
Joseph C. Wu, M.D., Ph.D.
Stanford University
Molecular and cellular mechanisms of cardiac regeneration
*
Mark Nan Wu, M.D., Ph.D.
University of Pennsylvania
Identification of novel genes that regulate sleep in Drosophila melanogaster
ABOUT THE FUND
The Burroughs Wellcome Fund is an independent, private foundation dedicated to advancing the medical sciences by supporting research and other scientific and educational activities. A majority of its grantmaking is made through competitive programs designed to support the career development of young scientists and to build capacity in undervalued research areas.
Contact: Russ Campbell
Burroughs Wellcome Fund
A New Generation Of Medicinal Products
What is a medicinal product? It is always the result of a subtle marriage between a compound (the active substance which treats a patient) and an appropriate excipient (a neutral substance in which the active substance is incorporated so that it can be absorbed by the body). Thus the necessary tablet, capsule or syrup is obtained. But what would happen if biodegradable materials were used instead of these neutral excipients? This was already possible with some active substances, and can now be applied to many others! The team led by Didier Bourissou in the Laboratory for Fundamental and Applied Heterochemistry (CNRS/University Toulouse 3), has indeed managed to develop a novel synthetic process for these materials which significantly increases their diversity.
Some biodegradable polymers such as polyesters have already been employed as excipients in pharmacology. But this was only possible when they were mixed with certain active substances such as anticancer drugs or growth hormones. And in the field of surgery, the secret of absorbable sutures does indeed reside in the use of these same polyesters.
What are the principles underlying these "new generation" drugs? The biodegradable excipient containing the active substance can take the form of an implant - a 1 cm-long rod about one millimetre in diameter - which is inserted just under the skin. This procedure is performed by a doctor and only takes a few minutes. The specificity of these polyesters is that they can be hydrolyzed; in other words, broken down by water, which is unlucky for them, as our bodies are full of this substance. Thus the excipient gradually breaks down, over a week, a month or three months, depending on its type, releasing the active substance it contains. Hence the major advantage of the technique: biodegradable excipients enable the controlled administration of sustained-release drugs. This is of considerable benefit in the setting of chronic diseases, as it avoids frequent, repeated intakes of medicines. Another positive point is that this method reduces side effects; by circumventing the digestive tract, the active substance passes directly into the bloodstream. Thus it is also possible to reduce the quantity of drug administered, as there is no longer any need to allow for its partial destruction as it passes through the digestive tract.
In view of these advantages, why can the technique not be extended to a broader range of active substances? Because, until now, we only knew how to make these biodegradable polymers using two monomers (the basic components of polymers), lactide and glycolide. It is rather like making a bead necklace when only green and red beads are available. And in the same way that such a two-coloured necklace would not match all outfits, so the polyesters obtained cannot be combined with just any active substance. Without accounting for the fact that when using these little reactive lactide and glycolide monomers, industrial preparation of the polymers requires lengthy reaction times at high temperatures (e.g. several hours at 140°C-160°C).
This is where Didier Bourissou's team same up with the idea of changing the recipe and ingredients in order to facilitate access to these polyesters and increase their diversity. Many tests later, they achieved their goal. In collaboration with Isochem, they have developed a new synthetic process for these polymers. This involves new elementary building blocks, the O-carboxy anhydrides, which are much more reactive (i.e. more beads for our necklace), so that the polyesters can be prepared under much less harsh laboratory conditions (e.g. a few minutes at 25°C). And above all, a much wider variety of polymers is available, thus multiplying the chances that an active substance will find its appropriate biodegradable excipient. These promising results have given rise to the filing of two patents.
An unquestioned advance in the daily routine of patients, this technique might also be popular with the major pharmaceutical companies, as it would constitute an added-value for traditional drugs which could be presented in a sustained-release formulation.
This work was carried out in the context of very strong international competition, and forms part of the cross-disciplinary CNRS "Chemistry for Sustainable Development" programme.
BIBLIOGRAPHY
An Activated Equivalent of Lactide toward Organocatalytic Ring-Opening Polymerization O. Thillaye du Boullay, E. Marchal, B. Martin-Vaca, F. P. Cossio, et D. Bourissou, J. Am. Chem. Soc. 27 Dec. 2006, 128, 16442.
CONTACTS
Didier Bourissou
Monica McCarthy
CNRS
Some biodegradable polymers such as polyesters have already been employed as excipients in pharmacology. But this was only possible when they were mixed with certain active substances such as anticancer drugs or growth hormones. And in the field of surgery, the secret of absorbable sutures does indeed reside in the use of these same polyesters.
What are the principles underlying these "new generation" drugs? The biodegradable excipient containing the active substance can take the form of an implant - a 1 cm-long rod about one millimetre in diameter - which is inserted just under the skin. This procedure is performed by a doctor and only takes a few minutes. The specificity of these polyesters is that they can be hydrolyzed; in other words, broken down by water, which is unlucky for them, as our bodies are full of this substance. Thus the excipient gradually breaks down, over a week, a month or three months, depending on its type, releasing the active substance it contains. Hence the major advantage of the technique: biodegradable excipients enable the controlled administration of sustained-release drugs. This is of considerable benefit in the setting of chronic diseases, as it avoids frequent, repeated intakes of medicines. Another positive point is that this method reduces side effects; by circumventing the digestive tract, the active substance passes directly into the bloodstream. Thus it is also possible to reduce the quantity of drug administered, as there is no longer any need to allow for its partial destruction as it passes through the digestive tract.
In view of these advantages, why can the technique not be extended to a broader range of active substances? Because, until now, we only knew how to make these biodegradable polymers using two monomers (the basic components of polymers), lactide and glycolide. It is rather like making a bead necklace when only green and red beads are available. And in the same way that such a two-coloured necklace would not match all outfits, so the polyesters obtained cannot be combined with just any active substance. Without accounting for the fact that when using these little reactive lactide and glycolide monomers, industrial preparation of the polymers requires lengthy reaction times at high temperatures (e.g. several hours at 140°C-160°C).
This is where Didier Bourissou's team same up with the idea of changing the recipe and ingredients in order to facilitate access to these polyesters and increase their diversity. Many tests later, they achieved their goal. In collaboration with Isochem, they have developed a new synthetic process for these polymers. This involves new elementary building blocks, the O-carboxy anhydrides, which are much more reactive (i.e. more beads for our necklace), so that the polyesters can be prepared under much less harsh laboratory conditions (e.g. a few minutes at 25°C). And above all, a much wider variety of polymers is available, thus multiplying the chances that an active substance will find its appropriate biodegradable excipient. These promising results have given rise to the filing of two patents.
An unquestioned advance in the daily routine of patients, this technique might also be popular with the major pharmaceutical companies, as it would constitute an added-value for traditional drugs which could be presented in a sustained-release formulation.
This work was carried out in the context of very strong international competition, and forms part of the cross-disciplinary CNRS "Chemistry for Sustainable Development" programme.
BIBLIOGRAPHY
An Activated Equivalent of Lactide toward Organocatalytic Ring-Opening Polymerization O. Thillaye du Boullay, E. Marchal, B. Martin-Vaca, F. P. Cossio, et D. Bourissou, J. Am. Chem. Soc. 27 Dec. 2006, 128, 16442.
CONTACTS
Didier Bourissou
Monica McCarthy
CNRS
Grant To Study How Cells Sense Electric Fields
Learning how living cells can detect and respond to electric fields is the aim of a $570,000, three-year grant from the National Science Foundation to Min Zhao, professor of dermatology and ophthalmology at the UC Davis Health System and Center for Neuroscience.
Living cells are already known to respond to electric fields, as well as being able to sense light, temperature and chemical signals. Understanding this mechanism would establish a new biological signaling mechanism, with implications for engineering tissues and wound healing as well as in basic science, Zhao said.
Zhao and colleagues will use the grant to generate hundreds of thousands of genetic mutations in the amoeba Dictyostelium discoideum. They will collaborate with Tingrui Pan, professor of biomedical engineering, to develop methods to quickly screen thousands of mutant amoebae for those that do not respond to electric fields. Those defective amoebae will allow the scientists to home in on the genes and molecules responsible.
Dictyostelium was selected for the study because it is the simplest cell to work with that also moves, Zhao said.
In previous work, Zhao and his collaborators found that wounds generate a weak electric field that guides cells moving in to repair the wound.
"The big question is, how do the cells detect the electric field?" Zhao said. He believes that there is a molecule or set of molecules within cells that respond to electric fields.
Source:
Andy Fell
University of California - Davis
Living cells are already known to respond to electric fields, as well as being able to sense light, temperature and chemical signals. Understanding this mechanism would establish a new biological signaling mechanism, with implications for engineering tissues and wound healing as well as in basic science, Zhao said.
Zhao and colleagues will use the grant to generate hundreds of thousands of genetic mutations in the amoeba Dictyostelium discoideum. They will collaborate with Tingrui Pan, professor of biomedical engineering, to develop methods to quickly screen thousands of mutant amoebae for those that do not respond to electric fields. Those defective amoebae will allow the scientists to home in on the genes and molecules responsible.
Dictyostelium was selected for the study because it is the simplest cell to work with that also moves, Zhao said.
In previous work, Zhao and his collaborators found that wounds generate a weak electric field that guides cells moving in to repair the wound.
"The big question is, how do the cells detect the electric field?" Zhao said. He believes that there is a molecule or set of molecules within cells that respond to electric fields.
Source:
Andy Fell
University of California - Davis
News From The American Chemical Society March 26, 2008
First evidence that blocking key energy protein kills cancer cells
Researchers in Taiwan report for the first time that blocking a key energy-supplying protein kills cancer cells. The finding, described as the first to test possible medical uses of so-called ATP-synthase inhibitors, may lead to new and more effective anti-cancer medications, according to their report, which is scheduled for the April 4 issue of ACS' monthly Journal of Proteome Research.
In the new study, Hsueh-Fen Juan and colleagues focused on ATP synthase, a key protein involved in producing the energy-rich molecules of ATP that power all life processes. For years researchers thought that the protein existed only in mitochondria, structures located inside cells that convert nutrients into energy. Recent studies found high levels of ATP synthase on the surface of cancer cells, but until now the medical implications went unexplored.
The researchers analyzed tissue samples from breast cancer patients and found for the first time that the surface of breast cancer cells contains high levels of ATP synthase. In cell studies, exposing breast cancer cells to a substance that blocks ATP synthase killed the cancer cells but did not harm normal cells, the researchers say. The findings suggest that ATP synthase inhibitors may represent a new approach for fighting breast cancer and other cancer types, they say. - MTS
ARTICLE: "Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B"
CONTACT:
Hsueh-Fen Juan, Ph.D.
National Taiwan University
Taipei, Taiwan
Electric shocks boost plants' production of commercially useful chemicals
Now for some "shocking" news about plants: Exposing plants to electricity can boost production of useful plant chemicals and may provide a cheaper, safer, and more efficient method for producing medicines, pesticides, and other commercially important plant-based materials, researchers in Arizona and Oklahoma report. Their study is scheduled for the April 4 issue of ACS' Biotechnology Progress, a bi-monthly journal.
Researchers have known for years that plants can produce a diverse array of substances as part of their natural response to environmental factors such as microbial infection, sunlight, and chemical exposure. To boost levels of plant chemicals for commercial purposes, scientists have often turned to synthetic chemical additives as well as genetic engineering, which can be expensive and potentially harmful. A better method is needed, scientists say.
In the new study, Hans VanEtten and colleagues studied the effects of electricity on the ability of the pea plant to produce pisatin, an antifungal substance. They found that exposing pea plants to certain sub-lethal doses of electric current produced 13 times higher amounts of pisatin than plants that were not exposed to electricity. The researchers observed similar increases in plant chemicals produced by a variety of other plants when exposed to electricity. There were no adverse effects on the plants. - MTS
ARTICLE: "Sub-lethal Levels of Electric Current Elicit the Biosynthesis of Plant Secondary Metabolites"
CONTACT:
Hans VanEtten, Ph.D.
University of Arizona
Tucson, Arizona 85721
Chemical signaling may power nanomachines
In a finding that could provide controlled motion in futuristic nanomachines used for drug delivery, fuel cells, and other applications, researchers in Pennsylvania report that chemical signaling between synthetic microcapsules can trigger and direct movement of these capsules. Their study is scheduled for the currrent isssue of ACS Nano, a monthly journal.
Researchers theorize that synthetic capsules can communicate with each other by physically shuffling chemical signals from capsule to capsule, much like passing water through a fireman's bucket brigade. Scientists recently suggested that this same signaling process also appears capable of sending cues to direct cell movement.
In the new study, Anna C. Balazs and colleagues used computer models to simulate the chemical signaling. They modeled a porous polymer microcapsule filled with nanonparticles to imitate a biological cell. When placed next to an empty capsule, nanoparticles from the filled capsule initiated the motion of the empty capsule, which in turn caused the movement of the filled "signaling" capsule. The same locomotion process could be engineered into futuristic nanomachines to help direct their movement through the body or through fuel cells, the researchers suggest. - MTS
ARTICLE:"Modeling Microcapsules That Communicate through Nanoparticles To Undergo Self-Propelled Motion"
CONTACT:
Anna C. Balazs, Ph.D.
University of Pittsburgh
Pittsburgh, Pennsylvania 15261
Elevated concentrations of metals in China's e-waste recycling workshops
In a case study on how not to recycle electronic waste (e-waste), scientists in the United States and Hong Kong have documented serious environmental contamination with potentially toxic metals from crude e-waste recycling in a village located in southeast China. Recycling methods used in family-run workshops could pose a serious health risk to residents of the area through ingestion and inhalation of contaminated dust, the researchers say. Their study is scheduled for the April 15 issue of ACS' Environmental Science & Technology, a semi-monthly journal.
The process of discarding computers and other consumer electronics has emerged as one of the fastest growing segments of the global waste stream. Known as e-waste, these scrapped electronic goods contain lead, copper and other hazardous materials, which can release dangerous toxins that cause air and water contamination. Up to 50-million tons of e-waste is generated worldwide each year - enough to fill a line of garbage collection trucks stretching halfway around the world - according to the United Nations Environment Program.
China is now the destination for 70 percent of the computers, TVs, cell phones, and other e-waste recycled globally each year. Ming H. Wong and colleagues collected dust samples from roads adjacent to e-waste processing workshops in Guiya, China, to find that lead levels were 330 and 371 times higher than non e-waste sites located 5 miles and 19 miles away. Copper levels were 106 and 155 times higher. "Currently, there are no guidelines or regulations for heavy metals in dust. It is hoped that the results can serve as a case study for similar e-waste activities in countries such as Africa, India and Vietnam where e-waste is becoming a growing problem, so that the same mistakes could be prevented." - JS
ARTICLE: "Heavy Metals Concentrations of Surface Dust from e-Waste Recycling and Its Human Health Implications in Southeast China"
CONTACT:
Ming H. Wong, Ph.D.
Hong Kong Baptist University
Hong Kong, China
Debate sharpens over fertilizing the oceans to control global warming
As millions of people prepare to fertilize their lawns and gardens this spring, scientists are still in the midst of intensive hand-wringing over the pros and cons of fertilizing the world's oceans in an effort to control global warming, according to an article scheduled for the March 31 issue of Chemical & Engineering News, ACS' weekly newsmagazine.
C&EN Associate Editor Rachel A. Petkewich explains that in theory, ocean fertilization would remove carbon dioxide from the atmosphere by spurring the growth of tiny marine plants termed plankton that need CO2 for growth. First proposed years ago, ocean fertilization has taken on new dimensions now that hundreds of start-up companies are preparing to offer ocean-fertilization services, Petkewich says.
Although fertilization can stimulate the growth of plankton and draw down atmospheric carbon dioxide, scientists do not know whether it would be effective in permanently keeping the carbon dioxide sequestered in the oceans. Environmental groups worry about safety aspects, and government agencies are concerned about the lack of laws to regulate ocean fertilization, the article suggests.
ARTICLE: "Fertilizing the ocean with iron"
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Source: Michael Woods
American Chemical Society
Researchers in Taiwan report for the first time that blocking a key energy-supplying protein kills cancer cells. The finding, described as the first to test possible medical uses of so-called ATP-synthase inhibitors, may lead to new and more effective anti-cancer medications, according to their report, which is scheduled for the April 4 issue of ACS' monthly Journal of Proteome Research.
In the new study, Hsueh-Fen Juan and colleagues focused on ATP synthase, a key protein involved in producing the energy-rich molecules of ATP that power all life processes. For years researchers thought that the protein existed only in mitochondria, structures located inside cells that convert nutrients into energy. Recent studies found high levels of ATP synthase on the surface of cancer cells, but until now the medical implications went unexplored.
The researchers analyzed tissue samples from breast cancer patients and found for the first time that the surface of breast cancer cells contains high levels of ATP synthase. In cell studies, exposing breast cancer cells to a substance that blocks ATP synthase killed the cancer cells but did not harm normal cells, the researchers say. The findings suggest that ATP synthase inhibitors may represent a new approach for fighting breast cancer and other cancer types, they say. - MTS
ARTICLE: "Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B"
CONTACT:
Hsueh-Fen Juan, Ph.D.
National Taiwan University
Taipei, Taiwan
Electric shocks boost plants' production of commercially useful chemicals
Now for some "shocking" news about plants: Exposing plants to electricity can boost production of useful plant chemicals and may provide a cheaper, safer, and more efficient method for producing medicines, pesticides, and other commercially important plant-based materials, researchers in Arizona and Oklahoma report. Their study is scheduled for the April 4 issue of ACS' Biotechnology Progress, a bi-monthly journal.
Researchers have known for years that plants can produce a diverse array of substances as part of their natural response to environmental factors such as microbial infection, sunlight, and chemical exposure. To boost levels of plant chemicals for commercial purposes, scientists have often turned to synthetic chemical additives as well as genetic engineering, which can be expensive and potentially harmful. A better method is needed, scientists say.
In the new study, Hans VanEtten and colleagues studied the effects of electricity on the ability of the pea plant to produce pisatin, an antifungal substance. They found that exposing pea plants to certain sub-lethal doses of electric current produced 13 times higher amounts of pisatin than plants that were not exposed to electricity. The researchers observed similar increases in plant chemicals produced by a variety of other plants when exposed to electricity. There were no adverse effects on the plants. - MTS
ARTICLE: "Sub-lethal Levels of Electric Current Elicit the Biosynthesis of Plant Secondary Metabolites"
CONTACT:
Hans VanEtten, Ph.D.
University of Arizona
Tucson, Arizona 85721
Chemical signaling may power nanomachines
In a finding that could provide controlled motion in futuristic nanomachines used for drug delivery, fuel cells, and other applications, researchers in Pennsylvania report that chemical signaling between synthetic microcapsules can trigger and direct movement of these capsules. Their study is scheduled for the currrent isssue of ACS Nano, a monthly journal.
Researchers theorize that synthetic capsules can communicate with each other by physically shuffling chemical signals from capsule to capsule, much like passing water through a fireman's bucket brigade. Scientists recently suggested that this same signaling process also appears capable of sending cues to direct cell movement.
In the new study, Anna C. Balazs and colleagues used computer models to simulate the chemical signaling. They modeled a porous polymer microcapsule filled with nanonparticles to imitate a biological cell. When placed next to an empty capsule, nanoparticles from the filled capsule initiated the motion of the empty capsule, which in turn caused the movement of the filled "signaling" capsule. The same locomotion process could be engineered into futuristic nanomachines to help direct their movement through the body or through fuel cells, the researchers suggest. - MTS
ARTICLE:"Modeling Microcapsules That Communicate through Nanoparticles To Undergo Self-Propelled Motion"
CONTACT:
Anna C. Balazs, Ph.D.
University of Pittsburgh
Pittsburgh, Pennsylvania 15261
Elevated concentrations of metals in China's e-waste recycling workshops
In a case study on how not to recycle electronic waste (e-waste), scientists in the United States and Hong Kong have documented serious environmental contamination with potentially toxic metals from crude e-waste recycling in a village located in southeast China. Recycling methods used in family-run workshops could pose a serious health risk to residents of the area through ingestion and inhalation of contaminated dust, the researchers say. Their study is scheduled for the April 15 issue of ACS' Environmental Science & Technology, a semi-monthly journal.
The process of discarding computers and other consumer electronics has emerged as one of the fastest growing segments of the global waste stream. Known as e-waste, these scrapped electronic goods contain lead, copper and other hazardous materials, which can release dangerous toxins that cause air and water contamination. Up to 50-million tons of e-waste is generated worldwide each year - enough to fill a line of garbage collection trucks stretching halfway around the world - according to the United Nations Environment Program.
China is now the destination for 70 percent of the computers, TVs, cell phones, and other e-waste recycled globally each year. Ming H. Wong and colleagues collected dust samples from roads adjacent to e-waste processing workshops in Guiya, China, to find that lead levels were 330 and 371 times higher than non e-waste sites located 5 miles and 19 miles away. Copper levels were 106 and 155 times higher. "Currently, there are no guidelines or regulations for heavy metals in dust. It is hoped that the results can serve as a case study for similar e-waste activities in countries such as Africa, India and Vietnam where e-waste is becoming a growing problem, so that the same mistakes could be prevented." - JS
ARTICLE: "Heavy Metals Concentrations of Surface Dust from e-Waste Recycling and Its Human Health Implications in Southeast China"
CONTACT:
Ming H. Wong, Ph.D.
Hong Kong Baptist University
Hong Kong, China
Debate sharpens over fertilizing the oceans to control global warming
As millions of people prepare to fertilize their lawns and gardens this spring, scientists are still in the midst of intensive hand-wringing over the pros and cons of fertilizing the world's oceans in an effort to control global warming, according to an article scheduled for the March 31 issue of Chemical & Engineering News, ACS' weekly newsmagazine.
C&EN Associate Editor Rachel A. Petkewich explains that in theory, ocean fertilization would remove carbon dioxide from the atmosphere by spurring the growth of tiny marine plants termed plankton that need CO2 for growth. First proposed years ago, ocean fertilization has taken on new dimensions now that hundreds of start-up companies are preparing to offer ocean-fertilization services, Petkewich says.
Although fertilization can stimulate the growth of plankton and draw down atmospheric carbon dioxide, scientists do not know whether it would be effective in permanently keeping the carbon dioxide sequestered in the oceans. Environmental groups worry about safety aspects, and government agencies are concerned about the lack of laws to regulate ocean fertilization, the article suggests.
ARTICLE: "Fertilizing the ocean with iron"
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Source: Michael Woods
American Chemical Society
Researchers Show Leaky Muscle Cells Lead To Fatigue
What do marathoners and heart failure patients have in common? More than you think according to new findings by physiologists at Columbia University Medical Center.
The new study shows that the fatigue that marathoners and other extreme athletes feel at the end of a race is caused by a tiny leak inside their muscles that probably also saps the energy from patients with heart failure.
The leak which allows calcium to continuously leak inside muscle cells weakens the force produced by the muscle and also turns on a protein-digesting enzyme that damages the muscle fibers. The new study found the leak was present in the muscle of mice after an intense three-week daily swimming regimen and in human athletes after three days of daily intense cycling. The same leak was previously discovered by Marks and colleagues in the muscles of animals with heart failure.
The new study also found that an experimental drug developed by the researchers alleviated muscle fatigue in mice after exercise, suggesting that the drug also may provide relief from the severe exhaustion that prevents patients with chronic heart failure from getting out of bed or fixing dinner.
The results will be published in the online edition of the Proceedings of the National Academy of Sciences at 5 p.m. ET on February 11, 2008.
"The study does not mean exercise is bad for you," says the study's senior author, Andrew Marks, M.D., chair of the Department of Physiology and Cellular Biophysics, and director of the Clyde and Helen Wu Center for Molecular Cardiology at Columbia University Medical Center. "We only saw the leak in animals and human athletes that exercised three hours a day at very high intensities for several days or weeks in a row until they were exhausted." He notes that athletes' muscles also will return to normal after several days of rest and any muscle damage will be repaired after several days or weeks depending on the degree of exercise.
However, the arm, leg and breathing muscles of patients with heart failure never have a chance to recover. "People with chronic heart failure are subject to this same kind of muscle leak and damage constantly even without doing any exercise," Marks says. "One of these patients' most debilitating symptoms is muscle weakness and fatigue, which can be so bad they can't get out of bed, brush their teeth, or feed themselves."
This fatigue experienced by heart failure patients does not stem from a reduction in the amount of blood and oxygen supplied to the muscles by the heart, as one might expect. Instead, Marks' previous research in muscles of mice with heart failure suggested that fatigue in patients stems from the calcium leak, which reduced the ability of a single muscle to contract repeatedly before losing force.
"We then had a hunch that the process that produces fatigue in heart failure patients also may be responsible for the fatigue felt by athletes after a marathon or extreme training," says the study's first author, Andrew Bellinger, Ph.D., who is currently finishing his M.D. at Columbia University's College of Physicians & Surgeons. "Our new paper shows that fatigue in both patients and athletes probably stems from the same leak."
Fatigue Can Be Alleviated With Experimental Drug
The researchers then used the similarity between athletes and patients to their advantage to see if an experimental drug could increase exercise capacity and reduce fatigue.
The researchers gave the drug which plugs the leak of calcium to mice before the animals started a 3-week regimen of swimming. Without the drugs, mice are exhausted after three weeks of daily 3-hour swims. With the drug, the mice were still energetic, had lost less exercise capacity after 3 weeks, and their muscles showed fewer signs of calcium leakage, atrophy, and less muscle damage.
The cyclists in the current study were not given the drug, which is not yet available for people.
Plans are underway to test the drug at other medical centers in patients with heart failure to see if it relieves fatigue and improves heart function. Even if successful, it will take several years before the drug will be commercially available.
Study Also Provides Explanation for Muscle Fatigue Besides Lactic Acid
The calcium leak also provides a new explanation for the muscle soreness and fatigue that marathoners and other athletes can experience for weeks after crossing the finish line.
Physiologists have recently largely discarded the 100 year-old theory that lactic acid accumulation in the muscle cells produces fatigue and limits athletic performance. New theories have been exploring the role of calcium in this process. The involvement of defects in calcium handling in limiting muscle performance and producing exercise fatigue makes sense because the flow of calcium in and out of the muscle cell controls muscle contraction.
The discovery of the calcium leak in fatigued animals and athletes is the first time anyone has pinpointed a precise mechanism for the involvement of a defect in calcium handling in limiting exercise capacity.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree. Among the most selective medical schools in the country, the school is home to the largest medical research enterprise in New York State and one of the largest in the country. For more information visit cumc.columbia.
Columbia University Medical Center
701 W. 168th St., HHSC 206
New York, NY 10032
United States
cumc.columbia
The new study shows that the fatigue that marathoners and other extreme athletes feel at the end of a race is caused by a tiny leak inside their muscles that probably also saps the energy from patients with heart failure.
The leak which allows calcium to continuously leak inside muscle cells weakens the force produced by the muscle and also turns on a protein-digesting enzyme that damages the muscle fibers. The new study found the leak was present in the muscle of mice after an intense three-week daily swimming regimen and in human athletes after three days of daily intense cycling. The same leak was previously discovered by Marks and colleagues in the muscles of animals with heart failure.
The new study also found that an experimental drug developed by the researchers alleviated muscle fatigue in mice after exercise, suggesting that the drug also may provide relief from the severe exhaustion that prevents patients with chronic heart failure from getting out of bed or fixing dinner.
The results will be published in the online edition of the Proceedings of the National Academy of Sciences at 5 p.m. ET on February 11, 2008.
"The study does not mean exercise is bad for you," says the study's senior author, Andrew Marks, M.D., chair of the Department of Physiology and Cellular Biophysics, and director of the Clyde and Helen Wu Center for Molecular Cardiology at Columbia University Medical Center. "We only saw the leak in animals and human athletes that exercised three hours a day at very high intensities for several days or weeks in a row until they were exhausted." He notes that athletes' muscles also will return to normal after several days of rest and any muscle damage will be repaired after several days or weeks depending on the degree of exercise.
However, the arm, leg and breathing muscles of patients with heart failure never have a chance to recover. "People with chronic heart failure are subject to this same kind of muscle leak and damage constantly even without doing any exercise," Marks says. "One of these patients' most debilitating symptoms is muscle weakness and fatigue, which can be so bad they can't get out of bed, brush their teeth, or feed themselves."
This fatigue experienced by heart failure patients does not stem from a reduction in the amount of blood and oxygen supplied to the muscles by the heart, as one might expect. Instead, Marks' previous research in muscles of mice with heart failure suggested that fatigue in patients stems from the calcium leak, which reduced the ability of a single muscle to contract repeatedly before losing force.
"We then had a hunch that the process that produces fatigue in heart failure patients also may be responsible for the fatigue felt by athletes after a marathon or extreme training," says the study's first author, Andrew Bellinger, Ph.D., who is currently finishing his M.D. at Columbia University's College of Physicians & Surgeons. "Our new paper shows that fatigue in both patients and athletes probably stems from the same leak."
Fatigue Can Be Alleviated With Experimental Drug
The researchers then used the similarity between athletes and patients to their advantage to see if an experimental drug could increase exercise capacity and reduce fatigue.
The researchers gave the drug which plugs the leak of calcium to mice before the animals started a 3-week regimen of swimming. Without the drugs, mice are exhausted after three weeks of daily 3-hour swims. With the drug, the mice were still energetic, had lost less exercise capacity after 3 weeks, and their muscles showed fewer signs of calcium leakage, atrophy, and less muscle damage.
The cyclists in the current study were not given the drug, which is not yet available for people.
Plans are underway to test the drug at other medical centers in patients with heart failure to see if it relieves fatigue and improves heart function. Even if successful, it will take several years before the drug will be commercially available.
Study Also Provides Explanation for Muscle Fatigue Besides Lactic Acid
The calcium leak also provides a new explanation for the muscle soreness and fatigue that marathoners and other athletes can experience for weeks after crossing the finish line.
Physiologists have recently largely discarded the 100 year-old theory that lactic acid accumulation in the muscle cells produces fatigue and limits athletic performance. New theories have been exploring the role of calcium in this process. The involvement of defects in calcium handling in limiting muscle performance and producing exercise fatigue makes sense because the flow of calcium in and out of the muscle cell controls muscle contraction.
The discovery of the calcium leak in fatigued animals and athletes is the first time anyone has pinpointed a precise mechanism for the involvement of a defect in calcium handling in limiting exercise capacity.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree. Among the most selective medical schools in the country, the school is home to the largest medical research enterprise in New York State and one of the largest in the country. For more information visit cumc.columbia.
Columbia University Medical Center
701 W. 168th St., HHSC 206
New York, NY 10032
United States
cumc.columbia
Mayo Clinic Researchers Discover And Manipulate Molecular Interplay That Moves Cancer Cells
Based on research that reveals new insight into mechanisms that allow invasive tumor cells to move, researchers at the Mayo Clinic campus in Florida have a new understanding about how to stop cancer from spreading. A cancer that spreads elsewhere in the body, known as metastasis, is the process that most often leads to death from the disease.
In the March 29 online issue of Nature Cell Biology, researchers say that a molecule known as protein kinase D1 (PKD1) is key to the ability of a tumor cell to "remodel" its structure, enabling it to migrate and invade. The researchers found that if PKD1 is active, tumor cells cannot move, a finding they say explains why PKD1 is silenced in some invasive cancers.
During metastasis, invasive cancer cells respond to biological signals to move away from a primary tumor. Multiple research groups at Mayo Clinic in Florida are especially interested in this process. One team, led by cancer biologist Peter Storz, Ph.D., has been investigating a process known as actin remodeling at the leading edge - the most forward point - of these migrating tumor cells.
"The events that reorganize the actin cytoskeleton at the leading edge are complex - a multitude of molecules act in concert," Dr. Storz says. "But it appears that PKD1 must be turned off if cancer cells are to migrate."
Actin filaments help make up the cytoskeleton of cells. For cancer cells to move, the actin-based cell structure has to be continually reorganized, Dr. Storz says, and to do this, new actin filaments need to be generated to shift the cell forward.
Dr. Storz' group discovered that PKD1 was critical to this process. The researchers found that PKD1 inhibits another protein known as slingshot, which regulates the severing of existing actin structures so that new actin filaments can be synthesized, an event that is essential for cell movement.
The researchers used methods to deplete tumor cells of PKD1 and found that their motility increased. They then expressed activated PKD1 in tumor cells and found that movement was blocked. PKD1 is therefore a negative regulator of directed cell migration, and if PKD1 is not expressed in tumor cells, slingshot will become active and will contribute to the reorganization of actin, and a tumor cell will move, according to researchers.
"This makes sense, because other investigators have found that PKD1 is down-regulated, or turned off, in invasive forms of gastric, prostate, and breast cancer," says Dr. Storz.
So far, investigators have identified a number of players along the pathways that regulate cancer cell movement, from the molecule (RhoaA) that activates PKD1, to the well-known protein (cofilin) that disassembles actin filaments and which is regulated by slingshot. When PKD1 is activated, cofilin does not function and so the cell cannot move.
"Now that we have identified PKD1 as key regulator in processes regulating actin-based directed tumor cell movement, we can begin to think about designing treatments to stop invasive cancer cells from metastasizing," says Dr. Storz. "The basic mechanisms we have uncovered are key to developing those strategies."
Notes:
Co-authors include Tim Eiseler, Ph.D., Heike Döppler, and Irene Yan from the Mayo Clinic Department of Cancer Biology; and Kanae Kitatani, Ph.D., and Kensaku Mizuno, Ph.D., from the Graduate School of Life Sciences at Tohoku University in Japan.
The study was funded by Mayo Foundation and the Mayo Comprehensive Cancer Center, the National Cancer Institute, a 'Friends for an Earlier Breast Cancer Test' Grant, and by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Source:
Paul Scotti
Mayo Clinic
In the March 29 online issue of Nature Cell Biology, researchers say that a molecule known as protein kinase D1 (PKD1) is key to the ability of a tumor cell to "remodel" its structure, enabling it to migrate and invade. The researchers found that if PKD1 is active, tumor cells cannot move, a finding they say explains why PKD1 is silenced in some invasive cancers.
During metastasis, invasive cancer cells respond to biological signals to move away from a primary tumor. Multiple research groups at Mayo Clinic in Florida are especially interested in this process. One team, led by cancer biologist Peter Storz, Ph.D., has been investigating a process known as actin remodeling at the leading edge - the most forward point - of these migrating tumor cells.
"The events that reorganize the actin cytoskeleton at the leading edge are complex - a multitude of molecules act in concert," Dr. Storz says. "But it appears that PKD1 must be turned off if cancer cells are to migrate."
Actin filaments help make up the cytoskeleton of cells. For cancer cells to move, the actin-based cell structure has to be continually reorganized, Dr. Storz says, and to do this, new actin filaments need to be generated to shift the cell forward.
Dr. Storz' group discovered that PKD1 was critical to this process. The researchers found that PKD1 inhibits another protein known as slingshot, which regulates the severing of existing actin structures so that new actin filaments can be synthesized, an event that is essential for cell movement.
The researchers used methods to deplete tumor cells of PKD1 and found that their motility increased. They then expressed activated PKD1 in tumor cells and found that movement was blocked. PKD1 is therefore a negative regulator of directed cell migration, and if PKD1 is not expressed in tumor cells, slingshot will become active and will contribute to the reorganization of actin, and a tumor cell will move, according to researchers.
"This makes sense, because other investigators have found that PKD1 is down-regulated, or turned off, in invasive forms of gastric, prostate, and breast cancer," says Dr. Storz.
So far, investigators have identified a number of players along the pathways that regulate cancer cell movement, from the molecule (RhoaA) that activates PKD1, to the well-known protein (cofilin) that disassembles actin filaments and which is regulated by slingshot. When PKD1 is activated, cofilin does not function and so the cell cannot move.
"Now that we have identified PKD1 as key regulator in processes regulating actin-based directed tumor cell movement, we can begin to think about designing treatments to stop invasive cancer cells from metastasizing," says Dr. Storz. "The basic mechanisms we have uncovered are key to developing those strategies."
Notes:
Co-authors include Tim Eiseler, Ph.D., Heike Döppler, and Irene Yan from the Mayo Clinic Department of Cancer Biology; and Kanae Kitatani, Ph.D., and Kensaku Mizuno, Ph.D., from the Graduate School of Life Sciences at Tohoku University in Japan.
The study was funded by Mayo Foundation and the Mayo Comprehensive Cancer Center, the National Cancer Institute, a 'Friends for an Earlier Breast Cancer Test' Grant, and by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Source:
Paul Scotti
Mayo Clinic
To A Mosquito, Matchmaking Means 'Singing' In Perfect Harmony
Researchers have new insight into the sex lives of the much-maligned mosquitoes that are responsible for the vast majority of malaria deaths, according to a report published online on December 31st in Current Biology, a Cell Press publication. In finding a partner of the right species type, male and female mosquitoes depend on their ability to "sing" in perfect harmony. Those tones are produced and varied based on the frequency of their wing beats in flight.
"Everyone must be familiar with the maddening whine a mosquito makes as it hones in for a bite," said Gabriella Gibson of the University of Greenwich at Medway. "There's no doubt many of us have wondered why it makes its presence so obvious - surely, after all of these centuries of blood-feeding, selection should have favored a more stealthy approach that would leave mosquitoes less vulnerable to the defensive attacks of its unsettled host. Our findings suggest that mosquitoes rely on the sounds they make to attract a mate of the right species, a behavior that is far more vulnerable to selection than avoiding the risk of being squashed by the rare host that is still awake at feeding time."
The Anopheles gambiae mosquitoes in fact include a considerable amount of genetic diversity, representing a complex of seven species and several chromosomal forms. And that diversity comes with real consequences for humans, explained Gibson and Ian Russell of the University of Sussex. The complexity of malaria epidemiology and control is due in part to the mosquito's remarkable genetic plasticity, enabling its adaptation to a widening range of human-influenced habitats.
The new results help to explain how those different mosquito forms manage to reproductively isolate themselves and maintain that genetic diversity, even while some, including the "M" and "S" forms found in Burkina Faso that were the subject of the current study, can be found traveling together in the very same swarms.
Gibson and Russell's team first discovered that male and female mosquitoes harmonize with each other. Gibson said that this is analogous to two partially deaf singers - one alto and the other soprano - who can hear low frequencies, but perhaps not their own or each other's songs. Instead, they listen to the terrible dissonance if one or the other goes a bit sharp or flat, which they can get rid of by adjusting their respective tones until the dissonance diminishes to nothing.
"They can do this even if they each sing a different note, say a 'middle C' and a 'G' four tones higher," Russell said. "By listening and subtly altering their pitch to minimize the dissonance, they achieve their goal of 'singing' in a perfect harmony that we, but not they, can hear."
The researchers have now shown that two mosquitoes don't harmonize successfully if they are of the same sex or if they are not the same type of mosquito. They might try for a while, Gibson explained, but they never find that harmony and eventually give up trying.
And that leads Gibson to another take-home of the study. "Even the most 'lowly creatures,' such as mosquitoes, have highly evolved neurosensory systems that can process relatively simple auditory inputs to produce motor outputs enabling them to distinguish between other types of mosquito that are so closely related we need to analyze their DNA to tell them apart."
The researchers include C. Pennetier, University of Sussex, U.K., University of Greenwich at Medway, Kent, U.K., B. Warren, University of Sussex, U.K.; R. Dabire, Institut de Recherche en Science de la Sante/Centre Muraz, Burkina Faso; I.J. Russell, University of Sussex, U.K.; and G. Gibson, University of Sussex, U.K., University of Greenwich at Medway, Kent, U.K.
Source: Cathleen Genova
Cell Press
"Everyone must be familiar with the maddening whine a mosquito makes as it hones in for a bite," said Gabriella Gibson of the University of Greenwich at Medway. "There's no doubt many of us have wondered why it makes its presence so obvious - surely, after all of these centuries of blood-feeding, selection should have favored a more stealthy approach that would leave mosquitoes less vulnerable to the defensive attacks of its unsettled host. Our findings suggest that mosquitoes rely on the sounds they make to attract a mate of the right species, a behavior that is far more vulnerable to selection than avoiding the risk of being squashed by the rare host that is still awake at feeding time."
The Anopheles gambiae mosquitoes in fact include a considerable amount of genetic diversity, representing a complex of seven species and several chromosomal forms. And that diversity comes with real consequences for humans, explained Gibson and Ian Russell of the University of Sussex. The complexity of malaria epidemiology and control is due in part to the mosquito's remarkable genetic plasticity, enabling its adaptation to a widening range of human-influenced habitats.
The new results help to explain how those different mosquito forms manage to reproductively isolate themselves and maintain that genetic diversity, even while some, including the "M" and "S" forms found in Burkina Faso that were the subject of the current study, can be found traveling together in the very same swarms.
Gibson and Russell's team first discovered that male and female mosquitoes harmonize with each other. Gibson said that this is analogous to two partially deaf singers - one alto and the other soprano - who can hear low frequencies, but perhaps not their own or each other's songs. Instead, they listen to the terrible dissonance if one or the other goes a bit sharp or flat, which they can get rid of by adjusting their respective tones until the dissonance diminishes to nothing.
"They can do this even if they each sing a different note, say a 'middle C' and a 'G' four tones higher," Russell said. "By listening and subtly altering their pitch to minimize the dissonance, they achieve their goal of 'singing' in a perfect harmony that we, but not they, can hear."
The researchers have now shown that two mosquitoes don't harmonize successfully if they are of the same sex or if they are not the same type of mosquito. They might try for a while, Gibson explained, but they never find that harmony and eventually give up trying.
And that leads Gibson to another take-home of the study. "Even the most 'lowly creatures,' such as mosquitoes, have highly evolved neurosensory systems that can process relatively simple auditory inputs to produce motor outputs enabling them to distinguish between other types of mosquito that are so closely related we need to analyze their DNA to tell them apart."
The researchers include C. Pennetier, University of Sussex, U.K., University of Greenwich at Medway, Kent, U.K., B. Warren, University of Sussex, U.K.; R. Dabire, Institut de Recherche en Science de la Sante/Centre Muraz, Burkina Faso; I.J. Russell, University of Sussex, U.K.; and G. Gibson, University of Sussex, U.K., University of Greenwich at Medway, Kent, U.K.
Source: Cathleen Genova
Cell Press
Winners Of 2011 Student Travel Awards Announced By Biophysical Society
The Biophysical Society has announced the winners of its student travel award to attend the Biophysical Society's 55th Annual Meeting at the Baltimore Convention Center in Baltimore, Maryland, March 5-9, 2011. The recipients of this competitive award are selected based on scientific merit, with priority given to those who will present a paper at the conference. Each awardee receives a travel grant and will be recognized at a reception on Saturday, March 5.
The 2011 recipients of the Student Travel Award are:
Stacey Barnaby, Fordham University, ELLAGIC ACID NANOTUBULAR AND POLY-CATIONIC CONJUGATES AS NANO-CARRIERS FOR DELIVERY INTO MAMMALIAN CELLS.
Claudio Berti, University of Bologna, Italy, A NOVEL BROWNIAN-DYNAMICS ALGORITHM FOR THE SIMULATION OF ION CONDUCTION THROUGH MEMBRANE PORES.
Elizabeth Bode, University of Manchester, United Kingdom, CHANGES OF SERCA ACTIVITY HAVE PROPORTIONATELY SMALLER EFFECTS ON SARCOPLASMIC RETICULUM CALCIUM CONTENT.
Urska Bukovnik, Kansas State University, SYNTHETIC PEPTIDE-BASED CHANNELS: CANDIDATES FOR TREATMENTS OF CHANNELOPATHIES.
Margaret Elvekrog, Columbia University, THE ROLE OF INITIATION FACTOR 3 STRUCTURAL DYNAMICS IN REGULATING THE FIDELITY OF TRANSLATION INITIATION.
Sebastian Fiedler, University of Kaiserslautem, Germany, PROTEIN UNFOLDING AND REFOLDING BY MULTIDIMENSIONAL SPECTROSCOPY.
Maria Frushicheva, University of Southern California, COMPUTATIONAL ENZYME DESIGN: REFINING ARTIFICIAL ENZYMES AND EXPLORING PATHS OF DIRECTED EVOLUTION.
Ece Gaffarogullari, University of Minnesota, ROLE OF N-MYRISTOYLATION OF CAMP-DEPENDENT PROTEIN KINASE A IN RECOGNITION AND PHOSPHORYLATION OF MEMBRANE-BOUND SUBSTRATES.
Maarten Gees, Katholieke Universiteit Leuven, Belgium, MOLECULAR DETERMINANTS OF TRPV1 STIMULATION BY MUSTARD OIL.
Andree Gravel, Universite du Quebec a Montreal, Canada, THE SELECTIVITY FILTER OF THE HERG CHANNEL - NMR STUDY OF ITS STRUCTURE AND INTERACTION WITH MEMBRANES AND DRUGS INVOLVED IN THE LONG QT SYNDROME.
Michael Green, Willamette University, STUDIES OF THE FORCE-DEPENDENT MOTOR ACTIVITY OF MYOSIN I.
Nicola Harris, University of Bristol, United Kingdom, INVESTIGATIONS INTO THE REVERSIBLE FOLDING OF THE TWO DOMAIN HELICAL TRANSPORTER LACTOSE PERMEASE.
James Henderson, University of Chicago, CHARACTERIZING A DETERGENT-LIKE COMMONALITY AMONG ANTIMICROBIAL PEPTIDES WITH STRUCTURAL AND MECHANISTIC DIFFERENCES.
Jacqueline Hill Tudor, Case Western Reserve University, PACAP-EVOKED ADRENAL EXCITATION IS DUE TO MEMBRANE DEPOLARIZATION AND FACILITATION OF AN LVA CALCIUM CHANNEL.
Derek Ho, University of Guelph, Canada, CHARACTERIZATION OF THE COLICIN E1 CHANNEL USING GENETICALLY ENCODED FLUORESCENCE.
Annas Javed, University of Texas, CONTROLLED PHOTO ELECTRO THERMAL GENERATION OF MICRO BUBBLE FOR MANIPULATION OF CELLS.
Robin Johnson, Univeristy of Michigan, DIRECT OBSERVATION OF SINGLE OLIGOMERS OF THE ALZHEIMER'S AMYLOID-ОІ PEPTIDE ON LIVE CELL MEMBRANES.
David Jones, Simon Fraser University, Canada, TURRET HISTIDINES IN PH MODULATION OF THE CARDIAC VOLTAGE-GATED SODIUM CHANNEL.
Sarah Kampert, University of Michigan, COMBINATION OF PHOSPHOMIMETIC SUBSTITUTIONS WITHIN CARDIAC TROPONIN I CAUSE FUNCTIONAL CROSS-TALK.
Robert Keller, University of Essex, United Kingdom, INVESTIGATING NUCLEOTIDE EXCISION DNA REPAIR BY SINGLE-MOLECULE IMAGING OF QUANTUM DOT LABELED PROTEINS REVEALS UNIQUE SCANNING MECHANISMS.
Elena Koslover, Stanford University, TARGET SITE LOCALIZATION DYNAMICS OF DNA-BINDING PROTEINS IN VIVO.
Pradeep Kota, University of North Carolina, ENGINEERED ALLOSTERIC ACTIVATION OF KINASES IN LIVING CELLS.
Eileen Krenzel, Boston University, RELATIVE AFFINITIES OF FATTY ACID BINDING SITES ON HUMAN SERUM ALBUMIN PROBED BY 2D-NMR.
Alex Kreutzberger, University of North Carolina, ON THE ORIGIN OF MULTI-EXPONENTIAL KINETICS IN PEPTIDE BINDING TO PHOSPHOLIPID VESICLES.
Jane Lee, University of California, Merced, USING SIMPLE WATER:VACUUM ENERGETICS TO MODEL PHOSPHOLIPID BILAYER ELECTROPERMEABILIZATION.
Shih-Wei Liu, National Taiwan University, Taiwan, DIRECT OBSERVATION OF REPLICATIVE HELICASE DNAC BY SINGLE-MOLECULE TETHERED PARTICLE MOTION (TPM) EXPERIMENTS.
Campion Loong, Flordia State University, FLEXIBILITY CHANGE IN HUMAN CARDIAC О±-TROPOMYOSIN E180G MUTANT: POSSIBLE LINK TO CARDIAC HYPERTROPHY.
Benjamin Machta, Cornell University, CRITICALITY IN PLASMA MEMBRANES.
Matthew Eddy, Massachusetts Institute of Technology, INVESTIGATING VDAC GATING VIA MAGIC ANGLE SPINNING NMR AND ELECTROPHYSIOLOGICAL MEASUREMENTS UNDER EXTREME PH CONDITIONS: IMPLICATIONS FOR THE VOLTAGE-GATING MECHANISM.
Boern Meier, Ludwig-Maximillians University, Germany, DYNAMICS OF INTRACELLULAR SIGNALING IN SPATIO-TEMPORALLY VARYING CHEMOTACTIC GRADIENT FIELDS.
Sandrine Morlot, University of Geneva, Switzerland, QUANTITATIVE ANALYSIS OF MEMBRANE DEFORMATION AND FISSION INDUCED BY DYNAMIN GTPASE ACTIVITY.
Heather Orrell, University of California, Merced, MULTIVALENT CATION REGULATION OF CARDIAC CALSEQUESTRIN: A SPECTROSCOPIC AND ELECTROPHYSIOLOGICAL STUDY.
Wei Ouyang, Syracuse University, PROBING THE RNA BINDING SURFACE OF THE HIV-1 NUCLEOCAPSID PROTEIN BY SITE-DIRECTED MUTAGENESIS.
* Tatiana Perevozchikova, University of Tennessee, STRUCTURAL VARIATIONS IN THE AGGREGATION PATHWAYS OF NORMAL AND PATHOLOGICAL HUNTINGTIN-LIKE PEPTIDES.
Ashlee Plummer, North Carolina State University, MAKING SUBSTRATES OUT OF INHIBITORS: DISTAL CAVITY MUTATIONS IN DEHALOPEROXIDASE FROM AMPHITRITE ORNATA.
Srinivas Ramachandran, University of North Carolina, THERMODYNAMIC STABILITY OF HISTONE H3 IS A NECESSARY BUT NOT SUFFICIENT DRIVING FORCE FOR ITS EVOLUTIONARY CONSERVATION.
Anu Rambhadran, University of Texas Health Science Center, CONFORMATIONAL CHANGES IN THE EXTRACELLULAR DOMAIN ON GLUTAMATE RECEPTORS.
Fabian Romano, University of Massachusetts, Amherst, INSIGHTS INTO THE MEMBRANE-INTERACTION PROPERTIES OF THE PSEUDOMONAS AERUGINOSA TYPE III SECRETION TRANSLOCATOR POPD.
Samer Salamekh, University of Michigan, MOLECULAR BASIS OF THE INTERACTION BETWEEN ZINC AND THE AMYLOIDOGENIC ISLET AMYLOID POLYPEPTIDE.
Kanayo Satoh, RIKEN Brain Science Institute, Japan, VISUALIZATION OF CALCIUM PUMPING ACTIVITY IN LIVING CELLS WITH A NOVEL FRET-BASED SERCA PUMP SENSOR.
Mark Seeger, Northwestern University, THE KINESIN-1 C-TERMINAL TAIL IS INTRINSICALLY DISORDERED.
Kathrin Spendier, University of New Mexico, MODELING THE COALESCENCE KINETICS OF CELL SURFACE RECEPTOR CLUSTERS.
Iehab Talukder, Stony Brook University, CONSTRAINING GATING ACTIONS OF SPECIFIC SUBUNITS DURING NMDA RECEPTOR ACTIVATION.
Luca Tubiana, Scuola Internazionale Superiore di Studi Avanzati, Italy, SIMULATIONS OF VIRAL DNA PACKAGING AND EJECTION: GEOMETRICAL ORDER AND TOPOLOGICAL DISORDER.
Cameron Turtle, University of Washington, REDUCING THIN FILAMENT CA2+ AFFINITY WITH A CTNC VARIANT (L57Q) REDUCES FORCE BUT ENHANCES CROSS-BRIDGE DEPENDENCE OF COOPERATIVE ACTIVATION IN DEMEMBRANATED RAT TRABECULAE.
Lea Veras, Carnegie Mellon University, MOLECULAR MECHANISMS OF Ca2+ SELECTIVITY AND Mg2+ BLOCK OF NMDA RECEPTORS.
BГ©la VoГџ, Max Planck Institute for Biophysical Chemistry, Germany, MLOK1 LIGAND BINDING SIMULATIONS: INDUCED FIT VERSUS CONFORMATIONAL SELECTION.
Rauta Yakubu, University of Missouri, MONITORING PROTEIN ASSOCIATION WITH A MEMBRANE BILAYER USING ULTRAVIOLET RESONANCE RAMAN (UVRR) SPECTROSCOPY.
David Yampolsky, Vanderbilt University, EFFECTS OF A DISULFIDE CROSSLINK (XL) ON THE TRYPSIN CLEAVAGE PATTERN OF RABBIT CARDIAC TROPOMYOSIN (TM).
Source:
Ellen R. Weiss
Biophysical Society
The 2011 recipients of the Student Travel Award are:
Stacey Barnaby, Fordham University, ELLAGIC ACID NANOTUBULAR AND POLY-CATIONIC CONJUGATES AS NANO-CARRIERS FOR DELIVERY INTO MAMMALIAN CELLS.
Claudio Berti, University of Bologna, Italy, A NOVEL BROWNIAN-DYNAMICS ALGORITHM FOR THE SIMULATION OF ION CONDUCTION THROUGH MEMBRANE PORES.
Elizabeth Bode, University of Manchester, United Kingdom, CHANGES OF SERCA ACTIVITY HAVE PROPORTIONATELY SMALLER EFFECTS ON SARCOPLASMIC RETICULUM CALCIUM CONTENT.
Urska Bukovnik, Kansas State University, SYNTHETIC PEPTIDE-BASED CHANNELS: CANDIDATES FOR TREATMENTS OF CHANNELOPATHIES.
Margaret Elvekrog, Columbia University, THE ROLE OF INITIATION FACTOR 3 STRUCTURAL DYNAMICS IN REGULATING THE FIDELITY OF TRANSLATION INITIATION.
Sebastian Fiedler, University of Kaiserslautem, Germany, PROTEIN UNFOLDING AND REFOLDING BY MULTIDIMENSIONAL SPECTROSCOPY.
Maria Frushicheva, University of Southern California, COMPUTATIONAL ENZYME DESIGN: REFINING ARTIFICIAL ENZYMES AND EXPLORING PATHS OF DIRECTED EVOLUTION.
Ece Gaffarogullari, University of Minnesota, ROLE OF N-MYRISTOYLATION OF CAMP-DEPENDENT PROTEIN KINASE A IN RECOGNITION AND PHOSPHORYLATION OF MEMBRANE-BOUND SUBSTRATES.
Maarten Gees, Katholieke Universiteit Leuven, Belgium, MOLECULAR DETERMINANTS OF TRPV1 STIMULATION BY MUSTARD OIL.
Andree Gravel, Universite du Quebec a Montreal, Canada, THE SELECTIVITY FILTER OF THE HERG CHANNEL - NMR STUDY OF ITS STRUCTURE AND INTERACTION WITH MEMBRANES AND DRUGS INVOLVED IN THE LONG QT SYNDROME.
Michael Green, Willamette University, STUDIES OF THE FORCE-DEPENDENT MOTOR ACTIVITY OF MYOSIN I.
Nicola Harris, University of Bristol, United Kingdom, INVESTIGATIONS INTO THE REVERSIBLE FOLDING OF THE TWO DOMAIN HELICAL TRANSPORTER LACTOSE PERMEASE.
James Henderson, University of Chicago, CHARACTERIZING A DETERGENT-LIKE COMMONALITY AMONG ANTIMICROBIAL PEPTIDES WITH STRUCTURAL AND MECHANISTIC DIFFERENCES.
Jacqueline Hill Tudor, Case Western Reserve University, PACAP-EVOKED ADRENAL EXCITATION IS DUE TO MEMBRANE DEPOLARIZATION AND FACILITATION OF AN LVA CALCIUM CHANNEL.
Derek Ho, University of Guelph, Canada, CHARACTERIZATION OF THE COLICIN E1 CHANNEL USING GENETICALLY ENCODED FLUORESCENCE.
Annas Javed, University of Texas, CONTROLLED PHOTO ELECTRO THERMAL GENERATION OF MICRO BUBBLE FOR MANIPULATION OF CELLS.
Robin Johnson, Univeristy of Michigan, DIRECT OBSERVATION OF SINGLE OLIGOMERS OF THE ALZHEIMER'S AMYLOID-ОІ PEPTIDE ON LIVE CELL MEMBRANES.
David Jones, Simon Fraser University, Canada, TURRET HISTIDINES IN PH MODULATION OF THE CARDIAC VOLTAGE-GATED SODIUM CHANNEL.
Sarah Kampert, University of Michigan, COMBINATION OF PHOSPHOMIMETIC SUBSTITUTIONS WITHIN CARDIAC TROPONIN I CAUSE FUNCTIONAL CROSS-TALK.
Robert Keller, University of Essex, United Kingdom, INVESTIGATING NUCLEOTIDE EXCISION DNA REPAIR BY SINGLE-MOLECULE IMAGING OF QUANTUM DOT LABELED PROTEINS REVEALS UNIQUE SCANNING MECHANISMS.
Elena Koslover, Stanford University, TARGET SITE LOCALIZATION DYNAMICS OF DNA-BINDING PROTEINS IN VIVO.
Pradeep Kota, University of North Carolina, ENGINEERED ALLOSTERIC ACTIVATION OF KINASES IN LIVING CELLS.
Eileen Krenzel, Boston University, RELATIVE AFFINITIES OF FATTY ACID BINDING SITES ON HUMAN SERUM ALBUMIN PROBED BY 2D-NMR.
Alex Kreutzberger, University of North Carolina, ON THE ORIGIN OF MULTI-EXPONENTIAL KINETICS IN PEPTIDE BINDING TO PHOSPHOLIPID VESICLES.
Jane Lee, University of California, Merced, USING SIMPLE WATER:VACUUM ENERGETICS TO MODEL PHOSPHOLIPID BILAYER ELECTROPERMEABILIZATION.
Shih-Wei Liu, National Taiwan University, Taiwan, DIRECT OBSERVATION OF REPLICATIVE HELICASE DNAC BY SINGLE-MOLECULE TETHERED PARTICLE MOTION (TPM) EXPERIMENTS.
Campion Loong, Flordia State University, FLEXIBILITY CHANGE IN HUMAN CARDIAC О±-TROPOMYOSIN E180G MUTANT: POSSIBLE LINK TO CARDIAC HYPERTROPHY.
Benjamin Machta, Cornell University, CRITICALITY IN PLASMA MEMBRANES.
Matthew Eddy, Massachusetts Institute of Technology, INVESTIGATING VDAC GATING VIA MAGIC ANGLE SPINNING NMR AND ELECTROPHYSIOLOGICAL MEASUREMENTS UNDER EXTREME PH CONDITIONS: IMPLICATIONS FOR THE VOLTAGE-GATING MECHANISM.
Boern Meier, Ludwig-Maximillians University, Germany, DYNAMICS OF INTRACELLULAR SIGNALING IN SPATIO-TEMPORALLY VARYING CHEMOTACTIC GRADIENT FIELDS.
Sandrine Morlot, University of Geneva, Switzerland, QUANTITATIVE ANALYSIS OF MEMBRANE DEFORMATION AND FISSION INDUCED BY DYNAMIN GTPASE ACTIVITY.
Heather Orrell, University of California, Merced, MULTIVALENT CATION REGULATION OF CARDIAC CALSEQUESTRIN: A SPECTROSCOPIC AND ELECTROPHYSIOLOGICAL STUDY.
Wei Ouyang, Syracuse University, PROBING THE RNA BINDING SURFACE OF THE HIV-1 NUCLEOCAPSID PROTEIN BY SITE-DIRECTED MUTAGENESIS.
* Tatiana Perevozchikova, University of Tennessee, STRUCTURAL VARIATIONS IN THE AGGREGATION PATHWAYS OF NORMAL AND PATHOLOGICAL HUNTINGTIN-LIKE PEPTIDES.
Ashlee Plummer, North Carolina State University, MAKING SUBSTRATES OUT OF INHIBITORS: DISTAL CAVITY MUTATIONS IN DEHALOPEROXIDASE FROM AMPHITRITE ORNATA.
Srinivas Ramachandran, University of North Carolina, THERMODYNAMIC STABILITY OF HISTONE H3 IS A NECESSARY BUT NOT SUFFICIENT DRIVING FORCE FOR ITS EVOLUTIONARY CONSERVATION.
Anu Rambhadran, University of Texas Health Science Center, CONFORMATIONAL CHANGES IN THE EXTRACELLULAR DOMAIN ON GLUTAMATE RECEPTORS.
Fabian Romano, University of Massachusetts, Amherst, INSIGHTS INTO THE MEMBRANE-INTERACTION PROPERTIES OF THE PSEUDOMONAS AERUGINOSA TYPE III SECRETION TRANSLOCATOR POPD.
Samer Salamekh, University of Michigan, MOLECULAR BASIS OF THE INTERACTION BETWEEN ZINC AND THE AMYLOIDOGENIC ISLET AMYLOID POLYPEPTIDE.
Kanayo Satoh, RIKEN Brain Science Institute, Japan, VISUALIZATION OF CALCIUM PUMPING ACTIVITY IN LIVING CELLS WITH A NOVEL FRET-BASED SERCA PUMP SENSOR.
Mark Seeger, Northwestern University, THE KINESIN-1 C-TERMINAL TAIL IS INTRINSICALLY DISORDERED.
Kathrin Spendier, University of New Mexico, MODELING THE COALESCENCE KINETICS OF CELL SURFACE RECEPTOR CLUSTERS.
Iehab Talukder, Stony Brook University, CONSTRAINING GATING ACTIONS OF SPECIFIC SUBUNITS DURING NMDA RECEPTOR ACTIVATION.
Luca Tubiana, Scuola Internazionale Superiore di Studi Avanzati, Italy, SIMULATIONS OF VIRAL DNA PACKAGING AND EJECTION: GEOMETRICAL ORDER AND TOPOLOGICAL DISORDER.
Cameron Turtle, University of Washington, REDUCING THIN FILAMENT CA2+ AFFINITY WITH A CTNC VARIANT (L57Q) REDUCES FORCE BUT ENHANCES CROSS-BRIDGE DEPENDENCE OF COOPERATIVE ACTIVATION IN DEMEMBRANATED RAT TRABECULAE.
Lea Veras, Carnegie Mellon University, MOLECULAR MECHANISMS OF Ca2+ SELECTIVITY AND Mg2+ BLOCK OF NMDA RECEPTORS.
BГ©la VoГџ, Max Planck Institute for Biophysical Chemistry, Germany, MLOK1 LIGAND BINDING SIMULATIONS: INDUCED FIT VERSUS CONFORMATIONAL SELECTION.
Rauta Yakubu, University of Missouri, MONITORING PROTEIN ASSOCIATION WITH A MEMBRANE BILAYER USING ULTRAVIOLET RESONANCE RAMAN (UVRR) SPECTROSCOPY.
David Yampolsky, Vanderbilt University, EFFECTS OF A DISULFIDE CROSSLINK (XL) ON THE TRYPSIN CLEAVAGE PATTERN OF RABBIT CARDIAC TROPOMYOSIN (TM).
Source:
Ellen R. Weiss
Biophysical Society
A Key To Aggressive Breast Cancer Discovered By UC Davis Researchers
In trying to find out why HER2-positive breast cancer can be more aggressive than other forms of the disease, UC Davis Cancer Center researchers have surprisingly discovered that HER2 itself is the culprit. By shutting down its own regulator gene, HER2 creates a permissive environment for tumor growth.
Building on recent research showing that the regulator - labeled LRIG1 and commonly called "Lig-1" - limits the growth-promoting signals of HER2, the research team set out to clarify the role of Lig-1 in breast cancer.
They found that, when compared to healthy breast tissue, the regulator is significantly suppressed.
"This suppression assists HER2 in its own over-expression and in driving the growth of cancer cells," said Colleen Sweeney, associate professor of biochemistry and molecular medicine and senior author of the study, which appears in this month's issue of Cancer Research. "HER2 is clearly taking an active role its own ability to be successful in promoting cancer."
Sweeney added that the study results could lead to new treatments aimed at restoring or replacing functions of the regulator. This is good news for patients because, in addition to being more aggressive, HER2-positive breast cancer tends to be less responsive to currently available treatments. The gene is over-expressed in about one-quarter to one-third of breast cancer cases.
Sweeney and colleagues began by studying mouse models of breast cancer with genomes that carry extra copies of HER2. They noticed an excess of HER2 protein in the resulting tumors, but it was not over-expressed in adjacent healthy tissues that also carried extra copies of the HER2 gene.
"That suggested to us that extra copies of HER2 alone are not enough to explain its over-expression. If it was, HER2 would have been over-expressed in both normal and tumor tissues from these mice," she said.
Given that observation, the team set out to determine what, exactly, created the permissive environment for HER2 over-expression. Given its tumor-suppressor role, Lig-1 levels were compared in the mouse models.
They found that Lig-1 was greatly diminished in tumor tissues when compared to the normal tissues. The researchers next conducted a series of laboratory experiments using human breast cancer cell lines and a technique called RNA interference that allows for selective depletion of cellular proteins.
Interestingly, they found the same results in the human breast cancers that they found in mice. In fact, 60 percent of 67 tumors analyzed showed a loss of the Lig-1 protein and its levels were, on average, 33 percent lower in tumor tissue versus healthy breast tissue.
"There was a clear inverse relationship between Lig-1 and HER2," said Sweeney. "When we depleted Lig-1, cancer cells grew almost 50 percent faster, while the opposite occurred when we restored Lig-1 to healthy levels. We also found that depleting HER2 levels resulted in an increase in Lig-1 levels, while activating HER2 resulted in Lig-1 depletion."
According to Sweeney, the results may help explain why, even among patients with HER2-positive breast cancer, the disease process can vary dramatically.
"We think Lig-1 levels could be linked to prognosis. Patients with more of the regulator gene's functions intact are going to have a better outcome than those with less," she said.
Results of the current study further support the notion that Lig-1 serves as a tumor suppressor gene, though more work is needed to confirm this outcome. Sweeney and her team are gathering more evidence to support this theory and to determine whether or not Lig-1 levels are truly predictive of outcome for HER2-positive patients. If so, it will suggest that, while this type of test is not available today, these patients should in the future be screened for Lig-1 activity in order to better define treatment subgroups.
"It's clear that stratifying breast cancer patients as either HER2-positive or HER2-negative is not telling the whole story. This research takes us a step further in the right direction toward better understanding types of breast cancer and treatment targets for those different types," Sweeney said.
Additional study authors were lead author Jamie Miller, a recent graduate of the Sweeney lab; co-authors David Shattuck, Ellen Ingalla, Lily Yen and Kermit Carraway of UC Davis Cancer Center; and Alexander Borowsky, Larry Young and Robert Cardiff of the UC Davis Department of Medical Pathology and Laboratory Medicine.
This research highlights the ongoing collaborative efforts of the UC Davis Breast Cancer Research Program. It was supported by National Institutes of Health grants to Sweeney and Carraway and predoctoral fellowships from the Department of Defense Breast Cancer Research Program to Miller and Shattuck.
Designated by the National Cancer Institute, UC Davis Cancer Center cares for 9,000 patients each year. The center's Breast Cancer Program provides comprehensive, multidisciplinary services for patients with all stages of the disease. Patients receive their care in one location, from a team of top academic physicians and researchers with expertise in hematology and oncology, surgical oncology, radiation oncology, pathology, plastic and reconstructive surgery, and diagnostic radiology/mammography. These experts work together to develop individualized treatment plans for each patient. For more information, visit ucdmc.ucdavis/cancer.
Public Affairs
UC Davis Health System
4900 Broadway, Suite 1200
Sacramento, CA 95820
Web address: ucdmc.ucdavis/newsroom/
Source: Karen Finney
University of California - Davis - Health System
Building on recent research showing that the regulator - labeled LRIG1 and commonly called "Lig-1" - limits the growth-promoting signals of HER2, the research team set out to clarify the role of Lig-1 in breast cancer.
They found that, when compared to healthy breast tissue, the regulator is significantly suppressed.
"This suppression assists HER2 in its own over-expression and in driving the growth of cancer cells," said Colleen Sweeney, associate professor of biochemistry and molecular medicine and senior author of the study, which appears in this month's issue of Cancer Research. "HER2 is clearly taking an active role its own ability to be successful in promoting cancer."
Sweeney added that the study results could lead to new treatments aimed at restoring or replacing functions of the regulator. This is good news for patients because, in addition to being more aggressive, HER2-positive breast cancer tends to be less responsive to currently available treatments. The gene is over-expressed in about one-quarter to one-third of breast cancer cases.
Sweeney and colleagues began by studying mouse models of breast cancer with genomes that carry extra copies of HER2. They noticed an excess of HER2 protein in the resulting tumors, but it was not over-expressed in adjacent healthy tissues that also carried extra copies of the HER2 gene.
"That suggested to us that extra copies of HER2 alone are not enough to explain its over-expression. If it was, HER2 would have been over-expressed in both normal and tumor tissues from these mice," she said.
Given that observation, the team set out to determine what, exactly, created the permissive environment for HER2 over-expression. Given its tumor-suppressor role, Lig-1 levels were compared in the mouse models.
They found that Lig-1 was greatly diminished in tumor tissues when compared to the normal tissues. The researchers next conducted a series of laboratory experiments using human breast cancer cell lines and a technique called RNA interference that allows for selective depletion of cellular proteins.
Interestingly, they found the same results in the human breast cancers that they found in mice. In fact, 60 percent of 67 tumors analyzed showed a loss of the Lig-1 protein and its levels were, on average, 33 percent lower in tumor tissue versus healthy breast tissue.
"There was a clear inverse relationship between Lig-1 and HER2," said Sweeney. "When we depleted Lig-1, cancer cells grew almost 50 percent faster, while the opposite occurred when we restored Lig-1 to healthy levels. We also found that depleting HER2 levels resulted in an increase in Lig-1 levels, while activating HER2 resulted in Lig-1 depletion."
According to Sweeney, the results may help explain why, even among patients with HER2-positive breast cancer, the disease process can vary dramatically.
"We think Lig-1 levels could be linked to prognosis. Patients with more of the regulator gene's functions intact are going to have a better outcome than those with less," she said.
Results of the current study further support the notion that Lig-1 serves as a tumor suppressor gene, though more work is needed to confirm this outcome. Sweeney and her team are gathering more evidence to support this theory and to determine whether or not Lig-1 levels are truly predictive of outcome for HER2-positive patients. If so, it will suggest that, while this type of test is not available today, these patients should in the future be screened for Lig-1 activity in order to better define treatment subgroups.
"It's clear that stratifying breast cancer patients as either HER2-positive or HER2-negative is not telling the whole story. This research takes us a step further in the right direction toward better understanding types of breast cancer and treatment targets for those different types," Sweeney said.
Additional study authors were lead author Jamie Miller, a recent graduate of the Sweeney lab; co-authors David Shattuck, Ellen Ingalla, Lily Yen and Kermit Carraway of UC Davis Cancer Center; and Alexander Borowsky, Larry Young and Robert Cardiff of the UC Davis Department of Medical Pathology and Laboratory Medicine.
This research highlights the ongoing collaborative efforts of the UC Davis Breast Cancer Research Program. It was supported by National Institutes of Health grants to Sweeney and Carraway and predoctoral fellowships from the Department of Defense Breast Cancer Research Program to Miller and Shattuck.
Designated by the National Cancer Institute, UC Davis Cancer Center cares for 9,000 patients each year. The center's Breast Cancer Program provides comprehensive, multidisciplinary services for patients with all stages of the disease. Patients receive their care in one location, from a team of top academic physicians and researchers with expertise in hematology and oncology, surgical oncology, radiation oncology, pathology, plastic and reconstructive surgery, and diagnostic radiology/mammography. These experts work together to develop individualized treatment plans for each patient. For more information, visit ucdmc.ucdavis/cancer.
Public Affairs
UC Davis Health System
4900 Broadway, Suite 1200
Sacramento, CA 95820
Web address: ucdmc.ucdavis/newsroom/
Source: Karen Finney
University of California - Davis - Health System
How Bleach Kills Bacteria
Developed more than 200 years ago and found in households around the world, chlorine bleach is among the most widely used disinfectants, yet scientists never have understood exactly how the familiar product kills bacteria.
New research from the University of Michigan, however, reveals key details in the process by which bleach works its antimicrobial magic.
In a study published in the Nov. 14 issue of the journal Cell, a team led by molecular biologist Ursula Jakob describes a mechanism by which hypochlorite, the active ingredient of household bleach, attacks essential bacterial proteins, ultimately killing the bugs.
"As so often happens in science, we did not set out to address this question," said Jakob, an associate professor of molecular, cellular and developmental biology. "But when we stumbled on the answer midway through a different project, we were all very excited."
Jakob and her team were studying a bacterial protein known as heat shock protein 33 (Hsp33), which is classified as a molecular chaperone. The main job of chaperones is to protect proteins from unfavorable interactions, a function that's particularly important when cells are under conditions of stress, such as the high temperatures that result from fever.
"At high temperatures, proteins begin to lose their three-dimensional molecular structure and start to clump together and form large, insoluble aggregates, just like when you boil an egg," said lead author Jeannette Winter, who was a postdoctoral fellow in Jakob's lab. And like eggs, which once boiled never turn liquid again, aggregated proteins usually remain insoluble, and the stressed cells eventually die.
Jakob and her research team figured out that bleach and high temperatures have very similar effects on proteins. Just like heat, the hypochlorite in bleach causes proteins to lose their structure and form large aggregates.
"Many of the proteins that hypochlorite attacks are essential for bacterial growth, so inactivating those proteins likely kills the bacteria," said second author Marianne Ilbert, a postdoctoral fellow in Jakob's lab.
These findings are not only important for understanding how bleach keeps our kitchen countertops sanitary, but they may lead to insights into how we fight off bacterial infections. Our own immune cells produce significant amounts of hypochlorite as a first line of defense to kill invading microorganisms. Unfortunately, hypochlorite damages not just bacterial cells, but ours as well. It is the uncontrolled production of hypochlorite acid that is thought to cause tissue damage at sites of chronic inflammation.
How did studying the protein Hsp33 lead to the bleach discovery? The researchers learned that hypochlorite, rather than damaging Hsp33 as it does most proteins, actually revs up the molecular chaperone. When bacteria encounter the disinfectant, Hsp33 jumps into action to protect bacterial proteins against bleach-induced aggregation.
"With Hsp33, bacteria have evolved a very clever system that directly senses the insult, responds to it and increases the bacteria's resistance to bleach," Jakob said.
For more information:
Ursula Jakob
Cell: cell/
Source: Nancy Ross-Flanigan
University of Michigan
New research from the University of Michigan, however, reveals key details in the process by which bleach works its antimicrobial magic.
In a study published in the Nov. 14 issue of the journal Cell, a team led by molecular biologist Ursula Jakob describes a mechanism by which hypochlorite, the active ingredient of household bleach, attacks essential bacterial proteins, ultimately killing the bugs.
"As so often happens in science, we did not set out to address this question," said Jakob, an associate professor of molecular, cellular and developmental biology. "But when we stumbled on the answer midway through a different project, we were all very excited."
Jakob and her team were studying a bacterial protein known as heat shock protein 33 (Hsp33), which is classified as a molecular chaperone. The main job of chaperones is to protect proteins from unfavorable interactions, a function that's particularly important when cells are under conditions of stress, such as the high temperatures that result from fever.
"At high temperatures, proteins begin to lose their three-dimensional molecular structure and start to clump together and form large, insoluble aggregates, just like when you boil an egg," said lead author Jeannette Winter, who was a postdoctoral fellow in Jakob's lab. And like eggs, which once boiled never turn liquid again, aggregated proteins usually remain insoluble, and the stressed cells eventually die.
Jakob and her research team figured out that bleach and high temperatures have very similar effects on proteins. Just like heat, the hypochlorite in bleach causes proteins to lose their structure and form large aggregates.
"Many of the proteins that hypochlorite attacks are essential for bacterial growth, so inactivating those proteins likely kills the bacteria," said second author Marianne Ilbert, a postdoctoral fellow in Jakob's lab.
These findings are not only important for understanding how bleach keeps our kitchen countertops sanitary, but they may lead to insights into how we fight off bacterial infections. Our own immune cells produce significant amounts of hypochlorite as a first line of defense to kill invading microorganisms. Unfortunately, hypochlorite damages not just bacterial cells, but ours as well. It is the uncontrolled production of hypochlorite acid that is thought to cause tissue damage at sites of chronic inflammation.
How did studying the protein Hsp33 lead to the bleach discovery? The researchers learned that hypochlorite, rather than damaging Hsp33 as it does most proteins, actually revs up the molecular chaperone. When bacteria encounter the disinfectant, Hsp33 jumps into action to protect bacterial proteins against bleach-induced aggregation.
"With Hsp33, bacteria have evolved a very clever system that directly senses the insult, responds to it and increases the bacteria's resistance to bleach," Jakob said.
For more information:
Ursula Jakob
Cell: cell/
Source: Nancy Ross-Flanigan
University of Michigan
Nanoscale Changes In Collagen Are A Tipoff To Bone Health
Using a technique that provides detailed images of nanoscale structures, researchers at the University of Michigan and Detroit's Henry Ford Hospital have discovered changes in the collagen component of bone that directly relate to bone health.
Their findings, published online Dec. 16 in the journal Bone, could lead to new methods of diagnosing osteoporosis and other diseases affecting collagen-containing tissues.
Bone is a composite material made up of a flexible collagen matrix impregnated with and surrounded by a stiffer, stronger mineral component. Though much is known about the importance of bone health to overall health, there's a critical lack of knowledge about the sub-microscopic structure of bone and how collagen and mineral - and the interactions between them - contribute to properties of healthy and diseased bone.
"Our initial question was, could we discover more about the nanoscale structure of the collagen in bone, using the technique of atomic force microscopy," said Mark Banaszak Holl, a U-M professor with joint appointments in chemistry and macromolecular science and engineering.
The atomic force microscope, one of the most valuable tools for imaging, measuring and manipulating matter at the nanoscale level, works something like a phonograph with a motion detector attached to its needle. As the tip systematically moves across a bumpy surface, the motion detector records its every movement. The result is a three-dimensional image of the surface's contours.
Using such an instrument, the researchers were able to see and measure key features of collagen fibrils in mouse bone. Each collagen fibril is made up of many individual collagen molecules packed together in a staggered array that resembles a railroad track.
"For each fibril, we measured the mean spacing of the 'railroad track' cross hatches," said post doctoral associate Joseph Wallace, the paper's lead author. Wallace, Banaszak Holl and coworkers found that not all fibrils had the same mean spacing, a finding that ran counter to conventional wisdom in the field.
"As opposed to a single value, our data indicate that normal bone contains a distribution of collagen fibril spacings," Wallace said.
Next, the team wanted to know if the distribution of fibril spacings differed in bone from healthy and diseased individuals. To address that question, they collaborated with Clifford Les of Henry Ford Hospital, who has been studying how bone changes when estrogen wanes, as it does in menopause. To model the age-related estrogen depletion that occurs in humans, Les uses sheep that have had their ovaries removed. The sheep exhibit some of the same symptoms as menopausal women, and they undergo some bone remodeling, but they don't develop osteoporosis.
When the researchers compared bone from normal and ovariectomized sheep, they found striking differences in fibril spacing distributions, suggesting that estrogen depletion has a significant effect on the spacing.
"This ability to measure fibril spacing and to distinguish between normal and diseased bone not only gives us a powerful method to study the mechanism of disease at the nanoscale, but it also has important implications to the future diagnosis of disease in bone and perhaps other collagenous tissues," said Banaszak Holl. "Collagen is the most common protein in the mammalian body. It's in bones, teeth, tendons, skin, arteries. We basically don't work well when it's not working well, so there are many diseases related to problems with collagen. We're very excited about developing this method as a diagnostic for all kinds of diseases of structural collagen."
The technique could be a powerful complement to the current gold standard for diagnosing osteoporosis: measuring bone mineral density (BMD) with dual energy X-ray absorptiometry (DEXA). Although widely used, DEXA isn't ideal, because people with normal BMD can still get fractures, and abnormalities often don't show up until after a fracture has occurred. Changes in collagen, on the other hand, may be apparent earlier in the disease's progression.
To further explore the method's potential, the researchers plan to use it to study collagen fibril spacing in human patients with and without osteoporosis. U-M has filed for patent protection and is seeking a commercialization partner to help bring the technology to market.
"This project is an example of what happens if you put the right group of people together on a problem," said Banaszak Holl. Wallace, a biomedical engineer, had experience working with bone in previous research; Banaszak Holl's lab group brought expertise in surface analysis; Les contributed knowledge about bone biology and understanding of the sheep model; and coauthors Bradford Orr, director of the Applied Physics Program, and Blake Erickson, a biophysics graduate student, are skilled in data analysis.
"All these different pieces were necessary to solve the problem," Banaszak Holl said.
The research was funded by the National Institutes of Health (National Institute of Dental and Craniofacial Research and National Institute of Arthritis and Musculoskeletal and Skin Diseases).
Related Links:
Mark Banaszak Holl
Distribution of type I collagen morphologies in bone: Relation to estrogen depletion
Source:
Nancy Ross-Flanigan
University of Michigan
Their findings, published online Dec. 16 in the journal Bone, could lead to new methods of diagnosing osteoporosis and other diseases affecting collagen-containing tissues.
Bone is a composite material made up of a flexible collagen matrix impregnated with and surrounded by a stiffer, stronger mineral component. Though much is known about the importance of bone health to overall health, there's a critical lack of knowledge about the sub-microscopic structure of bone and how collagen and mineral - and the interactions between them - contribute to properties of healthy and diseased bone.
"Our initial question was, could we discover more about the nanoscale structure of the collagen in bone, using the technique of atomic force microscopy," said Mark Banaszak Holl, a U-M professor with joint appointments in chemistry and macromolecular science and engineering.
The atomic force microscope, one of the most valuable tools for imaging, measuring and manipulating matter at the nanoscale level, works something like a phonograph with a motion detector attached to its needle. As the tip systematically moves across a bumpy surface, the motion detector records its every movement. The result is a three-dimensional image of the surface's contours.
Using such an instrument, the researchers were able to see and measure key features of collagen fibrils in mouse bone. Each collagen fibril is made up of many individual collagen molecules packed together in a staggered array that resembles a railroad track.
"For each fibril, we measured the mean spacing of the 'railroad track' cross hatches," said post doctoral associate Joseph Wallace, the paper's lead author. Wallace, Banaszak Holl and coworkers found that not all fibrils had the same mean spacing, a finding that ran counter to conventional wisdom in the field.
"As opposed to a single value, our data indicate that normal bone contains a distribution of collagen fibril spacings," Wallace said.
Next, the team wanted to know if the distribution of fibril spacings differed in bone from healthy and diseased individuals. To address that question, they collaborated with Clifford Les of Henry Ford Hospital, who has been studying how bone changes when estrogen wanes, as it does in menopause. To model the age-related estrogen depletion that occurs in humans, Les uses sheep that have had their ovaries removed. The sheep exhibit some of the same symptoms as menopausal women, and they undergo some bone remodeling, but they don't develop osteoporosis.
When the researchers compared bone from normal and ovariectomized sheep, they found striking differences in fibril spacing distributions, suggesting that estrogen depletion has a significant effect on the spacing.
"This ability to measure fibril spacing and to distinguish between normal and diseased bone not only gives us a powerful method to study the mechanism of disease at the nanoscale, but it also has important implications to the future diagnosis of disease in bone and perhaps other collagenous tissues," said Banaszak Holl. "Collagen is the most common protein in the mammalian body. It's in bones, teeth, tendons, skin, arteries. We basically don't work well when it's not working well, so there are many diseases related to problems with collagen. We're very excited about developing this method as a diagnostic for all kinds of diseases of structural collagen."
The technique could be a powerful complement to the current gold standard for diagnosing osteoporosis: measuring bone mineral density (BMD) with dual energy X-ray absorptiometry (DEXA). Although widely used, DEXA isn't ideal, because people with normal BMD can still get fractures, and abnormalities often don't show up until after a fracture has occurred. Changes in collagen, on the other hand, may be apparent earlier in the disease's progression.
To further explore the method's potential, the researchers plan to use it to study collagen fibril spacing in human patients with and without osteoporosis. U-M has filed for patent protection and is seeking a commercialization partner to help bring the technology to market.
"This project is an example of what happens if you put the right group of people together on a problem," said Banaszak Holl. Wallace, a biomedical engineer, had experience working with bone in previous research; Banaszak Holl's lab group brought expertise in surface analysis; Les contributed knowledge about bone biology and understanding of the sheep model; and coauthors Bradford Orr, director of the Applied Physics Program, and Blake Erickson, a biophysics graduate student, are skilled in data analysis.
"All these different pieces were necessary to solve the problem," Banaszak Holl said.
The research was funded by the National Institutes of Health (National Institute of Dental and Craniofacial Research and National Institute of Arthritis and Musculoskeletal and Skin Diseases).
Related Links:
Mark Banaszak Holl
Distribution of type I collagen morphologies in bone: Relation to estrogen depletion
Source:
Nancy Ross-Flanigan
University of Michigan
Chronic Jet-Lag Conditions Hasten Death In Aged Mice
Researchers have found that aged mice undergoing weekly light-cycle shifts--similar to those that humans experience with jet lag or rotating shift work--experienced significantly higher death rates than did old mice kept on a normal daylight schedule over the same eight-week period. The findings may not come as a great surprise to exhausted globe-trotting business travelers, but the research nonetheless provides, in rather stark terms, new insight into how the disruption of circadian rhythms can impact well-being and physiology, and how those impacts might change with age. The mouse study is reported by a group led by Gene Block and Alec Davidson of the University of Virginia and appears in the November 7th issue of the journal Current Biology, published by Cell Press.
The researchers were led to examine a possible link between jet lag and mortality by something they had noticed in an earlier, unrelated study: A surprising fraction of old (but genetically altered) rats exposed to a six-hour advance in their light cycle died after the shift in schedule.
In the new work, the researchers examined the mortality link in earnest by looking at how young mice and old mice fared when subjected to two different types of light-cycle shifts. In one regimen, mice experienced a six-hour forward shift once a week, while in the other, mice experienced a six-hour backward shift. A "control" group of young and old mice did not experience any schedule shifts.
The researchers found that the young mice generally survived well under the various conditions. In contrast, the light-cycle shifts had a marked effect on the survivorship of the old mice. While 83% of old mice survived under the normal schedule, 68% survived under the backward-shift regimen and 47% survived under the forward-shift regimen.
Past work has also linked changes in light schedule with death in other animals and under different experimental circumstances, but the findings here indicate that there may be a differential effect of mortality depending on the direction of the schedule shift--forward or backward. Schedule "advancers" did more poorly in the present experiment than did "delayers."
Notably, the researchers found that chronic stress--as measured by daily corticosterone levels--did not increase in the old mice experiencing the light-cycle shifts. The underlying cause of the increased mortality is not yet clear, but could involve sleep deprivation or immune-system disruption.
The body's physiological reaction to time change may be complex. Past research has indicated that circadian clocks govern physiological rhythms in a great variety of tissues in the body, and that different aspects of the physiological clock can adjust to schedule changes at different rates. The researchers speculate that the internal lack of synchrony among different physiological oscillations may have serious health consequences that are exacerbated in aged animals.
The researchers include A.J. Davidson, M.T Sellix, J. Daniel, S. Yamazaki, M. Menaker and G.D. Block of the University of Virginia. This work was supported by NIA grant F32 AG22741-01 to AJD, NINDS grant RO1 NS051278 to SY, NSBRI grant NCC9-58-167 and NIMH grant RO1 MH56647 to MM, and NIMH grant RO1 MH062517 to GDB.
Davidson et al.: "Correspondence: Chronic jet-lag increases mortality in aged mice." Publishing in Current Biology 16, R914-R916, November 7, 2006 DOI 10.1016/j.cub.2006.09.058. current-biology/
Contact: Heidi Hardman
Cell Press
The researchers were led to examine a possible link between jet lag and mortality by something they had noticed in an earlier, unrelated study: A surprising fraction of old (but genetically altered) rats exposed to a six-hour advance in their light cycle died after the shift in schedule.
In the new work, the researchers examined the mortality link in earnest by looking at how young mice and old mice fared when subjected to two different types of light-cycle shifts. In one regimen, mice experienced a six-hour forward shift once a week, while in the other, mice experienced a six-hour backward shift. A "control" group of young and old mice did not experience any schedule shifts.
The researchers found that the young mice generally survived well under the various conditions. In contrast, the light-cycle shifts had a marked effect on the survivorship of the old mice. While 83% of old mice survived under the normal schedule, 68% survived under the backward-shift regimen and 47% survived under the forward-shift regimen.
Past work has also linked changes in light schedule with death in other animals and under different experimental circumstances, but the findings here indicate that there may be a differential effect of mortality depending on the direction of the schedule shift--forward or backward. Schedule "advancers" did more poorly in the present experiment than did "delayers."
Notably, the researchers found that chronic stress--as measured by daily corticosterone levels--did not increase in the old mice experiencing the light-cycle shifts. The underlying cause of the increased mortality is not yet clear, but could involve sleep deprivation or immune-system disruption.
The body's physiological reaction to time change may be complex. Past research has indicated that circadian clocks govern physiological rhythms in a great variety of tissues in the body, and that different aspects of the physiological clock can adjust to schedule changes at different rates. The researchers speculate that the internal lack of synchrony among different physiological oscillations may have serious health consequences that are exacerbated in aged animals.
The researchers include A.J. Davidson, M.T Sellix, J. Daniel, S. Yamazaki, M. Menaker and G.D. Block of the University of Virginia. This work was supported by NIA grant F32 AG22741-01 to AJD, NINDS grant RO1 NS051278 to SY, NSBRI grant NCC9-58-167 and NIMH grant RO1 MH56647 to MM, and NIMH grant RO1 MH062517 to GDB.
Davidson et al.: "Correspondence: Chronic jet-lag increases mortality in aged mice." Publishing in Current Biology 16, R914-R916, November 7, 2006 DOI 10.1016/j.cub.2006.09.058. current-biology/
Contact: Heidi Hardman
Cell Press
New Gene Involved In Autophagy, The Cellular Recycling Programme, Identified By Researchers
All cells are equipped with a recycling programme to collect and remove unnecessary cellular components. Autophagy sequesters and digests aged organelles, damaged proteins and other components, which, if not disintegrated and recycled, threaten cell viability. Researchers at the Institute for Research in Biomedicine (IRB Barcelona) led by Antonio Zorzano, head of the Molecular Medicine Programme and senior professor of the University of Barcelona, have identified a new gene that favours cell autophagy. The article has been published in EMBO Reports, which highlights it in the section "Hot off the press".
One of the main challenges in biomedicine is to decipher the complete map of genes - and their products, the proteins - that regulates autophagy in cells. "The interest lies in its association with human diseases", says Zorzano. There is increasing evidence of a link between autophagy and the appearance and progression of cancer, neurodegenerative pathologies, infections and aging. For example, several studies demonstrate that some neurodegenerative diseases caused by the abnormal aggregation of proteins, such as Huntington's disease, are associated with reduced autophagy. Pharmacological induction of this process could help to remove the cellular protein aggregates and to relieve the symptoms.
Caroline Mauvezin, PhD student with Zorzano and first author of the article, says that "it is possible to envisage future therapies based on the modulation of autophagy". However, further knowledge about this pathway and its components are required as well as a complete understanding of the precise role of autophagy in each disease in order to be able to manipulate it for therapeutic purposes. "We have identified a new player and now we have to study it in depth", says Mauvezin.
DOR favours autophagy
The study reveals that the DOR protein is involved in the initial, and most unknown, stages of autophagy. DOR facilitates the formation of autophagosomes, the structures that envelop, capture and transport components to lysosomes. Autophagosomes fuse to lysosomes to form autolysosomes, where several enzymes finally remove the unwanted or harmful intracellular debris.
Using in vitro cells and the fruit fly Drosophila, the researchers have demonstrated that the autophagic capacity of a cell decreases in the absence of DOR. This new gene in the autophagic pathway opens up many avenues of study, for example examining whether DOR is active or silenced in tumour cells. But the scientists are prudent with respect to the planning of future studies. "First we have to determine the precise function of DOR in the autophagic pathway in rat models in vivo, in order to determine its relevance and to identify all the proteins that it is associated with in this context", explains Zorzano.
Reference article:
The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells.
Mauvezin C, Orpinell M, Francis VA, Mansilla F, Duran J, Ribas V, PalacГn M, Boya P, Teleman AA, Zorzano A.
EMBO Rep. 2010 Jan;11(1):37-44.
Source:
SГІnia Armengou
Institute for Research in Biomedicine (IRB Barcelona)
One of the main challenges in biomedicine is to decipher the complete map of genes - and their products, the proteins - that regulates autophagy in cells. "The interest lies in its association with human diseases", says Zorzano. There is increasing evidence of a link between autophagy and the appearance and progression of cancer, neurodegenerative pathologies, infections and aging. For example, several studies demonstrate that some neurodegenerative diseases caused by the abnormal aggregation of proteins, such as Huntington's disease, are associated with reduced autophagy. Pharmacological induction of this process could help to remove the cellular protein aggregates and to relieve the symptoms.
Caroline Mauvezin, PhD student with Zorzano and first author of the article, says that "it is possible to envisage future therapies based on the modulation of autophagy". However, further knowledge about this pathway and its components are required as well as a complete understanding of the precise role of autophagy in each disease in order to be able to manipulate it for therapeutic purposes. "We have identified a new player and now we have to study it in depth", says Mauvezin.
DOR favours autophagy
The study reveals that the DOR protein is involved in the initial, and most unknown, stages of autophagy. DOR facilitates the formation of autophagosomes, the structures that envelop, capture and transport components to lysosomes. Autophagosomes fuse to lysosomes to form autolysosomes, where several enzymes finally remove the unwanted or harmful intracellular debris.
Using in vitro cells and the fruit fly Drosophila, the researchers have demonstrated that the autophagic capacity of a cell decreases in the absence of DOR. This new gene in the autophagic pathway opens up many avenues of study, for example examining whether DOR is active or silenced in tumour cells. But the scientists are prudent with respect to the planning of future studies. "First we have to determine the precise function of DOR in the autophagic pathway in rat models in vivo, in order to determine its relevance and to identify all the proteins that it is associated with in this context", explains Zorzano.
Reference article:
The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells.
Mauvezin C, Orpinell M, Francis VA, Mansilla F, Duran J, Ribas V, PalacГn M, Boya P, Teleman AA, Zorzano A.
EMBO Rep. 2010 Jan;11(1):37-44.
Source:
SГІnia Armengou
Institute for Research in Biomedicine (IRB Barcelona)
Evolution - How to get a head
An anatomical study of an obscure sea creature called a sea spider resolves a decades-long zoological debate, according to research in this week's Nature from Amy Maxmen and colleagues.
The bodies of arthropods (jointed-limbed creatures including insects, spiders and crustaceans) are divided into segments, each of which bears a pair of limbs and the appropriate neural wiring needed to service them.
So much is clear from the bodies - the heads, however, are more complicated, as the original segmental relationships have been obscured by hundreds of millions of years of evolution. Much debate concerns the frontmost segment, which is limbless in modern arthropods.
Did this segment once bear limbs? Work on a group of ancient and bizarre fossil arthropods suggests that the first segment often bore appendages, sometimes huge and spectacular claws, but evidence from modern arthropods has been unclear.
(pp1144-1148; N&V)
NATURE PUBLISHING GROUP REFERENCE
The Macmillan Building,
4 Crinan Street,
London,
N1 9XW,
nature
The bodies of arthropods (jointed-limbed creatures including insects, spiders and crustaceans) are divided into segments, each of which bears a pair of limbs and the appropriate neural wiring needed to service them.
So much is clear from the bodies - the heads, however, are more complicated, as the original segmental relationships have been obscured by hundreds of millions of years of evolution. Much debate concerns the frontmost segment, which is limbless in modern arthropods.
Did this segment once bear limbs? Work on a group of ancient and bizarre fossil arthropods suggests that the first segment often bore appendages, sometimes huge and spectacular claws, but evidence from modern arthropods has been unclear.
(pp1144-1148; N&V)
NATURE PUBLISHING GROUP REFERENCE
The Macmillan Building,
4 Crinan Street,
London,
N1 9XW,
nature
New Findings May Improve Treatment Of Inherited Breast Cancer
Scientists have identified some of the elusive downstream molecules that play a critical role in the development and progression of familial breast cancer. The research, published by Cell Press in the October 10th issue of the journal Molecular Cell, also identifies a compound found in grapes and red wine as an excellent candidate for treatment of some forms of breast cancer.
About 8% of breast cancer cases are caused by mutations in tumor suppressor genes, such as breast cancer associated gene-1 (BRCA1). BRCA1 is the most frequently mutated tumor suppressor gene found in inherited breast cancers and BRCA1 mutation carriers have a 50-80% risk of developing breast cancer by age 70. "Although work with animal models of BRCA1 mutation has provided some insight into the many biological processes linked with BRCA1, very little is known about the downstream mediators of BRCA1 function in tumor suppression," says lead study author Dr. Chu-Xia Deng from the Genetics of Development and Diseases Branch at the National Institutes of Health.
Dr. Deng and colleagues were interested in investigating the relationship among BRCA1, SIRT1 and Survivin. SIRT1 is a protein and histone deacetylase involved in numerous critical cell processes including metabolism, DNA repair and programmed cell death, known as apoptosis. Although SIRT1 has been implicated in tumorigenesis, no concrete role in cancer initiation or progression has been identified. Survivin is an apoptosis inhibitor that is dramatically elevated in many types of tumors. Research has suggested that Survivin may serve to maintain the tumor and promote growth.
The researchers found that BRCA1 functioned as a tumor suppressor by maintaining SIRT1 expression, which in turn inhibited Survivin expression. When BRCA1 was not functioning properly, SIRT levels decreased and Survivin levels increased, allowing BRCA1-deficient cells to overcome apoptosis and undergo malignant transformation.
They went on to show that the compound resveratrol strongly inhibited BRCA1-mutant tumor growth in cultured cells and animal models. Resveratrol is an important constituent of traditional Japanese and Chinese medicine that has recently been shown to inhibit some types of cancer by inducing apoptosis with very little associated toxicity. In the current paper, resveratrol enhanced SIRT1 activity, this leading to reduced Survivin expression and subsequent apoptosis of BRCA1 deficient cancer cells.
These findings identify SIRT1 and Survivin as downstream mediators of BRCA1-regulated tumor suppression and identify resveratrol as a potent inhibitor of BRCA1-mutant cancer cells. "Resveratrol may serve as an excellent compound for targeted therapy for BRCA1 associated breast cancers," says Dr. Deng.
The researchers include Rui-Hong Wang, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Yin Zheng, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Hyun-Seok Kim, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Xiaoling Xu, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Liu Cao, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Tyler Luhasen, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Mi-Hye Lee, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Cuiying Xiao, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Athanassios Vassilopoulos, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Weiping Chen, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Kevin Gardner, National Cancer Institute, National Institutes of Health, Bethesda, MD; Yan-Gao Man, Armed Forces Institute of Pathology, Washington, DC; Mien-Chie Hung, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Toren Finkel, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and Chu-Xia Deng, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Source: Cathleen Genova
Cell Press
About 8% of breast cancer cases are caused by mutations in tumor suppressor genes, such as breast cancer associated gene-1 (BRCA1). BRCA1 is the most frequently mutated tumor suppressor gene found in inherited breast cancers and BRCA1 mutation carriers have a 50-80% risk of developing breast cancer by age 70. "Although work with animal models of BRCA1 mutation has provided some insight into the many biological processes linked with BRCA1, very little is known about the downstream mediators of BRCA1 function in tumor suppression," says lead study author Dr. Chu-Xia Deng from the Genetics of Development and Diseases Branch at the National Institutes of Health.
Dr. Deng and colleagues were interested in investigating the relationship among BRCA1, SIRT1 and Survivin. SIRT1 is a protein and histone deacetylase involved in numerous critical cell processes including metabolism, DNA repair and programmed cell death, known as apoptosis. Although SIRT1 has been implicated in tumorigenesis, no concrete role in cancer initiation or progression has been identified. Survivin is an apoptosis inhibitor that is dramatically elevated in many types of tumors. Research has suggested that Survivin may serve to maintain the tumor and promote growth.
The researchers found that BRCA1 functioned as a tumor suppressor by maintaining SIRT1 expression, which in turn inhibited Survivin expression. When BRCA1 was not functioning properly, SIRT levels decreased and Survivin levels increased, allowing BRCA1-deficient cells to overcome apoptosis and undergo malignant transformation.
They went on to show that the compound resveratrol strongly inhibited BRCA1-mutant tumor growth in cultured cells and animal models. Resveratrol is an important constituent of traditional Japanese and Chinese medicine that has recently been shown to inhibit some types of cancer by inducing apoptosis with very little associated toxicity. In the current paper, resveratrol enhanced SIRT1 activity, this leading to reduced Survivin expression and subsequent apoptosis of BRCA1 deficient cancer cells.
These findings identify SIRT1 and Survivin as downstream mediators of BRCA1-regulated tumor suppression and identify resveratrol as a potent inhibitor of BRCA1-mutant cancer cells. "Resveratrol may serve as an excellent compound for targeted therapy for BRCA1 associated breast cancers," says Dr. Deng.
The researchers include Rui-Hong Wang, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Yin Zheng, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Hyun-Seok Kim, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Xiaoling Xu, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Liu Cao, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Tyler Luhasen, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Mi-Hye Lee, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Cuiying Xiao, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Athanassios Vassilopoulos, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Weiping Chen, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Kevin Gardner, National Cancer Institute, National Institutes of Health, Bethesda, MD; Yan-Gao Man, Armed Forces Institute of Pathology, Washington, DC; Mien-Chie Hung, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Toren Finkel, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and Chu-Xia Deng, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Source: Cathleen Genova
Cell Press
Exercise Prevents Fatty Liver Disease According To New Study
It's easy to go to the gym on a regular basis right after a person buys the gym membership. It's also easy to skip the gym one day, then the next day and the day after that. A new University of Missouri study indicates that the negative effects of skipping exercise can occur in a short period. The researchers found that a sudden transition to a sedentary lifestyle can quickly lead to symptoms of nonalcoholic fatty liver disease (hepatic steatosis), which affects at least 75 percent of obese people.
"We found that the cessation of daily exercise dramatically activates specific precursors known to promote hepatic steatosis," said Jamal Ibdah, professor of medicine and medical pharmacology and physiology in the MU School of Medicine. "This study has important implications for obese humans who continually stop and start exercise programs. Our findings strongly suggest that a sudden transition to a sedentary lifestyle increases susceptibility to nonalcoholic fatty liver disease."
Nonalcoholic fatty liver disease is a reversible condition that causes fat to accumulate in liver cells of obese people. As Westernized societies are experiencing a weight gain epidemic, the prevalence of the disease is growing, Ibdah said.
In the study, researchers gave obese rats access to voluntary running wheels for 16 weeks. Scientists then locked the wheels, and transitioned the animals to a sedentary condition. After 173 hours, or about seven days, the rats began showing signs of factors responsible for promoting hepatic steatosis. In the animals tested immediately at the end of 16 weeks of voluntary running, there were no signs of hepatic steatosis.
"Physical activity prevented fatty liver disease by 100 percent in an animal model of fatty liver disease," said Frank Booth, a professor in the MU College of Veterinary Medicine and the MU School of Medicine and a research investigator in the Dalton Cardiovascular Research Center. "In contrast, 100 percent of the group that did not have physical activity had fatty liver disease. This is a remarkable event. It is rare in medicine for any treatment to prevent any disease by 100 percent."
The study, "Cessation of Daily Exercise Dramatically Alters Precursors of Hepatic Steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats," was published in The Journal of Physiology.
Source: Kelsey Jackson
University of Missouri-Columbia
"We found that the cessation of daily exercise dramatically activates specific precursors known to promote hepatic steatosis," said Jamal Ibdah, professor of medicine and medical pharmacology and physiology in the MU School of Medicine. "This study has important implications for obese humans who continually stop and start exercise programs. Our findings strongly suggest that a sudden transition to a sedentary lifestyle increases susceptibility to nonalcoholic fatty liver disease."
Nonalcoholic fatty liver disease is a reversible condition that causes fat to accumulate in liver cells of obese people. As Westernized societies are experiencing a weight gain epidemic, the prevalence of the disease is growing, Ibdah said.
In the study, researchers gave obese rats access to voluntary running wheels for 16 weeks. Scientists then locked the wheels, and transitioned the animals to a sedentary condition. After 173 hours, or about seven days, the rats began showing signs of factors responsible for promoting hepatic steatosis. In the animals tested immediately at the end of 16 weeks of voluntary running, there were no signs of hepatic steatosis.
"Physical activity prevented fatty liver disease by 100 percent in an animal model of fatty liver disease," said Frank Booth, a professor in the MU College of Veterinary Medicine and the MU School of Medicine and a research investigator in the Dalton Cardiovascular Research Center. "In contrast, 100 percent of the group that did not have physical activity had fatty liver disease. This is a remarkable event. It is rare in medicine for any treatment to prevent any disease by 100 percent."
The study, "Cessation of Daily Exercise Dramatically Alters Precursors of Hepatic Steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats," was published in The Journal of Physiology.
Source: Kelsey Jackson
University of Missouri-Columbia
Potential Treatment For Huntington's Disease Identified
MassGeneral Institute for Neurodegererative Disorders (MIND) researchers have identified a compound that may lead to a treatment that could protect against the effects of Huntington's Disease (HD). Their report, which will appear in the Proceedings of the National Academy of Sciences, describes how a small molecule called C2-8 appears to delay the loss of motor control and reduce neurological damage in a mouse model of the disorder. The study is receiving early online release.
"We found that C2-8 slows the progress of HD in a mouse model and might do the same thing in human patients, if it or its biochemical relatives can be translated into a drug," says Steven Hersch, MD, PhD, of MIND and the Massachusetts General Hospital (MGH) Department of Neurology, who led the study. "What we don't know yet is precisely how it works, what molecules it interacts with in cells and how potent it might be."
C2-8 was first identified as a candidate treatment for HD by MIND researcher Aleksey Kazantsev, PhD, based on its ability to block the aggregation of the mutant huntingtin protein in yeast and animal tissue and to improve function in a fruit fly model. The current study was designed to further investigate its potential as a therapeutic drug. The researchers first confirmed that oral doses of C2-8 can cross the blood-brain barrier and are nontoxic in a mouse model of HD. They also found that C2-8 does not interact with a number of molecules predictive of negative side effects.
HD mice that were treated with C2-8 starting at the age of 24 days scored significantly better on tests of strength, endurance and coordination than did HD mice that did not receive the molecule. While treatment significantly delayed progressive motor disability, the animals receiving C2-8 did not live longer. Examination of brain cells from the striatum, the area of the brain where the deterioration of HD occurs, showed that treated mice had less shrinkage of brain cells and smaller aggregates of huntingtin protein than did untreated HD mice.
"We've both validated that compounds reducing the aggregation of mutant huntingtin are potential HD drugs -- so that strategy is one that other scientists should pursue -- and shown that C2-8 has potential as the basis of a neuroprotective treatment," says Hersch. "We now need to confirm those results in a different mouse model, see whether similar compounds may be more potent than C2-8 and search for the enzyme or receptor it is binding to." Hersch is an associate professor of Neurology at Harvard Medical School.
Vanita Chopra, PhD, and Jonathan Fox, PhD, of MIND and MGH-Neurology are co-first author of the PNAS study. Additional co-authors are Greg Lieberman, Kathryn Dorsey, Kazantsev and Anne B. Young, MD, PhD, of MIND/MGH-Neurology; Wayne Matson, PhD, Boston University School of Medicine; Peter Waldmeier, PhD, Novartis Institute for Biomedical Research, Basel, Switzerland; and David Houseman, PhD, Massachusetts Institute of Technology. The study was supported by the Discovery of Novel Huntington's Disease Therapeutics Fund, MIND and the Massachusetts General Hospital.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Source: Sue McGreevey
Massachusetts General Hospital
"We found that C2-8 slows the progress of HD in a mouse model and might do the same thing in human patients, if it or its biochemical relatives can be translated into a drug," says Steven Hersch, MD, PhD, of MIND and the Massachusetts General Hospital (MGH) Department of Neurology, who led the study. "What we don't know yet is precisely how it works, what molecules it interacts with in cells and how potent it might be."
C2-8 was first identified as a candidate treatment for HD by MIND researcher Aleksey Kazantsev, PhD, based on its ability to block the aggregation of the mutant huntingtin protein in yeast and animal tissue and to improve function in a fruit fly model. The current study was designed to further investigate its potential as a therapeutic drug. The researchers first confirmed that oral doses of C2-8 can cross the blood-brain barrier and are nontoxic in a mouse model of HD. They also found that C2-8 does not interact with a number of molecules predictive of negative side effects.
HD mice that were treated with C2-8 starting at the age of 24 days scored significantly better on tests of strength, endurance and coordination than did HD mice that did not receive the molecule. While treatment significantly delayed progressive motor disability, the animals receiving C2-8 did not live longer. Examination of brain cells from the striatum, the area of the brain where the deterioration of HD occurs, showed that treated mice had less shrinkage of brain cells and smaller aggregates of huntingtin protein than did untreated HD mice.
"We've both validated that compounds reducing the aggregation of mutant huntingtin are potential HD drugs -- so that strategy is one that other scientists should pursue -- and shown that C2-8 has potential as the basis of a neuroprotective treatment," says Hersch. "We now need to confirm those results in a different mouse model, see whether similar compounds may be more potent than C2-8 and search for the enzyme or receptor it is binding to." Hersch is an associate professor of Neurology at Harvard Medical School.
Vanita Chopra, PhD, and Jonathan Fox, PhD, of MIND and MGH-Neurology are co-first author of the PNAS study. Additional co-authors are Greg Lieberman, Kathryn Dorsey, Kazantsev and Anne B. Young, MD, PhD, of MIND/MGH-Neurology; Wayne Matson, PhD, Boston University School of Medicine; Peter Waldmeier, PhD, Novartis Institute for Biomedical Research, Basel, Switzerland; and David Houseman, PhD, Massachusetts Institute of Technology. The study was supported by the Discovery of Novel Huntington's Disease Therapeutics Fund, MIND and the Massachusetts General Hospital.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Source: Sue McGreevey
Massachusetts General Hospital
Defective Sperm Cells Inside The Body Tagged By Quality Control Mechanism
Defective sperm cells do not pass through the body unnoticed. A new University of Missouri study provides evidence that the body recognizes and tags defective sperm cells while they undergo maturation in the epididymis, a sperm storage gland attached to the testis. According to researchers, only the best sperm that have the highest chance of succeeding in fertilization will survive the production process without a "tag."
A small protein called ubiquitin marks abnormal sperm cells, including cells that have two heads, two tails or are otherwise misshaped. This "recycling tag" on the sperm cell tells the body which cells need to be broken back down into amino acids. This provides evidence that there is an active removal process or marking of defective sperm during the epididymal passage.
"Fertilization is, in a way, a numbers game," said Peter Sutovsky, associate professor of animal sciences, clinical obstetrics and gynecology in the MU College of Agriculture, Food and Natural Resources. "You need a certain number of normal sperm cells to reach the egg. If too many are tagged with ubiquitin, there may be not enough to fertilize an egg."
This study suggests that the male reproductive system must be able to evaluate and control the quality of the sperm to insure an optimal chance of fertilization. High levels of ubiquitin in the sperm can indicate low-sperm count or infertility. This process of quality control has been found in both humans and other mammals including bulls, boars and rats.
"In many cases, the cells that are tagged with ubiquitin are obviously abnormal with two tails or two heads, but many of them look like they don't have defects," Sutovsky said. "Oftentimes, these cells may look normal but lack proteins that are important to fertility."
Once sperm cells are tagged as defective, it is unlikely that the process can be reversed. Sutovsky stresses the importance of a healthy lifestyle to reduce the likelihood of abnormal sperm cells. He suggests avoiding exposure to toxic chemicals, abstaining from smoking and maintaining a healthy diet. He suggests people who work with toxins on a daily basis should minimize their exposure by wearing protective clothing and respirators.
The study was published in the Journal of Cellular Physiology.
Source: Jennifer Faddis
University of Missouri-Columbia
A small protein called ubiquitin marks abnormal sperm cells, including cells that have two heads, two tails or are otherwise misshaped. This "recycling tag" on the sperm cell tells the body which cells need to be broken back down into amino acids. This provides evidence that there is an active removal process or marking of defective sperm during the epididymal passage.
"Fertilization is, in a way, a numbers game," said Peter Sutovsky, associate professor of animal sciences, clinical obstetrics and gynecology in the MU College of Agriculture, Food and Natural Resources. "You need a certain number of normal sperm cells to reach the egg. If too many are tagged with ubiquitin, there may be not enough to fertilize an egg."
This study suggests that the male reproductive system must be able to evaluate and control the quality of the sperm to insure an optimal chance of fertilization. High levels of ubiquitin in the sperm can indicate low-sperm count or infertility. This process of quality control has been found in both humans and other mammals including bulls, boars and rats.
"In many cases, the cells that are tagged with ubiquitin are obviously abnormal with two tails or two heads, but many of them look like they don't have defects," Sutovsky said. "Oftentimes, these cells may look normal but lack proteins that are important to fertility."
Once sperm cells are tagged as defective, it is unlikely that the process can be reversed. Sutovsky stresses the importance of a healthy lifestyle to reduce the likelihood of abnormal sperm cells. He suggests avoiding exposure to toxic chemicals, abstaining from smoking and maintaining a healthy diet. He suggests people who work with toxins on a daily basis should minimize their exposure by wearing protective clothing and respirators.
The study was published in the Journal of Cellular Physiology.
Source: Jennifer Faddis
University of Missouri-Columbia
$11.6M NIH Grant To Study Novel Mechanisms Of Heart Failure Received By Jefferson
Scientists at Jefferson Medical College have received a five-year, $11.6 million grant from the National Heart, Lung and Blood Institute to study molecular mechanisms of cardiac injury that lead to heart failure and potential repair processes that occur in the adult failing heart. This project aims to find data that can be translated into novel therapeutic strategies to improve the failing heart.
"This study is unique in that we're not only studying factors that contribute to heart failure but we are also looking for cellular and molecular mechanisms that promote repair for the damaged heart," said principal investigator Walter J. Koch, PhD., the W.W Smith Professor of Medicine and director of the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College of Thomas Jefferson University. "We will have four core facilities and four different labs working on this grant from a host of different angles. While much of the project will focus on the science of failure and repair, it is also clinically relevant in that we are working with stem cells and pharmaceutical drugs already being given to patients."
An advantage of this type of NIH Program Project Grant is that the four primary projects can be supported by core units. This grant supports four core areas: administrative, surgical, molecular and gene therapy and four main laboratories. In addition to Dr. Koch's leadership in these areas, leaders of these facilities are Andrea Eckhart, Ph.D., Patrick Most, M.D., Erhe Gao, M.D., Ph.D. and Joseph Rabinowitz, Ph.D., all faculty members in the Center for Translational Medicine.
Dr. Koch's group is studying how the enzyme GRK5, which plays a novel role in heart cell signaling and function, is involved in regulating heart cell gene transcription. Gene transcription is part of the two-step process that cells use to read a gene and produce a protein. According to Dr. Koch, abnormal increases in gene transcription are involved in heart failure and heart enlargement.
Another group led by Arthur Feldman, M.D., PhD., the Magee Professor and Chair of Medicine at Jefferson Medical College, will focus on the role of adenosine receptors in the heart. While much is known about their role in protecting the heart when it's deprived of oxygen during a heart attack, little is known about what part it plays in healing the heart after injury and in heart failure. Two major adenosine receptor types in the heart appear to have opposite effects. Chronic signaling through one type appears to be detrimental to the heart, resulting in heart failure; whereas signaling through the other receptor appears beneficial. Too much expression of the latter can help repair a heart in failure. Dr. Feldman's research team wants to more closely study the adenosine receptors in the failing heart.
Steven R. Houser, PhD., chair of the Department of Physiology and director of the Cardiovascular Research Center at Temple University's School of Medicine, will investigate how the influx of calcium ions can potentially damage the heart or aid in its regeneration, depending on the calcium channels involved. Previous data indicates that an influx of calcium through one type (L) of channel can increase heart damage in the failing heart. But Dr. Houser has found that within the adult heart there are small cells that appear to come from resident cardiac stem cells. These heart cells depend on the (T) type calcium channel and probably aid in normal heart regeneration, though there are too few to repair the heart during a heart attack. Dr. Houser would like to study the calcium signaling characteristics of these heart stem cells to try to understand what mobilizes them, and he is seeking to understand their regenerative potential.
Thomas Force, M.D., the James C. Wilson Professor of Medicine at Jefferson Medical College, has found that a certain type of cancer drug called a tyrosine kinase inhibitor (including the very successful leukemia drug Gleevec), which interferes with a particular enzyme, can cause heart failure. But because the damage appears to be reversible, one theory says that the drugs, instead of damaging the heart cells, may actually hurt heart stem cells and prevent repair. Some early results in the laboratory with stem cell cultured with Gleevec seem to support the theory. Dr. Force's group will continue to test the tyrosine kinase inhibitor drugs to better understand how they affect cardiac stem cells.
Source: Rick Cushman
Thomas Jefferson University
View drug information on Gleevec.
"This study is unique in that we're not only studying factors that contribute to heart failure but we are also looking for cellular and molecular mechanisms that promote repair for the damaged heart," said principal investigator Walter J. Koch, PhD., the W.W Smith Professor of Medicine and director of the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College of Thomas Jefferson University. "We will have four core facilities and four different labs working on this grant from a host of different angles. While much of the project will focus on the science of failure and repair, it is also clinically relevant in that we are working with stem cells and pharmaceutical drugs already being given to patients."
An advantage of this type of NIH Program Project Grant is that the four primary projects can be supported by core units. This grant supports four core areas: administrative, surgical, molecular and gene therapy and four main laboratories. In addition to Dr. Koch's leadership in these areas, leaders of these facilities are Andrea Eckhart, Ph.D., Patrick Most, M.D., Erhe Gao, M.D., Ph.D. and Joseph Rabinowitz, Ph.D., all faculty members in the Center for Translational Medicine.
Dr. Koch's group is studying how the enzyme GRK5, which plays a novel role in heart cell signaling and function, is involved in regulating heart cell gene transcription. Gene transcription is part of the two-step process that cells use to read a gene and produce a protein. According to Dr. Koch, abnormal increases in gene transcription are involved in heart failure and heart enlargement.
Another group led by Arthur Feldman, M.D., PhD., the Magee Professor and Chair of Medicine at Jefferson Medical College, will focus on the role of adenosine receptors in the heart. While much is known about their role in protecting the heart when it's deprived of oxygen during a heart attack, little is known about what part it plays in healing the heart after injury and in heart failure. Two major adenosine receptor types in the heart appear to have opposite effects. Chronic signaling through one type appears to be detrimental to the heart, resulting in heart failure; whereas signaling through the other receptor appears beneficial. Too much expression of the latter can help repair a heart in failure. Dr. Feldman's research team wants to more closely study the adenosine receptors in the failing heart.
Steven R. Houser, PhD., chair of the Department of Physiology and director of the Cardiovascular Research Center at Temple University's School of Medicine, will investigate how the influx of calcium ions can potentially damage the heart or aid in its regeneration, depending on the calcium channels involved. Previous data indicates that an influx of calcium through one type (L) of channel can increase heart damage in the failing heart. But Dr. Houser has found that within the adult heart there are small cells that appear to come from resident cardiac stem cells. These heart cells depend on the (T) type calcium channel and probably aid in normal heart regeneration, though there are too few to repair the heart during a heart attack. Dr. Houser would like to study the calcium signaling characteristics of these heart stem cells to try to understand what mobilizes them, and he is seeking to understand their regenerative potential.
Thomas Force, M.D., the James C. Wilson Professor of Medicine at Jefferson Medical College, has found that a certain type of cancer drug called a tyrosine kinase inhibitor (including the very successful leukemia drug Gleevec), which interferes with a particular enzyme, can cause heart failure. But because the damage appears to be reversible, one theory says that the drugs, instead of damaging the heart cells, may actually hurt heart stem cells and prevent repair. Some early results in the laboratory with stem cell cultured with Gleevec seem to support the theory. Dr. Force's group will continue to test the tyrosine kinase inhibitor drugs to better understand how they affect cardiac stem cells.
Source: Rick Cushman
Thomas Jefferson University
View drug information on Gleevec.
VGX Pharmaceuticals Submits Device Master File To FDA For CELLECTRA(TM) Electroporator
VGX Pharmaceuticals announced the submission of a Device Master File (MAF) to the U.S. Food and Drug Administration (FDA) for its patented CELLECTRA™ adaptive constant current electroporation device. The Company has been developing the CELLECTRA™ electroporator as its lead clinical medical device for delivering DNA vaccine and therapy products. Numerous preclinical efficacy studies have shown that delivery of DNA-based product candidates with the CELLECTRA™ device optimizes DNA uptake and its subsequent expression in the target tissue, and results in enhanced immune responses in animals.
Filing of the MAF, which includes technical, manufacturing, and clinical and non-clinical information about a medical device, marks an important milestone for VGX Pharmaceuticals. It facilitates the FDA review of the CELLECTRA™ device when Investigational New Drug (IND) applications for DNA-based product candidates are filed that reference its use. VGX Pharmaceuticals recently completed a pain and tolerability clinical trial in healthy volunteers without the presence of a DNA vaccine demonstrating that electroporation with the CELLECTRA™ device is well tolerated.
"This MAF submission brings the CELLECTRA™ device another step closer to becoming the device of choice for DNA vaccines and therapies," stated Dr. J. Joseph Kim, President and Chief Executive Officer. "Our aggressive development strategy will continue to validate the value of our vertically-integrated DNA Vaccines and Therapeutics Platform, which includes SynCon™ DNA-based product candidates, the CELLECTRA™ device, and efficient and scalable cGMP manufacturing facilities."
VGX Pharmaceuticals plans to file three INDs for its SynCon™ DNA-based product candidates during the first two quarters of 2008: VGX-3100, a therapeutic vaccine for the treatment for cervical cancer; VGX-3200, a therapeutic based on human growth hormone releasing hormone for cancer-related cachexia (wasting or heavy weight loss); and VGX-3400, a pandemic avian flu vaccine.
About VGX Pharmaceuticals
VGX Pharmaceuticals is a biopharmaceutical company with small molecule and biologic product candidates for the treatment of infectious diseases, cancer, and inflammatory diseases. The Company's clinical development programs include PICTOVIR™ for HIV infection, which is in Phase II clinical trials, and PENNVAX™-B, a DNA vaccine for HIV infection, which is in 2 separate Phase I clinical trials. The Company's lead compound for inflammatory diseases, VGX-1027, is also in Phase I clinical trials. VGX's research pipeline includes a new generation of SynCon™ DNA vaccines and therapeutics as well as the CELLECTRA™ electroporator, a patented DNA delivery device. The product candidates and technology programs are protected by the Company's extensive global intellectual property portfolio.
VGX Pharmaceuticals
Filing of the MAF, which includes technical, manufacturing, and clinical and non-clinical information about a medical device, marks an important milestone for VGX Pharmaceuticals. It facilitates the FDA review of the CELLECTRA™ device when Investigational New Drug (IND) applications for DNA-based product candidates are filed that reference its use. VGX Pharmaceuticals recently completed a pain and tolerability clinical trial in healthy volunteers without the presence of a DNA vaccine demonstrating that electroporation with the CELLECTRA™ device is well tolerated.
"This MAF submission brings the CELLECTRA™ device another step closer to becoming the device of choice for DNA vaccines and therapies," stated Dr. J. Joseph Kim, President and Chief Executive Officer. "Our aggressive development strategy will continue to validate the value of our vertically-integrated DNA Vaccines and Therapeutics Platform, which includes SynCon™ DNA-based product candidates, the CELLECTRA™ device, and efficient and scalable cGMP manufacturing facilities."
VGX Pharmaceuticals plans to file three INDs for its SynCon™ DNA-based product candidates during the first two quarters of 2008: VGX-3100, a therapeutic vaccine for the treatment for cervical cancer; VGX-3200, a therapeutic based on human growth hormone releasing hormone for cancer-related cachexia (wasting or heavy weight loss); and VGX-3400, a pandemic avian flu vaccine.
About VGX Pharmaceuticals
VGX Pharmaceuticals is a biopharmaceutical company with small molecule and biologic product candidates for the treatment of infectious diseases, cancer, and inflammatory diseases. The Company's clinical development programs include PICTOVIR™ for HIV infection, which is in Phase II clinical trials, and PENNVAX™-B, a DNA vaccine for HIV infection, which is in 2 separate Phase I clinical trials. The Company's lead compound for inflammatory diseases, VGX-1027, is also in Phase I clinical trials. VGX's research pipeline includes a new generation of SynCon™ DNA vaccines and therapeutics as well as the CELLECTRA™ electroporator, a patented DNA delivery device. The product candidates and technology programs are protected by the Company's extensive global intellectual property portfolio.
VGX Pharmaceuticals
Knowledge Of P53 Exploited For A Novel Way Of Increasing Specificity Of Cancer Treatments
Healthy cells need not be destroyed during cancer treatment
Researchers from the p53 Laboratory of Singapore's Agency for Science, Technology and Research (A*STAR), have made a finding that makes feasible a unique method of cancer treatment. Their work, published online in the leading journal Cell Death and Differentiation, offers new insight on how to tap on the properties of p53, the 'guardian of the genome' , to more effectively kill cancer cells while sparing normal cells.
The researchers, led by Dr Cheok Chit Fang and Prof David Lane, the co-discoverer of the p53 gene in 1979, achieved this by exploiting one of the key functions of p53 - the control of the cell cycle.
Activating p53 halts the cell cycle and prevents endoreduplication, a process by which a cell accumulates excess genetic material by duplicating its existing genetic material without actually dividing. If endoreduplication happens in human cells, they die. Deliberately inducing endoreduplication in cancer cells through chemical means has been explored as a means of killing off cancer cells. However, as the drugs used are not highly specific to cancer cells, many normal cells are also killed in the process.
Fortunately, in many cancers, the cancer cells lack working copies of p53. By using a drug that activates p53 in healthy cells and temporarily induces the cells to stop the production of genetic material, endoreduplication is prevented. Cancer cells which lack working copies of p53 are thus left susceptible to a second drug that induces endoreduplication, resulting in tumour-specific killing. The activation of p53 is reversible and the normal cells resume their function once the cancer cells have been killed.
Said Prof David Lane, Director of the p53 Laboratory and A*STAR's Chief Scientist, "We are proposing a unique combination of drugs which may have therapeutic benefits and could potentially alleviate the side effects of currently available cancer treatments. The clinical approval of nutlin or nutlin-like drugs will allow such exciting concepts to be tested in the clinic. We hope that this work encourages further breakthroughs in p53 research and brings more efficient and cost-effective treatments for the millions of cancer patients worldwide."
Dr Cheok said, "One the most difficult problems in treating cancer is ensuring that normal, healthy cells are not killed over the course of treatment. Many of the currently available methods of treatment, such as chemotherapy and radiation therapy, damage normal cells in the process of killing cancer cells. We are using our knowledge of p53 to overcome this difficulty."
Dr Cheok was among the first few Singaporeans to embark on a PhD scholarship from A*STAR in 2001 . After receiving her PhD from the University of Oxford, she began her post-doctoral training under the tutelage of Prof Lane in 2006. She is also an Assistant Professor and a Senior Research Fellow at the Department of Biochemistry at the Yong Loo Lin School of Medicine, NUS.
Prof Lane added, "We are proud of Chit Fang for having made this significant finding so early in her scientific career. It gives me great pleasure to have her as part of my team working on deepening our understanding of how to use basic science findings to develop new therapies."
Source:
Joshua Tan
Agency for Science, Technology and Research (A*STAR), Singapore
Researchers from the p53 Laboratory of Singapore's Agency for Science, Technology and Research (A*STAR), have made a finding that makes feasible a unique method of cancer treatment. Their work, published online in the leading journal Cell Death and Differentiation, offers new insight on how to tap on the properties of p53, the 'guardian of the genome' , to more effectively kill cancer cells while sparing normal cells.
The researchers, led by Dr Cheok Chit Fang and Prof David Lane, the co-discoverer of the p53 gene in 1979, achieved this by exploiting one of the key functions of p53 - the control of the cell cycle.
Activating p53 halts the cell cycle and prevents endoreduplication, a process by which a cell accumulates excess genetic material by duplicating its existing genetic material without actually dividing. If endoreduplication happens in human cells, they die. Deliberately inducing endoreduplication in cancer cells through chemical means has been explored as a means of killing off cancer cells. However, as the drugs used are not highly specific to cancer cells, many normal cells are also killed in the process.
Fortunately, in many cancers, the cancer cells lack working copies of p53. By using a drug that activates p53 in healthy cells and temporarily induces the cells to stop the production of genetic material, endoreduplication is prevented. Cancer cells which lack working copies of p53 are thus left susceptible to a second drug that induces endoreduplication, resulting in tumour-specific killing. The activation of p53 is reversible and the normal cells resume their function once the cancer cells have been killed.
Said Prof David Lane, Director of the p53 Laboratory and A*STAR's Chief Scientist, "We are proposing a unique combination of drugs which may have therapeutic benefits and could potentially alleviate the side effects of currently available cancer treatments. The clinical approval of nutlin or nutlin-like drugs will allow such exciting concepts to be tested in the clinic. We hope that this work encourages further breakthroughs in p53 research and brings more efficient and cost-effective treatments for the millions of cancer patients worldwide."
Dr Cheok said, "One the most difficult problems in treating cancer is ensuring that normal, healthy cells are not killed over the course of treatment. Many of the currently available methods of treatment, such as chemotherapy and radiation therapy, damage normal cells in the process of killing cancer cells. We are using our knowledge of p53 to overcome this difficulty."
Dr Cheok was among the first few Singaporeans to embark on a PhD scholarship from A*STAR in 2001 . After receiving her PhD from the University of Oxford, she began her post-doctoral training under the tutelage of Prof Lane in 2006. She is also an Assistant Professor and a Senior Research Fellow at the Department of Biochemistry at the Yong Loo Lin School of Medicine, NUS.
Prof Lane added, "We are proud of Chit Fang for having made this significant finding so early in her scientific career. It gives me great pleasure to have her as part of my team working on deepening our understanding of how to use basic science findings to develop new therapies."
Source:
Joshua Tan
Agency for Science, Technology and Research (A*STAR), Singapore
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