Research into the evolution of protein design by a University of Houston professor will be featured among nearly 20 presentations at the 2005 Nano Summit Research Conference July 28.
Kurt L. Krause, an associate professor of biology and biochemistry at UH, will give a presentation at 11 a.m. on the "Role of Protein Design in Bionanotechnology."
Sponsored by the Nanotechnology Foundation of Texas, the 2005 Nano Summit is a daylong forum for Texas natural science, engineering and medical researchers to meet and exchange information on their respective areas of expertise. With a focus on major nanoscience research activities across Texas, the conference also is of benefit to corporate research and development executives, as well as students in related disciplines. UH is a co-host of the event.
Held from 8:30 a.m. to 6:30 p.m. at the Edwin Hornberger Conference Center in the Texas Medical Center in Houston, the Nano Summit will provide presentations, a poster session and networking opportunities that cover leading nanotechnology research and practical applications in life science, materials science, energy, electronics and semiconductors. Both presenters and attendees will be able to explore the specific research needs and opportunities associated with the multidisciplinary field that is nanotechnology.
Krause's work deals with the significant effort in bionanotechnology today being devoted to the use of naturally occurring proteins in the diagnosis and treatment of disease and as reagents in bioengineering applications. The proteins used in these experiments are almost always naturally occurring and derived from living organisms. However, these proteins are not optimized to carry out anything other than their natural role. Krause proposes that if the widespread use of proteins in nanotechnology is to be achieved, then much more will need to be done in the area of protein design.
He will discuss current advances in the use of selection and randomization to intelligently evolve protein function, as well as the role of these advances in the application of nanotechnology. For instance, in Krause's laboratory, what starts off as a mere molecule may soon become a potential drug to treat HIV, one of the diseases he actively targets with his research.
uh/newsroom
понедельник, 6 июня 2011 г.
Researchers Identify The Gene Responsible For A Rare Form Of Congenital Anemia
The latest electronic edition of the journal Nature Genetics reports the discovery of a new gene responsible for congenital sideroblastic anemia, a rare disease, mainly characterized by the presence of ringed sideroblasts in the patients' bone marrow. This Genome Canada project, co-directed by Dr. Mark Samuels, an investigator with the Sainte-Justine University Hospital Research Center and a professor at the UniversitГ© de MontrГ©al Department of Medicine, is being conducted under the Atlantic Medical Genetics and Genomics Initiative (AMGGI).
The clinical research team identified three families from Canada's Maritime provinces, each with a child suffering from this disease. Even though these families were not related officially, it seemed very likely that it was possible to establish a genealogical link uniting them generations ago and that they exhibited what is called a founder effect.
Thanks to the new technologies developed by the Human Genome Project, the AMGGI's molecular analysis team succeeded in delimiting a genomic region likely to contain the gene responsible for congenital sideroblastic anemia in these families.
The direct resequencing of this gene made it possible to identify a causal mutation in a gene to which no physiological role could have been attributed. Subsequently, in collaboration with researchers in the United States, the team identified 10 additional causal mutations of this gene in other unexplained cases of congenital sideroblastic anemia. In collaboration with the laboratory of Dr. Louis Saint-Amant of the UniversitГ© de MontrГ©al's Department of Pathology, the research team showed a direct role of the gene in hemoglobin synthesis in zebra fish.
The gene identified is part of a gene family involved in the transport of nutrients to and from the mitochondria, the power plant of the cells. Some mutations of other members of this gene family cause distinct genetic diseases in humans, but this is the first disease of this type associated with the SLC25A38 gene.
The identification of the causal gene can now offer patients and their family members direct molecular confirmation of their condition, allowing them to know whether they are sufferers or asymptomatic carriers of the disease. More generally, this discovery shows that even well-known scientific processes, such as hemoglobin biosynthesis, still have surprises in store.
Source:
MГ©lanie Dallaire
University of Montreal
The clinical research team identified three families from Canada's Maritime provinces, each with a child suffering from this disease. Even though these families were not related officially, it seemed very likely that it was possible to establish a genealogical link uniting them generations ago and that they exhibited what is called a founder effect.
Thanks to the new technologies developed by the Human Genome Project, the AMGGI's molecular analysis team succeeded in delimiting a genomic region likely to contain the gene responsible for congenital sideroblastic anemia in these families.
The direct resequencing of this gene made it possible to identify a causal mutation in a gene to which no physiological role could have been attributed. Subsequently, in collaboration with researchers in the United States, the team identified 10 additional causal mutations of this gene in other unexplained cases of congenital sideroblastic anemia. In collaboration with the laboratory of Dr. Louis Saint-Amant of the UniversitГ© de MontrГ©al's Department of Pathology, the research team showed a direct role of the gene in hemoglobin synthesis in zebra fish.
The gene identified is part of a gene family involved in the transport of nutrients to and from the mitochondria, the power plant of the cells. Some mutations of other members of this gene family cause distinct genetic diseases in humans, but this is the first disease of this type associated with the SLC25A38 gene.
The identification of the causal gene can now offer patients and their family members direct molecular confirmation of their condition, allowing them to know whether they are sufferers or asymptomatic carriers of the disease. More generally, this discovery shows that even well-known scientific processes, such as hemoglobin biosynthesis, still have surprises in store.
Source:
MГ©lanie Dallaire
University of Montreal
Blood-Brain Barrier Used As Therapy Delivery System By University Of Iowa Scientists
The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.
Working with animal models of a group of fatal neurological disorders called lysosomal storage diseases, the UI team found that these diseases cause unique and disease-specific alterations to the blood vessels of the blood brain barrier. The scientists used these distinct alterations to target the brain with gene therapy, which reversed the neurological damage caused by the diseases.
The findings, which were published in Nature Medicine's Advance Online Publication (AOP), could lead to a new non-invasive approach for treating neurological damage caused by lysosomal storage diseases.
"This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain," said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. "This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.
"In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons," she added.
Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.
Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.
"Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials," said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. "In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected."
To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.
The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.
The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.
The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.
In addition to Davidson, the research team included UI postdoctoral researcher Yong Hong Chen, Ph.D., and Michael Chang, M.D., Ph.D., who was a student in the UI Medical Scientist Training Program when the study was conducted.
The study was funded by grants from the National Institutes of Health and from the Batten Disease Support and Research Association.
Source:
Jennifer Brown
University of Iowa
Working with animal models of a group of fatal neurological disorders called lysosomal storage diseases, the UI team found that these diseases cause unique and disease-specific alterations to the blood vessels of the blood brain barrier. The scientists used these distinct alterations to target the brain with gene therapy, which reversed the neurological damage caused by the diseases.
The findings, which were published in Nature Medicine's Advance Online Publication (AOP), could lead to a new non-invasive approach for treating neurological damage caused by lysosomal storage diseases.
"This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain," said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. "This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.
"In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons," she added.
Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.
Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.
"Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials," said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. "In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected."
To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.
The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.
The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.
The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.
In addition to Davidson, the research team included UI postdoctoral researcher Yong Hong Chen, Ph.D., and Michael Chang, M.D., Ph.D., who was a student in the UI Medical Scientist Training Program when the study was conducted.
The study was funded by grants from the National Institutes of Health and from the Batten Disease Support and Research Association.
Source:
Jennifer Brown
University of Iowa
Misfolded Proteins: The Fundamental Problem Is Aging
Proteins are essential for all biological activities and the health of the cell. Misfolded and damaged proteins spell trouble and are common to all human neurodegenerative diseases and many other age-associated diseases. But when during a lifespan do proteins start to misbehave?
A new Northwestern University study reports that protein damage can be detected much earlier than we had thought, long before individuals exhibit symptoms. But the study also suggests if we intervene early enough, the damage could be delayed.
In studying seven different proteins of the worm C. elegans, the researchers discovered that each protein misfolds at the same point: during early adulthood and long before the animal shows any behavioral, or physiological, change. (Each protein had a minor mutation that affects folding.)
The misfolding coincided with the loss of a critical protective cellular mechanism: the ability to activate the heat shock response, an ancient genetic switch that senses damaged proteins and protects cells by preventing protein misfolding.
The results will be published online during the week of Aug. 24 by the Proceedings of the National Academy of Sciences (PNAS).
"I didn't expect the results to be so dramatic, for these different proteins that vary in concentration and are expressed in diverse tissues to collapse at the same time," said lead researcher Richard I. Morimoto. "This suggests the animal's protective cellular stress response becomes deficient during aging."
Could the damaging events of protein misfolding be prevented or at least delayed?
To find out, the researchers gave the animals the equivalent of a vitamin, boosting the heat shock response early in the animal's development, prior to protein damage. Now, instead of misfolding around day four, the equivalent of early adulthood in the worm, the proteins didn't start misfolding until day 12. (Behavioral changes didn't appear for at least three days after misfolding. The average lifespan of the worm is 21 days.)
"Our data suggest that, in terms of therapeutics, you have to start early to prevent damage and keep cells healthy," said Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology in Northwestern's Weinberg College of Arts and Sciences. "When you see a loss of function, it's too late."
Genes that regulate lifespan were first discovered in C. elegans. The transparent roundworm is a favorite organism of biologists because its biochemical environment and fundamental mechanisms are similar to that of human beings and its genome, or complete genetic sequence, is known.
The title of the PNAS paper is "Collapse of Proteostasis Represents an Early Molecular Event in C. elegans Aging." In addition to Morimoto, other authors of the paper are Anat Ben-Zvi and Elizabeth A. Miller, both from Northwestern.
Source:
Megan Fellman
Northwestern University
A new Northwestern University study reports that protein damage can be detected much earlier than we had thought, long before individuals exhibit symptoms. But the study also suggests if we intervene early enough, the damage could be delayed.
In studying seven different proteins of the worm C. elegans, the researchers discovered that each protein misfolds at the same point: during early adulthood and long before the animal shows any behavioral, or physiological, change. (Each protein had a minor mutation that affects folding.)
The misfolding coincided with the loss of a critical protective cellular mechanism: the ability to activate the heat shock response, an ancient genetic switch that senses damaged proteins and protects cells by preventing protein misfolding.
The results will be published online during the week of Aug. 24 by the Proceedings of the National Academy of Sciences (PNAS).
"I didn't expect the results to be so dramatic, for these different proteins that vary in concentration and are expressed in diverse tissues to collapse at the same time," said lead researcher Richard I. Morimoto. "This suggests the animal's protective cellular stress response becomes deficient during aging."
Could the damaging events of protein misfolding be prevented or at least delayed?
To find out, the researchers gave the animals the equivalent of a vitamin, boosting the heat shock response early in the animal's development, prior to protein damage. Now, instead of misfolding around day four, the equivalent of early adulthood in the worm, the proteins didn't start misfolding until day 12. (Behavioral changes didn't appear for at least three days after misfolding. The average lifespan of the worm is 21 days.)
"Our data suggest that, in terms of therapeutics, you have to start early to prevent damage and keep cells healthy," said Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology in Northwestern's Weinberg College of Arts and Sciences. "When you see a loss of function, it's too late."
Genes that regulate lifespan were first discovered in C. elegans. The transparent roundworm is a favorite organism of biologists because its biochemical environment and fundamental mechanisms are similar to that of human beings and its genome, or complete genetic sequence, is known.
The title of the PNAS paper is "Collapse of Proteostasis Represents an Early Molecular Event in C. elegans Aging." In addition to Morimoto, other authors of the paper are Anat Ben-Zvi and Elizabeth A. Miller, both from Northwestern.
Source:
Megan Fellman
Northwestern University
Prevention Of Dangerous Corn Toxin Hinges On Defining Gene's Role
Discovery that a specific gene is integral to both fungal invasion of corn and development of a potentially deadly toxin in the kernels may lead to ways to control the pathogen and the poison.
Purdue University researchers evaluated the fungal gene ZFR1 and found that it is vital to the process of the fungus growing on corn kernels. Production of the toxin decreased when the scientists disabled the gene.
At certain levels, the toxin can cause illness in humans and most domestic livestock. Horses and pigs are at particular risk and can develop fatal diseases by ingesting feed containing one of a group of toxins called fumonisins (few-mahn-ah-sins). About $40 million of the U.S. corn crop is lost annually due to presence of these toxins, according to experts.
"Our main research question has been what triggers toxin production when the fungus attacks the corn kernel; it appears that kernel starch plays an important role," said Charles Woloshuk, a Purdue plant pathologist. "When ZFR1 is deleted, the resulting mutant fungus has a problem transporting sugars that are produced from the degradation of kernel starch."
The resulting sugars must be transported to cells as fuel for other biochemical processes.
"The pathogen - the fungus Fusarium verticillioides - has a number of putative sugar transporter genes that are expressed during its growth on kernels and toxin production," Woloshuk said. "Disruption of ZFR1 also affects expression of the sugar transporter genes."
Woloshuk and his colleague, Bert Bluhm, now at the University of Arkansas, report in the current issue of Molecular Plant Pathology that when the gene ZFR1 is turned off, it reduces manifestation of genes involved in production of the most prevalent and dangerous fumonisin, FB1.
The researchers studied ZFR1 regulation of fungal growth and toxin production in the starch-rich areas of corn kernels and the conversion of starch to glucose, glucose recognition and the expression of sugar transporter genes. From this information, Woloshuk and his team identified a specific sugar transporter, FST1 (fusarium sugar transporter1), that is necessary for FB1 production.
Although FST1 is required for FB1 production, it is not involved with the fungus infecting corn kernels. This led the scientists to hypothesize that FST1 acts as a molecular sensor necessary for toxin production.
Kernels with lower starch content, most notably immature kernels, don't support toxin production, Woloshuk said. This is evidence that the kernel makeup dictates how this pathogen controls toxin production.
Corn and fungal growth were unaffected when the sugar transporter gene was disrupted, but toxin production on the kernels was cut by about 82 percent, Woloshuk said.
When fusarium invades corn in the field, it causes an ear rot disease. Even knowing that ear rot is present doesn't help identify corn containing toxin because obvious signs of the fungus don't correlate with presence of toxins. The only way to confirm toxin is present is to test for it. Testing is so expensive, however, that it usually isn't done unless the disease is highly evident.
Weather and insect damage impact development of a variety of fungi and toxins and also influence the level of poisons that are present. Toxins are more likely to develop in corn when hot, dry weather is followed by highly humid or wet weather.
The group of toxins associated with varieties of fusarium species are known as mycotoxins. Some clinical evidence links these toxins with certain human cancers.
Grains grown for cereal and feeds are susceptible to one or more of the fusarium fungi species. Wheat and barley attacked by one of the species closely related to Fusarium verticillioides can develop head blight and accumulate mycotoxins, causing billions of dollars in crop losses worldwide.
Further study is needed because the researchers still don't know what triggers the biochemical process that regulates ZFR1 and consequently leads to toxin production, Woloshuk said. The scientists also are investigating the sugar transporter genes to discover if they have other roles in the fungus and what molecular interactions between the fungus and the plant allow infection and toxin production.
"We're closer to finding some of the triggers in corn that assist the fungus in toxin production," Woloshuk said.
The other researchers involved in this study were Department of Botany and Plant Pathology doctoral student Hun Kim and Robert Butchko of the USDA National Center for Agricultural Utilization Research Service in Peoria, Ill. Bluhm is a former graduate student in Woloshuk's laboratory who recently joined the University of Arkansas faculty as an assistant professor.
A USDA-National Research Initiative grant provided support for this work.
Writer: Susan A. Steeves
Related Web sites:
Purdue Department of Botany and Plant Pathology
USDA-Agricultural Research Service, Crop Production & Pest Control Research Unit
National Center for Agricultural Utilization Research Service
Molecular Plant Pathology
Click here for abstract on the research in this release.
Source: Susan A. Steeves
Purdue University
Purdue University researchers evaluated the fungal gene ZFR1 and found that it is vital to the process of the fungus growing on corn kernels. Production of the toxin decreased when the scientists disabled the gene.
At certain levels, the toxin can cause illness in humans and most domestic livestock. Horses and pigs are at particular risk and can develop fatal diseases by ingesting feed containing one of a group of toxins called fumonisins (few-mahn-ah-sins). About $40 million of the U.S. corn crop is lost annually due to presence of these toxins, according to experts.
"Our main research question has been what triggers toxin production when the fungus attacks the corn kernel; it appears that kernel starch plays an important role," said Charles Woloshuk, a Purdue plant pathologist. "When ZFR1 is deleted, the resulting mutant fungus has a problem transporting sugars that are produced from the degradation of kernel starch."
The resulting sugars must be transported to cells as fuel for other biochemical processes.
"The pathogen - the fungus Fusarium verticillioides - has a number of putative sugar transporter genes that are expressed during its growth on kernels and toxin production," Woloshuk said. "Disruption of ZFR1 also affects expression of the sugar transporter genes."
Woloshuk and his colleague, Bert Bluhm, now at the University of Arkansas, report in the current issue of Molecular Plant Pathology that when the gene ZFR1 is turned off, it reduces manifestation of genes involved in production of the most prevalent and dangerous fumonisin, FB1.
The researchers studied ZFR1 regulation of fungal growth and toxin production in the starch-rich areas of corn kernels and the conversion of starch to glucose, glucose recognition and the expression of sugar transporter genes. From this information, Woloshuk and his team identified a specific sugar transporter, FST1 (fusarium sugar transporter1), that is necessary for FB1 production.
Although FST1 is required for FB1 production, it is not involved with the fungus infecting corn kernels. This led the scientists to hypothesize that FST1 acts as a molecular sensor necessary for toxin production.
Kernels with lower starch content, most notably immature kernels, don't support toxin production, Woloshuk said. This is evidence that the kernel makeup dictates how this pathogen controls toxin production.
Corn and fungal growth were unaffected when the sugar transporter gene was disrupted, but toxin production on the kernels was cut by about 82 percent, Woloshuk said.
When fusarium invades corn in the field, it causes an ear rot disease. Even knowing that ear rot is present doesn't help identify corn containing toxin because obvious signs of the fungus don't correlate with presence of toxins. The only way to confirm toxin is present is to test for it. Testing is so expensive, however, that it usually isn't done unless the disease is highly evident.
Weather and insect damage impact development of a variety of fungi and toxins and also influence the level of poisons that are present. Toxins are more likely to develop in corn when hot, dry weather is followed by highly humid or wet weather.
The group of toxins associated with varieties of fusarium species are known as mycotoxins. Some clinical evidence links these toxins with certain human cancers.
Grains grown for cereal and feeds are susceptible to one or more of the fusarium fungi species. Wheat and barley attacked by one of the species closely related to Fusarium verticillioides can develop head blight and accumulate mycotoxins, causing billions of dollars in crop losses worldwide.
Further study is needed because the researchers still don't know what triggers the biochemical process that regulates ZFR1 and consequently leads to toxin production, Woloshuk said. The scientists also are investigating the sugar transporter genes to discover if they have other roles in the fungus and what molecular interactions between the fungus and the plant allow infection and toxin production.
"We're closer to finding some of the triggers in corn that assist the fungus in toxin production," Woloshuk said.
The other researchers involved in this study were Department of Botany and Plant Pathology doctoral student Hun Kim and Robert Butchko of the USDA National Center for Agricultural Utilization Research Service in Peoria, Ill. Bluhm is a former graduate student in Woloshuk's laboratory who recently joined the University of Arkansas faculty as an assistant professor.
A USDA-National Research Initiative grant provided support for this work.
Writer: Susan A. Steeves
Related Web sites:
Purdue Department of Botany and Plant Pathology
USDA-Agricultural Research Service, Crop Production & Pest Control Research Unit
National Center for Agricultural Utilization Research Service
Molecular Plant Pathology
Click here for abstract on the research in this release.
Source: Susan A. Steeves
Purdue University
Renal Transplant Recipients' Genetic Makeup Does Not Negatively Impact Fluvastatin Use
Scientists report that when people with a transplanted kidney take fluvastatin, a drug against cardiovascular disease, their response to the drug is not influenced by their genetic composition.
People who receive a transplanted kidney are at risk of developing potentially fatal premature cardiovascular disease. One way to prevent this from happening is by taking fluvastatin, a drug that significantly reduces myocardial infarction and cardiac death. But patients' genetic makeup has been reported to prevent similar cholesterol-lowering drugs, such as pravastatin, from working properly.
To examine potential effects of a genetic makeup on the efficacy of fluvastatin after patients receive a kidney transplant, Hallvard Holdaas and colleagues examined 42 genetic variations previously reported to affect fluvastatin metabolism, cholesterol regulation, cardiovascular disease, and the functioning of a transplanted kidney.
The scientists compared the effects of these genetic variations in 707 renal transplant patients who received fluvastatin and 697 patients who received a placebo and showed that the variations do not increase risks of developing a cardiovascular disease or a kidney disease. Consequently, statin therapy continues to be recommended to patients who received a transplanted kidney, regardless of their genetic makeup, the researchers concluded.
Article: "Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients," by Jonathan B. Singer, Hallvard Holdaas, Alan G. Jardine, Bengt Fellstrom, Ingrid Os, Georgina Bermann, and Joanne M. Meyer, on behalf of the Assessment of Lescol in Renal Transplantation (ALERT) Study Investigators
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
View drug information on Lescol.
People who receive a transplanted kidney are at risk of developing potentially fatal premature cardiovascular disease. One way to prevent this from happening is by taking fluvastatin, a drug that significantly reduces myocardial infarction and cardiac death. But patients' genetic makeup has been reported to prevent similar cholesterol-lowering drugs, such as pravastatin, from working properly.
To examine potential effects of a genetic makeup on the efficacy of fluvastatin after patients receive a kidney transplant, Hallvard Holdaas and colleagues examined 42 genetic variations previously reported to affect fluvastatin metabolism, cholesterol regulation, cardiovascular disease, and the functioning of a transplanted kidney.
The scientists compared the effects of these genetic variations in 707 renal transplant patients who received fluvastatin and 697 patients who received a placebo and showed that the variations do not increase risks of developing a cardiovascular disease or a kidney disease. Consequently, statin therapy continues to be recommended to patients who received a transplanted kidney, regardless of their genetic makeup, the researchers concluded.
Article: "Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients," by Jonathan B. Singer, Hallvard Holdaas, Alan G. Jardine, Bengt Fellstrom, Ingrid Os, Georgina Bermann, and Joanne M. Meyer, on behalf of the Assessment of Lescol in Renal Transplantation (ALERT) Study Investigators
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.
For more information about ASBMB, see the Society's Web site at asbmb.
View drug information on Lescol.
Avian Influenza Survivors' Antibodies Effective At Neutralising H5N1 Strain
Adults who have recovered from the potentially deadly H5N1 strain of avian influenza may hold the key to future treatments for the virus, according to an international team of researchers. In a study published in the open access journal PLoS Medicine, the researchers have shown how specific antibodies taken from avian flu survivors in Vietnam can be reproduced in the laboratory and prove effective at neutralising the virus in culture vitro and in mice.
The H5N1 influenza virus has caused disease and death in millions of poultry across the globe and occasionally has been transmitted to humans, often fatally. By mid-May 2007, according to the World Health Organization, there had been 306 known cases in humans, 185 of them fatal.
Now, doctors based at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, the Institute for Research in Biomedicine in Bellinzona, Switzerland and the National Institute of Allergy and Infectious Diseases in Bethesda, US, have shown that monoclonal antibodies generated from blood of human survivors of the H5N1 virus are effective at both preventing infection in mice and neutralising the virus in those already infected. The research had been fast-tracked for funding by the UK's Wellcome Trust and is also supported by grants from the National Institutes of Health in the US and the Swiss National Science Foundation.
The researchers found that the antibodies provided significant immunity to mice that were subsequently infected with the Vietnam strain of H5N1. This reduced significantly the amount of virus found in the lungs and almost completely prevented the virus reaching the brain or spleen. In those people in Vietnam who died from the H5N1 strain, the virus was found to have spread from the lungs; this was not the case in those who survived.
"We have shown that this technique can work to prevent and neutralise infection by the H5N1 'bird flu' virus in mice," says Dr Cameron Simmons, a Wellcome Trust researcher at the Oxford University Clinical Research Unit, Vietnam. "We are optimistic that these antibodies, if delivered at the right time and at the right amount, could also provide a clinical benefit to humans with H5N1 infections."
"In particular, we found that it was possible to administer the treatment up to 72 hours after infection. This is particularly important as people who have become infected with the virus do not tend to report to their local healthcare facilities until several days after the onset of illness."
The antibodies were discovered in the laboratory of Professor Antonio Lanzavecchia at the Institute for Research in Biomedicine in Switzerland. The researchers used a new technique that allows them to rapidly reproduce human monoclonal antibodies starting from a small sample of blood.
"We can't say for certain that a pandemic influenza virus will resemble the H5N1 strain that we have been studying or that the monoclonal antibodies generated using our technique will be able to tackle such a virus," says Professor Lanzavecchia. "Nevertheless, we are encouraged by the broad neutralizing activity of these antibodies in the lab and the moderate doses required."
Using administered antibodies has a historical precedent. During the 1918 Spanish H1N1 influenza pandemic, there were multiple reports of physicians administering blood taken from survivors to patients infected with the disease. A recent review suggested that this treatment was associated with a halving in mortality. However, directly administering blood carries a risk of infection with other blood diseases, such as Hepatitis C and HIV.
Contact: Craig Brierley
Wellcome Trust
The H5N1 influenza virus has caused disease and death in millions of poultry across the globe and occasionally has been transmitted to humans, often fatally. By mid-May 2007, according to the World Health Organization, there had been 306 known cases in humans, 185 of them fatal.
Now, doctors based at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, the Institute for Research in Biomedicine in Bellinzona, Switzerland and the National Institute of Allergy and Infectious Diseases in Bethesda, US, have shown that monoclonal antibodies generated from blood of human survivors of the H5N1 virus are effective at both preventing infection in mice and neutralising the virus in those already infected. The research had been fast-tracked for funding by the UK's Wellcome Trust and is also supported by grants from the National Institutes of Health in the US and the Swiss National Science Foundation.
The researchers found that the antibodies provided significant immunity to mice that were subsequently infected with the Vietnam strain of H5N1. This reduced significantly the amount of virus found in the lungs and almost completely prevented the virus reaching the brain or spleen. In those people in Vietnam who died from the H5N1 strain, the virus was found to have spread from the lungs; this was not the case in those who survived.
"We have shown that this technique can work to prevent and neutralise infection by the H5N1 'bird flu' virus in mice," says Dr Cameron Simmons, a Wellcome Trust researcher at the Oxford University Clinical Research Unit, Vietnam. "We are optimistic that these antibodies, if delivered at the right time and at the right amount, could also provide a clinical benefit to humans with H5N1 infections."
"In particular, we found that it was possible to administer the treatment up to 72 hours after infection. This is particularly important as people who have become infected with the virus do not tend to report to their local healthcare facilities until several days after the onset of illness."
The antibodies were discovered in the laboratory of Professor Antonio Lanzavecchia at the Institute for Research in Biomedicine in Switzerland. The researchers used a new technique that allows them to rapidly reproduce human monoclonal antibodies starting from a small sample of blood.
"We can't say for certain that a pandemic influenza virus will resemble the H5N1 strain that we have been studying or that the monoclonal antibodies generated using our technique will be able to tackle such a virus," says Professor Lanzavecchia. "Nevertheless, we are encouraged by the broad neutralizing activity of these antibodies in the lab and the moderate doses required."
Using administered antibodies has a historical precedent. During the 1918 Spanish H1N1 influenza pandemic, there were multiple reports of physicians administering blood taken from survivors to patients infected with the disease. A recent review suggested that this treatment was associated with a halving in mortality. However, directly administering blood carries a risk of infection with other blood diseases, such as Hepatitis C and HIV.
Contact: Craig Brierley
Wellcome Trust
Magnetic Nanoparticles To Simultaneously Diagnose, Monitor And Treat
Whether it's magnetic nanoparticles (mNPs) giving an army of 'therapeutically armed' white blood cells direction to invade a deadly tumour's territory, or the use of mNPs to target specific nerve channels and induce nerve-led behaviour (such as the life-dependant thumping of our hearts), mNPs have come a long way in the past decade.
The future for mNPs however appears even brighter. With the design of 'theranostic' molecules, mNPs could play a crucial role in developing one-stop tools to simultaneously diagnose, monitor and treat a wide range of common diseases and injuries.
Multifunctional particles, modelled on viral particles such as the flu and HIV, are being researched and developed to carry signal-generating sub-molecules and drugs, able to reach target areas through a safe sprinkling of tiny mNPs and external magnetic forces, creating a medical means to confirm specific ailments and automatically release healing drugs while inside a living system.
A landmark selection of review articles published this week in IOP Publishing's Journal of Physics D: Applied Physics, 'Progress in Applications of Magnetic Nanoparticles in Biomedicine', shows just how far magnetic nanoparticles for application in biomedicine have come and what exciting promise they hold for the future.
The magnetic component of the direction-giving nanoparticles is usually an iron-based compound called ferric oxide which is coated in a biocompatible surface, sometimes using, for example, fatty acids, to provide stability during the particles journey through one's body. For biomedicine, the particles are useful because you can add specific signal triggering molecules to identify certain conditions, or dyes to help in medical imaging, or therapeutic agents to remedy a wide-range of afflictions.
Already well documented, mNPs have sparked interest after being attached to stem cells and used in vivo to remedy heart injury in rats. On humans, in 2007, Berlin's CharitГ© Hospital used a technique which involved mNPs, called hyperthermia, to destroy a particularly severe form of brain cancer in 14 patients. The technique, utilising well-tested knowledge that tumour cells are more sensitive to temperature increases than healthy cells, uses mNPs to direct nano-heaters towards the inoperable tumours and, essentially, cook them to death.
Dr Catherine Berry, one of the review paper's authors from the Centre for Cell Engineering in Glasgow, writes, "One of the main forerunners in the development of multifunctional particles for theranostics is magnetic nanoparticles. Following recent advances in nanotechnology, the composition, size, morphology and surface chemistry of particles can all be tailored which, in combination with their magnetic nanoscale phenomena, makes them highly desirable."
Source: Joe Winters
Institute of Physics
The future for mNPs however appears even brighter. With the design of 'theranostic' molecules, mNPs could play a crucial role in developing one-stop tools to simultaneously diagnose, monitor and treat a wide range of common diseases and injuries.
Multifunctional particles, modelled on viral particles such as the flu and HIV, are being researched and developed to carry signal-generating sub-molecules and drugs, able to reach target areas through a safe sprinkling of tiny mNPs and external magnetic forces, creating a medical means to confirm specific ailments and automatically release healing drugs while inside a living system.
A landmark selection of review articles published this week in IOP Publishing's Journal of Physics D: Applied Physics, 'Progress in Applications of Magnetic Nanoparticles in Biomedicine', shows just how far magnetic nanoparticles for application in biomedicine have come and what exciting promise they hold for the future.
The magnetic component of the direction-giving nanoparticles is usually an iron-based compound called ferric oxide which is coated in a biocompatible surface, sometimes using, for example, fatty acids, to provide stability during the particles journey through one's body. For biomedicine, the particles are useful because you can add specific signal triggering molecules to identify certain conditions, or dyes to help in medical imaging, or therapeutic agents to remedy a wide-range of afflictions.
Already well documented, mNPs have sparked interest after being attached to stem cells and used in vivo to remedy heart injury in rats. On humans, in 2007, Berlin's CharitГ© Hospital used a technique which involved mNPs, called hyperthermia, to destroy a particularly severe form of brain cancer in 14 patients. The technique, utilising well-tested knowledge that tumour cells are more sensitive to temperature increases than healthy cells, uses mNPs to direct nano-heaters towards the inoperable tumours and, essentially, cook them to death.
Dr Catherine Berry, one of the review paper's authors from the Centre for Cell Engineering in Glasgow, writes, "One of the main forerunners in the development of multifunctional particles for theranostics is magnetic nanoparticles. Following recent advances in nanotechnology, the composition, size, morphology and surface chemistry of particles can all be tailored which, in combination with their magnetic nanoscale phenomena, makes them highly desirable."
Source: Joe Winters
Institute of Physics
Novel Gateway For The Treatment Of Cancer Opened By Unsuccessful Anxiety Drug
Cancer cells have multiple ways to avoid apoptosis, programmed cell death the means by which organisms deal with defective cells. One defense is to produce quantities of phosphatic acid, a phospholipid constituent of cellular membranes.
Unlike other phospholipids, phosphatidic acid also acts as a signaling molecule for cells promoting cellular growth and preventing apoptosis. Finnish and Danish researchers have now shown that phosphatidic acid may well be a target molecule for novel anti-cancer drugs.
Siramesine is a drug molecule developed and synthesized by Lundbeck A/S for the treatment of anxiety. Its development was discontinued due to unsatisfying efficacy in clinical trials in 2002. Later professor Marja Jäättelä and co-workers at the Danish cancer institute discovered that siramesine effectively inhibits the growth of both cultured cancer cells as well as solid tumors in mice. Siramesine is known to bind sigma-receptors, which physiological role remains unknown, on the cellular surface and this interaction was also believed to underlie its anti-tumor actions.
Researchers at the University of Helsinki, Finland, lead by Professor Paavo Kinnunen, studied the interaction of this drug with different phospholipids using biophysical methods and different model cellular membranes. In addition a computer simulation was performed as collaboration with MEMPHYS, Odense, Denmark, to further their understanding of this interaction.
"The key finding of our study was that siramesine avidly and specifically binds to phosphatidic acid", says MD Mikko Parry from Helsinki Biophysics & Biomembrane group at the Institute of Biomedicine, University of Helsinki.
"Importantly, this is the first time it's shown that a lipid second messenger can act as a drug target: it is a totally new mechanism of action and constitutes a novel paradigm for developing new, more effective anti-cancer drugs."
Source: Professor Paavo Kinnunen
University of Helsinki
Unlike other phospholipids, phosphatidic acid also acts as a signaling molecule for cells promoting cellular growth and preventing apoptosis. Finnish and Danish researchers have now shown that phosphatidic acid may well be a target molecule for novel anti-cancer drugs.
Siramesine is a drug molecule developed and synthesized by Lundbeck A/S for the treatment of anxiety. Its development was discontinued due to unsatisfying efficacy in clinical trials in 2002. Later professor Marja Jäättelä and co-workers at the Danish cancer institute discovered that siramesine effectively inhibits the growth of both cultured cancer cells as well as solid tumors in mice. Siramesine is known to bind sigma-receptors, which physiological role remains unknown, on the cellular surface and this interaction was also believed to underlie its anti-tumor actions.
Researchers at the University of Helsinki, Finland, lead by Professor Paavo Kinnunen, studied the interaction of this drug with different phospholipids using biophysical methods and different model cellular membranes. In addition a computer simulation was performed as collaboration with MEMPHYS, Odense, Denmark, to further their understanding of this interaction.
"The key finding of our study was that siramesine avidly and specifically binds to phosphatidic acid", says MD Mikko Parry from Helsinki Biophysics & Biomembrane group at the Institute of Biomedicine, University of Helsinki.
"Importantly, this is the first time it's shown that a lipid second messenger can act as a drug target: it is a totally new mechanism of action and constitutes a novel paradigm for developing new, more effective anti-cancer drugs."
Source: Professor Paavo Kinnunen
University of Helsinki
Analysis Of Modern-Day Genomes Finds Evidence For Ancient Environmental Change And A Massive Expansion In Genetic Diversity
About 580 million years ago, life on Earth began a rapid period of change called the Cambrian Explosion, a period defined by the birth of new life forms over many millions of years that ultimately helped bring about the modern diversity of animals. Fossils help palaeontologists chronicle the evolution of life since then, but drawing a picture of life during the 3 billion years that preceded the Cambrian Period is challenging, because the soft-bodied Precambrian cells rarely left fossil imprints. However, those early life forms did leave behind one abundant microscopic fossil: DNA.
Because all living organisms inherit their genomes from ancestral genomes, computational biologists at MIT reasoned that they could use modern-day genomes to reconstruct the evolution of ancient microbes. They combined information from the ever-growing genome library with their own mathematical model that takes into account the ways that genes evolve: new gene families can be born and inherited; genes can be swapped or horizontally transferred between organisms; genes can be duplicated in the same genome; and genes can be lost.
The scientists traced thousands of genes from 100 modern genomes back to those genes' first appearance on Earth to create a genomic fossil telling not only when genes came into being but also which ancient microbes possessed those genes. The work suggests that the collective genome of all life underwent an expansion between 3.3 and 2.8 billion years ago, during which time 27 percent of all presently existing gene families came into being.
Eric Alm, a professor in the Department of Civil and Environmental Engineering and the Department of Biological Engineering, and Lawrence David, who recently received his Ph.D. from MIT and is now a Junior Fellow in the Harvard Society of Fellows, have named this period the Archean Expansion.
Because so many of the new genes they identified are related to oxygen, Alm and David first thought that the emergence of oxygen might be responsible for the Archean Expansion. Oxygen did not exist in the Earth's atmosphere until about 2.5 billion years ago when it began to accumulate, likely killing off vast numbers of anerobic life forms in the Great Oxidation Event.
"The Great Oxidation Event was probably the most catastrophic event in the history of cellular life, but we don't have any biological record of it," says Alm.
Closer inspection, however, showed that oxygen-utilizing genes didn't appear until the tail end of the Archean Expansion 2.8 billion years ago, which is more consistent with the date geochemists assign to the Great Oxidation Event.
Instead, Alm and David believe they've detected the birth of modern electron transport, the biochemical process responsible for shuttling electrons within cellular membranes. Electron transport is used to breathe oxygen and by plants and some microbes during photosynthesis when they harvest energy directly from the sun. A form of photosynthesis called oxygenic photosynthesis is believed to be responsible for generating the oxygen associated with the Great Oxidation Event, and is responsible for the oxygen we breathe today.
The evolution of electron transport during the Archean Expansion would have enabled several key stages in the history of life, including photosynthesis and respiration, both of which could lead to much larger amounts of energy being harvested and stored in the biosphere.
"Our results can't say if the development of electron transport directly caused the Archean Expansion," says David. "Nonetheless, we can speculate that having access to a much larger energy budget enabled the biosphere to host larger and more complex microbial ecosystems."
David and Alm also went on to investigate how microbial genomes evolved after the Archean Expansion by looking at the metals and molecules associated with the genes and how those changed in abundance over time. They found an increasing percentage of genes using oxygen, and enzymes associated with copper and molybdenum, which is consistent with the geological record of evolution.
"What is really remarkable about these findings is that they prove that the histories of very ancient events are recorded in the shared DNA of living organisms," says Alm. "And now that we are beginning to understand how to decode that history, I have hope that we can reconstruct some of the earliest events in the evolution of life in great detail."
Source:
Denise Brehm
Massachusetts Institute of Technology, Department of Civil and Environmental Engineering
Because all living organisms inherit their genomes from ancestral genomes, computational biologists at MIT reasoned that they could use modern-day genomes to reconstruct the evolution of ancient microbes. They combined information from the ever-growing genome library with their own mathematical model that takes into account the ways that genes evolve: new gene families can be born and inherited; genes can be swapped or horizontally transferred between organisms; genes can be duplicated in the same genome; and genes can be lost.
The scientists traced thousands of genes from 100 modern genomes back to those genes' first appearance on Earth to create a genomic fossil telling not only when genes came into being but also which ancient microbes possessed those genes. The work suggests that the collective genome of all life underwent an expansion between 3.3 and 2.8 billion years ago, during which time 27 percent of all presently existing gene families came into being.
Eric Alm, a professor in the Department of Civil and Environmental Engineering and the Department of Biological Engineering, and Lawrence David, who recently received his Ph.D. from MIT and is now a Junior Fellow in the Harvard Society of Fellows, have named this period the Archean Expansion.
Because so many of the new genes they identified are related to oxygen, Alm and David first thought that the emergence of oxygen might be responsible for the Archean Expansion. Oxygen did not exist in the Earth's atmosphere until about 2.5 billion years ago when it began to accumulate, likely killing off vast numbers of anerobic life forms in the Great Oxidation Event.
"The Great Oxidation Event was probably the most catastrophic event in the history of cellular life, but we don't have any biological record of it," says Alm.
Closer inspection, however, showed that oxygen-utilizing genes didn't appear until the tail end of the Archean Expansion 2.8 billion years ago, which is more consistent with the date geochemists assign to the Great Oxidation Event.
Instead, Alm and David believe they've detected the birth of modern electron transport, the biochemical process responsible for shuttling electrons within cellular membranes. Electron transport is used to breathe oxygen and by plants and some microbes during photosynthesis when they harvest energy directly from the sun. A form of photosynthesis called oxygenic photosynthesis is believed to be responsible for generating the oxygen associated with the Great Oxidation Event, and is responsible for the oxygen we breathe today.
The evolution of electron transport during the Archean Expansion would have enabled several key stages in the history of life, including photosynthesis and respiration, both of which could lead to much larger amounts of energy being harvested and stored in the biosphere.
"Our results can't say if the development of electron transport directly caused the Archean Expansion," says David. "Nonetheless, we can speculate that having access to a much larger energy budget enabled the biosphere to host larger and more complex microbial ecosystems."
David and Alm also went on to investigate how microbial genomes evolved after the Archean Expansion by looking at the metals and molecules associated with the genes and how those changed in abundance over time. They found an increasing percentage of genes using oxygen, and enzymes associated with copper and molybdenum, which is consistent with the geological record of evolution.
"What is really remarkable about these findings is that they prove that the histories of very ancient events are recorded in the shared DNA of living organisms," says Alm. "And now that we are beginning to understand how to decode that history, I have hope that we can reconstruct some of the earliest events in the evolution of life in great detail."
Source:
Denise Brehm
Massachusetts Institute of Technology, Department of Civil and Environmental Engineering
Nanoscience: Weak Force. Strong Effect
The van der Waals force, a weak attractive force, is solely responsible
for
binding certain organic molecules to metallic surfaces. In a model for
organic devices, it is this force alone that binds an organic film to a
metallic substrate. This data, recently published in Physical Review
Letters, represents the latest findings from a National Research Network
(NRN) supported by the Austrian Science Fund FWF. These findings mean that
numerous calculation models for the physical interactions between thin
films
and their carrier materials will need to be revised.
Although they fulfil complex functions when used, for example, as computer
chips, inorganic semiconductors have a simple construction that greatly
limits their application. The same does not apply to semiconductors made
of
organic materials. Because organic molecules are extremely flexible, they
can be used in a whole new range of applications. However, before this
advantage can be exploited to the full, scientists need to have a better
understanding of the far greater complexity of these materials over their
inorganic counterparts.
Up & Down
Organic semiconductors are manufactured by applying thin films of an
electrically conductive organic material to a carrier surface. When
carrying
out this process, it is important to understand the interactions that
occur
at the interfaces between the carrier material and the organic material. A
team from the "Interface controlled and functionalised organic thin films"
National Research Network (NRN) at the University of Leoben has made an
important contribution to scientific understanding in precisely this
field.
Using complex calculations, the team has been able to show that a thin
film
of organic thiophene is held on to a copper surface solely by the van der
Waals force. The team calculated that the adsorption energy involved is
-0.50 eV.
The spokesperson for the NRN, Prof. Helmut Sitter from the Institute of
Semiconductor and Solid State Physics at Johannes Kepler University (JKU)
in
Linz, explains: "The van der Waals force is a weakly interacting force
between atoms that occurs as a result of asymmetric charge distribution in
atoms. We now know that this exerts a highly significant influence on the
kinds of extremely thin material films used to manufacture organic
semiconductors. Indeed, this force can successfully bind the materials
entirely on its own. However, due to its weakness, several previous
methods
used to calculate the interactions between different materials have
attached
only minor importance to this force, or have ignored it altogether." This
would also seem to provide some explanation for why the generalized
gradient
approximation (GGA) often used in such instances has been unable to
satisfactorily explain the bonding behaviour in thin layers. In fact,
these
newly published results could explain the discrepancies that have long
been
found between various experimental data and models for calculating the
interaction between thin layers.
Publications, Prizes, Products
The new data adds to our fundamental understanding of the interactions
that
take place at interfaces. The influence of the van der Waals force also
indicates that no charge is transferred between the atoms of the organic
materials and their substrates in the calculated system. This finding is
of
key significance to the production and functionality of organic
semiconductors.
Several articles in the Advanced Materials journal this year demonstrate
how
research carried out by members of the NRN maintains a steady focus on
practical applications. As a result of one such article, the Institute of
Experimental Physics at JKU won the official Innovation Prize of the
Province of Upper Austria. It is no surprise that three spin-off
companies В¬
run almost exclusively by graduates from the Institutes involved in the
NRN
В¬ have already been established as a direct result of the findings. One of
these companies, Nanoident, was declared "Entrepreneur of the Year 2007"
by
Ernst & Young Austria.
Prof. Sitter believes that all of these achievements, together with an
article by the NRN published in SCIENCE in the summer of this year, prove
how this National Research Network has successfully combined fundamental
research, applied research and technology transfer - with the support of
the
FWF.
Due to a server upgrade image and text will not be available online until
Tuesday, 20th November 2007, 09.00 a.m. CET onwards:
see here.
Original publication: Importance of Van Der Waals Interaction for Organic
Molecule-Metal Junctions: Adsorption of Thiophene on Cu(110) as a
Prototype,
P. Sony, P. Puschnig, D. Nabok & C. Ambrosch-Draxl. Phys. Rev. Lett. 99,
176401 (2007).
fwf.ac.at
for
binding certain organic molecules to metallic surfaces. In a model for
organic devices, it is this force alone that binds an organic film to a
metallic substrate. This data, recently published in Physical Review
Letters, represents the latest findings from a National Research Network
(NRN) supported by the Austrian Science Fund FWF. These findings mean that
numerous calculation models for the physical interactions between thin
films
and their carrier materials will need to be revised.
Although they fulfil complex functions when used, for example, as computer
chips, inorganic semiconductors have a simple construction that greatly
limits their application. The same does not apply to semiconductors made
of
organic materials. Because organic molecules are extremely flexible, they
can be used in a whole new range of applications. However, before this
advantage can be exploited to the full, scientists need to have a better
understanding of the far greater complexity of these materials over their
inorganic counterparts.
Up & Down
Organic semiconductors are manufactured by applying thin films of an
electrically conductive organic material to a carrier surface. When
carrying
out this process, it is important to understand the interactions that
occur
at the interfaces between the carrier material and the organic material. A
team from the "Interface controlled and functionalised organic thin films"
National Research Network (NRN) at the University of Leoben has made an
important contribution to scientific understanding in precisely this
field.
Using complex calculations, the team has been able to show that a thin
film
of organic thiophene is held on to a copper surface solely by the van der
Waals force. The team calculated that the adsorption energy involved is
-0.50 eV.
The spokesperson for the NRN, Prof. Helmut Sitter from the Institute of
Semiconductor and Solid State Physics at Johannes Kepler University (JKU)
in
Linz, explains: "The van der Waals force is a weakly interacting force
between atoms that occurs as a result of asymmetric charge distribution in
atoms. We now know that this exerts a highly significant influence on the
kinds of extremely thin material films used to manufacture organic
semiconductors. Indeed, this force can successfully bind the materials
entirely on its own. However, due to its weakness, several previous
methods
used to calculate the interactions between different materials have
attached
only minor importance to this force, or have ignored it altogether." This
would also seem to provide some explanation for why the generalized
gradient
approximation (GGA) often used in such instances has been unable to
satisfactorily explain the bonding behaviour in thin layers. In fact,
these
newly published results could explain the discrepancies that have long
been
found between various experimental data and models for calculating the
interaction between thin layers.
Publications, Prizes, Products
The new data adds to our fundamental understanding of the interactions
that
take place at interfaces. The influence of the van der Waals force also
indicates that no charge is transferred between the atoms of the organic
materials and their substrates in the calculated system. This finding is
of
key significance to the production and functionality of organic
semiconductors.
Several articles in the Advanced Materials journal this year demonstrate
how
research carried out by members of the NRN maintains a steady focus on
practical applications. As a result of one such article, the Institute of
Experimental Physics at JKU won the official Innovation Prize of the
Province of Upper Austria. It is no surprise that three spin-off
companies В¬
run almost exclusively by graduates from the Institutes involved in the
NRN
В¬ have already been established as a direct result of the findings. One of
these companies, Nanoident, was declared "Entrepreneur of the Year 2007"
by
Ernst & Young Austria.
Prof. Sitter believes that all of these achievements, together with an
article by the NRN published in SCIENCE in the summer of this year, prove
how this National Research Network has successfully combined fundamental
research, applied research and technology transfer - with the support of
the
FWF.
Due to a server upgrade image and text will not be available online until
Tuesday, 20th November 2007, 09.00 a.m. CET onwards:
see here.
Original publication: Importance of Van Der Waals Interaction for Organic
Molecule-Metal Junctions: Adsorption of Thiophene on Cu(110) as a
Prototype,
P. Sony, P. Puschnig, D. Nabok & C. Ambrosch-Draxl. Phys. Rev. Lett. 99,
176401 (2007).
fwf.ac.at
Commercialization Of Novel UD Gene-Repair Technology
OrphageniX Inc., a new biotechnology company founded by University of Delaware researchers, has been established in Wilmington to develop and commercialize UD-patented technologies for repairing genes that cause rare, hereditary diseases such as sickle cell anemia and spinal muscular atrophy.
Eric Kmiec, professor of biological sciences, and Hetal Parekh-Olmedo, senior research associate, both in the UD College of Arts and Sciences, co-founded and incubated OrphageniX at UD's Delaware Biotechnology Institute in the Delaware Technology Park in 2005.
Kmiec holds 14 UD patents for gene-editing technologies and is widely regarded as a pioneer in the field.
There are more than 5,000 rare or "orphan" diseases, so named because each affects fewer than 200,000 people nationwide. A number of these diseases are caused by a single-point mutation in a gene--which is like a spelling error, a single "letter" out of place, in its DNA code. The DNA nucleotide adenine (A), for example, might be replaced by guanine (G), cytosine (C) or thymidine (T).
Kmiec and Parekh-Olmedo discovered a way to introduce a tiny fragment of DNA into a diseased cell to replace the defective portion, triggering the cell to heal itself.
This method, which focuses on correcting a patient's genes to make their own proteins, offers a safer approach than treating a patient's genes with foreign genes or protein replacements, and eventually may lead to cures for rare diseases, according to Michael Herr, president and chief executive officer of OrphageniX.
Herr previously was the director of science and technology at the University City Science Center of Philadelphia.
Sickle cell anemia and spinal muscular atrophy are among the diseases that OrphageniX is targeting, according to Herr.
Sickle cell anemia affects an estimated 72,000 Americans, mostly African Americans. Those afflicted with the disease produce sickle- or crescent-shaped blood cells instead of smooth, round blood cells. These "sickle cells" tend to get stuck in the blood vessels, blocking the flow of blood to the limbs and organs, often causing pain, organ damage and anemia in the process.
Spinal muscular atrophy is a genetic disease caused by the progressive degeneration of motor neurons in the spinal cord, resulting in weakness and wasting of the voluntary muscles. Weakness is often more severe in the legs than in the arms. The disease affects approximately one in 6,000 babies, and about one in 40 people are genetic carriers, according to Families of Spinal Muscular Atrophy.
Herr said the company's immediate strategy is to advance the new technologies to clinical trials, assemble a leadership team around its UD founders, and identify strategic partners.
OrphageniX is located at 300 Water Street in Wilmington. The company's web site is orphagenix/.
Contact: Tracey Bryant
University of Delaware
Eric Kmiec, professor of biological sciences, and Hetal Parekh-Olmedo, senior research associate, both in the UD College of Arts and Sciences, co-founded and incubated OrphageniX at UD's Delaware Biotechnology Institute in the Delaware Technology Park in 2005.
Kmiec holds 14 UD patents for gene-editing technologies and is widely regarded as a pioneer in the field.
There are more than 5,000 rare or "orphan" diseases, so named because each affects fewer than 200,000 people nationwide. A number of these diseases are caused by a single-point mutation in a gene--which is like a spelling error, a single "letter" out of place, in its DNA code. The DNA nucleotide adenine (A), for example, might be replaced by guanine (G), cytosine (C) or thymidine (T).
Kmiec and Parekh-Olmedo discovered a way to introduce a tiny fragment of DNA into a diseased cell to replace the defective portion, triggering the cell to heal itself.
This method, which focuses on correcting a patient's genes to make their own proteins, offers a safer approach than treating a patient's genes with foreign genes or protein replacements, and eventually may lead to cures for rare diseases, according to Michael Herr, president and chief executive officer of OrphageniX.
Herr previously was the director of science and technology at the University City Science Center of Philadelphia.
Sickle cell anemia and spinal muscular atrophy are among the diseases that OrphageniX is targeting, according to Herr.
Sickle cell anemia affects an estimated 72,000 Americans, mostly African Americans. Those afflicted with the disease produce sickle- or crescent-shaped blood cells instead of smooth, round blood cells. These "sickle cells" tend to get stuck in the blood vessels, blocking the flow of blood to the limbs and organs, often causing pain, organ damage and anemia in the process.
Spinal muscular atrophy is a genetic disease caused by the progressive degeneration of motor neurons in the spinal cord, resulting in weakness and wasting of the voluntary muscles. Weakness is often more severe in the legs than in the arms. The disease affects approximately one in 6,000 babies, and about one in 40 people are genetic carriers, according to Families of Spinal Muscular Atrophy.
Herr said the company's immediate strategy is to advance the new technologies to clinical trials, assemble a leadership team around its UD founders, and identify strategic partners.
OrphageniX is located at 300 Water Street in Wilmington. The company's web site is orphagenix/.
Contact: Tracey Bryant
University of Delaware
Molecular Pathway May Predict Chemotherapy Effectiveness
A common molecular pathway could help physicians predict which lung cancer patients will benefit from chemotherapy drugs, according to new research from a multidisciplinary team at the University of Cincinnati (UC).
Known as the retinoblastoma (RB) tumor suppressor, this fundamental molecule regulates cell proliferation in the body. Research has shown that the RB pathway is either entirely inactive or altered in most human cancers. Scientists are beginning to use its actions as a "biomarker" for how tumors will respond to different therapies.
Michael Reed, MD, and his UC colleagues found that "turning off" the RB pathway in lung cancer cells resulted in an altered response to chemotherapy agents and more cancer cell death. They report their findings in the September 2007 issue of the journal Cancer Research.
"Dissecting the RB pathway will help us better understand how chemotherapy works and predict which patients might benefit from therapy and which ones won't," explains Reed, assistant professor of surgery at UC and a thoracic surgeon at University Hospital.
"As pathways are further defined, we could choose agents that are targeted to an individual tumor's molecular characteristics," he adds.
A previous UC study, published in the January 2007 issue of the Journal of Clinical Investigation, showed that when this pathway is disrupted or shut off in breast cancer, the tumor resists anti-estrogen drugs and the cancer continues to grow in spite of the therapy.
For this laboratory study, Reed's team shut off the RB pathway in human non-small cell lung cancer cells and exposed them to chemotherapy agents representative of those currently used to treat lung cancer patients.
Their results showed that when RB was turned off, the cancer cells continued to divide, but became more susceptible to the drugs, so the tumors stopped growing.
"But the minute you take away the chemotherapy, the cells take off again," says Reed. "This suggests that it's not just loss of RB that affects therapy response -- it could be changes at various steps in cellular signaling that result in different outcomes."
"The traditional way of thinking of cancer -- one cancer gene to treat and you're done -- is obviously not the best approach to treating this disease," he adds. "These are complex, overlapping molecular pathways. Dissecting them and determining how to use that information to apply combinations of chemotherapeutic agents will allow for individualization of therapy."
Next year, Reed and his colleagues expect to begin testing the RB tumor suppressor in human tumor tissue samples from the UC Thoracic Tumor Registry and compare them to patients with known outcomes.
According to the American Cancer Society, more than 213,000 Americans will be diagnosed with lung cancer in 2007. Because most people are diagnosed late, the five-year survival rate is only 14 percent -- compared with 86 percent for breast cancer, 61 percent for colon cancer and 96 percent for prostate cancer.
This study was funded by a grant from the National Institutes of Health and UC College of Medicine Dean's Discovery Fund and the UC cancer research program. UC study collaborators include Erik Knudsen, PhD, and William Zagorski.
Source: Amanda Harper
University of Cincinnati
Known as the retinoblastoma (RB) tumor suppressor, this fundamental molecule regulates cell proliferation in the body. Research has shown that the RB pathway is either entirely inactive or altered in most human cancers. Scientists are beginning to use its actions as a "biomarker" for how tumors will respond to different therapies.
Michael Reed, MD, and his UC colleagues found that "turning off" the RB pathway in lung cancer cells resulted in an altered response to chemotherapy agents and more cancer cell death. They report their findings in the September 2007 issue of the journal Cancer Research.
"Dissecting the RB pathway will help us better understand how chemotherapy works and predict which patients might benefit from therapy and which ones won't," explains Reed, assistant professor of surgery at UC and a thoracic surgeon at University Hospital.
"As pathways are further defined, we could choose agents that are targeted to an individual tumor's molecular characteristics," he adds.
A previous UC study, published in the January 2007 issue of the Journal of Clinical Investigation, showed that when this pathway is disrupted or shut off in breast cancer, the tumor resists anti-estrogen drugs and the cancer continues to grow in spite of the therapy.
For this laboratory study, Reed's team shut off the RB pathway in human non-small cell lung cancer cells and exposed them to chemotherapy agents representative of those currently used to treat lung cancer patients.
Their results showed that when RB was turned off, the cancer cells continued to divide, but became more susceptible to the drugs, so the tumors stopped growing.
"But the minute you take away the chemotherapy, the cells take off again," says Reed. "This suggests that it's not just loss of RB that affects therapy response -- it could be changes at various steps in cellular signaling that result in different outcomes."
"The traditional way of thinking of cancer -- one cancer gene to treat and you're done -- is obviously not the best approach to treating this disease," he adds. "These are complex, overlapping molecular pathways. Dissecting them and determining how to use that information to apply combinations of chemotherapeutic agents will allow for individualization of therapy."
Next year, Reed and his colleagues expect to begin testing the RB tumor suppressor in human tumor tissue samples from the UC Thoracic Tumor Registry and compare them to patients with known outcomes.
According to the American Cancer Society, more than 213,000 Americans will be diagnosed with lung cancer in 2007. Because most people are diagnosed late, the five-year survival rate is only 14 percent -- compared with 86 percent for breast cancer, 61 percent for colon cancer and 96 percent for prostate cancer.
This study was funded by a grant from the National Institutes of Health and UC College of Medicine Dean's Discovery Fund and the UC cancer research program. UC study collaborators include Erik Knudsen, PhD, and William Zagorski.
Source: Amanda Harper
University of Cincinnati
Minocycline, Microglia, And Amyloidosis
Rong Fan, Feng Xu, Mary Lou Previti, Judianne Davis, Alicia M. Grande, John K. Robinson, and William E. Van Nostrand
Amyloid- (A') can accumulate not only as parenchymal plaques in brain, but also the fibrillary deposits in cerebral vasculature. Early and severe vascular deposits in cerebral amyloid angiopathy (CAA) result from inherited A' mutations and are associated with a strong local neuroinflammatory reaction. The latter seems to correlate with amyloid extending from vessels into brain parenchyma. This week, Fan et al. measured the effects of a neural anti-inflammatory drug in Tg-SwDI mice. Decoding the name, the mouse is a transgenic strain that expresses human amyloid precursor protein carrying the Dutch- and Iowa-type familial CAA mutations. The anti-inflammatory drug minocycline did not affect fibrillar amyloid deposits in the microvasculature of Tg-SwDI mice, nor was total soluble or insoluble A' reduced. Minocycline also did not alter the number of reactive astrocytes. However, minocycline did reduce the number and activation state of microglia. After 4 weeks of treatment, 1-year-old mice displayed improved learning memory performance in a maze task.
News tips from the Journal of Neuroscience
Contact: Sara Harris
Society for Neuroscience
Amyloid- (A') can accumulate not only as parenchymal plaques in brain, but also the fibrillary deposits in cerebral vasculature. Early and severe vascular deposits in cerebral amyloid angiopathy (CAA) result from inherited A' mutations and are associated with a strong local neuroinflammatory reaction. The latter seems to correlate with amyloid extending from vessels into brain parenchyma. This week, Fan et al. measured the effects of a neural anti-inflammatory drug in Tg-SwDI mice. Decoding the name, the mouse is a transgenic strain that expresses human amyloid precursor protein carrying the Dutch- and Iowa-type familial CAA mutations. The anti-inflammatory drug minocycline did not affect fibrillar amyloid deposits in the microvasculature of Tg-SwDI mice, nor was total soluble or insoluble A' reduced. Minocycline also did not alter the number of reactive astrocytes. However, minocycline did reduce the number and activation state of microglia. After 4 weeks of treatment, 1-year-old mice displayed improved learning memory performance in a maze task.
News tips from the Journal of Neuroscience
Contact: Sara Harris
Society for Neuroscience
Stefanie Dimmeler cleared of scientific misconduct
At its meeting on 5 July 2005, the Joint Committee of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) noted the fact that the case against Professor Stefanie Dimmeler, a cardiologist at the University of Frankfurt accused of scientific misconduct, has been closed. Following its investigations and after hearing Professor Dimmeler, the Committee of Inquiry on Allegations of Scientific Misconduct exonerated her from all allegations of scientific misconduct. This decision clears the way for her to be awarded the 2005 Leibniz Prize, which had so far been withheld due to questions concerning a number of publications from her institute.
In Professor Dimmeler's case a formal investigation was launched after the DFG received indications of irregularities and mistakes in three publications from her institute. The mistakes, which were admitted and subsequently corrected by publication of an erratum, only concern the figures used as representative examples in these publications. The findings published in the papers had all proven to be sound and reproducible. The false images had been prepared and selected for the publication by an experienced postdoc in Professor Dimmeler's research group.
As a result of this experience, Professor Dimmeler has now taken steps to ensure higher quality control by personally inspecting the primary data accompanying each figure. The Leibniz Prize certificate and the accompanying award letter will now be sent to Professor Dimmeler.
Deutsche Forschungsgemeinschaft
dfg
In Professor Dimmeler's case a formal investigation was launched after the DFG received indications of irregularities and mistakes in three publications from her institute. The mistakes, which were admitted and subsequently corrected by publication of an erratum, only concern the figures used as representative examples in these publications. The findings published in the papers had all proven to be sound and reproducible. The false images had been prepared and selected for the publication by an experienced postdoc in Professor Dimmeler's research group.
As a result of this experience, Professor Dimmeler has now taken steps to ensure higher quality control by personally inspecting the primary data accompanying each figure. The Leibniz Prize certificate and the accompanying award letter will now be sent to Professor Dimmeler.
Deutsche Forschungsgemeinschaft
dfg
Researchers Describe How Cells Take Out The Trash To Prevent Disease
Garbage collectors are important for removing trash; without them waste accumulates and can quickly become a health hazard. Similarly, individual cells that make up such biological organisms as humans also have sophisticated methods for managing waste.
For example, cells have developed complex systems for recycling, reusing and disposing of damaged, nonfunctional waste proteins. When such systems malfunction and these proteins accumulate, they can become toxic, resulting in many diseases, including Alzheimer's, cystic fibrosis and developmental disorders.
Scott Emr, director of the Weill Institute for Cell and Molecular Biology at Cornell, and colleagues, describe in detail how cells recycle protein waste in two recent papers appearing in the journals Cell and Developmental Cell.
"We are interested in understanding how cells deal with garbage," said Emr. "It's really a very sophisticated recycling system."
Cells use enzymes known as proteases to break down proteins into their component amino acids in the cytoplasm -- the fluid inside the cell's surface membrane. Those amino acids are then reused to make new proteins. But water-insoluble proteins embedded in the cell's membrane require a much more complicated recycling process.
Emr's paper in Cell identifies a family of proteins that controls the removal of unwanted water-insoluble proteins from the membrane. The research advances understanding of how cells recognize which proteins out of hundreds on a cell's surface should be removed. For example, hormone receptors at a cell's surface signal such processes within the cell as growth and proliferation. To inactivate these receptors and terminate the growth signal, receptors are tagged for removal. Failure to inactivate can lead to developmental diseases and cancer.
The researchers, including postdoctoral fellows Jason MacGurn and Chris Stefan, identified nine related proteins in yeast, which they named the "arrestin-related trafficking" adaptors or ARTs. Each of these proteins identifies and binds to a different set of membrane proteins. Once bound, the ART protein links to an enzyme that attaches a chemical tag for that protein's removal. The ARTs are found in both yeast and humans, suggesting the fundamental nature of their function.
Once the protein is tagged, the piece of membrane with the targeted protein forms a packet, called a vesicle, that enters the cell's cytoplasm. There, the vesicle enters a larger membrane body called an endosome, which in turn dumps it into another compartment called the lysosome, where special enzymes break apart big molecules to their core units: proteins to amino acids, membranes to fatty acids, carbohydrates to sugars and nucleic acids to nucleotides, and those basic materials are then reused.
The paper in Developmental Cell, co-authored by Emr with postdoctoral fellows David Teis and Suraj Saksena, describes for the first time how a set of four proteins assemble into a highly ordered complex. This complex encircles membrane proteins that must be disposed of in the lysosome. Emr's lab was the first to identify and characterize these protein complexes (known as ESCRTs). The Developmental Cell paper describes the order of events in which the ESCRT complexes encircle and deliver "waste" proteins into vesicles destined for recycling in the lysosome.
Emr's ESCRT discovery has allowed researchers to better understand how the AIDS virus is released from its host cell. HIV hijacks the cell's ESCRT machinery during virus budding. "So, if you block the function of ESCRTs, you could block HIV release," said Emr.
Blaine Friedlander
Cornell University Communications
For example, cells have developed complex systems for recycling, reusing and disposing of damaged, nonfunctional waste proteins. When such systems malfunction and these proteins accumulate, they can become toxic, resulting in many diseases, including Alzheimer's, cystic fibrosis and developmental disorders.
Scott Emr, director of the Weill Institute for Cell and Molecular Biology at Cornell, and colleagues, describe in detail how cells recycle protein waste in two recent papers appearing in the journals Cell and Developmental Cell.
"We are interested in understanding how cells deal with garbage," said Emr. "It's really a very sophisticated recycling system."
Cells use enzymes known as proteases to break down proteins into their component amino acids in the cytoplasm -- the fluid inside the cell's surface membrane. Those amino acids are then reused to make new proteins. But water-insoluble proteins embedded in the cell's membrane require a much more complicated recycling process.
Emr's paper in Cell identifies a family of proteins that controls the removal of unwanted water-insoluble proteins from the membrane. The research advances understanding of how cells recognize which proteins out of hundreds on a cell's surface should be removed. For example, hormone receptors at a cell's surface signal such processes within the cell as growth and proliferation. To inactivate these receptors and terminate the growth signal, receptors are tagged for removal. Failure to inactivate can lead to developmental diseases and cancer.
The researchers, including postdoctoral fellows Jason MacGurn and Chris Stefan, identified nine related proteins in yeast, which they named the "arrestin-related trafficking" adaptors or ARTs. Each of these proteins identifies and binds to a different set of membrane proteins. Once bound, the ART protein links to an enzyme that attaches a chemical tag for that protein's removal. The ARTs are found in both yeast and humans, suggesting the fundamental nature of their function.
Once the protein is tagged, the piece of membrane with the targeted protein forms a packet, called a vesicle, that enters the cell's cytoplasm. There, the vesicle enters a larger membrane body called an endosome, which in turn dumps it into another compartment called the lysosome, where special enzymes break apart big molecules to their core units: proteins to amino acids, membranes to fatty acids, carbohydrates to sugars and nucleic acids to nucleotides, and those basic materials are then reused.
The paper in Developmental Cell, co-authored by Emr with postdoctoral fellows David Teis and Suraj Saksena, describes for the first time how a set of four proteins assemble into a highly ordered complex. This complex encircles membrane proteins that must be disposed of in the lysosome. Emr's lab was the first to identify and characterize these protein complexes (known as ESCRTs). The Developmental Cell paper describes the order of events in which the ESCRT complexes encircle and deliver "waste" proteins into vesicles destined for recycling in the lysosome.
Emr's ESCRT discovery has allowed researchers to better understand how the AIDS virus is released from its host cell. HIV hijacks the cell's ESCRT machinery during virus budding. "So, if you block the function of ESCRTs, you could block HIV release," said Emr.
Blaine Friedlander
Cornell University Communications
Alzheimer's, Parkinson's, Type 2 Diabetes Similar At Molecular Level
Alzheimer's disease, Parkinson's disease, type 2 diabetes, the human version of mad cow disease, and other degenerative diseases are more closely related at the molecular level than scientists realized, a team reports this week in an advanced online publication of the journal Nature.
While still preliminary, the research, could help scientists develop tools for diagnosing such diseases, and potentially for treating them through "structure-based drug design," said David Eisenberg, a UCLA chemist and molecular biologist who is part of the research team.
The researchers studied the harmful rope-like structures known as amyloid fibrils--linked protein molecules that form in the brain. The fibrils contain a stack of water-tight "molecular zippers."
"With each disease, a different protein transforms into amyloid fibrils, but all of these diseases are similar at the molecular level," Eisenberg said.
If the molecular zipper is universal in amyloid fibrils, as Eisenberg believes, is it possible to pry open the zipper or prevent its formation?
Eisenberg's research team used X-ray analysis and a sophisticated computer algorithm to study proteins known to be associated with human diseases. When the computer said a protein will form an amyloid fibril, it almost always did. And one team member is experimenting with various compounds to break up the fibrils.
"Structural analysis of micro-crystals of proteins is an example of how basic research can have a profound impact on our understanding of health, biotechnology and other practical issues," said Parag Chitnis, program director in National Science Foundation's (NSF) Division of Molecular and Cellular Biosciences.
NSF, the Howard Hughes Medical Institute and the National Institutes of Health supported the research.
The National Science Foundation (NSF) is an independent federal agency that supports fundamental research and education across all fields of science and engineering, with an annual budget of $5.58 billion. NSF funds reach all 50 states through grants to nearly 1,700 universities and institutions. Each year, NSF receives about 40,000 competitive requests for funding, and makes nearly 10,000 new funding awards. The NSF also awards over $400 million in professional and service contracts yearly.
Useful NSF Web Sites:
NSF Home Page: nsf/
NSF News: nsf/news/
Science and Engineering Statistics: nsf/statistics/
Awards Searches: nsf/awardsearch/
Contact: Cheryl Dybas
National Science Foundation
While still preliminary, the research, could help scientists develop tools for diagnosing such diseases, and potentially for treating them through "structure-based drug design," said David Eisenberg, a UCLA chemist and molecular biologist who is part of the research team.
The researchers studied the harmful rope-like structures known as amyloid fibrils--linked protein molecules that form in the brain. The fibrils contain a stack of water-tight "molecular zippers."
"With each disease, a different protein transforms into amyloid fibrils, but all of these diseases are similar at the molecular level," Eisenberg said.
If the molecular zipper is universal in amyloid fibrils, as Eisenberg believes, is it possible to pry open the zipper or prevent its formation?
Eisenberg's research team used X-ray analysis and a sophisticated computer algorithm to study proteins known to be associated with human diseases. When the computer said a protein will form an amyloid fibril, it almost always did. And one team member is experimenting with various compounds to break up the fibrils.
"Structural analysis of micro-crystals of proteins is an example of how basic research can have a profound impact on our understanding of health, biotechnology and other practical issues," said Parag Chitnis, program director in National Science Foundation's (NSF) Division of Molecular and Cellular Biosciences.
NSF, the Howard Hughes Medical Institute and the National Institutes of Health supported the research.
The National Science Foundation (NSF) is an independent federal agency that supports fundamental research and education across all fields of science and engineering, with an annual budget of $5.58 billion. NSF funds reach all 50 states through grants to nearly 1,700 universities and institutions. Each year, NSF receives about 40,000 competitive requests for funding, and makes nearly 10,000 new funding awards. The NSF also awards over $400 million in professional and service contracts yearly.
Useful NSF Web Sites:
NSF Home Page: nsf/
NSF News: nsf/news/
Science and Engineering Statistics: nsf/statistics/
Awards Searches: nsf/awardsearch/
Contact: Cheryl Dybas
National Science Foundation
Inflammatory Response To Dying Cells' Distress Calls May Be Helpful Or Harmful
Cells are coded with several programs for self-destruction. Many cells die peacefully. Others cause a ruckus on their way out.
Some programmed cell death pathways simply and quietly remove unwanted cells, noted a team of University of Washington (UW) researchers who study the mechanisms of cell destruction.
Then there is the alarm-ringing death of a potentially dangerous cell, such as a cell infected with Salmonella, they added. These dying cells spill chemical signals and get a protective response. The resulting inflammation, which the body launches in self-defense, can at times backfire and damage vital tissues.
A research team lead by Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine, named this type of cell death "pyroptosis," Greek for going down in flames. Cell death that doesn't cause inflammation is called "apoptosis": to drop gently like leaves from a tree.
An enzyme inside cells, called caspase-1, plays a critical role in both harmful inflammation and in resistance to infection, Cookson and his colleagues noted. It's not just responsible for cell death, but also for the production of inflammatory proteins that are released from the dying cell. Mice deficient in caspase-1 are susceptible to infection, yet resistant to toxic shock, tissue injury from lack of oxygen, and inflammatory bowel disease.
The Cookson lab has done many studies of caspase-1 and how it mediates the pathway of pro-inflammatory programmed cell death. The lab's most recent study will be published the week of March 10 to March 14 in the online Early Edition of the Proceedings of the National Academy of Sciences. The study looked at how two different noxious stimuli, anthrax toxin and Salmonella infection, trigger the caspase-1-mediated cell death pathway. UW graduate students Susan Fink and Tessa Bergsbaken conducted this study.
The researchers found that each of these stimuli took an independent route to activate caspase-1; however, these two distinct mechanisms of activation eventually converged on a common pathway of cell death. This common pathway featured cleavage of the cell's DNA, activation of inflammatory chemical messengers, and the final jettison of the cells contents. The spillage occurs after nano-scale pores form in the cell membrane, much like punctures in a water balloon.
According to Cookson, these findings are helping to create research models for studying a broadly important pathway of pro-inflammatory programmed cell death. The findings also support the notion that diverse disease agents can use different mechanisms to elicit this pathway.
"Examining this system provides insight into mechanisms of both beneficial and pathological cell death, and the strategies that infectious disease agents employ to manipulate the body's responses," Cookson said. His group's previous studies of Yersinia, the plague pathogen, revealed that cell death mechanisms can be re-directed from a passive, non-inflammatory pathway, to a more beneficial inflammatory pathway. This finding suggests the possibility of treating diseases by modulating cell death pathways.
"In addition to its protective role in fighting infection," Cookson added, "caspase-1 also plays a role in many medical conditions characterized by cell death and inflammation." These conditions include organ damage in the heart, brain, lungs, nerves, and kidneys. Understanding pro-inflammatory cell death pathways may lead to new therapies against fatal or disabling diseases, such as serious infections, heart attack, cancer and stroke.
Cookson is part of the National Institutes of Health-funded Microscale Life Sciences Center, a collaboration among scientists and engineers from the UW, the University of Arizona, the Fred Hutchinson Cancer Research Center, and Brandeis University. The scientists work to discover basic mechanisms in the formation, growth, and decline of human cells. Their aim is to develop biotechnology to combat widespread diseases and environmental threats to human health.
Source: Leila Gray
University of Washington
Some programmed cell death pathways simply and quietly remove unwanted cells, noted a team of University of Washington (UW) researchers who study the mechanisms of cell destruction.
Then there is the alarm-ringing death of a potentially dangerous cell, such as a cell infected with Salmonella, they added. These dying cells spill chemical signals and get a protective response. The resulting inflammation, which the body launches in self-defense, can at times backfire and damage vital tissues.
A research team lead by Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine, named this type of cell death "pyroptosis," Greek for going down in flames. Cell death that doesn't cause inflammation is called "apoptosis": to drop gently like leaves from a tree.
An enzyme inside cells, called caspase-1, plays a critical role in both harmful inflammation and in resistance to infection, Cookson and his colleagues noted. It's not just responsible for cell death, but also for the production of inflammatory proteins that are released from the dying cell. Mice deficient in caspase-1 are susceptible to infection, yet resistant to toxic shock, tissue injury from lack of oxygen, and inflammatory bowel disease.
The Cookson lab has done many studies of caspase-1 and how it mediates the pathway of pro-inflammatory programmed cell death. The lab's most recent study will be published the week of March 10 to March 14 in the online Early Edition of the Proceedings of the National Academy of Sciences. The study looked at how two different noxious stimuli, anthrax toxin and Salmonella infection, trigger the caspase-1-mediated cell death pathway. UW graduate students Susan Fink and Tessa Bergsbaken conducted this study.
The researchers found that each of these stimuli took an independent route to activate caspase-1; however, these two distinct mechanisms of activation eventually converged on a common pathway of cell death. This common pathway featured cleavage of the cell's DNA, activation of inflammatory chemical messengers, and the final jettison of the cells contents. The spillage occurs after nano-scale pores form in the cell membrane, much like punctures in a water balloon.
According to Cookson, these findings are helping to create research models for studying a broadly important pathway of pro-inflammatory programmed cell death. The findings also support the notion that diverse disease agents can use different mechanisms to elicit this pathway.
"Examining this system provides insight into mechanisms of both beneficial and pathological cell death, and the strategies that infectious disease agents employ to manipulate the body's responses," Cookson said. His group's previous studies of Yersinia, the plague pathogen, revealed that cell death mechanisms can be re-directed from a passive, non-inflammatory pathway, to a more beneficial inflammatory pathway. This finding suggests the possibility of treating diseases by modulating cell death pathways.
"In addition to its protective role in fighting infection," Cookson added, "caspase-1 also plays a role in many medical conditions characterized by cell death and inflammation." These conditions include organ damage in the heart, brain, lungs, nerves, and kidneys. Understanding pro-inflammatory cell death pathways may lead to new therapies against fatal or disabling diseases, such as serious infections, heart attack, cancer and stroke.
Cookson is part of the National Institutes of Health-funded Microscale Life Sciences Center, a collaboration among scientists and engineers from the UW, the University of Arizona, the Fred Hutchinson Cancer Research Center, and Brandeis University. The scientists work to discover basic mechanisms in the formation, growth, and decline of human cells. Their aim is to develop biotechnology to combat widespread diseases and environmental threats to human health.
Source: Leila Gray
University of Washington
Microbes Beating Medicine
Deaths from previously treatable infections will become more common unless there is investment in the science needed to tackle antibiotic resistance - the Royal Society has warned in a report published few days ago.
The report(1), produced by European Academies Science Advisory Council (EASAC) of which the Royal Society is a member, highlights the ever growing problem of antibiotic resistance in pathogens such as MRSA, Clostridium difficile, E-coli and infectious diseases such as tuberculosis, pneumonia and meningitis.
Scientists from across Europe are calling for the EU and Member States to provide greater support for the development of simple and cheap means of identifying specific infections as early as possible and greater support for drug companies who are seeking to develop new treatments. The report also urges greater awareness and monitoring of the problem, more prudent use of antibiotics, more effective containment of the spread of resistance and greater cooperation and coordination across Europe.
Hospital acquired infections are believed to account for 175,000 deaths in Europe each year, many of which are attributable to antibiotic resistance.
Professor Volker ter Meulen, President of the Leopoldina Academy of Sciences, Germany and Chair the report's working group, said: "The problem of antibiotic resistance is growing. Our concern is that the European policy makers are not doing enough to stimulate the development of new antibacterial drugs and encourage the sharing of information between Member States. This is vital to identify patterns and tackle resistance.
"For example, research and development for new antibiotic drugs is not an attractive option for drug companies in comparison with treatments for long-term chronic illnesses - which offer a better return on investment. Drug companies will need to be incentivised to continue valuable antibiotic R&D."
Antibiotic resistance is not just a problem for hospitals and patients but for everyone. Business will be hit, with employees off work. There is also the danger that antibiotic resistant pathogens could enter the food chain via livestock.
Professor Richard Moxon, based at the University of Oxford and a member of the working group, said: "It is crucially important to rebuild European academic capability in microbiology and clinical infectious disease infrastructure. But antibiotic resistance is not just a medical issue. Social habits may lead to increased cases of resistance - such as GPs over-prescribing general antibiotics instead of ones designed to treat specific pathogens. In some EU states antibiotics can even be bought without prescriptions.
"All factors that could lead to antibiotic resistance or be affected by it need to be considered. Government departments across the EU responsible for public health, environment, industry and scientific research have to work together to take action to tackle this problem."
In monitoring the trend of drug resistance across Europe, the observation and recording of resistance is extremely valuable. The European Commission is responsible for coordinating this surveillance, and gathers information from Member States to plot the spread of infections. However the report found that data collected is of a variable standard - making comparisons between countries difficult.
"Knowing where the problems are most common is extremely valuable to predict possible impacts on the economy, to bring about changes in healthcare practice and inform research funders throughout Europe on where research funding should be focused," added Professor ter Meulen
1. 'Tackling antibacterial resistance in Europe'
2. EASAC - the European Academies Science Advisory Council - is made up of the national science academies of the EU member states to enable them to collaborate with each other in providing advice to European policy-makers.
3. The Royal Society, the UK's national academy of science, celebrates its 350th anniversary in 2010. Its five anniversary goals are to:
4В· Invest in future scientific leaders and in innovation
- Influence policymaking with the best scientific advice
- Invigorate science and mathematics education
- Increase access to science internationally
- Inspire an interest in the joy, wonder and fulfilment of scientific discovery
Royal Society, UK
The report(1), produced by European Academies Science Advisory Council (EASAC) of which the Royal Society is a member, highlights the ever growing problem of antibiotic resistance in pathogens such as MRSA, Clostridium difficile, E-coli and infectious diseases such as tuberculosis, pneumonia and meningitis.
Scientists from across Europe are calling for the EU and Member States to provide greater support for the development of simple and cheap means of identifying specific infections as early as possible and greater support for drug companies who are seeking to develop new treatments. The report also urges greater awareness and monitoring of the problem, more prudent use of antibiotics, more effective containment of the spread of resistance and greater cooperation and coordination across Europe.
Hospital acquired infections are believed to account for 175,000 deaths in Europe each year, many of which are attributable to antibiotic resistance.
Professor Volker ter Meulen, President of the Leopoldina Academy of Sciences, Germany and Chair the report's working group, said: "The problem of antibiotic resistance is growing. Our concern is that the European policy makers are not doing enough to stimulate the development of new antibacterial drugs and encourage the sharing of information between Member States. This is vital to identify patterns and tackle resistance.
"For example, research and development for new antibiotic drugs is not an attractive option for drug companies in comparison with treatments for long-term chronic illnesses - which offer a better return on investment. Drug companies will need to be incentivised to continue valuable antibiotic R&D."
Antibiotic resistance is not just a problem for hospitals and patients but for everyone. Business will be hit, with employees off work. There is also the danger that antibiotic resistant pathogens could enter the food chain via livestock.
Professor Richard Moxon, based at the University of Oxford and a member of the working group, said: "It is crucially important to rebuild European academic capability in microbiology and clinical infectious disease infrastructure. But antibiotic resistance is not just a medical issue. Social habits may lead to increased cases of resistance - such as GPs over-prescribing general antibiotics instead of ones designed to treat specific pathogens. In some EU states antibiotics can even be bought without prescriptions.
"All factors that could lead to antibiotic resistance or be affected by it need to be considered. Government departments across the EU responsible for public health, environment, industry and scientific research have to work together to take action to tackle this problem."
In monitoring the trend of drug resistance across Europe, the observation and recording of resistance is extremely valuable. The European Commission is responsible for coordinating this surveillance, and gathers information from Member States to plot the spread of infections. However the report found that data collected is of a variable standard - making comparisons between countries difficult.
"Knowing where the problems are most common is extremely valuable to predict possible impacts on the economy, to bring about changes in healthcare practice and inform research funders throughout Europe on where research funding should be focused," added Professor ter Meulen
1. 'Tackling antibacterial resistance in Europe'
2. EASAC - the European Academies Science Advisory Council - is made up of the national science academies of the EU member states to enable them to collaborate with each other in providing advice to European policy-makers.
3. The Royal Society, the UK's national academy of science, celebrates its 350th anniversary in 2010. Its five anniversary goals are to:
4В· Invest in future scientific leaders and in innovation
- Influence policymaking with the best scientific advice
- Invigorate science and mathematics education
- Increase access to science internationally
- Inspire an interest in the joy, wonder and fulfilment of scientific discovery
Royal Society, UK
UD Awarded $11M For Osteoarthritis Research And Unique Mentoring Program For Women Scientists
The University of Delaware has been awarded $11 million from the National Institutes of Health for leading-edge, "translational" research on osteoarthritis that includes a unique mentoring program to foster the development of women biomedical researchers at UD.
The grant, led by Thomas Buchanan, professor and chairperson of the Department of Mechanical Engineering, is the second five-year award to UD's Center for Biomedical Engineering Research from NIH's Centers of Biomedical Research Excellence Program. The center received a $6.4 million grant in 2002.
The wearing down of cartilage, the natural cushion between the bones and joints, causes osteoarthritis, the most common form of arthritis. The disease typically affects the knees, hips, back and hands.
According to Buchanan, the latest grant will enable UD to continue building the infrastructure and expertise to address the mechanisms of osteoarthritis, its prevention and treatment by examining the disease from the integrated perspectives of tissue mechanics, biomechanics, physical therapy and clinical intervention.
The program will involve 14 faculty in three of UD's seven colleges, including the departments of biological sciences and physical therapy in the College of Arts and Sciences, mechanical engineering in the College of Engineering, and health, nutrition and exercise sciences in the College of Health Sciences. Researchers from Alfred I. duPont Hospital for Children and the Kessler Medical Rehabilitation Research and Education Corporation will serve as collaborators.
"What we have at UD that's really unique is a collection of people to address osteoarthritis across multiple levels, which is what translational medicine is all about," Buchanan said.
"We have people who can look at the proteins that are important to the healing of cartilage, for example, to people who can create biomechanical models showing the movement of bones and joints, to people who can conduct the clinical studies critical to the development of therapies. We can span lots of disciplines, which is what's exciting here," he noted.
Buchanan said the program's focus on mentoring women in science and engineering evolved after the request for research proposals was circulated at UD. Women faculty submitted the top-five research proposals.
"We wanted to find ways to use this program as an opportunity to promote their role," he noted.
Nationally, women continue to be underrepresented in the academic ranks of science, technology, engineering and mathematics. At UD, the percentages of all tenured/tenure-track women faculty are 17 percent in the natural sciences and 10 percent in engineering, according to Buchanan.
"Mechanical engineering, for example, traditionally has been a male discipline although many of our new faculty are women," Buchanan said of the UD department he chairs. "Our goal is to find good faculty mentors and start working with these new hires to see the discipline change. We need better mentoring to help with the process."
The grant's chief components, Buchanan said, are to create a core facility for mentoring women in science and engineering, to establish a new lab focusing on cytomechanics, or cell mechanics, and to advance five integrated research projects in osteoarthritis.
L. Pamela Cook, professor of mathematical sciences, associate dean of engineering and chairperson of UD's Commission on the Status of Women, is assisting with the development of a strong internal networking and support system for women faculty in science and engineering. Professional development workshops, establishment of a faculty ombudswoman and University-wide presentations on gender issues, including promotion and tenure, are being planned.
Women faculty are directing the grant's five research projects. Two are led by senior faculty, who also are helping to mentor the junior faculty in charge of the remaining projects.
Mary C. Farach-Carson, professor of biological sciences and director of UD's Center for Translational Cancer Research, and Catherine Kirn-Safran, research assistant professor of biological sciences, are leading a team to define the structural and functional roles of the biomolecule perlecan in cartilage biology. The biomolecule's heparan sulfate chains are believed to be critical to the maintenance of cartilage in adults and the regrowth of damaged cartilage.
Liyun Wang, assistant professor of mechanical engineering, is exploring the pathway of communication between bone and cartilage. Experiments have shown that bone cells from osteoarthritic patients can cause cartilage to break down. Wang is combining lab techniques with mathematical modeling to characterize the movement of molecules through bones in normal and osteoarthritic joints.
Lynn Snyder-Mackler, Alumni Distinguished Professor of Physical Therapy and director of the Graduate Program in Biomechanics and Movement Sciences at UD, is leading a research team to determine if rehabilitation that normalizes quadriceps strength between the limbs after total knee replacement--one of the most common surgeries in the U.S.-- will ultimately decrease the progression of osteoarthritis of the hip and knee.
Jill Higginson, assistant professor of mechanical engineering, is investigating the muscle forces and coordination strategies used during walking in individuals with age-related osteoarthritis of the knee. A combination of MRI, gait analysis, electromyography and biomechanical modeling and simulation will be employed to determine the most effective nonsurgical interventions.
Katherine Rudolph, assistant professor of physical therapy, is working to understand how quadriceps strength, knee stiffness, proprioception and instability contribute to osteoarthritis of the knee. The study will help researchers understand the strategies that can be used to improve knee function without further joint damage and aid in developing screening tools to identify patients who will benefit from rehabilitation programs.
Contact: Tracey Bryant
University of Delaware
The grant, led by Thomas Buchanan, professor and chairperson of the Department of Mechanical Engineering, is the second five-year award to UD's Center for Biomedical Engineering Research from NIH's Centers of Biomedical Research Excellence Program. The center received a $6.4 million grant in 2002.
The wearing down of cartilage, the natural cushion between the bones and joints, causes osteoarthritis, the most common form of arthritis. The disease typically affects the knees, hips, back and hands.
According to Buchanan, the latest grant will enable UD to continue building the infrastructure and expertise to address the mechanisms of osteoarthritis, its prevention and treatment by examining the disease from the integrated perspectives of tissue mechanics, biomechanics, physical therapy and clinical intervention.
The program will involve 14 faculty in three of UD's seven colleges, including the departments of biological sciences and physical therapy in the College of Arts and Sciences, mechanical engineering in the College of Engineering, and health, nutrition and exercise sciences in the College of Health Sciences. Researchers from Alfred I. duPont Hospital for Children and the Kessler Medical Rehabilitation Research and Education Corporation will serve as collaborators.
"What we have at UD that's really unique is a collection of people to address osteoarthritis across multiple levels, which is what translational medicine is all about," Buchanan said.
"We have people who can look at the proteins that are important to the healing of cartilage, for example, to people who can create biomechanical models showing the movement of bones and joints, to people who can conduct the clinical studies critical to the development of therapies. We can span lots of disciplines, which is what's exciting here," he noted.
Buchanan said the program's focus on mentoring women in science and engineering evolved after the request for research proposals was circulated at UD. Women faculty submitted the top-five research proposals.
"We wanted to find ways to use this program as an opportunity to promote their role," he noted.
Nationally, women continue to be underrepresented in the academic ranks of science, technology, engineering and mathematics. At UD, the percentages of all tenured/tenure-track women faculty are 17 percent in the natural sciences and 10 percent in engineering, according to Buchanan.
"Mechanical engineering, for example, traditionally has been a male discipline although many of our new faculty are women," Buchanan said of the UD department he chairs. "Our goal is to find good faculty mentors and start working with these new hires to see the discipline change. We need better mentoring to help with the process."
The grant's chief components, Buchanan said, are to create a core facility for mentoring women in science and engineering, to establish a new lab focusing on cytomechanics, or cell mechanics, and to advance five integrated research projects in osteoarthritis.
L. Pamela Cook, professor of mathematical sciences, associate dean of engineering and chairperson of UD's Commission on the Status of Women, is assisting with the development of a strong internal networking and support system for women faculty in science and engineering. Professional development workshops, establishment of a faculty ombudswoman and University-wide presentations on gender issues, including promotion and tenure, are being planned.
Women faculty are directing the grant's five research projects. Two are led by senior faculty, who also are helping to mentor the junior faculty in charge of the remaining projects.
Mary C. Farach-Carson, professor of biological sciences and director of UD's Center for Translational Cancer Research, and Catherine Kirn-Safran, research assistant professor of biological sciences, are leading a team to define the structural and functional roles of the biomolecule perlecan in cartilage biology. The biomolecule's heparan sulfate chains are believed to be critical to the maintenance of cartilage in adults and the regrowth of damaged cartilage.
Liyun Wang, assistant professor of mechanical engineering, is exploring the pathway of communication between bone and cartilage. Experiments have shown that bone cells from osteoarthritic patients can cause cartilage to break down. Wang is combining lab techniques with mathematical modeling to characterize the movement of molecules through bones in normal and osteoarthritic joints.
Lynn Snyder-Mackler, Alumni Distinguished Professor of Physical Therapy and director of the Graduate Program in Biomechanics and Movement Sciences at UD, is leading a research team to determine if rehabilitation that normalizes quadriceps strength between the limbs after total knee replacement--one of the most common surgeries in the U.S.-- will ultimately decrease the progression of osteoarthritis of the hip and knee.
Jill Higginson, assistant professor of mechanical engineering, is investigating the muscle forces and coordination strategies used during walking in individuals with age-related osteoarthritis of the knee. A combination of MRI, gait analysis, electromyography and biomechanical modeling and simulation will be employed to determine the most effective nonsurgical interventions.
Katherine Rudolph, assistant professor of physical therapy, is working to understand how quadriceps strength, knee stiffness, proprioception and instability contribute to osteoarthritis of the knee. The study will help researchers understand the strategies that can be used to improve knee function without further joint damage and aid in developing screening tools to identify patients who will benefit from rehabilitation programs.
Contact: Tracey Bryant
University of Delaware
Systems With Brain-Computer Link On The Brink Of Breakthrough, Study Finds
Systems that directly connect silicon circuits with brains are under intensive development all over the world, and are nearing commercial application in many areas, according to a study just placed online.
Neurobiologist Theodore W. Berger of the University of Southern California chaired the eight-member committee which compiled the "International Assessment of Research and Development in Brain-Computer Interfaces," published in October by the World Technology Evaluation Center, Inc., of Baltimore MD
The report is now downloadable online at the WTEC website.
Berger, who holds the David Packard Chair at the USC Viterbi School of Engineering and is Director of the USC Center for Neural Engineering contributed the introduction and two chapters of the report, which encompassed dozens of research institutes in Europe and Asia.
The other committee members (and chapter authors) included John K. Chapin (SUNY Downstate Medical Center); Greg A. Gerhardt (University of Kentucky); Dennis J. McFarland (Wadsworth Center); JosГ© C. Principe (University of Florida); Dawn M. Taylor (Case Western Reserve); and Patrick A. Tresco (University of Utah).
The report contains three overall findings on Brain-Computer Interface (BCI) work worldwide:
* BCI research is extensive and rapidly growing, as is growth in the interfaces between multiple key scientific areas, including biomedical engineering, neuroscience, computer science, electrical and computer engineering, materials science and nanotechnology, and neurology and neurosurgery.
* BCI research is rapidly approaching first-generation medical practice - clinical trials of invasive BCI technologies and significant home use of noninvasive, electroencephalography (EEG-based) BCIs. The panel predicts that BCIs soon will markedly influence the medical device industry, and additionally BCI research will rapidly accelerate in non-medical arenas of commerce as well, particularly in the gaming, automotive, and robotics industries.
* The focus of BCI research throughout the world was decidedly uneven, with invasive BCIs almost exclusively centered in North America, noninvasive BCI systems evolving primarily from European and Asian efforts. BCI research in Asia, and particularly China, is accelerating, with advanced algorithm development for EEG-based systems currently a hallmark of China's BCI program. Future BCI research in China is clearly developing toward invasive BCI systems, so BCI researchers in the US will soon have a strong competitor.
The chapters of the report offer detailed discussion of specific work from around the world, work on Sensor Technology, Biotic-Abiotic Interfaces, BMI/BCI Modeling and Signal Processing, Hardware Implementation, Functional Electrical Stimulation and Rehabilitation Applications of BCIs, Noninvasive Communication Systems, Cognitive and Emotional Neuroprostheses, and BCI issues arising out of research organization-funding, translation-commercialization, and education and training.
With respect to translation and commercialization, the Committee found that BCI research in Europe and Japan was much more tightly tied to industry compared to what is seen in the U.S., with multiple high-level mechanisms for jointly funding academic and industrial partnerships dedicated to BCIs, and mechanisms for translational research that increased the probability of academic prototypes reaching industrial paths for commercialization.
A consortium including the National Science Foundation, The United States Army Telemedicine and Advanced Technology Research Center, the National Institute of Neurological Disorders and Stroke, the National Space Biomedical Research Institute, National Institute of Biomedical Imaging and Bioengineering, and the Margot Anderson Brain Restoration Foundation commissioned the report.
The World Technology Evaluation Center, Inc. wtec/ specializes in conducting international technology assessments via expert review, having conducted more than 60 such studies since 1989.
Source: Eric Mankin
University of Southern California
Neurobiologist Theodore W. Berger of the University of Southern California chaired the eight-member committee which compiled the "International Assessment of Research and Development in Brain-Computer Interfaces," published in October by the World Technology Evaluation Center, Inc., of Baltimore MD
The report is now downloadable online at the WTEC website.
Berger, who holds the David Packard Chair at the USC Viterbi School of Engineering and is Director of the USC Center for Neural Engineering contributed the introduction and two chapters of the report, which encompassed dozens of research institutes in Europe and Asia.
The other committee members (and chapter authors) included John K. Chapin (SUNY Downstate Medical Center); Greg A. Gerhardt (University of Kentucky); Dennis J. McFarland (Wadsworth Center); JosГ© C. Principe (University of Florida); Dawn M. Taylor (Case Western Reserve); and Patrick A. Tresco (University of Utah).
The report contains three overall findings on Brain-Computer Interface (BCI) work worldwide:
* BCI research is extensive and rapidly growing, as is growth in the interfaces between multiple key scientific areas, including biomedical engineering, neuroscience, computer science, electrical and computer engineering, materials science and nanotechnology, and neurology and neurosurgery.
* BCI research is rapidly approaching first-generation medical practice - clinical trials of invasive BCI technologies and significant home use of noninvasive, electroencephalography (EEG-based) BCIs. The panel predicts that BCIs soon will markedly influence the medical device industry, and additionally BCI research will rapidly accelerate in non-medical arenas of commerce as well, particularly in the gaming, automotive, and robotics industries.
* The focus of BCI research throughout the world was decidedly uneven, with invasive BCIs almost exclusively centered in North America, noninvasive BCI systems evolving primarily from European and Asian efforts. BCI research in Asia, and particularly China, is accelerating, with advanced algorithm development for EEG-based systems currently a hallmark of China's BCI program. Future BCI research in China is clearly developing toward invasive BCI systems, so BCI researchers in the US will soon have a strong competitor.
The chapters of the report offer detailed discussion of specific work from around the world, work on Sensor Technology, Biotic-Abiotic Interfaces, BMI/BCI Modeling and Signal Processing, Hardware Implementation, Functional Electrical Stimulation and Rehabilitation Applications of BCIs, Noninvasive Communication Systems, Cognitive and Emotional Neuroprostheses, and BCI issues arising out of research organization-funding, translation-commercialization, and education and training.
With respect to translation and commercialization, the Committee found that BCI research in Europe and Japan was much more tightly tied to industry compared to what is seen in the U.S., with multiple high-level mechanisms for jointly funding academic and industrial partnerships dedicated to BCIs, and mechanisms for translational research that increased the probability of academic prototypes reaching industrial paths for commercialization.
A consortium including the National Science Foundation, The United States Army Telemedicine and Advanced Technology Research Center, the National Institute of Neurological Disorders and Stroke, the National Space Biomedical Research Institute, National Institute of Biomedical Imaging and Bioengineering, and the Margot Anderson Brain Restoration Foundation commissioned the report.
The World Technology Evaluation Center, Inc. wtec/ specializes in conducting international technology assessments via expert review, having conducted more than 60 such studies since 1989.
Source: Eric Mankin
University of Southern California
Future Therapies For Stroke May Block Cell Death
A new therapy to re-activate silenced genes in patients who suffer from neurodegenerative diseases or stroke is being developed by researchers at the University of Illinois at Chicago and Cornell University.
During and after a stroke, certain cellular events take place that lead to the death of brain cells. Compounds that inhibit a group of enzymes called histone deacetylases can modulate gene expression, and in some cases produce cellular proteins that are actually neuroprotective -- they are able to block cell death.
"For the first time, we show which one of the 11 histone deacetylase enzymes might be the best target to achieve cellular neuroprotection," said the study's lead investigator, Alan Kozikowski, professor of medicinal chemistry and pharmacognosy and director of the drug discovery program at UIC. "This work gives us a good direction to follow in testing histone deacetylase inhibitors in animal models for diseases such as Parkinson's and Huntington's disease, and even stroke."
Stroke can cause permanent neurological damage or even death if not promptly diagnosed and treated. It is the third-leading cause of death and the leading cause of adult disability in the United States.
A great deal of research has gone into developing histone deacetylase inhibitors as novel therapeutics, but the majority of the work has been directed toward cancer, Kozikowski said -- in which case, paradoxically, the compounds are employed to stimulate the death of rapidly multiplying cells. The molecule known as SAHA recently received approval by the Food and Drug Administration for use in cancer therapy and is the first of the histone deacetylase inhibitors to be marketed.
"The use of histone deacetylase inhibitors in medicine would thus appear to hold tremendous promise," Kozikowski said. But to be clinically useful, he said, drugs must be designed that are able to discriminate between various forms of histone deacetylase.
Kozikowski said the new findings, performed in collaboration with Dr. Brett Langley at the Burke-Cornell Medical Research Institute in White Plains, N.Y., are significant, and that "other exciting results are on the horizon." Researchers at the Mayo Clinic have found that other histone deacetylase inhibitors they have designed show promise for pancreatic cancer, while yet another, in work performed at the Walter Reed Army Institute of Research, may be effective against malaria.
"This is a new area of drug discovery for the 22nd century," Kozikowski said.
The study is published in the Journal of Medicinal Chemistry. It was funded by grants from the U.S. Department of Defense and other sources.
For more information about UIC, visit uic/.
Contact: Sam Hostettler
University of Illinois at Chicago
During and after a stroke, certain cellular events take place that lead to the death of brain cells. Compounds that inhibit a group of enzymes called histone deacetylases can modulate gene expression, and in some cases produce cellular proteins that are actually neuroprotective -- they are able to block cell death.
"For the first time, we show which one of the 11 histone deacetylase enzymes might be the best target to achieve cellular neuroprotection," said the study's lead investigator, Alan Kozikowski, professor of medicinal chemistry and pharmacognosy and director of the drug discovery program at UIC. "This work gives us a good direction to follow in testing histone deacetylase inhibitors in animal models for diseases such as Parkinson's and Huntington's disease, and even stroke."
Stroke can cause permanent neurological damage or even death if not promptly diagnosed and treated. It is the third-leading cause of death and the leading cause of adult disability in the United States.
A great deal of research has gone into developing histone deacetylase inhibitors as novel therapeutics, but the majority of the work has been directed toward cancer, Kozikowski said -- in which case, paradoxically, the compounds are employed to stimulate the death of rapidly multiplying cells. The molecule known as SAHA recently received approval by the Food and Drug Administration for use in cancer therapy and is the first of the histone deacetylase inhibitors to be marketed.
"The use of histone deacetylase inhibitors in medicine would thus appear to hold tremendous promise," Kozikowski said. But to be clinically useful, he said, drugs must be designed that are able to discriminate between various forms of histone deacetylase.
Kozikowski said the new findings, performed in collaboration with Dr. Brett Langley at the Burke-Cornell Medical Research Institute in White Plains, N.Y., are significant, and that "other exciting results are on the horizon." Researchers at the Mayo Clinic have found that other histone deacetylase inhibitors they have designed show promise for pancreatic cancer, while yet another, in work performed at the Walter Reed Army Institute of Research, may be effective against malaria.
"This is a new area of drug discovery for the 22nd century," Kozikowski said.
The study is published in the Journal of Medicinal Chemistry. It was funded by grants from the U.S. Department of Defense and other sources.
For more information about UIC, visit uic/.
Contact: Sam Hostettler
University of Illinois at Chicago
New Research To Cut Animal Testing, UK
Researchers at The University of Manchester have been awarded 130,000 pounds to develop new techniques to reduce the need for animals in drug testing.
Current checks to establish whether a new drug is carcinogenic can be inconclusive and require further testing on live animals to establish whether they are harmful or not.
Dr Richard Walmsley and colleagues at the University spin-out company he founded, Gentronix, have developed techniques using cultured human cells to more effectively weed out cancer-causing compounds.
"The current pre-animal tests that are used are highly sensitive and so most carcinogens are identified," said Dr Walmsley, who is based in the Faculty of Life Sciences.
"Unfortunately, such tests have poor specificity and a lot of safe compounds are also wrongly identified as potential carcinogens. This means that animal testing is still carried out, in case such compounds turn out to be safe.
"The testing process developed at Gentronix has proven very reliable at telling us whether a drug will cause cancer but some chemicals, called promutagens, only become carcinogenic once they have passed through the body's liver.
"This grant will help us develop new non-animal experiments to identify these other toxic compounds and so reduce the need for animal testing."
The funding - awarded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) - will help the scientists establish new genotoxicity tests using cultured human liver cells.
It is hoped the new test will not only reduce the number of compounds that are tested on animals but also ensure harmless chemicals that could prove to be useful new drugs are not falsely labelled as carcinogens.
"I don't believe that animal testing will disappear from drug safety assessment in the short term as you can't ask human volunteers to take novel drugs straight from testing done in tube tests," said Dr Walmsley.
"But if we can refine the pre-animal tests and increase people's confidence in them, then we will be able to reduce the number of chemicals that are tested on live animals."
Gentronix was founded by Dr Walmsley in July 1999 to commercialise technology developed at what was the University of Manchester Institute of Science and Technology (UMIST) - now part of The University of Manchester. This innovative biotechnology company aims to accelerate the pace of drug development in the pharmaceutical industry by developing a range of productivity-enhancing tools for scientists in the drug-discovery field.
The NC3Rs grant will help fund two researchers for the project for a year and contribute towards new equipment.
Further details about Gentronix can be found at gentronix/
Information about NC3Rs can be found on its website: nc3rs.uk/
Contact: Aeron Haworth
University of Manchester
Current checks to establish whether a new drug is carcinogenic can be inconclusive and require further testing on live animals to establish whether they are harmful or not.
Dr Richard Walmsley and colleagues at the University spin-out company he founded, Gentronix, have developed techniques using cultured human cells to more effectively weed out cancer-causing compounds.
"The current pre-animal tests that are used are highly sensitive and so most carcinogens are identified," said Dr Walmsley, who is based in the Faculty of Life Sciences.
"Unfortunately, such tests have poor specificity and a lot of safe compounds are also wrongly identified as potential carcinogens. This means that animal testing is still carried out, in case such compounds turn out to be safe.
"The testing process developed at Gentronix has proven very reliable at telling us whether a drug will cause cancer but some chemicals, called promutagens, only become carcinogenic once they have passed through the body's liver.
"This grant will help us develop new non-animal experiments to identify these other toxic compounds and so reduce the need for animal testing."
The funding - awarded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) - will help the scientists establish new genotoxicity tests using cultured human liver cells.
It is hoped the new test will not only reduce the number of compounds that are tested on animals but also ensure harmless chemicals that could prove to be useful new drugs are not falsely labelled as carcinogens.
"I don't believe that animal testing will disappear from drug safety assessment in the short term as you can't ask human volunteers to take novel drugs straight from testing done in tube tests," said Dr Walmsley.
"But if we can refine the pre-animal tests and increase people's confidence in them, then we will be able to reduce the number of chemicals that are tested on live animals."
Gentronix was founded by Dr Walmsley in July 1999 to commercialise technology developed at what was the University of Manchester Institute of Science and Technology (UMIST) - now part of The University of Manchester. This innovative biotechnology company aims to accelerate the pace of drug development in the pharmaceutical industry by developing a range of productivity-enhancing tools for scientists in the drug-discovery field.
The NC3Rs grant will help fund two researchers for the project for a year and contribute towards new equipment.
Further details about Gentronix can be found at gentronix/
Information about NC3Rs can be found on its website: nc3rs.uk/
Contact: Aeron Haworth
University of Manchester
Bone Formation And Strength Controlled By Notch
Notch, a protein known to govern the determination of cell differentiation into different kinds of tissues in embryos, plays a critical role in bone formation and strength later in life, said researchers from Baylor College of Medicine in Houston in a report that appears online in the journal Nature Medicine. Their findings may provide a basis for understanding osteoporosis and in diseases in which there is too much bone.
"We knew that Notch is important in patterning the skeleton," said Dr. Brendan Lee, professor of molecular and human genetics and pediatrics at BCM and a Howard Hughes Medical Institute investigator. "After this initial patterning of the skeleton, we saw a dimorphic or two-pronged function for Notch. If there was an increase of Notch activity in bone cells, we get a lot more bone. Notch stimulates early proliferation of osteoblastic cells (cells responsible for bone formation). However, when they 'knocked out' the Notch function in such cells in the laboratory, they found osteoporosis or the loss of bone, similar to age-related osteoporosis in humans."
"Mice had an acceptable amount of bone at birth, but as they got older, they lost more and more bone," said Lee, senior author of the report. "Loss of Notch signaling might relate to what happens when we get older."
They found that the osteoblasts, which promote bone formation, worked fine when they abolished Notch function in bone forming cells. However, the animals lacked the ability to regulate activity of osteoclasts, whose primary function is to resorb or remove bone. Many women who have osteoporosis actually have a similar problem, an imbalance of bone formation vs. bone resorption. They make enough bone but they resorb bone cells at an abnormally high rate.
In the laboratory, Lee and his colleagues found that when animals were bred to lack Notch, they lost also the ability to suppress bone resorption. That balance between bone formation and resorption allows organisms to maintain a healthy skeleton.
Future studies may look at the possiblity that loss of Notch interferes with the natural signal between osteoblasts and osteoclasts (bone resorbing cells) and prevents the homeostasis or natural balance between the two.
That means the protein Notch and the cellular pathways that express and control it might be targets for drugs to treat bone disorders, said Lee, also a researcher in the Dan L. Duncan Cancer Center at BCM.
The work demonstrates the importance of going from patients to the laboratory and back again, he said. This study began with patients who suffer from a problem called spondylocostal dysplasia. These children and adults have problems with the pattern of their spine. They have fusions of parts of the spine or ribs. Several years ago, other scientists showed that a mutation of the pathway for Notch causes some of these problems. "Our care of these patients suggested to us that Notch may have important function even after the establishment of this initial pattern of the skeleton."
Notch also plays a role in other disorders, including those of the blood and cancer.
"Notch is important in the blood system," said Lee. "It regulates whether a stem cell becomes a 'T' or a 'B' cell. When Notch is mutated in the blood system, it causes cancer."
That knowledge led him and his colleagues to look at the protein in bone.
"This is a complex system and it is why personalized medicine is important," said Lee. "By identifying all of the major (cellular) pathways that contribute to a specific trait or feature like bone mass in each person, we could one day develop therapies specific for that person."
Others who took part in this work include Feyza Engin, Tao Yang, Guang Zhou, Terry Bertin, Ming Ming Jiang, Yuqing Chen, Lisa Wang, Hui Zheng and Richard E. Sutton, all of BCM, and Zhenqiang Yao and Brendan F Boyce at the University of Rochester Medical Center in New York.
Funding for this work came from the National Institutes of Health. The article can be found at nature/nm/index.html
Source: Glenna Picton
Baylor College of Medicine
"We knew that Notch is important in patterning the skeleton," said Dr. Brendan Lee, professor of molecular and human genetics and pediatrics at BCM and a Howard Hughes Medical Institute investigator. "After this initial patterning of the skeleton, we saw a dimorphic or two-pronged function for Notch. If there was an increase of Notch activity in bone cells, we get a lot more bone. Notch stimulates early proliferation of osteoblastic cells (cells responsible for bone formation). However, when they 'knocked out' the Notch function in such cells in the laboratory, they found osteoporosis or the loss of bone, similar to age-related osteoporosis in humans."
"Mice had an acceptable amount of bone at birth, but as they got older, they lost more and more bone," said Lee, senior author of the report. "Loss of Notch signaling might relate to what happens when we get older."
They found that the osteoblasts, which promote bone formation, worked fine when they abolished Notch function in bone forming cells. However, the animals lacked the ability to regulate activity of osteoclasts, whose primary function is to resorb or remove bone. Many women who have osteoporosis actually have a similar problem, an imbalance of bone formation vs. bone resorption. They make enough bone but they resorb bone cells at an abnormally high rate.
In the laboratory, Lee and his colleagues found that when animals were bred to lack Notch, they lost also the ability to suppress bone resorption. That balance between bone formation and resorption allows organisms to maintain a healthy skeleton.
Future studies may look at the possiblity that loss of Notch interferes with the natural signal between osteoblasts and osteoclasts (bone resorbing cells) and prevents the homeostasis or natural balance between the two.
That means the protein Notch and the cellular pathways that express and control it might be targets for drugs to treat bone disorders, said Lee, also a researcher in the Dan L. Duncan Cancer Center at BCM.
The work demonstrates the importance of going from patients to the laboratory and back again, he said. This study began with patients who suffer from a problem called spondylocostal dysplasia. These children and adults have problems with the pattern of their spine. They have fusions of parts of the spine or ribs. Several years ago, other scientists showed that a mutation of the pathway for Notch causes some of these problems. "Our care of these patients suggested to us that Notch may have important function even after the establishment of this initial pattern of the skeleton."
Notch also plays a role in other disorders, including those of the blood and cancer.
"Notch is important in the blood system," said Lee. "It regulates whether a stem cell becomes a 'T' or a 'B' cell. When Notch is mutated in the blood system, it causes cancer."
That knowledge led him and his colleagues to look at the protein in bone.
"This is a complex system and it is why personalized medicine is important," said Lee. "By identifying all of the major (cellular) pathways that contribute to a specific trait or feature like bone mass in each person, we could one day develop therapies specific for that person."
Others who took part in this work include Feyza Engin, Tao Yang, Guang Zhou, Terry Bertin, Ming Ming Jiang, Yuqing Chen, Lisa Wang, Hui Zheng and Richard E. Sutton, all of BCM, and Zhenqiang Yao and Brendan F Boyce at the University of Rochester Medical Center in New York.
Funding for this work came from the National Institutes of Health. The article can be found at nature/nm/index.html
Source: Glenna Picton
Baylor College of Medicine
TWAS Prizes In Biology - China And Brazil
This year, the judges awarded two prizes in biology.
Huanming Yang, Beijing Genomics Institute, China, won the Prize in Biology:
for his outstanding achievements and contributions in genomics and bioinformatics research.
Jerson Silva, Instituto de Bioquimica Medica, Federal University of Rio de Janeiro, Brazil, won the Prize in Biology:
for his pioneering work with high pressure in biotechnology and structural biology that has yielded new insights into protein folding, virus assembly and protein misfolding diseases.
China was the only developing country to play a role in the sequencing of the human genome, which was published in 2001. As director of the Beijing Genomics Institute since 1999, Huanming Yang was a key player in this effort. Since then, Yang's group in China has published the complete genome sequence of Indica rice and the silkmoth, and steady progress is being made on the genomes of other commercially important species, including the chicken, pig and soybean.
Yang and his team also made international headlines when they announced that they had sequenced the genome of the SARS virus in just a few days. Information derived from the sequence led to the development of diagnostic kits for the virus that greatly facilitated the control of the disease throughout China.
Currently, Yang and other scientists at the Beijing Institute of Genomics are working on another project linked with the human genome as part of the International HapMap Consortium. The aim is to compare the genomes of three different races of human beings and to identify all the single base substitutions in blocks of DNA (or haplotypes) between them. Scientists believe that these variations are at the root of such ailments as heart disease and asthma, the incidence of which varies between races.
Yang has also promoted science for developing countries in developing countries, and promotes the ethical use of genomic data and open access publishing for all the information generated at the Beijing Institute of Genomics.
Among his various honours, Yang received the Award for Outstanding Science and Technology Achievement from the government of China in 2002, was nominated Research Leader of the Year by Scientific American magazine in 2002, and won the Nikkei Asia Prize for Science, 2003.
Huanming Yang works at the Beijing Genomics Institute, Chinese Academy of Sciences, Beijing Airport Industrial Zone B-6, Beijing 101300, China
Proteins are complex macromolecules that perform a wide range of functions in all living organisms. However, they are made of relatively simple subunits, amino acids. Indeed, the diversity of all the proteins in all the living organisms on Earth is based on combinations of just 20 different amino acids. It is how each protein twists and folds its chain of amino acids into a three-dimensional form that gives it its specific characteristics.
Jerson Silva has spent his career analysing how proteins fold into the correct shapes and how they form supramolecular complexes such as virus particles. In 1992, for example, he predicted the potential of high pressure to induce partially folded and molten-globule protein states. A year later, these predictions were confirmed for pressure-denatured proteins. Silva also showed that such partially denatured proteins contained a significant amount of water and predicted a role for water in the action of pressure on proteins.
In addition, using a combination of high pressures and sub-zero temperatures, Silva demonstrated that the interaction between protein molecules and such nucleic acid molecules as DNA depends on the 'entropy' or 'disorder' in the system, and that the nature of such protein-nucleic acid interactions is crucial for the assembly of virus particles that contain little else other than protein and nucleic acid.
More recently, Silva and his colleagues have expanded their work, exploring biophysical approaches to the study of diseases caused by the misfolding of proteins. Such ailments include Parkinson's disease and bovine spongiform encephalopathy (BSE, or 'mad cow disease').
Silva was nominated a fellow of the John Simon Guggenhem Foundation in 1991, an international fellow of the Howard Hughes Medical Institute (1997-2001), and elected to the Brazilian Academy of Sciences in 1998.
Jerson Silva works at the Centro Nacional de Ressonancia Magnetica Nuclear de Macromoleculas (CNRNM), Instituto de Bioquimica Medica (CCS), Federal University of Rio de Janeiro, Ilha do Fundao, 21941-590 Rio de Janeiro, Brazil
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Huanming Yang, Beijing Genomics Institute, China, won the Prize in Biology:
for his outstanding achievements and contributions in genomics and bioinformatics research.
Jerson Silva, Instituto de Bioquimica Medica, Federal University of Rio de Janeiro, Brazil, won the Prize in Biology:
for his pioneering work with high pressure in biotechnology and structural biology that has yielded new insights into protein folding, virus assembly and protein misfolding diseases.
China was the only developing country to play a role in the sequencing of the human genome, which was published in 2001. As director of the Beijing Genomics Institute since 1999, Huanming Yang was a key player in this effort. Since then, Yang's group in China has published the complete genome sequence of Indica rice and the silkmoth, and steady progress is being made on the genomes of other commercially important species, including the chicken, pig and soybean.
Yang and his team also made international headlines when they announced that they had sequenced the genome of the SARS virus in just a few days. Information derived from the sequence led to the development of diagnostic kits for the virus that greatly facilitated the control of the disease throughout China.
Currently, Yang and other scientists at the Beijing Institute of Genomics are working on another project linked with the human genome as part of the International HapMap Consortium. The aim is to compare the genomes of three different races of human beings and to identify all the single base substitutions in blocks of DNA (or haplotypes) between them. Scientists believe that these variations are at the root of such ailments as heart disease and asthma, the incidence of which varies between races.
Yang has also promoted science for developing countries in developing countries, and promotes the ethical use of genomic data and open access publishing for all the information generated at the Beijing Institute of Genomics.
Among his various honours, Yang received the Award for Outstanding Science and Technology Achievement from the government of China in 2002, was nominated Research Leader of the Year by Scientific American magazine in 2002, and won the Nikkei Asia Prize for Science, 2003.
Huanming Yang works at the Beijing Genomics Institute, Chinese Academy of Sciences, Beijing Airport Industrial Zone B-6, Beijing 101300, China
Proteins are complex macromolecules that perform a wide range of functions in all living organisms. However, they are made of relatively simple subunits, amino acids. Indeed, the diversity of all the proteins in all the living organisms on Earth is based on combinations of just 20 different amino acids. It is how each protein twists and folds its chain of amino acids into a three-dimensional form that gives it its specific characteristics.
Jerson Silva has spent his career analysing how proteins fold into the correct shapes and how they form supramolecular complexes such as virus particles. In 1992, for example, he predicted the potential of high pressure to induce partially folded and molten-globule protein states. A year later, these predictions were confirmed for pressure-denatured proteins. Silva also showed that such partially denatured proteins contained a significant amount of water and predicted a role for water in the action of pressure on proteins.
In addition, using a combination of high pressures and sub-zero temperatures, Silva demonstrated that the interaction between protein molecules and such nucleic acid molecules as DNA depends on the 'entropy' or 'disorder' in the system, and that the nature of such protein-nucleic acid interactions is crucial for the assembly of virus particles that contain little else other than protein and nucleic acid.
More recently, Silva and his colleagues have expanded their work, exploring biophysical approaches to the study of diseases caused by the misfolding of proteins. Such ailments include Parkinson's disease and bovine spongiform encephalopathy (BSE, or 'mad cow disease').
Silva was nominated a fellow of the John Simon Guggenhem Foundation in 1991, an international fellow of the Howard Hughes Medical Institute (1997-2001), and elected to the Brazilian Academy of Sciences in 1998.
Jerson Silva works at the Centro Nacional de Ressonancia Magnetica Nuclear de Macromoleculas (CNRNM), Instituto de Bioquimica Medica (CCS), Federal University of Rio de Janeiro, Ilha do Fundao, 21941-590 Rio de Janeiro, Brazil
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News From The Journal Of Clinical Investigation
Timing is everything when treating viral infections
A new study by Robert Mittler and colleagues from Emory University School of Medicine, Atlanta, has indicated that the timing of treatment with an immune-modifying drug, relative to when a mouse becomes infected with a virus, is crucial in determining whether the treatment is effective or not.
If mice were treated with an antibody that stimulates the molecule CD137 (also known as 4-1BB) before being infected, or within 48 hours of being infected, with the virus LCMV Armstrong the immune response failed to clear the virus. By contrast, if treatment was delayed until more than 72 hours after infection the immune response was enhanced and rapidly cleared the virus. Further analysis revealed that early treatment with CD137-specific antibody caused large numbers of immune cells known as CD4+ and CD8+ T cells to die by day 8 of the infection. These data have important implications for the development of CD137 agonists as vaccine adjuvants, something that is currently ongoing.
TITLE: Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time-dependent
AUTHOR CONTACT:
Robert S. Mittler
Emory University School of Medicine, Atlanta, Georgia, USA.
Two stimuli better than one at inducing mucus production
Individuals with cystic fibrosis (CF) are highly susceptible to both bacterial and fungal infection of their airways. In a new study, Jeffrey Wine and colleagues at Stanford University have provided a potential explanation for the vulnerability of individuals with CF to airway infections.
Although the airway glands of healthy individuals produce mucus when stimulated with either acetylcholine (ACh) or vasoactive peptide (VIP), the airway glands of individuals with CF produce mucus only when stimulated with ACh. The authors found that low levels of VIP and ACh were synergistic in their ability to induce the airway glands of healthy individuals to produce mucus; no synergy was observed for airway glands from individuals with CF. These data provide support for the hypothesis that low levels of VIP and ACh stimulate background levels of mucus secretion and that this is an important component of airway immune defense against bacterial and fungal infection that is absent in individuals with CF.
TITLE: Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
AUTHOR CONTACT:
Jeffrey J. Wine
Stanford University, Stanford, California, USA.
TLR4 makes blood loss damaging to the kidney
During transplantation it is necessary that the organ being transplanted spends some time without a blood supply; that is, it finds itself in ischemic conditions. Upon reconnection of the blood supply in its new recipient the organ is subject to ischemia/reperfusion injury (IRI), something that negatively affects short- and long-term graft survival. Understanding the molecular mechanisms that trigger IRI are therefore an area of intensive investigation.
A new study in mice by Huiling Wu and colleagues at the University of Sydney, Australia, has indicated a central role for TLR4 in mediating IRI in the kidney. Ischemia in the kidney was shown to increase the expression of TLR4 on kidney tubule cells and infiltrating immune cells and mice lacking TLR4 were protected from kidney dysfunction following ischemia. Expression of TLR4 by kidney tubule cells had the dominant role in mediating kidney damage after ischemia. Signaling through TLR4 on kidney tubule cells induced the production of proinflammatory cytokines, leading the authors to conclude that TLR4-mediated signaling causes kidney damage after ischemia by initiating an inflammatory response.
TITLE: TLR4 activation mediates kidney ischemia/reperfusion injury
AUTHOR CONTACT:
Huiling Wu
University of Sydney, Sydney, New South Wales, Australia.
TREM-1 has the guts to mediate inflammation
In a new study, Christoph Mueller and colleagues at the University of Bern, Switzerland, have identified a crucial role for the cell surface protein TREM-1 in mediating chronic inflammation in the intestine of mice and humans.
Immune cells known as macrophages in the intestines of mice and humans do not normally express TREM-1. However, in this study, expression of TREM-1 by these cells was shown to be increased in individuals with inflammatory bowel disease (IBD) and in mice with colitis; levels of TREM-1 expression correlated directly with the severity of the intestinal inflammation in both IBD patients and mice with colitis. The severity of disease in mouse models of colitis was reduced by administration of a TREM-1 antagonist peptide either before or after clinical signs of the disease could be detected. These data led the authors to suggest that TREM-1 expression levels might provide a marker to assess disease activity in individuals with IBD and that TREM-1 might be a viable target for the development of therapeutics to treat individuals with chronic inflammatory diseases such as IBD.
TITLE: TREM-1-expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases
AUTHOR CONTACT:
Christoph Mueller
University of Bern, Bern, Switzerland.
Keeping T cells in check limits atherosclerosis
Atherosclerosis is a chronic inflammatory disease that often leads to heart attacks and strokes. T cells have an important role in the development of atherosclerosis and new data produced by Andrew Lichtman and colleagues at Brigham and Women's Hospital, Boston, have identified one way in which proatherogenic T cells are kept in check in mice.
Mice susceptible to developing atherosclerosis (LDLR-deficient mice) that lacked the cell surface receptors PD-L1 and PD-L2 were observed to develop more severe atherosclerotic disease than normal LDLR-deficient mice. The number of T cells in the atherosclerotic lesions in these mice was also greater than in the lesions of normal LDLR-deficient mice. Further analysis indicated that PD-L1 and PD-L2 are required to limit T cell activation by immune cells known as antigen-presenting cells and led the authors to conclude that PD-L1 and PD-L2 interactions with their ligand PD-1 are crucial for dampening the proatherogenic T cell response.
TITLE: Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice
AUTHOR CONTACT:
Andrew H. Lichtman
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Breaking down the molecular pathway to a neuromuscular disease
Slow-channel myasthenic syndrome (SCS) is an inherited disease that causes progressive muscle weakness. It is caused by mutations in acetylcholine receptor (AChR) genes that lead to the AChR being open for too long. Although this is known to cause calcium levels at the junction between nerves and the muscle to be much higher than normal, the molecular pathway that leads from high levels of calcium to muscle weakness has not be clearly defined. Using a mouse model of SCS, Christopher Gomez and colleagues at the University of Chicago, have found that calpain, which is a calcium-activated protein, and caspase 3 have an important role in mediating disease. The authors therefore suggested that inhibiting both these proteins, which mediate their effects by degrading other proteins, might be of therapeutic use for the treatment of individuals with SCS.
TITLE: Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome
AUTHOR CONTACT:
Christopher M. Gomez
University of Chicago, Chicago, Illinois, USA.
Source: Karen Honey
Journal of Clinical Investigation
A new study by Robert Mittler and colleagues from Emory University School of Medicine, Atlanta, has indicated that the timing of treatment with an immune-modifying drug, relative to when a mouse becomes infected with a virus, is crucial in determining whether the treatment is effective or not.
If mice were treated with an antibody that stimulates the molecule CD137 (also known as 4-1BB) before being infected, or within 48 hours of being infected, with the virus LCMV Armstrong the immune response failed to clear the virus. By contrast, if treatment was delayed until more than 72 hours after infection the immune response was enhanced and rapidly cleared the virus. Further analysis revealed that early treatment with CD137-specific antibody caused large numbers of immune cells known as CD4+ and CD8+ T cells to die by day 8 of the infection. These data have important implications for the development of CD137 agonists as vaccine adjuvants, something that is currently ongoing.
TITLE: Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time-dependent
AUTHOR CONTACT:
Robert S. Mittler
Emory University School of Medicine, Atlanta, Georgia, USA.
Two stimuli better than one at inducing mucus production
Individuals with cystic fibrosis (CF) are highly susceptible to both bacterial and fungal infection of their airways. In a new study, Jeffrey Wine and colleagues at Stanford University have provided a potential explanation for the vulnerability of individuals with CF to airway infections.
Although the airway glands of healthy individuals produce mucus when stimulated with either acetylcholine (ACh) or vasoactive peptide (VIP), the airway glands of individuals with CF produce mucus only when stimulated with ACh. The authors found that low levels of VIP and ACh were synergistic in their ability to induce the airway glands of healthy individuals to produce mucus; no synergy was observed for airway glands from individuals with CF. These data provide support for the hypothesis that low levels of VIP and ACh stimulate background levels of mucus secretion and that this is an important component of airway immune defense against bacterial and fungal infection that is absent in individuals with CF.
TITLE: Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
AUTHOR CONTACT:
Jeffrey J. Wine
Stanford University, Stanford, California, USA.
TLR4 makes blood loss damaging to the kidney
During transplantation it is necessary that the organ being transplanted spends some time without a blood supply; that is, it finds itself in ischemic conditions. Upon reconnection of the blood supply in its new recipient the organ is subject to ischemia/reperfusion injury (IRI), something that negatively affects short- and long-term graft survival. Understanding the molecular mechanisms that trigger IRI are therefore an area of intensive investigation.
A new study in mice by Huiling Wu and colleagues at the University of Sydney, Australia, has indicated a central role for TLR4 in mediating IRI in the kidney. Ischemia in the kidney was shown to increase the expression of TLR4 on kidney tubule cells and infiltrating immune cells and mice lacking TLR4 were protected from kidney dysfunction following ischemia. Expression of TLR4 by kidney tubule cells had the dominant role in mediating kidney damage after ischemia. Signaling through TLR4 on kidney tubule cells induced the production of proinflammatory cytokines, leading the authors to conclude that TLR4-mediated signaling causes kidney damage after ischemia by initiating an inflammatory response.
TITLE: TLR4 activation mediates kidney ischemia/reperfusion injury
AUTHOR CONTACT:
Huiling Wu
University of Sydney, Sydney, New South Wales, Australia.
TREM-1 has the guts to mediate inflammation
In a new study, Christoph Mueller and colleagues at the University of Bern, Switzerland, have identified a crucial role for the cell surface protein TREM-1 in mediating chronic inflammation in the intestine of mice and humans.
Immune cells known as macrophages in the intestines of mice and humans do not normally express TREM-1. However, in this study, expression of TREM-1 by these cells was shown to be increased in individuals with inflammatory bowel disease (IBD) and in mice with colitis; levels of TREM-1 expression correlated directly with the severity of the intestinal inflammation in both IBD patients and mice with colitis. The severity of disease in mouse models of colitis was reduced by administration of a TREM-1 antagonist peptide either before or after clinical signs of the disease could be detected. These data led the authors to suggest that TREM-1 expression levels might provide a marker to assess disease activity in individuals with IBD and that TREM-1 might be a viable target for the development of therapeutics to treat individuals with chronic inflammatory diseases such as IBD.
TITLE: TREM-1-expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases
AUTHOR CONTACT:
Christoph Mueller
University of Bern, Bern, Switzerland.
Keeping T cells in check limits atherosclerosis
Atherosclerosis is a chronic inflammatory disease that often leads to heart attacks and strokes. T cells have an important role in the development of atherosclerosis and new data produced by Andrew Lichtman and colleagues at Brigham and Women's Hospital, Boston, have identified one way in which proatherogenic T cells are kept in check in mice.
Mice susceptible to developing atherosclerosis (LDLR-deficient mice) that lacked the cell surface receptors PD-L1 and PD-L2 were observed to develop more severe atherosclerotic disease than normal LDLR-deficient mice. The number of T cells in the atherosclerotic lesions in these mice was also greater than in the lesions of normal LDLR-deficient mice. Further analysis indicated that PD-L1 and PD-L2 are required to limit T cell activation by immune cells known as antigen-presenting cells and led the authors to conclude that PD-L1 and PD-L2 interactions with their ligand PD-1 are crucial for dampening the proatherogenic T cell response.
TITLE: Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice
AUTHOR CONTACT:
Andrew H. Lichtman
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Breaking down the molecular pathway to a neuromuscular disease
Slow-channel myasthenic syndrome (SCS) is an inherited disease that causes progressive muscle weakness. It is caused by mutations in acetylcholine receptor (AChR) genes that lead to the AChR being open for too long. Although this is known to cause calcium levels at the junction between nerves and the muscle to be much higher than normal, the molecular pathway that leads from high levels of calcium to muscle weakness has not be clearly defined. Using a mouse model of SCS, Christopher Gomez and colleagues at the University of Chicago, have found that calpain, which is a calcium-activated protein, and caspase 3 have an important role in mediating disease. The authors therefore suggested that inhibiting both these proteins, which mediate their effects by degrading other proteins, might be of therapeutic use for the treatment of individuals with SCS.
TITLE: Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome
AUTHOR CONTACT:
Christopher M. Gomez
University of Chicago, Chicago, Illinois, USA.
Source: Karen Honey
Journal of Clinical Investigation
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