Scientists at the University of Bonn have discovered a new rare type of haemoglobin. Haemoglobin transports oxygen in the red blood corpuscles. When bound to oxygen it changes colour. The new haemoglobin type appears optically to be transporting little oxygen. Measurements of the blood oxygen level therefore present a similar picture to patients suffering from an inherited cardiac defect. After examining two patients, the scientists now understand that the new type of haemoglobin distorts the level of oxygen measured. The scientists have named the type 'Haemoglobin Bonn'. They have published their discovery in the current issue of the scientific journal Clinical Chemistry. The article can be downloaded from clinchem/cgi/content/full/54/3/594.
Haemoglobin transports oxygen to the body's cells and in return picks up carbon dioxide there. In doing so it changes colour. With an optical measuring instrument, known as a pulse oximeter, you can therefore measure whether there is enough oxygen present in the blood. The cause of anoxia can be an inherited cardiac defect, for example.
This was also the tentative diagnosis in the case of a four-year-old boy who was admitted to the Paediatric Clinic of the Bonn University Clinic. However, after a thorough examin-ation, the paediatricians Dr. Andreas Hornung and his colleagues did not find any cardiac defect. A low saturation of oxygen had also been previously found in the blood of the boy's 41-year-old father, again without apparent signs of a cardiac defect.
Dr. Berndt Zur from Professor Birgit Stoffel-Wagner's team at the Institute of Clinical Chemistry and Pharmacology examined the boy's and the father's haemoglobin. He eventually realised that they were dealing with a new type of the blood pigment. 'The pulse oximeter is put on a finger as a clip and X-rays it with infrared radiation,' he explains. 'Haemoglobin absorbs infrared light in the absence of oxygen. The lower the content of oxygen in the blood, the less light penetrates the finger and reaches the sensor of the oximeter.' But Haemoglobin Bonn absorbs a bit more infrared light than normal oxygen saturated haemoglobin, even when combined with oxygen. 'That's why, at first, we did not understand why the patients did not have any particular health problems,' Dr. Zur says.
Every human has two main heart ventricles. One pumps the blood through the arteries to the lungs, where the haemoglobin releases the carbon dioxide and takes on oxygen. The other one pumps the blood which is saturated with oxygen from the lungs to every cell in the body. Both ventricles must be separated by a wall in the heart, so that the oxygen-rich blood does not mix with the anoxaemic blood. But some people have a hole in this septum. In such cases, the pulse oximeter shows anoxia. Doctors therefore see this as a sign of a cardiac defect. Another cause is what is known as the Apnoea Syndrome. In the patients affected, breathing can cease for more than a minute. That is why the father of the 4-year-old received oxygen treatment at nights for some time. 'If we had known about Haemoglobin Bonn before, father and son could have been spared the fear of a cardiac defect or the Sleep Apnoea Syndrome,' Dr. Zur explains.
This release is available in German.
Source: Dr. Berndt Zur
University of Bonn
понедельник, 30 мая 2011 г.
Males And Females Protected From Hearing Loss By 'Female Sex Hormone'
The "female sex hormone" estradiol is present in both men and women, and is generated from testosterone in men by the protein aromatase. Estradiol plays various roles in addition to its gender-specific ones, including having effects on the hearing (auditory) system. In a new study, Barbara Canlon and colleagues at the Karolinska Institute in Stockholm, Sweden, investigated the role of estradiol-binding proteins, known as estrogen receptors, in response to auditory damage by examining hearing loss recovery in mice with deficiencies in various estrogen receptors. They found that mice deficient in only the estrogen receptor ER-beta had reduced recovery from auditory trauma, and that treatment with ER-beta-binding drugs protected mice from auditory damage. Furthermore, not only was ER-beta found in the ears of both male and female mice, but levels of the nerve-protecting protein BDNF were reduced in mice that lacked either ER-beta or aromatase. The authors therefore concluded that this identification of an auditory-protective role for the estrogen receptor ER-beta may enable the development of new treatments for hearing loss.
TITLE: Estrogen receptor-beta protects against acoustic trauma in mice
AUTHOR CONTACT:
Barbara Canlon
Karolinska Institute, Stockholm, Sweden
Source: Karen Honey
Journal of Clinical Investigation
View drug information on Estradiol.
TITLE: Estrogen receptor-beta protects against acoustic trauma in mice
AUTHOR CONTACT:
Barbara Canlon
Karolinska Institute, Stockholm, Sweden
Source: Karen Honey
Journal of Clinical Investigation
View drug information on Estradiol.
The Secret To Longevity May Be Hidden In Hydrogen Sulfide
Hydrogen sulfide, or H2S, the chemical that gives rotten eggs their sulfurous stench -- and the same compound that researchers at Fred Hutchinson Cancer Research Center successfully have used to put mice into a state of reversible metabolic hibernation -- has now been shown to significantly increase life span and heat tolerance in the nematode worm, or C. elegans.
These findings by Mark Roth, Ph.D., a member of the Center's Basic Sciences Division, and Dana Miller, Ph.D., a postdoctoral research fellow in Roth's lab, appear in the PNAS Online Early Edition, a publication of the Proceedings of the National Academy of Sciences of the United States of America.
In an effort to understand the mechanisms by which hydrogen sulfide induces hibernation in mice, the researchers turned to the tiny nematode, a workhorse of laboratory science because its biology is similar in many respects that of humans. For example, like humans, nematodes have a central nervous system and the ability to reproduce. The worms also are ideally suited for studying life span, because they normally live for only two to three weeks.
The researchers found, to their surprise, that nematodes that were raised in a carefully controlled atmosphere with low concentrations of H2S (50 parts per million in room air) did not hibernate. Instead, their metabolism and reproductive activity remained normal, their life span increased and they became more tolerant to heat than untreated worms.
The H2S-exposed worms lived eight times longer than untreated worms when moved from normal room air (22 C or 70 F) to a high-temperature environment (35 degrees Celsius, or 95 F). Roth and colleagues replicated these results in 15 independent experiments.
"Although the maximum extension of survival time varied between experiments, the effect was quite robust. On average, 77 percent of the worms exposed to H2S outlived the untreated worms," Roth said. The mean life span of worms grown in an atmosphere laced with hydrogen sulfide was 9.6 days greater than that of the untreated population, a longevity increase of 70 percent.
Most genes that influence life span in C. elegans act on one of three genetic pathways: those that control insulin/IGF (insulin growth factor) signaling, those that control mitochondrial function and those that modulate the effects of dietary restriction.
Roth and colleagues ruled out hydrogen sulfide's influence on each of these pathways. Instead, they suspect it acts through a different mechanism. One theory is that exposure to H2S naturally regulates the activity of a gene called SIR-2.1, which has been shown to influence life span in many organisms, including the nematode. Previous studies have found that over-expression of this gene increases the longevity of C. elegans by 18 percent to 20 percent.
"Further research into the genetic mechanisms that influence H2S-induced changes in nematodes may reveal similar mechanisms in higher organisms, including humans, with potentially wide-ranging implications in both basic research and clinical practice," Roth said. For example, understanding how H2S affects physiology in animals may lead to the development of drugs that could delay the onset of age-related diseases in humans such as cancer, Alzheimer's and heart disease.
Roth's hibernation research made headlines worldwide in April 2005 when he was the first to show that exposing mice to minute amounts of hydrogen sulfide could induce a state of reversible "hibernation on demand," dramatically reducing their core body temperature, respiration and need for oxygen. Roth envisions a future in which similar techniques could be used to "buy time" for critically ill patients who otherwise would face injury and death from insufficient blood and oxygen supply to organs and tissues.
Roth hypothesizes that H2S, a chemical normally produced in humans and animals, may help regulate body temperature and metabolic activity. Hydrogen sulfide is similar to oxygen at the molecular level because it binds at many of the same proteins. As a result, H2S competes for and interferes with the body's ability to use oxygen for energy production -- a process within the cell's power-generating machinery called oxidative phosphorylation.
The inhibition of this function, in turn, is what Roth and colleagues believe causes organisms such as mice to shut down metabolically and enter a hibernation-like state pending re-exposure to normal room air, after which they quickly regain normal function and metabolic activity with no long-term negative effects.
The National Institutes of Health, the NIH Center for Research Resources, the Caenorhabditis Genetics Center and a National Research Service Award Fellowship supported this work.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc/.
Source: Kristen Lidke Woodward
Fred Hutchinson Cancer Research Center
These findings by Mark Roth, Ph.D., a member of the Center's Basic Sciences Division, and Dana Miller, Ph.D., a postdoctoral research fellow in Roth's lab, appear in the PNAS Online Early Edition, a publication of the Proceedings of the National Academy of Sciences of the United States of America.
In an effort to understand the mechanisms by which hydrogen sulfide induces hibernation in mice, the researchers turned to the tiny nematode, a workhorse of laboratory science because its biology is similar in many respects that of humans. For example, like humans, nematodes have a central nervous system and the ability to reproduce. The worms also are ideally suited for studying life span, because they normally live for only two to three weeks.
The researchers found, to their surprise, that nematodes that were raised in a carefully controlled atmosphere with low concentrations of H2S (50 parts per million in room air) did not hibernate. Instead, their metabolism and reproductive activity remained normal, their life span increased and they became more tolerant to heat than untreated worms.
The H2S-exposed worms lived eight times longer than untreated worms when moved from normal room air (22 C or 70 F) to a high-temperature environment (35 degrees Celsius, or 95 F). Roth and colleagues replicated these results in 15 independent experiments.
"Although the maximum extension of survival time varied between experiments, the effect was quite robust. On average, 77 percent of the worms exposed to H2S outlived the untreated worms," Roth said. The mean life span of worms grown in an atmosphere laced with hydrogen sulfide was 9.6 days greater than that of the untreated population, a longevity increase of 70 percent.
Most genes that influence life span in C. elegans act on one of three genetic pathways: those that control insulin/IGF (insulin growth factor) signaling, those that control mitochondrial function and those that modulate the effects of dietary restriction.
Roth and colleagues ruled out hydrogen sulfide's influence on each of these pathways. Instead, they suspect it acts through a different mechanism. One theory is that exposure to H2S naturally regulates the activity of a gene called SIR-2.1, which has been shown to influence life span in many organisms, including the nematode. Previous studies have found that over-expression of this gene increases the longevity of C. elegans by 18 percent to 20 percent.
"Further research into the genetic mechanisms that influence H2S-induced changes in nematodes may reveal similar mechanisms in higher organisms, including humans, with potentially wide-ranging implications in both basic research and clinical practice," Roth said. For example, understanding how H2S affects physiology in animals may lead to the development of drugs that could delay the onset of age-related diseases in humans such as cancer, Alzheimer's and heart disease.
Roth's hibernation research made headlines worldwide in April 2005 when he was the first to show that exposing mice to minute amounts of hydrogen sulfide could induce a state of reversible "hibernation on demand," dramatically reducing their core body temperature, respiration and need for oxygen. Roth envisions a future in which similar techniques could be used to "buy time" for critically ill patients who otherwise would face injury and death from insufficient blood and oxygen supply to organs and tissues.
Roth hypothesizes that H2S, a chemical normally produced in humans and animals, may help regulate body temperature and metabolic activity. Hydrogen sulfide is similar to oxygen at the molecular level because it binds at many of the same proteins. As a result, H2S competes for and interferes with the body's ability to use oxygen for energy production -- a process within the cell's power-generating machinery called oxidative phosphorylation.
The inhibition of this function, in turn, is what Roth and colleagues believe causes organisms such as mice to shut down metabolically and enter a hibernation-like state pending re-exposure to normal room air, after which they quickly regain normal function and metabolic activity with no long-term negative effects.
The National Institutes of Health, the NIH Center for Research Resources, the Caenorhabditis Genetics Center and a National Research Service Award Fellowship supported this work.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc/.
Source: Kristen Lidke Woodward
Fred Hutchinson Cancer Research Center
'Green' Alternative For Improving Water Quality
Algae--already being eyed for biofuel production--could be put to use right away to remove nitrogen and phosphorus in livestock manure runoff, according to an Agricultural Research Service (ARS) scientist. That could give resource managers a new eco-friendly option for reducing the level of agricultural pollutants that contaminate water quality in the Chesapeake Bay.
Microbiologist Walter Mulbry works at the ARS Environmental Management and Byproduct Utilization Research Unit in Beltsville, Md., which is located in the Chesapeake Bay watershed. In 2003, Mulbry set up four algal turf scrubber (ATS) raceways outside dairy barns in Beltsville. The shallow 100-foot raceways were covered with nylon netting that created a scaffold where the algae could grow.
For the next three years, from April until December, a submerged water pump at one end of the raceways circulated a mix of fresh water and raw or anaerobically digested dairy manure effluent over the algae. Within two to three weeks after the ATS system was started up every spring, the raceways supported thriving colonies of green filamentous algae.
Algae productivity was highest in the spring and declined during the summer, in part because of higher water temperatures and also because the raceways provided snails and midge larvae ample opportunity to graze on the algae.
Mulbry and his partners harvested wet algae every four to 12 days, dried it, and then analyzed the dried biomass for nitrogen and phosphorus levels. His results indicate that the ATS system recovered 60 to 90 percent of the nitrogen and 70 to 100 percent of the phosphorus from the manure effluents. They also calculated that the cost for this capture was comparable to other manure management practices--around $5 to $6 for each pound of nitrogen that was recovered and around $25 for each pound of phosphorus that was recovered.
Results from this research were published in Bioresource Technology.
Source:
Ann Perry
United States Department of Agriculture-Research, Education, and Economics
Microbiologist Walter Mulbry works at the ARS Environmental Management and Byproduct Utilization Research Unit in Beltsville, Md., which is located in the Chesapeake Bay watershed. In 2003, Mulbry set up four algal turf scrubber (ATS) raceways outside dairy barns in Beltsville. The shallow 100-foot raceways were covered with nylon netting that created a scaffold where the algae could grow.
For the next three years, from April until December, a submerged water pump at one end of the raceways circulated a mix of fresh water and raw or anaerobically digested dairy manure effluent over the algae. Within two to three weeks after the ATS system was started up every spring, the raceways supported thriving colonies of green filamentous algae.
Algae productivity was highest in the spring and declined during the summer, in part because of higher water temperatures and also because the raceways provided snails and midge larvae ample opportunity to graze on the algae.
Mulbry and his partners harvested wet algae every four to 12 days, dried it, and then analyzed the dried biomass for nitrogen and phosphorus levels. His results indicate that the ATS system recovered 60 to 90 percent of the nitrogen and 70 to 100 percent of the phosphorus from the manure effluents. They also calculated that the cost for this capture was comparable to other manure management practices--around $5 to $6 for each pound of nitrogen that was recovered and around $25 for each pound of phosphorus that was recovered.
Results from this research were published in Bioresource Technology.
Source:
Ann Perry
United States Department of Agriculture-Research, Education, and Economics
Not-So-Secret Intentions In The Brain
Every day we plan numerous actions, such as to return a book to a friend or to make an appointment. How and where the brain stores these intentions has been revealed by John-Dylan Haynes from the Max Planck Institute for Human Cognitive and Brain Sciences, in cooperation with researchers from London and Tokyo. For the first time they were able to "read" participants' intentions out of their brain activity. This was made possible by a new combination of functional magnetic resonance imaging and sophisticated computer algorithms (Current Biology).
Our secret intentions remain concealed until we put them into action -so we believe. Now researchers have been able to decode these secret intentions from patterns of their brain activity. They let subjects freely and covertly choose between two possible tasks - to either add or subtract two numbers. They were then asked to hold in mind their intention for a while until the relevant numbers were presented on a screen. The researchers were able to recognize the subjects intentions with 70% accuracy based alone on their brain activity - even before the participants had seen the numbers and had started to perform the calculation.
Participants made their choice covertly and initially did not know the two numbers they were supposed to add or subtract. Only a few seconds later the numbers appeared on a screen and the participants could perform the calculation. This ensured that the intention itself was being read out, rather than brain activity related to performing the calculation or pressing the buttons to indicate the response. "It has been previously assumed that freely selected plans might be stored in the middle regions of the prefrontal cortex, whereas plans following external instructions could be stored on the surface of the brain. We were able to confirm this theory in our experiments", Haynes explained.
The work of Haynes and his colleagues goes far beyond simply confirming previous theories. It has never before been possible to read out of brain activity how a person has decided to act in the future. The trick by which the invisible is made visible lies in a new method called "multivariate pattern recognition". A computer is programmed to recognize characteristic activation patterns in the brain that typically occur in association with specific thoughts. Once this computer has been "trained" it can be used to predict the decisions of subjects from their brain activity alone. An important technical innovation also lies in combining information across extended regions of the brain to strongly increase sensitivity.
The study also reveals fundamental principles about the way the brain stores intentions. "The experiments show that intentions are not encoded in single neurons but in a whole spatial pattern of brain activity", says Haynes. They furthermore reveal that different regions of the prefrontal cortex perform different operations. Regions towards the front of the brain store the intention until it is executed, whereas regions further back take over when subjects become active and start doing the calculation. "Intentions for future actions that are encoded in one part of the brain need to be copied to a different region to be executed", says Haynes.
These findings also raise hope for improvement of clinical and technical applications. Already today the first steps are being made in easing the lives of paralyzed patients with computer-assisted prosthetic devices and so-called brain computer interfaces. These devices focus on reading out the movement the patient intends to - but is unable to - perform. Previous research has shown that patients can move artificial limbs or computer cursors purely by the power of their mind. The current research by Haynes and colleagues now opens up a completely new perspective.
In future it will be possible to read even abstract thoughts and intentions out of patients' brains. One day even the intention to "open the blue folder" or "reply to the email" could be picked up by brain scanners and turned into the appropriate action.
Original work:
John-Dylan Haynes, Katsuyuki Sakai, Geraint Rees, Sam Gilbert, Chris Frith, Dick Passingham
Reading hidden intentions in the human brain
Current Biology, February 20th, 2007.
Contact: Prof. Dr. John-Dylan Haynes
Max-Planck-Gesellschaft
Our secret intentions remain concealed until we put them into action -so we believe. Now researchers have been able to decode these secret intentions from patterns of their brain activity. They let subjects freely and covertly choose between two possible tasks - to either add or subtract two numbers. They were then asked to hold in mind their intention for a while until the relevant numbers were presented on a screen. The researchers were able to recognize the subjects intentions with 70% accuracy based alone on their brain activity - even before the participants had seen the numbers and had started to perform the calculation.
Participants made their choice covertly and initially did not know the two numbers they were supposed to add or subtract. Only a few seconds later the numbers appeared on a screen and the participants could perform the calculation. This ensured that the intention itself was being read out, rather than brain activity related to performing the calculation or pressing the buttons to indicate the response. "It has been previously assumed that freely selected plans might be stored in the middle regions of the prefrontal cortex, whereas plans following external instructions could be stored on the surface of the brain. We were able to confirm this theory in our experiments", Haynes explained.
The work of Haynes and his colleagues goes far beyond simply confirming previous theories. It has never before been possible to read out of brain activity how a person has decided to act in the future. The trick by which the invisible is made visible lies in a new method called "multivariate pattern recognition". A computer is programmed to recognize characteristic activation patterns in the brain that typically occur in association with specific thoughts. Once this computer has been "trained" it can be used to predict the decisions of subjects from their brain activity alone. An important technical innovation also lies in combining information across extended regions of the brain to strongly increase sensitivity.
The study also reveals fundamental principles about the way the brain stores intentions. "The experiments show that intentions are not encoded in single neurons but in a whole spatial pattern of brain activity", says Haynes. They furthermore reveal that different regions of the prefrontal cortex perform different operations. Regions towards the front of the brain store the intention until it is executed, whereas regions further back take over when subjects become active and start doing the calculation. "Intentions for future actions that are encoded in one part of the brain need to be copied to a different region to be executed", says Haynes.
These findings also raise hope for improvement of clinical and technical applications. Already today the first steps are being made in easing the lives of paralyzed patients with computer-assisted prosthetic devices and so-called brain computer interfaces. These devices focus on reading out the movement the patient intends to - but is unable to - perform. Previous research has shown that patients can move artificial limbs or computer cursors purely by the power of their mind. The current research by Haynes and colleagues now opens up a completely new perspective.
In future it will be possible to read even abstract thoughts and intentions out of patients' brains. One day even the intention to "open the blue folder" or "reply to the email" could be picked up by brain scanners and turned into the appropriate action.
Original work:
John-Dylan Haynes, Katsuyuki Sakai, Geraint Rees, Sam Gilbert, Chris Frith, Dick Passingham
Reading hidden intentions in the human brain
Current Biology, February 20th, 2007.
Contact: Prof. Dr. John-Dylan Haynes
Max-Planck-Gesellschaft
Self-Healing Autonomous Material Comes To Life
You've seen it in movies: the human-like, robot assassin quickly regenerates its structure after being damaged beyond recognition. This "Terminator" scenario is becoming less far-fetched as recent advances in structural health monitoring systems have led to a variety of ways to identify damage to a structural system.
Now, in the Journal of Applied Physics, researchers at Arizona State University have created a material that may be able to not only sense damage in structural materials, such as cracking in a fiber-reinforced composite, but to even heal it. The aim of developing "autonomous adaptive structures" is to mimic the ability of biological systems such as bone to sense the presence of damage, halt its progression, and regenerate itself.
The novel autonomous material developed by Henry Sodano and colleagues uses "shape-memory" polymers with an embedded fiber-optic network that functions as both the damage detection sensor and thermal stimulus delivery system to produce a response that mimics the advanced sensory and healing traits shown in biological systems. An infrared laser transmits light through the fiber-optic system to locally heat the material, stimulating the toughening and healing mechanisms.
The material system is capable of increasing the toughness of a specimen by 11 times. After toughening the specimen, the crack can be closed using the shape-memory effect to recover an unprecedented 96 percent of the object's original strength. In fact, after the crack is closed, the new material is nearly five times as tough as the original specimen, even though it has been strained past its original failure strain point by a factor of four. The material and healing process can be applied while the structure is in operation, which has not been possible with existing healing techniques.
Source: American Institute of Physics (AIP)
Now, in the Journal of Applied Physics, researchers at Arizona State University have created a material that may be able to not only sense damage in structural materials, such as cracking in a fiber-reinforced composite, but to even heal it. The aim of developing "autonomous adaptive structures" is to mimic the ability of biological systems such as bone to sense the presence of damage, halt its progression, and regenerate itself.
The novel autonomous material developed by Henry Sodano and colleagues uses "shape-memory" polymers with an embedded fiber-optic network that functions as both the damage detection sensor and thermal stimulus delivery system to produce a response that mimics the advanced sensory and healing traits shown in biological systems. An infrared laser transmits light through the fiber-optic system to locally heat the material, stimulating the toughening and healing mechanisms.
The material system is capable of increasing the toughness of a specimen by 11 times. After toughening the specimen, the crack can be closed using the shape-memory effect to recover an unprecedented 96 percent of the object's original strength. In fact, after the crack is closed, the new material is nearly five times as tough as the original specimen, even though it has been strained past its original failure strain point by a factor of four. The material and healing process can be applied while the structure is in operation, which has not been possible with existing healing techniques.
Source: American Institute of Physics (AIP)
A Potentially Universal Mechanism Of Aging Identified By Researchers
Like our current financial crisis, the aging process might also be a product of excessive deregulation.
Researchers have discovered that DNA damage decreases a cell's ability to regulate which genes are turned on and off in particular settings. This mechanism, which applies both to fungus and to us, might represent a universal culprit for aging.
"This is the first potentially fundamental, root cause of aging that we've found," says Harvard Medical School professor of pathology David Sinclair. "There may very well be others, but our finding that aging in a simple yeast cell is directly relevant to aging in mammals comes as a surprise."
These findings appear in the November 28 issue of the journal Cell.
For some time, scientists have know that a group of genes called sirtuins are involved in the aging process. These genes, when stimulated by either the red-wine chemical resveratrol (web.med.harvard/sites/RELEASES/html/11_1Sinclair.html) or caloric restriction (web.med.harvard/sites/RELEASES/html/sinclair.html), appear to have a positive effect on both aging and health.
Nearly a decade ago, Sinclair and colleagues in the Massachusetts Institute of Technology lab of Leonard Guarente found that a particular sirtuin in yeast affected the aging process in two specific ways - it helped regulate gene activity in cells and repair breaks in DNA. As DNA damage accumulated over time, however, the sirtuin became too distracted to properly regulate gene activity, and as a result, characteristics of aging set in.
"For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast," says Sinclair. "But we decided to test of this same process occurs in mammals."
Philipp Oberdoerffer, a postdoctoral scientist in Sinclair's Harvard Medical School lab, used a sophisticated microarray platform to probe the mammalian version of the yeast sirtuin gene in mouse cells. The results in mice corroborated what Sinclair, Guarente, and colleagues had found in yeast ten years earlier.
Oberdoerffer found that a primary function of sirtuin in the mammalian system was to oversee patterns of gene expression (which genes are switch on and which are switch off). While all genes are present in all cells, only a select few need to be active at any given time. If the wrong genes are switched on, this can harm the cell. (In a kidney cell, for example, all liver genes are present, but switched off. If these genes were to become active, that could damage the kidney.) As a protective measure, sirtuins guard genes that should be off and ensure that they remain silent. To do this, they help preserve the molecular packaging - called chromatin - that shrink-wraps these genes tight and keeps them idle.
The problem for the cell, however, is that the sirtuin has another important job. When DNA is damaged by UV light or free radicals, sirtuins act as volunteer emergency responders. They leave their genomic guardian posts and aid the DNA repair mechanism at the site of damage.
During this unguarded interval, the chromatin wrapping may start to unravel, and the genes that are meant to stay silent may in fact come to life.
For the most part, sirtuins are able to return to their post and wrap the genes back in their packaging, before they cause permanent damage. As mice age, however, rates of DNA damage (typically caused by degrading mitochondria) increase. The authors found that this damage pulls sirtuins away from their posts more frequently. As a result, deregulation of gene expression becomes chronic. Chromatin unwraps in places where it shouldn't, as sirtuin guardians work overtime putting out fires around the genome, and the unwrapped genes never return to their silent state.
In fact, many of these haplessly activated genes are directly linked with aging phenotypes. The researchers found that a number of such unregulated mouse genes were persistently active in older mice.
"We then began wondering what would happen if we put more of the sirtuin back into the mice," says Oberdoerffer. "Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age."
That's precisely what happened. Using a mouse genetically altered to model lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or fed them the sirtuin activator resveratrol, which in turn extended their mean lifespan by 24 to 46 percent.
"It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author on the paper. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time."
Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these findings may have therapeutic relevance.
"According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results," says Oberdoerffer. "Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed - unlike actual mutations in DNA. We see here, through a proof-of-principal demonstration, that elements of aging can be reversed."
Recent findings by Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, also discovered that mice that lack sirtuin are susceptible to DNA damage and cancer, reinforcing Sinclair's and Oberdoerffer's data.
This research was funded by the National Institutes of Health, and the Glenn Foundation for Medical Research. David Sinclair is a consultant to Genocea, Shaklee and Sirtris, a GSK company developing sirtuin based drugs.
Written by David Cameron
Full citation:
Cell, November 28, 2008 Volume 135, Issue 6
"SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters Gene Expression during Aging"
Philipp Oberdoerffer(1), Shaday Michan(1), Michael McVay(1), Raul Mostoslavsky(2), James Vann(3), Sang-Kyu Park(3), Andrea Hartlerode(4), Judith Stegmuller(1,7), Angela Hafner(1), Patrick Loerch(1), Sarah M. Wright(5), Kevin D. Mills(5), Azad Bonni(1), Bruce A. Yankner(1), Ralph Scully(4), Tomas A. Prolla(3), Frederick W. Alt(6), and David A. Sinclair(1)
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA
Massachusetts General Hospital Cancer Center, Boston, MA
University of Wisconsin, Department of Genetics and Medical Genetics, Madison, WI
Beth Israel Deaconess Medical Center, Boston, MA
The Jackson Laboratory, Bar Harbor, ME
Howard Hughes Medical Institute, Children's Hospital Boston, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, MA
Present address: Max Planck Institute for Experimental Medicine, 37075 Gottingen, Germany
Harvard Medical School hms.harvard has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: David Cameron
Harvard Medical School
Researchers have discovered that DNA damage decreases a cell's ability to regulate which genes are turned on and off in particular settings. This mechanism, which applies both to fungus and to us, might represent a universal culprit for aging.
"This is the first potentially fundamental, root cause of aging that we've found," says Harvard Medical School professor of pathology David Sinclair. "There may very well be others, but our finding that aging in a simple yeast cell is directly relevant to aging in mammals comes as a surprise."
These findings appear in the November 28 issue of the journal Cell.
For some time, scientists have know that a group of genes called sirtuins are involved in the aging process. These genes, when stimulated by either the red-wine chemical resveratrol (web.med.harvard/sites/RELEASES/html/11_1Sinclair.html) or caloric restriction (web.med.harvard/sites/RELEASES/html/sinclair.html), appear to have a positive effect on both aging and health.
Nearly a decade ago, Sinclair and colleagues in the Massachusetts Institute of Technology lab of Leonard Guarente found that a particular sirtuin in yeast affected the aging process in two specific ways - it helped regulate gene activity in cells and repair breaks in DNA. As DNA damage accumulated over time, however, the sirtuin became too distracted to properly regulate gene activity, and as a result, characteristics of aging set in.
"For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast," says Sinclair. "But we decided to test of this same process occurs in mammals."
Philipp Oberdoerffer, a postdoctoral scientist in Sinclair's Harvard Medical School lab, used a sophisticated microarray platform to probe the mammalian version of the yeast sirtuin gene in mouse cells. The results in mice corroborated what Sinclair, Guarente, and colleagues had found in yeast ten years earlier.
Oberdoerffer found that a primary function of sirtuin in the mammalian system was to oversee patterns of gene expression (which genes are switch on and which are switch off). While all genes are present in all cells, only a select few need to be active at any given time. If the wrong genes are switched on, this can harm the cell. (In a kidney cell, for example, all liver genes are present, but switched off. If these genes were to become active, that could damage the kidney.) As a protective measure, sirtuins guard genes that should be off and ensure that they remain silent. To do this, they help preserve the molecular packaging - called chromatin - that shrink-wraps these genes tight and keeps them idle.
The problem for the cell, however, is that the sirtuin has another important job. When DNA is damaged by UV light or free radicals, sirtuins act as volunteer emergency responders. They leave their genomic guardian posts and aid the DNA repair mechanism at the site of damage.
During this unguarded interval, the chromatin wrapping may start to unravel, and the genes that are meant to stay silent may in fact come to life.
For the most part, sirtuins are able to return to their post and wrap the genes back in their packaging, before they cause permanent damage. As mice age, however, rates of DNA damage (typically caused by degrading mitochondria) increase. The authors found that this damage pulls sirtuins away from their posts more frequently. As a result, deregulation of gene expression becomes chronic. Chromatin unwraps in places where it shouldn't, as sirtuin guardians work overtime putting out fires around the genome, and the unwrapped genes never return to their silent state.
In fact, many of these haplessly activated genes are directly linked with aging phenotypes. The researchers found that a number of such unregulated mouse genes were persistently active in older mice.
"We then began wondering what would happen if we put more of the sirtuin back into the mice," says Oberdoerffer. "Our hypothesis was that with more sirtuins, DNA repair would be more efficient, and the mouse would maintain a youthful pattern gene expression into old age."
That's precisely what happened. Using a mouse genetically altered to model lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or fed them the sirtuin activator resveratrol, which in turn extended their mean lifespan by 24 to 46 percent.
"It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins redistribute with damage or aging, is also applicable to mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is not an author on the paper. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilize this redistribution of sirtuins over time."
Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these findings may have therapeutic relevance.
"According to this specific mechanism, while DNA damage exacerbates aging, the actual cause is not the DNA damage itself but the lack of gene regulation that results," says Oberdoerffer. "Lots of research has shown that this particular process of regulating gene activity, otherwise known as epigenetics, can be reversed - unlike actual mutations in DNA. We see here, through a proof-of-principal demonstration, that elements of aging can be reversed."
Recent findings by Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, also discovered that mice that lack sirtuin are susceptible to DNA damage and cancer, reinforcing Sinclair's and Oberdoerffer's data.
This research was funded by the National Institutes of Health, and the Glenn Foundation for Medical Research. David Sinclair is a consultant to Genocea, Shaklee and Sirtris, a GSK company developing sirtuin based drugs.
Written by David Cameron
Full citation:
Cell, November 28, 2008 Volume 135, Issue 6
"SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters Gene Expression during Aging"
Philipp Oberdoerffer(1), Shaday Michan(1), Michael McVay(1), Raul Mostoslavsky(2), James Vann(3), Sang-Kyu Park(3), Andrea Hartlerode(4), Judith Stegmuller(1,7), Angela Hafner(1), Patrick Loerch(1), Sarah M. Wright(5), Kevin D. Mills(5), Azad Bonni(1), Bruce A. Yankner(1), Ralph Scully(4), Tomas A. Prolla(3), Frederick W. Alt(6), and David A. Sinclair(1)
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA
Massachusetts General Hospital Cancer Center, Boston, MA
University of Wisconsin, Department of Genetics and Medical Genetics, Madison, WI
Beth Israel Deaconess Medical Center, Boston, MA
The Jackson Laboratory, Bar Harbor, ME
Howard Hughes Medical Institute, Children's Hospital Boston, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, MA
Present address: Max Planck Institute for Experimental Medicine, 37075 Gottingen, Germany
Harvard Medical School hms.harvard has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: David Cameron
Harvard Medical School
Yale Receives Major Gift From Dr. Raymond And Beverly Sackler To Launch New Institute For Biological, Physical & Engineering Sciences
Research collaboration among scientists working in the traditionally unrelated fields of biology, physics and engineering will accelerate at Yale, thanks to a gift from Dr. Raymond and Beverly Sackler.
"As a physician, I have believed that biomedical research could be accelerated by the application of tools routinely used by physicists and engineers," Dr. Sackler said.
Leading researchers from three different faculties at Yale - the School of Medicine, the School of Engineering and the faculty of Arts and Sciences - will be brought together through the programs of the new Sackler Institute for Biological, Physical and Engineering Sciences. Dr. Lynne Regan, who holds Professorships in both Molecular Biophysics and Biochemistry and Chemistry, has been appointed by the Provost to be the first Director of the Institute.
The institute will be organized around several overlapping and interconnected research thrusts. Each multidisciplinary group will address different aspects of a common quest: predicting biological behavior - at the molecular, cellular and whole organism levels.
There will be multiple components of the Institute when it is launched, including graduate fellowships for students interested in pursuing Ph.D. degrees which straddle the physical and life sciences, visiting scholars to bring faculty to Yale from other institutions engaged in interdisciplinary research, and intensive short courses in the summer to teach the multiple techniques which are used across the different disciplines.
"The Sacker Institute will bring together faculty from departments across the university and enable transformative research and teaching initiatives" Dr. Regan said. "We are very excited by the new opportunities this gift brings to Yale."
The fact that Yale had a track record for collaborative research is what appealed to the Institute's benefactors. "I have had valuable experiences at various universities in and outside the US, with scientists in the physical and biologic areas," Dr. Sackler said. "Several years ago, we established an Institute of Biophysics at Tel Aviv University, which has led to collaborative innovative and productive research amongst the physical, biological and engineering disciplines."
Interdisciplinary research has been a major focus of Yale's science, medicine and engineering efforts, according to University President Richard C. Levin. "The timing of this gift is perfect," Levin said. "The Sackler Institute will provide a tremendous boost to the cross-disciplinary interactions that have been growing at Yale among physical scientists, engineers, and life scientists. There is great potential in research and education that crosses the traditional boundaries of departments and disciplines."
Yale University
"As a physician, I have believed that biomedical research could be accelerated by the application of tools routinely used by physicists and engineers," Dr. Sackler said.
Leading researchers from three different faculties at Yale - the School of Medicine, the School of Engineering and the faculty of Arts and Sciences - will be brought together through the programs of the new Sackler Institute for Biological, Physical and Engineering Sciences. Dr. Lynne Regan, who holds Professorships in both Molecular Biophysics and Biochemistry and Chemistry, has been appointed by the Provost to be the first Director of the Institute.
The institute will be organized around several overlapping and interconnected research thrusts. Each multidisciplinary group will address different aspects of a common quest: predicting biological behavior - at the molecular, cellular and whole organism levels.
There will be multiple components of the Institute when it is launched, including graduate fellowships for students interested in pursuing Ph.D. degrees which straddle the physical and life sciences, visiting scholars to bring faculty to Yale from other institutions engaged in interdisciplinary research, and intensive short courses in the summer to teach the multiple techniques which are used across the different disciplines.
"The Sacker Institute will bring together faculty from departments across the university and enable transformative research and teaching initiatives" Dr. Regan said. "We are very excited by the new opportunities this gift brings to Yale."
The fact that Yale had a track record for collaborative research is what appealed to the Institute's benefactors. "I have had valuable experiences at various universities in and outside the US, with scientists in the physical and biologic areas," Dr. Sackler said. "Several years ago, we established an Institute of Biophysics at Tel Aviv University, which has led to collaborative innovative and productive research amongst the physical, biological and engineering disciplines."
Interdisciplinary research has been a major focus of Yale's science, medicine and engineering efforts, according to University President Richard C. Levin. "The timing of this gift is perfect," Levin said. "The Sackler Institute will provide a tremendous boost to the cross-disciplinary interactions that have been growing at Yale among physical scientists, engineers, and life scientists. There is great potential in research and education that crosses the traditional boundaries of departments and disciplines."
Yale University
Single-Celled Bacterium Works 24-7 Converting Light To Energy By Day, Moonlighting At Night
Researchers at Washington University in St. Louis have gained the first detailed insight into the way circadian rhythms govern global gene expression in Cyanothece, a type of cyanobacterium (blue-green algae) known to cycle between photosynthesis during the day and nitrogen fixation at night.
In general, this study shows that during the day, Cyanothece increases expression of genes governing photosynthesis and sugar production, as expected. At night, however, Cyanothece ramps up the expression of genes governing a surprising number of vital processes, including energy metabolism, nitrogen fixation, respiration, the translation of messenger RNA (mRNA) to proteins and the folding of these proteins into proper configurations.
The findings have implications for energy production and storage of clean, alternative biofuels.
The study was published in the April online issue of the Proceedings of the National Academy of Science. The research was funded by the U.S. Department of Energy in the context of a Biology Grand Challenge project administered by the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Laboratory.
Bacterial biological clock
"One of the mysteries in cellular physiology is this business of rhythm," said Himadri Pakrasi, Ph.D., the George William and Irene Koechig Freiberg Professor in Arts & Sciences and lead investigator of this project. "Circadian rhythm controls many physiological processes in higher organisms, including plants and people. Cyanothece are of great interest because, even though one cell lives less than a day, dividing every 10 to 14 hours, together they have a biological clock telling them when to do what over a 24-hour period. In fact, cyanobacteria are the only bacteria known to have a circadian behavior."
Why does such a short-lived, single-celled organism care what time it is? The answer, according to this study, is that the day-night cycle has a tremendous impact on the cell's physiology, cycling on and off many vital metabolic processes, not just the obvious ones.
Among the obvious cycling processes are photosynthesis and nitrogen fixation. It is difficult for one cell to perform these two functions because the processes are at odds with one another. Fixing nitrogen requires nitrogenase, a catalyst that helps the chemical reaction move forward. Unhelpfully, the oxygen produced by photosynthesis degrades nitrogenase, making nitrogen fixation difficult or impossible in photosynthetic organisms.
Other filamentous cyanobacteria perform photosynthesis and nitrogen fixation in different, separate cells. As a single-celled bacterium, however, Cyanothece cannot separate these antagonistic processes in space. But it can separate them in time.
Agreeing with previous studies, this study found that Cyanothece genes for photosynthesis turn on during the day and genes for nitrogen fixation turn on at night. The surprise is the tremendous impact the day-night cycle has on the overall physiology of the cell.
"It goes far beyond just the aspects of nitrogen fixation and photosynthesis," said Pakrasi, who also directs Washington University's International Center for Advanced Renewable Energy and Sustainability (I-CARES) to encourage and coordinate university-wide and external collaborative research in the areas of renewable energy and sustainability - including biofuels, carbon dioxide mitigation and coal-related issues. The university will invest more than $55 million in the initiative.
Cyanothece's 'Dark Period'
To see the effect of day-night cycles on the overall physiology of Cyanothece, lead author Jana Stöckel, Ph.D., Washington University post-doctoral researcher, and other members of this research team examined the expression of 5,000 genes, measuring the amount of messenger RNA for each gene in alternating dark and light periods over 48 hours. At a given time, the mRNA levels indicated what the cells were doing. For example, when the researchers identified high levels of many mRNAs encoding various protein components of the nitrogenase enzyme, they knew that the cells were fixing nitrogen at that time, in this case, during the dark periods.
Of the 5,000 genes studied, nearly 30 percent cycled on and off with changing light and dark periods. These particular genes, the study found, also govern major metabolic processes. Therefore, the cycling of mRNA transcription, Pakrasi said, "provides deep insight into the physiological behavior of the organism - day and night."
During the day, Cyanothece busies itself with photosynthesis. Using energy from sunlight, carbon dioxide from the atmosphere, and water, Cyanothece produces glucose, a sugar it stores in glycogen granules, filling its chemical gas tank. At night, the Cyanothece ramps up production of nitrogenase to fix nitrogen, as expected. Since nitrogen fixation requires a lot of energy, Cyanothece uses the glycogen stored through a process called respiration. Because respiration requires oxygen, the cells conveniently use up this by-product of photosynthesis, likely helping to protect nitrogenase from degradation.
Through this cyclic expression of genes, Cyanothece is essentially a living battery, storing energy from the sun for later use. This feat continues to elude scientists searching for ways to harness sunlight and produce energy on a large scale. With this in mind, a new project for the Pakrasi team seeks to use the machinery of Cyanothece - its energy storage strategy, its anaerobic conditions that protect important enzymes - as a biofactory to produce hydrogen from sunlight, the ultimate clean energy source.
Source: Gayle Geren
Washington University in St. Louis
In general, this study shows that during the day, Cyanothece increases expression of genes governing photosynthesis and sugar production, as expected. At night, however, Cyanothece ramps up the expression of genes governing a surprising number of vital processes, including energy metabolism, nitrogen fixation, respiration, the translation of messenger RNA (mRNA) to proteins and the folding of these proteins into proper configurations.
The findings have implications for energy production and storage of clean, alternative biofuels.
The study was published in the April online issue of the Proceedings of the National Academy of Science. The research was funded by the U.S. Department of Energy in the context of a Biology Grand Challenge project administered by the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Laboratory.
Bacterial biological clock
"One of the mysteries in cellular physiology is this business of rhythm," said Himadri Pakrasi, Ph.D., the George William and Irene Koechig Freiberg Professor in Arts & Sciences and lead investigator of this project. "Circadian rhythm controls many physiological processes in higher organisms, including plants and people. Cyanothece are of great interest because, even though one cell lives less than a day, dividing every 10 to 14 hours, together they have a biological clock telling them when to do what over a 24-hour period. In fact, cyanobacteria are the only bacteria known to have a circadian behavior."
Why does such a short-lived, single-celled organism care what time it is? The answer, according to this study, is that the day-night cycle has a tremendous impact on the cell's physiology, cycling on and off many vital metabolic processes, not just the obvious ones.
Among the obvious cycling processes are photosynthesis and nitrogen fixation. It is difficult for one cell to perform these two functions because the processes are at odds with one another. Fixing nitrogen requires nitrogenase, a catalyst that helps the chemical reaction move forward. Unhelpfully, the oxygen produced by photosynthesis degrades nitrogenase, making nitrogen fixation difficult or impossible in photosynthetic organisms.
Other filamentous cyanobacteria perform photosynthesis and nitrogen fixation in different, separate cells. As a single-celled bacterium, however, Cyanothece cannot separate these antagonistic processes in space. But it can separate them in time.
Agreeing with previous studies, this study found that Cyanothece genes for photosynthesis turn on during the day and genes for nitrogen fixation turn on at night. The surprise is the tremendous impact the day-night cycle has on the overall physiology of the cell.
"It goes far beyond just the aspects of nitrogen fixation and photosynthesis," said Pakrasi, who also directs Washington University's International Center for Advanced Renewable Energy and Sustainability (I-CARES) to encourage and coordinate university-wide and external collaborative research in the areas of renewable energy and sustainability - including biofuels, carbon dioxide mitigation and coal-related issues. The university will invest more than $55 million in the initiative.
Cyanothece's 'Dark Period'
To see the effect of day-night cycles on the overall physiology of Cyanothece, lead author Jana Stöckel, Ph.D., Washington University post-doctoral researcher, and other members of this research team examined the expression of 5,000 genes, measuring the amount of messenger RNA for each gene in alternating dark and light periods over 48 hours. At a given time, the mRNA levels indicated what the cells were doing. For example, when the researchers identified high levels of many mRNAs encoding various protein components of the nitrogenase enzyme, they knew that the cells were fixing nitrogen at that time, in this case, during the dark periods.
Of the 5,000 genes studied, nearly 30 percent cycled on and off with changing light and dark periods. These particular genes, the study found, also govern major metabolic processes. Therefore, the cycling of mRNA transcription, Pakrasi said, "provides deep insight into the physiological behavior of the organism - day and night."
During the day, Cyanothece busies itself with photosynthesis. Using energy from sunlight, carbon dioxide from the atmosphere, and water, Cyanothece produces glucose, a sugar it stores in glycogen granules, filling its chemical gas tank. At night, the Cyanothece ramps up production of nitrogenase to fix nitrogen, as expected. Since nitrogen fixation requires a lot of energy, Cyanothece uses the glycogen stored through a process called respiration. Because respiration requires oxygen, the cells conveniently use up this by-product of photosynthesis, likely helping to protect nitrogenase from degradation.
Through this cyclic expression of genes, Cyanothece is essentially a living battery, storing energy from the sun for later use. This feat continues to elude scientists searching for ways to harness sunlight and produce energy on a large scale. With this in mind, a new project for the Pakrasi team seeks to use the machinery of Cyanothece - its energy storage strategy, its anaerobic conditions that protect important enzymes - as a biofactory to produce hydrogen from sunlight, the ultimate clean energy source.
Source: Gayle Geren
Washington University in St. Louis
Michael J. Fox Foundation Continues To Lead Search For Biomarkers Of Parkinson's Disease
The Michael J. Fox
Foundation today announced the launch of Biomarkers 2007, a two-year,
$2-million funding program dedicated to research toward the discovery of an
objective biomarker, or "biological fingerprint," of Parkinson's disease.
This is the third funding round under the Foundation's Biomarkers program
designed to drive discovery of this crucial resource, which the Parkinson's
field currently lacks.
"Discovering a definitive biomarker for Parkinson's disease is
critical," said Sarah Orsay, MJFF's chief executive officer. "By adding
this tool to the Parkinson's research 'toolbox,' we would gain the ability
to objectively diagnose PD and to more accurately measure its progression.
And we would remove a significant hurdle to effective clinical testing of
new therapies, particularly treatments with potential to slow or stop the
disease rather than just mask its symptoms."
The development of neuroprotective therapies is greatly hindered by the
lack of markers capable of serving as objective endpoints for clinical
trials testing these treatments. In recognition of this issue, Biomarkers
2007 will exclusively accept proposals with a focus on biomarkers that can
have significant impact on neuroprotective trials. Among the most
significant challenges currently facing Parkinson's clinicians:
-- To measure whether a treatment alters the course or progression of the
disease, researchers currently can only measure changes in patients'
clinical features, or the time it takes to reach the onset of specific
disease-associated disabilities. Unfortunately, these endpoints leave a
great deal to be desired. They may vary drastically between patients or
clinical raters; require long trial durations before significant
effects are seen; and not be accurate measures of disease progression.
-- Clinical measures, though the most important means for determining the
ability of a treatment to improve overall patient well-being, generally
do not allow researchers to draw a clear distinction between symptom-
masking versus disease-modifying (neuroprotective) effects of therapies
being tested.
-- Current trials must select patients largely based on clinical criteria
that may not adequately reflect the highly variant nature of the
underlying etiology and pathogenesis of PD. Participation of
inappropriate patient subtypes in a trial could result in a seeming
lack of effect and ultimately halt further development of an otherwise
promising treatment.
-- Only limited measures exist in many trials to determine whether a
treatment is reaching its hoped-for target site in the brain and
exerting its desired biological action. This can hinder ability to
determine appropriate therapeutic dosing and lead to trial results
(especially if results are negative) that are difficult to interpret.
"Identification of markers that can address the significant limitations
of neuroprotective trials, or act as surrogate endpoints for clinical
outcomes, would greatly improve our ability to develop and test new
disease-modifying therapeutics for PD," said Gene Johnson, PhD, MJFF's
chief scientific advisor. "For this reason, the Foundation has deliberately
focused the current RFA on markers with potential to improve the way
neuroprotective and disease- modifying clinical trials are carried out."
The Michael J. Fox Foundation has been a field leader in spearheading
the search for a PD biomarker, with approximately $5 million in biomarker
research funded to date.
Pre-proposals under Biomarkers 2007 are required and must be submitted
online by 6 p.m. Eastern Daylight Time on Thursday, May 17, 2007.
Information about submitting pre-proposals online can be found on the
Foundation's Web site (michaeljfox). Pre-proposals will be
reviewed by the Foundation's scientific staff and a panel of scientific
experts. Applicants whose pre-proposals are determined to meet the review
criteria will be invited to submit full application proposals. Funding is
anticipated by November 2007.
About The Michael J. Fox Foundation
Founded in 2000, The Michael J. Fox Foundation for Parkinson's Research
is dedicated to ensuring the development of a cure for Parkinson's disease
within this decade through an aggressively funded research agenda. The
Foundation has funded over $90 million in research to date, either directly
or through partnerships.
Michael J. Fox Foundation
michaeljfox
Foundation today announced the launch of Biomarkers 2007, a two-year,
$2-million funding program dedicated to research toward the discovery of an
objective biomarker, or "biological fingerprint," of Parkinson's disease.
This is the third funding round under the Foundation's Biomarkers program
designed to drive discovery of this crucial resource, which the Parkinson's
field currently lacks.
"Discovering a definitive biomarker for Parkinson's disease is
critical," said Sarah Orsay, MJFF's chief executive officer. "By adding
this tool to the Parkinson's research 'toolbox,' we would gain the ability
to objectively diagnose PD and to more accurately measure its progression.
And we would remove a significant hurdle to effective clinical testing of
new therapies, particularly treatments with potential to slow or stop the
disease rather than just mask its symptoms."
The development of neuroprotective therapies is greatly hindered by the
lack of markers capable of serving as objective endpoints for clinical
trials testing these treatments. In recognition of this issue, Biomarkers
2007 will exclusively accept proposals with a focus on biomarkers that can
have significant impact on neuroprotective trials. Among the most
significant challenges currently facing Parkinson's clinicians:
-- To measure whether a treatment alters the course or progression of the
disease, researchers currently can only measure changes in patients'
clinical features, or the time it takes to reach the onset of specific
disease-associated disabilities. Unfortunately, these endpoints leave a
great deal to be desired. They may vary drastically between patients or
clinical raters; require long trial durations before significant
effects are seen; and not be accurate measures of disease progression.
-- Clinical measures, though the most important means for determining the
ability of a treatment to improve overall patient well-being, generally
do not allow researchers to draw a clear distinction between symptom-
masking versus disease-modifying (neuroprotective) effects of therapies
being tested.
-- Current trials must select patients largely based on clinical criteria
that may not adequately reflect the highly variant nature of the
underlying etiology and pathogenesis of PD. Participation of
inappropriate patient subtypes in a trial could result in a seeming
lack of effect and ultimately halt further development of an otherwise
promising treatment.
-- Only limited measures exist in many trials to determine whether a
treatment is reaching its hoped-for target site in the brain and
exerting its desired biological action. This can hinder ability to
determine appropriate therapeutic dosing and lead to trial results
(especially if results are negative) that are difficult to interpret.
"Identification of markers that can address the significant limitations
of neuroprotective trials, or act as surrogate endpoints for clinical
outcomes, would greatly improve our ability to develop and test new
disease-modifying therapeutics for PD," said Gene Johnson, PhD, MJFF's
chief scientific advisor. "For this reason, the Foundation has deliberately
focused the current RFA on markers with potential to improve the way
neuroprotective and disease- modifying clinical trials are carried out."
The Michael J. Fox Foundation has been a field leader in spearheading
the search for a PD biomarker, with approximately $5 million in biomarker
research funded to date.
Pre-proposals under Biomarkers 2007 are required and must be submitted
online by 6 p.m. Eastern Daylight Time on Thursday, May 17, 2007.
Information about submitting pre-proposals online can be found on the
Foundation's Web site (michaeljfox). Pre-proposals will be
reviewed by the Foundation's scientific staff and a panel of scientific
experts. Applicants whose pre-proposals are determined to meet the review
criteria will be invited to submit full application proposals. Funding is
anticipated by November 2007.
About The Michael J. Fox Foundation
Founded in 2000, The Michael J. Fox Foundation for Parkinson's Research
is dedicated to ensuring the development of a cure for Parkinson's disease
within this decade through an aggressively funded research agenda. The
Foundation has funded over $90 million in research to date, either directly
or through partnerships.
Michael J. Fox Foundation
michaeljfox
'Celldance 2008' Film And Image Contest Of American Society For Cell Biology
Like exotic fish threading their way through a tropical reef, Golgi "ribbons" swim through the submicroscopic ocean inside a living cell. "Triskelion" (three-legged) clathrin proteins swarm like angry bees around a particle wanting to enter the cell membrane. Doubled chromosomes divide like a graceful corps de ballet fluttering towards the wings.
The rarely seen but eerily beautiful world inside our cells is made visible in the videos, animations, and photographs named as winners of "Celldance 2008," the annual cell film and image contest for members of the American Society for Cell Biology (ASCB). The winning entries premiere this week at the ASCB Annual Meeting in San Francisco.
New to Celldance this year is a "still" image competition and a special "Public Outreach" video award category. Celldance winners receive cash and free registration at the ASCB's 48th Annual Meeting, Dec. 14 to 17. The public and the news media can see for themselves by downloading the winning entries through the ASCB's Image & Video Library at: tinyurl/6aj4zu. The 2008 Celldance "movie" poster which features "Harry Drosophila and the Deathly Knockout" can be seen here.
Celldance recognizes images and videos that are both scientifically important and visually engaging, says Rex Chisholm who chairs the ASCB's Public Information Committee, which started "Celldance" in 2005. Chisholm hailed this year's winners: "Even if you haven't studied cell biology since high school, these short videos and microscope stills are fascinating."
Chisholm continued, "Most cell biologists I know are in large part motivated by the beauty they see in cells every day of their professional life. In one sense working with cells is like working in an art gallery where the art changes every day."
Rachid Sougrat, a scientist at the National Institute of Child Health and Human Development at NIH in Bethesda, MD, won first place prize in the new Public Outreach video category, for "The Golgi Apparatus," a blend of live-action video microscopy and computer-generated animation complete with Golgi "ribbons" swimming serenely through the cell cytoskeleton.
Janet Iwasa of Harvard Medical School won the regular Celldance Video competition with "Clathrin-Mediated Endocytosis," a tour de force of scientific animation that begins with Iwasa introducing triskelion clathrin proteins. Suddenly, Iwasa's three-legged triskelions multiply and spin off to the tune of the "Flight of the Bumble Bee" into a self-assembling swarm, creating an endocytic vesicle for carrying outside substances into the cell.
Alexander Bird, a scientist at Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, took first place in the new "still" image competition which is run by the ASCB's Image and Video Library (IVL) Using green, blue, and purple fluorescent reagent stains, Bird tagged the microtubules separating the cell's 23 chromosome pairs as the cell passes through two critical stages of cell division called metaphase and anaphase.
All the Celldance winners including honorable mentions and runners-up can be seen at the IVL site through this URL: tinyurl/6aj4zu.
Source: Cathy Yarbrough
American Society for Cell Biology
The rarely seen but eerily beautiful world inside our cells is made visible in the videos, animations, and photographs named as winners of "Celldance 2008," the annual cell film and image contest for members of the American Society for Cell Biology (ASCB). The winning entries premiere this week at the ASCB Annual Meeting in San Francisco.
New to Celldance this year is a "still" image competition and a special "Public Outreach" video award category. Celldance winners receive cash and free registration at the ASCB's 48th Annual Meeting, Dec. 14 to 17. The public and the news media can see for themselves by downloading the winning entries through the ASCB's Image & Video Library at: tinyurl/6aj4zu. The 2008 Celldance "movie" poster which features "Harry Drosophila and the Deathly Knockout" can be seen here.
Celldance recognizes images and videos that are both scientifically important and visually engaging, says Rex Chisholm who chairs the ASCB's Public Information Committee, which started "Celldance" in 2005. Chisholm hailed this year's winners: "Even if you haven't studied cell biology since high school, these short videos and microscope stills are fascinating."
Chisholm continued, "Most cell biologists I know are in large part motivated by the beauty they see in cells every day of their professional life. In one sense working with cells is like working in an art gallery where the art changes every day."
Rachid Sougrat, a scientist at the National Institute of Child Health and Human Development at NIH in Bethesda, MD, won first place prize in the new Public Outreach video category, for "The Golgi Apparatus," a blend of live-action video microscopy and computer-generated animation complete with Golgi "ribbons" swimming serenely through the cell cytoskeleton.
Janet Iwasa of Harvard Medical School won the regular Celldance Video competition with "Clathrin-Mediated Endocytosis," a tour de force of scientific animation that begins with Iwasa introducing triskelion clathrin proteins. Suddenly, Iwasa's three-legged triskelions multiply and spin off to the tune of the "Flight of the Bumble Bee" into a self-assembling swarm, creating an endocytic vesicle for carrying outside substances into the cell.
Alexander Bird, a scientist at Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, took first place in the new "still" image competition which is run by the ASCB's Image and Video Library (IVL) Using green, blue, and purple fluorescent reagent stains, Bird tagged the microtubules separating the cell's 23 chromosome pairs as the cell passes through two critical stages of cell division called metaphase and anaphase.
All the Celldance winners including honorable mentions and runners-up can be seen at the IVL site through this URL: tinyurl/6aj4zu.
Source: Cathy Yarbrough
American Society for Cell Biology
Proof Of Concept For Oral Delivery Of Therapeutic Short Interfering RNA Molecules
Researchers at the University of Massachusetts Medical School (UMMS) report on a novel approach to the delivery of small bits of genetic material in order to silence genes using "RNA interference" - and in the process, discovered a potent method of suppressing inflammation in mice similar to what occurs in a range of human diseases.
In the April 30, 2009 issue of the journal Nature, Professor Michael P. Czech, PhD, and colleagues in the Program in Molecular Medicine at UMMS describe the engineering of small encapsulating particles containing short pieces of RNA that dramatically silenced genes in mice following oral administration in small doses. The paper, "Orally delivered siRNA targeting macrophage MAP4K4 suppresses systemic inflammation," provides a possible pathway to address the most common - and daunting - challenge in the new field of RNA therapeutics: how to deliver the short strands of RNA used in gene silencing to specific tissues and cell types.
"We are very encouraged by these results, which show that oral delivery of a therapeutic dose of small, interfering RNA (siRNA) to a specific cell type in an animal model is possible, and that evidence of gene silencing using this delivery system is measurable," said Dr. Czech.
The discovery in 1998 that short strands of RNA can silence the action of a given gene changed the scientific world's understanding of how genes are regulated. Highly specific and highly potent, "RNA interference" or "RNAi" has become both a crucial laboratory technique and widely studied for potential therapeutic applications; the explanation of the mechanism of RNAi was recognized with the 2006 Nobel Prize in Medicine, awarded to UMMS Professor Craig C. Mello, PhD, and collaborator Andrew Z. Fire, PhD, of Stanford University; since the discovery, laboratories around the world have focused on the potential of RNAi to silence genes with high specificity, low toxicity and minimal immune system response.
But how to deliver tiny strands of genetic material into cells in a living organism has been a formidable obstacle. In this paper, Czech and colleagues chose to target a particular type of cell in the immune system called a "macrophage," a type of white blood cell that engulfs and digests cellular debris and responds to invading organisms by stimulating the immune response. Because macrophages control the inflammatory response in diseases such as rheumatoid arthritis and atherosclerosis (a precursor to heart disease), they represent an attractive target for drug delivery.
To move short strands of RNA into the macrophages, the researchers exploited a distinctive characteristic of yeast particles: the ability to be engulfed and digested by macrophages. By using these yeast particles as a delivery shell, they were able to deliver siRNAs targeting a gene known for its key role in the inflammatory response - and turn it off. The macrophages carrying the RNAi moved throughout the organism as they circulated from the digestive system (where they first encountered the particles and engulfed them) with the result that over time, a large portion of the organism's macrophages exhibited gene silencing.
The method of treating yeast particles to remove components that would cause an immune response and generate oral delivery vehicles composed of "beta1,3-D glucan" was developed by UMMS research professor and paper co-author Gary R. Ostroff, PhD. The method of using glucan particles as a drug delivery system has been tested in a number of animal models. In December 2008, the Massachusetts Life Sciences Center awarded a three-year, $750,000 cooperative research grant to UMMS and biotech startup RXi Pharmaceuticals to investigate the development of a range of orally delivered RNAi therapeutics using the glucan particle model. (RXi was co-founded by Nobel Laureate Mello, who serves on its Scientific Advisory Board, and Czech.)
In the series of experiments, the researchers were able to silence gene expression both in vitro and in vivo, in a mouse model, at a range of doses and concentrations; oral delivery of as little as 20 micrograms per kilogram of body weight of siRNA silenced a signaling protein called MAP4K4, a key player in the inflammatory response in disease processes like arthritis. (By contrast, research studies evaluating intravenous injections of siRNAs often used concentrations from 12 to 500 times higher.)
"In the future, this paper will be viewed as a landmark in the process of translating RNAi into effective new therapies for human diseases," said Terence R. Flotte, MD, dean of the school of medicine at UMMS. "It addresses one of the most fundamental problems in the field, that of delivery of the RNAi molecule to the cells affected by the disease process."
Source:
Mark L. Shelton
University of Massachusetts Medical School
In the April 30, 2009 issue of the journal Nature, Professor Michael P. Czech, PhD, and colleagues in the Program in Molecular Medicine at UMMS describe the engineering of small encapsulating particles containing short pieces of RNA that dramatically silenced genes in mice following oral administration in small doses. The paper, "Orally delivered siRNA targeting macrophage MAP4K4 suppresses systemic inflammation," provides a possible pathway to address the most common - and daunting - challenge in the new field of RNA therapeutics: how to deliver the short strands of RNA used in gene silencing to specific tissues and cell types.
"We are very encouraged by these results, which show that oral delivery of a therapeutic dose of small, interfering RNA (siRNA) to a specific cell type in an animal model is possible, and that evidence of gene silencing using this delivery system is measurable," said Dr. Czech.
The discovery in 1998 that short strands of RNA can silence the action of a given gene changed the scientific world's understanding of how genes are regulated. Highly specific and highly potent, "RNA interference" or "RNAi" has become both a crucial laboratory technique and widely studied for potential therapeutic applications; the explanation of the mechanism of RNAi was recognized with the 2006 Nobel Prize in Medicine, awarded to UMMS Professor Craig C. Mello, PhD, and collaborator Andrew Z. Fire, PhD, of Stanford University; since the discovery, laboratories around the world have focused on the potential of RNAi to silence genes with high specificity, low toxicity and minimal immune system response.
But how to deliver tiny strands of genetic material into cells in a living organism has been a formidable obstacle. In this paper, Czech and colleagues chose to target a particular type of cell in the immune system called a "macrophage," a type of white blood cell that engulfs and digests cellular debris and responds to invading organisms by stimulating the immune response. Because macrophages control the inflammatory response in diseases such as rheumatoid arthritis and atherosclerosis (a precursor to heart disease), they represent an attractive target for drug delivery.
To move short strands of RNA into the macrophages, the researchers exploited a distinctive characteristic of yeast particles: the ability to be engulfed and digested by macrophages. By using these yeast particles as a delivery shell, they were able to deliver siRNAs targeting a gene known for its key role in the inflammatory response - and turn it off. The macrophages carrying the RNAi moved throughout the organism as they circulated from the digestive system (where they first encountered the particles and engulfed them) with the result that over time, a large portion of the organism's macrophages exhibited gene silencing.
The method of treating yeast particles to remove components that would cause an immune response and generate oral delivery vehicles composed of "beta1,3-D glucan" was developed by UMMS research professor and paper co-author Gary R. Ostroff, PhD. The method of using glucan particles as a drug delivery system has been tested in a number of animal models. In December 2008, the Massachusetts Life Sciences Center awarded a three-year, $750,000 cooperative research grant to UMMS and biotech startup RXi Pharmaceuticals to investigate the development of a range of orally delivered RNAi therapeutics using the glucan particle model. (RXi was co-founded by Nobel Laureate Mello, who serves on its Scientific Advisory Board, and Czech.)
In the series of experiments, the researchers were able to silence gene expression both in vitro and in vivo, in a mouse model, at a range of doses and concentrations; oral delivery of as little as 20 micrograms per kilogram of body weight of siRNA silenced a signaling protein called MAP4K4, a key player in the inflammatory response in disease processes like arthritis. (By contrast, research studies evaluating intravenous injections of siRNAs often used concentrations from 12 to 500 times higher.)
"In the future, this paper will be viewed as a landmark in the process of translating RNAi into effective new therapies for human diseases," said Terence R. Flotte, MD, dean of the school of medicine at UMMS. "It addresses one of the most fundamental problems in the field, that of delivery of the RNAi molecule to the cells affected by the disease process."
Source:
Mark L. Shelton
University of Massachusetts Medical School
New Culture System Leads To Anti-Viral Treatments For Hepatitis C
A new way of growing viruses in the laboratory developed by Japanese researchers could spell hope for the 170 million people infected with hepatitis C, only half of whom currently respond to drug treatments, scientists announced today (Tuesday 27 March 2007) at the Society for General Microbiology's 160th Meeting at the University of Manchester, UK, which will run from 26 29 March 2007.
"Until now we have been unable to grow hepatitis C virus in the laboratory, which has delayed our development of new treatments. Now, thanks to the system from Japan, we can explore the full life-cycle of the virus", says Dr Stephen Griffin from the University of Leeds, UK.
The scientists have identified a key protein which helps the viruses grow, called p7, by transporting molecules across membranes. A drug targeting a similar protein in the influenza virus was one of the first licensed anti-viral treatments. The Leeds research team has discovered that while the hepatitis viruses are growing, the same protein is crucial for stabilising new virus particles. This offers the hope that blocking its action could provide a new and effective way of combating hepatitis C.
Hepatitis C is now the leading cause of liver transplant surgery in developed countries. No vaccine is currently available to prevent the infection, and contamination through infected blood or other body fluids often happens without any obvious symptoms. This leaves many patients unaware that they have the disease until many years later when they develop liver disorders. Around one fifth of hepatitis C sufferers develop cirrhosis, and 5% will get liver cancer, leading to nearly 2 million deaths worldwide every year.
The current treatments are administered similarly to ones used for HIV, with doctors giving dual drug therapies to target different stages of the virus life-cycle in an attempt to overcome its natural drug resistance.
The new laboratory culture system will allow scientists to study the complete virus life-cycle, including how it builds new virus particles and how these in turn infect new cells.
"We have shown that the p7 protein can form seven sided pores in the cell membranes and alter acidity within the liver cells. We think this is crucial in forming new virus particles, so it is an ideal target for new types of drugs", says Dr Stephen Griffin. "A drug called amantadine, which can be used successfully by doctors against influenza infections, specifically blocks the action of p7. Encouragingly, some clinical trials of amantadine used alongside current treatments have improved patients' response. New drugs based on amantadine offer exciting possibilities for the future treatment of hepatitis C.
SOCIETY FOR GENERAL MICROBIOLOGY
Marlborough House
Basingstoke Road, Spencers Wood
Reading
RG7 1AG
socgenmicrobiol.uk
"Until now we have been unable to grow hepatitis C virus in the laboratory, which has delayed our development of new treatments. Now, thanks to the system from Japan, we can explore the full life-cycle of the virus", says Dr Stephen Griffin from the University of Leeds, UK.
The scientists have identified a key protein which helps the viruses grow, called p7, by transporting molecules across membranes. A drug targeting a similar protein in the influenza virus was one of the first licensed anti-viral treatments. The Leeds research team has discovered that while the hepatitis viruses are growing, the same protein is crucial for stabilising new virus particles. This offers the hope that blocking its action could provide a new and effective way of combating hepatitis C.
Hepatitis C is now the leading cause of liver transplant surgery in developed countries. No vaccine is currently available to prevent the infection, and contamination through infected blood or other body fluids often happens without any obvious symptoms. This leaves many patients unaware that they have the disease until many years later when they develop liver disorders. Around one fifth of hepatitis C sufferers develop cirrhosis, and 5% will get liver cancer, leading to nearly 2 million deaths worldwide every year.
The current treatments are administered similarly to ones used for HIV, with doctors giving dual drug therapies to target different stages of the virus life-cycle in an attempt to overcome its natural drug resistance.
The new laboratory culture system will allow scientists to study the complete virus life-cycle, including how it builds new virus particles and how these in turn infect new cells.
"We have shown that the p7 protein can form seven sided pores in the cell membranes and alter acidity within the liver cells. We think this is crucial in forming new virus particles, so it is an ideal target for new types of drugs", says Dr Stephen Griffin. "A drug called amantadine, which can be used successfully by doctors against influenza infections, specifically blocks the action of p7. Encouragingly, some clinical trials of amantadine used alongside current treatments have improved patients' response. New drugs based on amantadine offer exciting possibilities for the future treatment of hepatitis C.
SOCIETY FOR GENERAL MICROBIOLOGY
Marlborough House
Basingstoke Road, Spencers Wood
Reading
RG7 1AG
socgenmicrobiol.uk
Producing Medicines In Plant Seeds
Using plants to produce useful proteins could be an inexpensive alternative to current medicine production methods. Researchers from the Flanders Interuniversity Institute for Biotechnology (VIB) at Ghent University have succeeded in producing in plant seeds proteins that have a very strong resemblance to antibodies. They have also demonstrated that these antibody variants are just as active as the whole antibodies that occur naturally in humans. By virtue of their particular action, antibodies are very useful for therapeutic and diagnostic applications. From this research, it is now also clear that these kinds of antibody variants can be used in medical applications and that it is possible to produce them in the seeds of plants, which can have enormous advantages over conventional production methods.
Production of biotech medicines
A large number of today's medicines are made with the aid of biotechnology (and this number should only grow in the future). To do this, scientists use genetically modified bacteria, yeasts, or animal cells that are able to produce human proteins. These proteins are then purified and administered as medicines. Examples of such proteins are antibodies, which can be used, for instance, in the treatment of cancer. The conventional methods for producing antibodies work well, but they are expensive and have a limited production capacity. The high costs are primarily due to the need for well-equipped production labs and to the labor-intensive upkeep of the animal cells, which are needed as production units.
Plants: a possible alternative?
For a number of years now, the VIB researchers in Ghent - Bart Van Droogenbroeck, Ann Depicker and Geert De Jaeger- have been searching for ways to have plants produce useful proteins efficiently. Plants do offer a lot of advantages over conventional production methods. Because production with plants doesn't require expensive high-tech laboratories, scientists anticipate that, by working with plants, production costs will be 10 to 100 times lower. Another important advantage is that large-scale production is possible without having to make additional investments in expensive fermentors.
A good yield guaranteed
Several years ago, Geert De Jaeger and his colleagues succeeded in achieving a high yield of an antibody variant in plants, which had been very difficult to do up to that time. The trick the researchers used was to modify the plants in such a way that they would produce the antibody variant in their seeds. With their special technique, the scientists succeeded in producing seeds in which the desired protein is good for more than one third of the total protein amount. This is a huge proportion compared to other systems - normally, scientists succeed in replacing only 1% of the plant's proteins by the desired protein.
Plant seeds are especially attractive as production units. In addition to a high production capacity, they offer other important advantages over other parts of the plant. The seeds can be stored for a long time without losing the produced protein's effectiveness, so that a reserve can always be kept on hand. This means that the proteins can be isolated from the seeds at the moment that they are actually needed. With production in leaves, for example - or with conventional production methods - such lengthy storage is not possible: the protein must be isolated immediately after production. So, production in plant seeds provides the clear advantage of timely processing.
High production of an efficient antibody variant
The antibody variant that has been produced by Geert De Jaeger and his team has a very simple structure and has only one binding place for a particular substance. Bart Van Droogenbroeck and his colleagues, under the direction of Ann Depicker, are now showing that it is also possible to produce more complex antibody variants in large quantities in the seeds of the Arabidopsis plant. Over 10% of the proteins in the seeds of these plants are the desired antibody variant. As is the case with whole antibodies, these more complex antibody variants have two binding places for a specified substance. This close similarity to whole antibodies makes these antibody variants extremely useful for therapeutic and diagnostic applications.
However, the production of proteins in plants is completed in a different way than in humans. Therefore, to be certain that this different completion process does not affect the effectiveness of the potential medicine; the scientists have subjected the action of the antibody variant to an exhaustive battery of tests. These laboratory tests have shown that the antibody variants produced in plants are just as effective as whole human antibodies in protecting animal cells against infection with the Hepatitis A virus.
This is a significant step forward in making protein production in plants a real alternative to current production methods.
Contact: Sooike Stoops
VIB, Flanders Interuniversity Institute of Biotechnology
Production of biotech medicines
A large number of today's medicines are made with the aid of biotechnology (and this number should only grow in the future). To do this, scientists use genetically modified bacteria, yeasts, or animal cells that are able to produce human proteins. These proteins are then purified and administered as medicines. Examples of such proteins are antibodies, which can be used, for instance, in the treatment of cancer. The conventional methods for producing antibodies work well, but they are expensive and have a limited production capacity. The high costs are primarily due to the need for well-equipped production labs and to the labor-intensive upkeep of the animal cells, which are needed as production units.
Plants: a possible alternative?
For a number of years now, the VIB researchers in Ghent - Bart Van Droogenbroeck, Ann Depicker and Geert De Jaeger- have been searching for ways to have plants produce useful proteins efficiently. Plants do offer a lot of advantages over conventional production methods. Because production with plants doesn't require expensive high-tech laboratories, scientists anticipate that, by working with plants, production costs will be 10 to 100 times lower. Another important advantage is that large-scale production is possible without having to make additional investments in expensive fermentors.
A good yield guaranteed
Several years ago, Geert De Jaeger and his colleagues succeeded in achieving a high yield of an antibody variant in plants, which had been very difficult to do up to that time. The trick the researchers used was to modify the plants in such a way that they would produce the antibody variant in their seeds. With their special technique, the scientists succeeded in producing seeds in which the desired protein is good for more than one third of the total protein amount. This is a huge proportion compared to other systems - normally, scientists succeed in replacing only 1% of the plant's proteins by the desired protein.
Plant seeds are especially attractive as production units. In addition to a high production capacity, they offer other important advantages over other parts of the plant. The seeds can be stored for a long time without losing the produced protein's effectiveness, so that a reserve can always be kept on hand. This means that the proteins can be isolated from the seeds at the moment that they are actually needed. With production in leaves, for example - or with conventional production methods - such lengthy storage is not possible: the protein must be isolated immediately after production. So, production in plant seeds provides the clear advantage of timely processing.
High production of an efficient antibody variant
The antibody variant that has been produced by Geert De Jaeger and his team has a very simple structure and has only one binding place for a particular substance. Bart Van Droogenbroeck and his colleagues, under the direction of Ann Depicker, are now showing that it is also possible to produce more complex antibody variants in large quantities in the seeds of the Arabidopsis plant. Over 10% of the proteins in the seeds of these plants are the desired antibody variant. As is the case with whole antibodies, these more complex antibody variants have two binding places for a specified substance. This close similarity to whole antibodies makes these antibody variants extremely useful for therapeutic and diagnostic applications.
However, the production of proteins in plants is completed in a different way than in humans. Therefore, to be certain that this different completion process does not affect the effectiveness of the potential medicine; the scientists have subjected the action of the antibody variant to an exhaustive battery of tests. These laboratory tests have shown that the antibody variants produced in plants are just as effective as whole human antibodies in protecting animal cells against infection with the Hepatitis A virus.
This is a significant step forward in making protein production in plants a real alternative to current production methods.
Contact: Sooike Stoops
VIB, Flanders Interuniversity Institute of Biotechnology
New Study Shows That Important Gene Controls The Ability Of The Thymus To Produce Disease-fighting T-cells After An Organism's Birth
New research, just published by researchers from the University of Georgia, provides the first evidence that a key gene may be crucial to maintaining the production of the thymus and its disease-fighting T-cells after an animal's birth.
The discovery could help scientists find out how to turn the thymus back on so it could produce T-cells long after it normally shuts down most of its function, which, for humans, occurs by early adulthood. If the finding leads to further ways to manipulate the gene, the result could be a new avenue for the body to fight disease more effectively as the body ages.
The research was just published in the online edition of the journal Blood, a publication of the American Society of Hematology.
"Such things as infectious diseases, inflammation and heart problems are all related to immune response," said Nancy Manley, an associate professor of genetics and chair of UGA's Interdepartmental Developmental Biology Group. "You don't have to think far to see how understanding the effect of this gene could affect the quality of life for older people and others as well."
Other authors of the paper, beside Manley, are doctoral graduate student Lizhen Chen and assistant research scientist Shiyun Xiao, also of the University of Georgia.
The thymus is an organ located in the upper part of the human chest cavity, behind the sternum. This organ is the location where important systemic infection fighters called T-cells develop. Over the past two decades, T-cell counts have become part of everyday dialogue due to their importance in monitoring HIV/AIDS and other disorders.
The thymus slowly begins to shut down early in life and becomes largely inactive by early adulthood. Still, that's fine for most people, since an entire lifetime supply of T-cells is produced in that time. But, for some people, the loss of irreplaceable T-cells through disease can lead to chronic illnesses and a shortened life.
Until recently, scientists had thought that the thymus in adults was permanently shut down because no known regulatory mechanism existed that might allow doctors to "turn back on" the thymus if a person's T-cells were compromised. There are now some treatments currently in trials that can transiently rejuvenate the thymus and increase thymic output in humans.
The problem has been, though, that the mechanisms by which all this works are poorly understood, and all current treatments have systemic effects that can cause unacceptable side effects in all but the most seriously ill, who are more willing to tolerate them in exchange for possible benefit.
Now, however, Manley and her colleagues have shown for the first time that a gene called Foxn1 is required to maintain the postnatal thymus. Their results also suggest that changes in Foxn1 expression in important thymic epithelial cells (TECs) during aging contribute to the slow shut-down of the thymus with age.
"While this research was done in mice, it's not far-fetched to say that this points toward possible therapies for a huge variety of illnesses, from AIDS to age-related immunodeficiency disorders," said Manley.
One clear advantage of understanding how Foxn1 works in maintaining the thymus and T-cell production is that it could lead to narrowly targeted therapies that are less likely to cause collateral side effects in a patient.
Manley got into studying the Foxn1 gene through her work as a developmental biologist, but the discovery of how the gene works in maintaining the postnatal thymus came as a surprise. The mouse carrying the genetically altered Foxn1 gene was produced by happenstance rather than by design. It turns out that the engineered gene has normal fetal expression and thymus development, but after birth, the gene's expression decays much more rapidly than in normal mice, giving the scientists a way to rapidly assess just what the gene does in the growing animal.
"In effect, what happens in this model is that the gene 'ages' more rapidly than the mouse does," said Manley. "This has given us a tremendous ability to understand to a more accurate degree just what the gene is doing."
The irony that the new discovery may find its best uses in dealing with issues of aging and that Manley is a development biologist hasn't been lost on her.
"The truth is that aging and development aren't really different things," she said. "They're part of a continuum. The young thymus is like a turned-on spigot pumping out a diversity of T-cell types, and T-cells live a long time. Even after the spigot turns off, we don't really see any major changes in them for most people until they reach about 60 years of age. Then the rates of things like rheumatoid arthritis and cancer go up substantially. And, as we all know, older people get sick more often."
If, however, physicians were able selectively to turn T-cell production back on, then many diseases that currently afflict older people could become manageable if not, in cases, entirely absent. So if "60 is the new 40," as some people now say, that could theoretically change to "75 is the new 40." And that first number of the pair could be even higher.
"Would turning Foxn1 back on allow us to regenerate an aged thymus?" Manley asks. "We just don't know yet. But we are getting evidence now to say that it would allow it, and we will be working on that to see how it can happen. If we could delay when the thymus shuts off or have it work at a low level our entire lives, it has the potential to make a huge difference in so many health-related issues."
While the mouse model doesn't precisely mimic human response, it is close enough so that biologists and geneticists can often draw conclusions from mouse trials on how humans will respond.
Though the ability of science to manipulate this gene and potentially the production of T-cells isn't going to happen next week, it may not be that far down the road, either. Under best circumstances, the researchers should know within five to 10 years whether the therapeutic ability to turn back on the production of T-cells is possible.
University of Georgia
The discovery could help scientists find out how to turn the thymus back on so it could produce T-cells long after it normally shuts down most of its function, which, for humans, occurs by early adulthood. If the finding leads to further ways to manipulate the gene, the result could be a new avenue for the body to fight disease more effectively as the body ages.
The research was just published in the online edition of the journal Blood, a publication of the American Society of Hematology.
"Such things as infectious diseases, inflammation and heart problems are all related to immune response," said Nancy Manley, an associate professor of genetics and chair of UGA's Interdepartmental Developmental Biology Group. "You don't have to think far to see how understanding the effect of this gene could affect the quality of life for older people and others as well."
Other authors of the paper, beside Manley, are doctoral graduate student Lizhen Chen and assistant research scientist Shiyun Xiao, also of the University of Georgia.
The thymus is an organ located in the upper part of the human chest cavity, behind the sternum. This organ is the location where important systemic infection fighters called T-cells develop. Over the past two decades, T-cell counts have become part of everyday dialogue due to their importance in monitoring HIV/AIDS and other disorders.
The thymus slowly begins to shut down early in life and becomes largely inactive by early adulthood. Still, that's fine for most people, since an entire lifetime supply of T-cells is produced in that time. But, for some people, the loss of irreplaceable T-cells through disease can lead to chronic illnesses and a shortened life.
Until recently, scientists had thought that the thymus in adults was permanently shut down because no known regulatory mechanism existed that might allow doctors to "turn back on" the thymus if a person's T-cells were compromised. There are now some treatments currently in trials that can transiently rejuvenate the thymus and increase thymic output in humans.
The problem has been, though, that the mechanisms by which all this works are poorly understood, and all current treatments have systemic effects that can cause unacceptable side effects in all but the most seriously ill, who are more willing to tolerate them in exchange for possible benefit.
Now, however, Manley and her colleagues have shown for the first time that a gene called Foxn1 is required to maintain the postnatal thymus. Their results also suggest that changes in Foxn1 expression in important thymic epithelial cells (TECs) during aging contribute to the slow shut-down of the thymus with age.
"While this research was done in mice, it's not far-fetched to say that this points toward possible therapies for a huge variety of illnesses, from AIDS to age-related immunodeficiency disorders," said Manley.
One clear advantage of understanding how Foxn1 works in maintaining the thymus and T-cell production is that it could lead to narrowly targeted therapies that are less likely to cause collateral side effects in a patient.
Manley got into studying the Foxn1 gene through her work as a developmental biologist, but the discovery of how the gene works in maintaining the postnatal thymus came as a surprise. The mouse carrying the genetically altered Foxn1 gene was produced by happenstance rather than by design. It turns out that the engineered gene has normal fetal expression and thymus development, but after birth, the gene's expression decays much more rapidly than in normal mice, giving the scientists a way to rapidly assess just what the gene does in the growing animal.
"In effect, what happens in this model is that the gene 'ages' more rapidly than the mouse does," said Manley. "This has given us a tremendous ability to understand to a more accurate degree just what the gene is doing."
The irony that the new discovery may find its best uses in dealing with issues of aging and that Manley is a development biologist hasn't been lost on her.
"The truth is that aging and development aren't really different things," she said. "They're part of a continuum. The young thymus is like a turned-on spigot pumping out a diversity of T-cell types, and T-cells live a long time. Even after the spigot turns off, we don't really see any major changes in them for most people until they reach about 60 years of age. Then the rates of things like rheumatoid arthritis and cancer go up substantially. And, as we all know, older people get sick more often."
If, however, physicians were able selectively to turn T-cell production back on, then many diseases that currently afflict older people could become manageable if not, in cases, entirely absent. So if "60 is the new 40," as some people now say, that could theoretically change to "75 is the new 40." And that first number of the pair could be even higher.
"Would turning Foxn1 back on allow us to regenerate an aged thymus?" Manley asks. "We just don't know yet. But we are getting evidence now to say that it would allow it, and we will be working on that to see how it can happen. If we could delay when the thymus shuts off or have it work at a low level our entire lives, it has the potential to make a huge difference in so many health-related issues."
While the mouse model doesn't precisely mimic human response, it is close enough so that biologists and geneticists can often draw conclusions from mouse trials on how humans will respond.
Though the ability of science to manipulate this gene and potentially the production of T-cells isn't going to happen next week, it may not be that far down the road, either. Under best circumstances, the researchers should know within five to 10 years whether the therapeutic ability to turn back on the production of T-cells is possible.
University of Georgia
New Research Maps Brain And Gene Function In Patients With Borderline Personality Disorder
Mount Sinai researchers have found that real-time brain imaging suggests that patients with Borderline Personality Disorder (BPD) are physically unable to activate neurological networks that can help regulate emotion. The findings, by Harold W. Koenigsberg, MD, Professor of Psychiatry at Mount Sinai School of Medicine, were presented at the 11th International Congress of the International Society for the Study of Personality Disorders (ISSPD), held August 2123 at The Mount Sinai Medical Center in New York. The research will also be published in the journal Biological Psychiatry.
Using functional magnetic resonance imaging (MRI), Dr. Koenigsberg observed how the brains of people with BPD reacted to social and emotional stimuli. He found that when people with BPD attempted to control and reduce their reactions to disturbing emotional scenes, the anterior cingulated cortex and intraparetical sulci areas of the brain that are active in healthy people under the same conditions remained inactive in the BPD patients.
"This research shows that BPD patients are not able to use those parts of the brain that healthy people use to help regulate their emotions," said Dr. Koenigsberg. "This may explain why their emotional reactions are so extreme. The biological underpinnings of the disordered emotional control systems are central to borderline pathology. Studying which areas of the brain function differently in patients with borderline personality disorder can lead to more targeted uses of psychotherapy and medications, and also provide a link to connect the genetic basis of the disorder."
Borderline Personality Disorder is a common condition, affecting up to two percent of all adults in the United States, mostly women. Characteristics of BPD include being so emotionally over-reactive that they suffer alternating bouts of depression, anxiety and anger, are interpersonally hypersensitive, and are impelled to self-destructive and even suicidal behavior. Patients with BPD often exhibit other types of impulsive behaviors, including excessive spending, binge eating and risky sex. BPD often occurs together with other psychiatric problems, particularly bipolar disorder, depression, anxiety disorders, substance abuse, and other personality disorders. The disorder is found in 10 to 20 percent of people in psychiatric care, and about 10 percent of people with this condition ultimately die of suicide. Only recently have researchers begun to identify underlying biological factors associated with the condition.
Gene function and serotonin levels may also be contributing factors in BPD, according to research findings also presented at the ISSPD Congress by Larry Siever, MD, Professor of Psychiatry and Director of the Special Evaluation Program for Mood and Personality Disorders at Mount Sinai School of Medicine. Dr. Siever's research demonstrates how genes related to serotonin and neuropeptides in the brain may be altered in serious personality disorders such as BPD.
Dr. Siever's neuroimaging research suggests that a gene that controls production of a critical enzyme for the synthesis of serotonin, a brain chemical that modulates emotions and aggression, may be altered leading to reduced synthesis of serotonin in people with BPD and may be associated with increased aggression. This variant of gene may also be associated with reduced frontal lobe activation in the brain.
These studies were part of the 11th International Congress of the International Society for the Study of Personality Disorders, which took place August 21 - 23 at The Mount Sinai Medical Center in New York
Source: The Mount Sinai Medical Center
Using functional magnetic resonance imaging (MRI), Dr. Koenigsberg observed how the brains of people with BPD reacted to social and emotional stimuli. He found that when people with BPD attempted to control and reduce their reactions to disturbing emotional scenes, the anterior cingulated cortex and intraparetical sulci areas of the brain that are active in healthy people under the same conditions remained inactive in the BPD patients.
"This research shows that BPD patients are not able to use those parts of the brain that healthy people use to help regulate their emotions," said Dr. Koenigsberg. "This may explain why their emotional reactions are so extreme. The biological underpinnings of the disordered emotional control systems are central to borderline pathology. Studying which areas of the brain function differently in patients with borderline personality disorder can lead to more targeted uses of psychotherapy and medications, and also provide a link to connect the genetic basis of the disorder."
Borderline Personality Disorder is a common condition, affecting up to two percent of all adults in the United States, mostly women. Characteristics of BPD include being so emotionally over-reactive that they suffer alternating bouts of depression, anxiety and anger, are interpersonally hypersensitive, and are impelled to self-destructive and even suicidal behavior. Patients with BPD often exhibit other types of impulsive behaviors, including excessive spending, binge eating and risky sex. BPD often occurs together with other psychiatric problems, particularly bipolar disorder, depression, anxiety disorders, substance abuse, and other personality disorders. The disorder is found in 10 to 20 percent of people in psychiatric care, and about 10 percent of people with this condition ultimately die of suicide. Only recently have researchers begun to identify underlying biological factors associated with the condition.
Gene function and serotonin levels may also be contributing factors in BPD, according to research findings also presented at the ISSPD Congress by Larry Siever, MD, Professor of Psychiatry and Director of the Special Evaluation Program for Mood and Personality Disorders at Mount Sinai School of Medicine. Dr. Siever's research demonstrates how genes related to serotonin and neuropeptides in the brain may be altered in serious personality disorders such as BPD.
Dr. Siever's neuroimaging research suggests that a gene that controls production of a critical enzyme for the synthesis of serotonin, a brain chemical that modulates emotions and aggression, may be altered leading to reduced synthesis of serotonin in people with BPD and may be associated with increased aggression. This variant of gene may also be associated with reduced frontal lobe activation in the brain.
These studies were part of the 11th International Congress of the International Society for the Study of Personality Disorders, which took place August 21 - 23 at The Mount Sinai Medical Center in New York
Source: The Mount Sinai Medical Center
Rice Researcher Sees Link To Cardiovascular Disease, Osteoporosis
A research project at Rice University has brought scientists to the brink of comprehending a long-standing medical mystery that may link cardiovascular disease, osteoporosis and perhaps even Alzheimer's disease.
And for that, we can thank the rat.
The recent paper in Artery Research by Rice evolutionary biologist Michael Kohn and his team reports they have found that common rats with a genetic mutation have developed a resistance to rat poison, aka warfarin. That's good news for the rats, but it comes at a price. The mutation also leaves them susceptible to arterial calcification and, potentially, osteoporosis.
The discovery is certainly good news for humans.
In the mutated gene, the researchers found what could be the link that solves the calcification paradox, the puzzling association between metabolic bone disease and vascular calcification that has eluded researchers for years. Kohn, an assistant professor of ecology and evolutionary biology, collaborated with Roger Price of the Baylor College of Medicine and Hans-Joachim Pelz of the Julius Kuehn Institute in Germany.
Kohn said a good part of the answer lies in the vitamin K cycle, which is known to regulate the coagulation of blood - clotting. It's also suspected of helping keep calcium out of the body's vessels and in its bones, which has particular ramifications for postmenopausal women for whom loss of bone density is a nagging issue.
Warfarin has long served humans as a medicine called coumadin, because it interferes with the vitamin K cycle. In regulated doses, it thins the blood by reducing its ability to clot, helping prevent heart attacks, stroke and blood clots.
In bigger doses, it once excelled as rat poison; rats that ingested the poison would simply bleed to death. But a mutation in the gene Vkorc1 effectively blocks that interference.
"I have a feeling the mutation predated the introduction of warfarin," said Kohn. "But it was rare, because it causes side effects. It's not an advantageous mutation unless it's exposed to warfarin."
Poisoning rats without the mutation killed them, while those with the mutation multiplied. "And these rats, in the absence of poison, suffer from cardiovascular disease -- just like we do," said Kohn, adding that the kidneys of rats in the study were "calcified to an extent that is shocking."
His hope is that the equivalent gene in humans turns out to be the key to a number of ills.
"As you look at humans, this calcification of arteries is, I suspect, a very important precondition to thrombosis and stroke. So to find such a strong effect was shocking to us. We had a tough time publishing the paper because people might have thought it was too good to be true, that you can explain the effect to such a degree by looking at just one gene."
Kohn and his colleagues have begun a study on osteoporosis in rats that have the mutation, and early results are promising. "The prediction is the mutant rats have a lower bone density. And I think if we complete and confirm that as well, it would be a major "breakthrough. That means one gene, one mutation, explains the so-called calcification paradox."
Finally, he noted, Alzheimer's patients tend to be vitamin K-deficient, which opens up avenues for further study. "Could there be one mutation that explains osteoporosis, arteriosclerosis and Alzheimer's? That would be huge," said Kohn.
"I think the pathway of the vitamin K cycle is underrated in terms of its importance to some of these diseases. Gas6 is a vitamin K protein expressed in the brain, and there are many more vitamin K-dependent proteins we don't know about. The question is, if the recycling capability of the vitamin-K cycle is reduced, how many of these proteins can't do what they're supposed to do?
"I think we have some surprises in store."
Kohn said it's gratifying to know that evolutionary biology can help pave the path to personalized medicine. He credits the now-published findings with helping him land a recent grant of $900,000 from the National Institute of Heart Lung Blood disease at the National Institutes of Health. Kohn will now use mutant and normal rats to find additional genes that respond to warfarin, with two purposes: first, to see if rats have recruited additional genes to battle poisons that are more potent, and second, to attain the ultimate goal of fine-tuning doses of coumadin for humans.
Kohn's paper is available here.
Source: Mike Williams
Rice University
View drug information on Warfarin Sodium tablets.
And for that, we can thank the rat.
The recent paper in Artery Research by Rice evolutionary biologist Michael Kohn and his team reports they have found that common rats with a genetic mutation have developed a resistance to rat poison, aka warfarin. That's good news for the rats, but it comes at a price. The mutation also leaves them susceptible to arterial calcification and, potentially, osteoporosis.
The discovery is certainly good news for humans.
In the mutated gene, the researchers found what could be the link that solves the calcification paradox, the puzzling association between metabolic bone disease and vascular calcification that has eluded researchers for years. Kohn, an assistant professor of ecology and evolutionary biology, collaborated with Roger Price of the Baylor College of Medicine and Hans-Joachim Pelz of the Julius Kuehn Institute in Germany.
Kohn said a good part of the answer lies in the vitamin K cycle, which is known to regulate the coagulation of blood - clotting. It's also suspected of helping keep calcium out of the body's vessels and in its bones, which has particular ramifications for postmenopausal women for whom loss of bone density is a nagging issue.
Warfarin has long served humans as a medicine called coumadin, because it interferes with the vitamin K cycle. In regulated doses, it thins the blood by reducing its ability to clot, helping prevent heart attacks, stroke and blood clots.
In bigger doses, it once excelled as rat poison; rats that ingested the poison would simply bleed to death. But a mutation in the gene Vkorc1 effectively blocks that interference.
"I have a feeling the mutation predated the introduction of warfarin," said Kohn. "But it was rare, because it causes side effects. It's not an advantageous mutation unless it's exposed to warfarin."
Poisoning rats without the mutation killed them, while those with the mutation multiplied. "And these rats, in the absence of poison, suffer from cardiovascular disease -- just like we do," said Kohn, adding that the kidneys of rats in the study were "calcified to an extent that is shocking."
His hope is that the equivalent gene in humans turns out to be the key to a number of ills.
"As you look at humans, this calcification of arteries is, I suspect, a very important precondition to thrombosis and stroke. So to find such a strong effect was shocking to us. We had a tough time publishing the paper because people might have thought it was too good to be true, that you can explain the effect to such a degree by looking at just one gene."
Kohn and his colleagues have begun a study on osteoporosis in rats that have the mutation, and early results are promising. "The prediction is the mutant rats have a lower bone density. And I think if we complete and confirm that as well, it would be a major "breakthrough. That means one gene, one mutation, explains the so-called calcification paradox."
Finally, he noted, Alzheimer's patients tend to be vitamin K-deficient, which opens up avenues for further study. "Could there be one mutation that explains osteoporosis, arteriosclerosis and Alzheimer's? That would be huge," said Kohn.
"I think the pathway of the vitamin K cycle is underrated in terms of its importance to some of these diseases. Gas6 is a vitamin K protein expressed in the brain, and there are many more vitamin K-dependent proteins we don't know about. The question is, if the recycling capability of the vitamin-K cycle is reduced, how many of these proteins can't do what they're supposed to do?
"I think we have some surprises in store."
Kohn said it's gratifying to know that evolutionary biology can help pave the path to personalized medicine. He credits the now-published findings with helping him land a recent grant of $900,000 from the National Institute of Heart Lung Blood disease at the National Institutes of Health. Kohn will now use mutant and normal rats to find additional genes that respond to warfarin, with two purposes: first, to see if rats have recruited additional genes to battle poisons that are more potent, and second, to attain the ultimate goal of fine-tuning doses of coumadin for humans.
Kohn's paper is available here.
Source: Mike Williams
Rice University
View drug information on Warfarin Sodium tablets.
New Source Of Insulin-Producing Cells Identified By Joslin Researchers
Researchers at the Joslin Diabetes Center have shown that insulin-producing pancreatic beta cells can form after birth or after injury from progenitor cells within the pancreas that were not beta cells, a finding that contradicts a widely-cited earlier study that had concluded this is not possible.
The study, published online this week in the Proceedings of the National Academy of Sciences Early Edition, identifies the source of the progenitor cells as being pancreatic duct cells.
"This means that there is a population of pancreatic cells that can be stimulated, either within the body or outside the body, to become new beta cells, the cells that are lacking in diabetes," said Susan Bonner-Weir, Ph.D., the study's lead researcher and a Senior Investigator in the Section on Islet Transplantation and Cell Biology at Joslin and Associate Professor of Medicine at Harvard Medical School.
The experiments, conducted in animal models, suggest a new source of beta cells for replacement therapy to treat or cure diabetes.
In type 1 diabetes, the pancreas produces little or no insulin since the insulin producing beta cells are destroyed by the body's own immune system. While transplantation of human islets from donor pancreases has been successful in getting people with type 1 diabetes off insulin treatment, this insulin independence is only successful for a few years.
"One of the problems with islet transplantation is that while the proof of principal is there, we don't have enough islets to transplant and they go through a traumatic process during isolation," said Bonner-Weir. "Many islets are not in the greatest condition after being isolated from a pancreas."
The two major obstacles to islet transplants are the need for continued use of immunosuppressive drugs to prevent both rejection and return of autoimmune destruction and the lack of a reliable source of insulin producing islet cells.
Bonner-Weir's main research focus is the search for new sources of insulin-producing islet cells. In this study, in experiments in mice, Bonner-Weir's group used a similar lineage tracing system employed by a group from Dr. Douglas Melton's lab at Harvard. That group concluded in a paper published in Nature in 2004 that after birth, new beta cells only result from division of preexisting beta cells and that beta cells do not form from progenitor cells after birth.
"That conclusion, coming from such a well-respected group, was taken by many as fact and cast a cloud over this important research area," Bonner-Weir said.
However, earlier this year a group led by Xiaobo Xu in Belgium showed that islet progenitor cells within the adult pancreas could be activated to increase the number of beta cells by the process of differentiation rather than self-duplication, but the paper did not indicate the origin of these cells.
Bonner-Weir's paper complements the Belgium study by identifying the source of these cells as pancreatic duct cells.
In addition to finding that these duct cells can differentiate into insulin producing islet cells after birth and in regeneration after injury, the study showed that they can also become new acinar cells, a finding that has potential implications for pancreatic cancer, since the origin of the cancerous cells has been disputed.
Two lineage tracing experiments involved genetically marking the ductal cells and then following them. The first experiment, which involved one-month-old mice, found that between 30 to 40 percent of islets had beta cells that had formed after birth from duct cells. In the second experiment, conducted in adult mice, the Joslin researchers used same regeneration model employed in the Belgian study which is based on tying off the main pancreatic duct. Beyond the area of the tie some cells die, but others grow to regenerate the whole structure. In these adult mice, new islets and new acinar cells were again shown to have been formed from the preexisting duct cells.
"Our data provide strong support to the concept of a shared lineage of ductal, acinar and islet cells after birth, even in the adult. This means that there is a population of cells - we don't know if it is all of the cells or just some - that can be stimulated to become new islet cells," Bonner-Weir said.
She concluded: "Our identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replacement therapy for diabetes. While the ideal therapy would be to have those with diabetes regenerate their own islet cells, that is still a long way off."
This study was supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, the Juvenile Diabetes Research Foundation and the Diabetes Wellness Foundation as well as a number of private donors.
Others participating in the research included: Akari Inada, Cameron Nienaber, Hitoshi Katsuta, Jared Levine, Rita Morita and Arun Sharma, all of Joslin, and Yoshio Fujitani of Vanderbilt University.
About Joslin Diabetes Center
Joslin Diabetes Center is the world's preeminent diabetes research and clinical care organization. Joslin is dedicated to ensuring people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent nonprofit institution affiliated with Harvard Medical School. For more information about Joslin, visit joslin/.
Source: Marg Bonilla
Joslin Diabetes Center
The study, published online this week in the Proceedings of the National Academy of Sciences Early Edition, identifies the source of the progenitor cells as being pancreatic duct cells.
"This means that there is a population of pancreatic cells that can be stimulated, either within the body or outside the body, to become new beta cells, the cells that are lacking in diabetes," said Susan Bonner-Weir, Ph.D., the study's lead researcher and a Senior Investigator in the Section on Islet Transplantation and Cell Biology at Joslin and Associate Professor of Medicine at Harvard Medical School.
The experiments, conducted in animal models, suggest a new source of beta cells for replacement therapy to treat or cure diabetes.
In type 1 diabetes, the pancreas produces little or no insulin since the insulin producing beta cells are destroyed by the body's own immune system. While transplantation of human islets from donor pancreases has been successful in getting people with type 1 diabetes off insulin treatment, this insulin independence is only successful for a few years.
"One of the problems with islet transplantation is that while the proof of principal is there, we don't have enough islets to transplant and they go through a traumatic process during isolation," said Bonner-Weir. "Many islets are not in the greatest condition after being isolated from a pancreas."
The two major obstacles to islet transplants are the need for continued use of immunosuppressive drugs to prevent both rejection and return of autoimmune destruction and the lack of a reliable source of insulin producing islet cells.
Bonner-Weir's main research focus is the search for new sources of insulin-producing islet cells. In this study, in experiments in mice, Bonner-Weir's group used a similar lineage tracing system employed by a group from Dr. Douglas Melton's lab at Harvard. That group concluded in a paper published in Nature in 2004 that after birth, new beta cells only result from division of preexisting beta cells and that beta cells do not form from progenitor cells after birth.
"That conclusion, coming from such a well-respected group, was taken by many as fact and cast a cloud over this important research area," Bonner-Weir said.
However, earlier this year a group led by Xiaobo Xu in Belgium showed that islet progenitor cells within the adult pancreas could be activated to increase the number of beta cells by the process of differentiation rather than self-duplication, but the paper did not indicate the origin of these cells.
Bonner-Weir's paper complements the Belgium study by identifying the source of these cells as pancreatic duct cells.
In addition to finding that these duct cells can differentiate into insulin producing islet cells after birth and in regeneration after injury, the study showed that they can also become new acinar cells, a finding that has potential implications for pancreatic cancer, since the origin of the cancerous cells has been disputed.
Two lineage tracing experiments involved genetically marking the ductal cells and then following them. The first experiment, which involved one-month-old mice, found that between 30 to 40 percent of islets had beta cells that had formed after birth from duct cells. In the second experiment, conducted in adult mice, the Joslin researchers used same regeneration model employed in the Belgian study which is based on tying off the main pancreatic duct. Beyond the area of the tie some cells die, but others grow to regenerate the whole structure. In these adult mice, new islets and new acinar cells were again shown to have been formed from the preexisting duct cells.
"Our data provide strong support to the concept of a shared lineage of ductal, acinar and islet cells after birth, even in the adult. This means that there is a population of cells - we don't know if it is all of the cells or just some - that can be stimulated to become new islet cells," Bonner-Weir said.
She concluded: "Our identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replacement therapy for diabetes. While the ideal therapy would be to have those with diabetes regenerate their own islet cells, that is still a long way off."
This study was supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, the Juvenile Diabetes Research Foundation and the Diabetes Wellness Foundation as well as a number of private donors.
Others participating in the research included: Akari Inada, Cameron Nienaber, Hitoshi Katsuta, Jared Levine, Rita Morita and Arun Sharma, all of Joslin, and Yoshio Fujitani of Vanderbilt University.
About Joslin Diabetes Center
Joslin Diabetes Center is the world's preeminent diabetes research and clinical care organization. Joslin is dedicated to ensuring people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent nonprofit institution affiliated with Harvard Medical School. For more information about Joslin, visit joslin/.
Source: Marg Bonilla
Joslin Diabetes Center
Northeastern Researcher Develops Model To Track Concentration Of E. Coli Bacteria In The Lower Charles River
It is a common belief that the water quality of the Charles River and other lakes, streams and rivers is at its worst after a large rainfall because of pollutants carried by runoff. However, a recent study completed by researchers at Northeastern University in Boston found high concentrations of E. colibacteria in the Charles River after a long period of no rain. Ferdi Hellweger, Ph.D., Assistant Professor of Civil and Environmental Engineering and Acting Director of the Center for Urban Environmental Studies, both at Northeastern, used high-resolution monitoring and modeling to understand the fate and transport of E. coli bacteria in the lower section of the Charles River to determine what factors may lead to the increased concentration.
The results, which were published in the April issue of the Journal of the American Water Resources Association, go above and beyond the current data available about the water quality in the Charles and have the potential to impact the location of future beaches and their management.
Because current monitoring programs do not resolve the small-scale patterns of E. coli, Hellweger and his team carried out a high-resolution monitoring program. Using spatial and temporal surveys at different intervals and locations, Hellweger and his team gathered 757 samples along transects across and along the river, and over time at a fixed location. The results indicated an increased concentration of E. coli after a period of little rainfall. To make sense of these results, they developed a mathematical model of the river. The model accounts for various drivers, including upstream and downstream flow, wind, combined sewer overflow (CSO) and non-CSO flow from two major tributaries, the Muddy River and the Stony Brook. Based on hydrodynamics and die-off kinetics, the model reproduced the general patterns of E. coli in the water over space and time.
"Our analysis suggests that the Stony Brook and Muddy River are the predominant sources of E. coli in the lower Charles River," said Hellweger, whose interest in urban hydrology drove this research project. "However, it is important to determine where the bacteria go and their concentration at different times and locations."
One surprising finding was the effect of the New Charles River Dam, which when open, allows the Charles River to flow downstream and empty into the Boston Harbor. When it is closed, however, the Charles River acts more like a lake or a reservoir, creating a static environment. Thus, in addition to rainfall, the Dam operation cycle does affect the level of bacteria in the Charles River.
"Our study results show that water quality in the Charles River is impacted by several factors, including the New Charles River Dam," added Hellweger. "While the primary focus of the Dam is to control flooding and navigation, I think that taking water quality issues into account could help reduce public health risk to present boaters and future beachgoers in the Charles," added Hellweger.
Their model can be used to predict water quality in the lower Charles River, which can be used to evaluate various management scenarios and assess public health risk to swimmers at different times and locations.
In a 2002 study, 25% of surveyed beaches had at least one advisory or area closed, mostly due to unsafe levels of certain forms of bacteria. Exposure to unsafe levels of bacterial can sometimes result in recreational water illnesses (RWI), causing diarrhea, respiratory, skin, ear and eye infections.
Water pollution continues to be a public health threat, and because the Summer is quickly approaching, there will be a heightened interest in protecting people who spend time in the water. "My goal is to help make the Charles River a place where people can swim safely," said Hellweger.
About Northeastern
Founded in 1898, Northeastern University is a private research university located in the heart of Boston. Northeastern is a leader in interdisciplinary research, urban engagement, and the integration of classroom learning with real-world experience. The university's distinctive cooperative education program, where students alternate semesters of full-time study with semesters of paid work in fields relevant to their professional interests and major, is one of the largest and most innovative in the world. The University offers a comprehensive range of undergraduate and graduate programs leading to degrees through the doctorate in six undergraduate colleges, eight graduate schools, and two part-time divisions.
Northeastern
The results, which were published in the April issue of the Journal of the American Water Resources Association, go above and beyond the current data available about the water quality in the Charles and have the potential to impact the location of future beaches and their management.
Because current monitoring programs do not resolve the small-scale patterns of E. coli, Hellweger and his team carried out a high-resolution monitoring program. Using spatial and temporal surveys at different intervals and locations, Hellweger and his team gathered 757 samples along transects across and along the river, and over time at a fixed location. The results indicated an increased concentration of E. coli after a period of little rainfall. To make sense of these results, they developed a mathematical model of the river. The model accounts for various drivers, including upstream and downstream flow, wind, combined sewer overflow (CSO) and non-CSO flow from two major tributaries, the Muddy River and the Stony Brook. Based on hydrodynamics and die-off kinetics, the model reproduced the general patterns of E. coli in the water over space and time.
"Our analysis suggests that the Stony Brook and Muddy River are the predominant sources of E. coli in the lower Charles River," said Hellweger, whose interest in urban hydrology drove this research project. "However, it is important to determine where the bacteria go and their concentration at different times and locations."
One surprising finding was the effect of the New Charles River Dam, which when open, allows the Charles River to flow downstream and empty into the Boston Harbor. When it is closed, however, the Charles River acts more like a lake or a reservoir, creating a static environment. Thus, in addition to rainfall, the Dam operation cycle does affect the level of bacteria in the Charles River.
"Our study results show that water quality in the Charles River is impacted by several factors, including the New Charles River Dam," added Hellweger. "While the primary focus of the Dam is to control flooding and navigation, I think that taking water quality issues into account could help reduce public health risk to present boaters and future beachgoers in the Charles," added Hellweger.
Their model can be used to predict water quality in the lower Charles River, which can be used to evaluate various management scenarios and assess public health risk to swimmers at different times and locations.
In a 2002 study, 25% of surveyed beaches had at least one advisory or area closed, mostly due to unsafe levels of certain forms of bacteria. Exposure to unsafe levels of bacterial can sometimes result in recreational water illnesses (RWI), causing diarrhea, respiratory, skin, ear and eye infections.
Water pollution continues to be a public health threat, and because the Summer is quickly approaching, there will be a heightened interest in protecting people who spend time in the water. "My goal is to help make the Charles River a place where people can swim safely," said Hellweger.
About Northeastern
Founded in 1898, Northeastern University is a private research university located in the heart of Boston. Northeastern is a leader in interdisciplinary research, urban engagement, and the integration of classroom learning with real-world experience. The university's distinctive cooperative education program, where students alternate semesters of full-time study with semesters of paid work in fields relevant to their professional interests and major, is one of the largest and most innovative in the world. The University offers a comprehensive range of undergraduate and graduate programs leading to degrees through the doctorate in six undergraduate colleges, eight graduate schools, and two part-time divisions.
Northeastern
New Molecular Imaging Technologies For Detecting Cellular Processes
A group of researchers at Universidad Carlos III de Madrid (UC3M) have designed and developed a biomedical scanner that detects cellular processes at the molecular level and indicates malfunctioning of an organ before said malfunction can produce an anatomical change.
The work carried out by these scientists has ranged from the initial design of an electronic architecture for gamma ray detectors to industry transfer of a complete scanner, after having adequately validated a prototype through experimental studies at the Gregorio MaraГ±Гіn Hospital. The results of this research, headed by professors Juan JosГ© Vaquero and Manuel Desco, from the Department of de Bioengineering and Aerospace Engineering at UC3M, have been recently published in the journals IEEE Transactions on Nuclear Science (two articles) and Physics in Medicine and Biology (one article).
The electronic technology equipment designed by the researchers- which is in patent process-is based on molecular imaging, a type of biomedical imaging capable of detecting live cellular processes. "These techniques differ from conventional medical imaging in that the information they show is function not form, which means that they are capable of showing the malfunctioning of an organ before the malfunction turns into an anatomical change", Juan JosГ© Vaquero explained. "In other words", he added, "they allow for earlier detection of a possible anomaly, which enormously facilitates treatment". In addition to making an earlier diagnosis possible these types of scanners are used in biomedical research and in pharmaceutical laboratories, for example, to speed up the development of new medicines
The growth of molecular imaging in recent years, according to experts, is chiefly due to the narrowing of the gap between molecular biology and imaging technologies, and it is expected that an acceleration of the transfer of these techniques to clinical practice will be produced. In fact, some of the characteristics of molecular imaging itself are already present in techniques for clinical use in humans such as nuclear medicine imaging or magnetic resonance imaging. "Computerized tomograhy by a sole photon emission, better known by its Anglo-Saxon acronym SPECT, is probably the most widespread molecular imagining technique in clinical practice, and from there stems the interest in having preclinical systems which allow the study of human illnesses to be carried out on animals", Professor Manuel Desco pointed out.
The Department of Bioengineering and Aerospace Engineering at UC3M focuses on the development of preclinical molecular imaging scanners used in research work on animals. Obtaining good quality in these applications constitutes a much more difficult technical challenge than with humans, due to the large difference in size (with animals being approximately 280 times smaller). The research group has completed the development of SPECT type of system for laboratory animals at University installation, which has features placing it among the top on an international scale in terms of facilities and cost.
This UC3M research group, in addition to carrying out research which leads to scientific publications, focuses a large part of its interest on technology transfer so that it can be commercialized. The company, SEDECAL, the largest domestic manufacturer and exporter of electro-medical imaging equipment, is going to commercialize the system in the immediate future. The research team from this Madrid public university continues to work on new developments in the area of technology, in close contact with national industry. Part of the developments are under the framework of the AMIT (Advanced Molecular Imaging Technologies) Project from the most recent CENIT public funding, whose scientific coordination oversees this equipment at the UC3M.
Further information:
Tittle: Data acquisition electronics for gamma ray emission tomography using width-modulated leading-edge discriminators
Authors: E. Lage, G. Tapias, J. Villena, M. Desco, J.J. Vaquero
Magazine: PHYSICS IN MEDICINE AND BIOLOGY
Vol. 55 (2010), pp 4291-4308
Tittle: Effects of the Super Bialkali Photocathode on the Performance Characteristics of a Position-Sensitive Depth-of-Interaction PET Detector Module
Authors: Juan J. Vaquero, JosГ© M. UdГas, Jurgen Seidel, Samuel EspaГ±a, Manuel Desco
Magazine: IEEE TRANSACTIONS ON NUCLEAR SCIENCE
Vol. 57, N. 5, OCTOBER 2010, pp 2437-2441
Tittle: A SPECT Scanner for Rodent Imaging Based on Small-Area Gamma Cameras
Authors: Eduardo Lage, JosГ© L. Villena, Gustavo Tapias, Naira P. MartГnez, Maria L. Soto-Montenegro, MГіnica Abella, Alejandro Sisniega, Francisco Pino, DomГЁnec Ros, Javier PavГa, Manuel Desco, Juan J. Vaquero
Magazine: IEEE TRANSACTIONS ON NUCLEAR SCIENCE
Vol. 57, N. 5, OCTOBER 2010, pp 2524-2531
Source:
Ana Herrera
Carlos III University of Madrid
The work carried out by these scientists has ranged from the initial design of an electronic architecture for gamma ray detectors to industry transfer of a complete scanner, after having adequately validated a prototype through experimental studies at the Gregorio MaraГ±Гіn Hospital. The results of this research, headed by professors Juan JosГ© Vaquero and Manuel Desco, from the Department of de Bioengineering and Aerospace Engineering at UC3M, have been recently published in the journals IEEE Transactions on Nuclear Science (two articles) and Physics in Medicine and Biology (one article).
The electronic technology equipment designed by the researchers- which is in patent process-is based on molecular imaging, a type of biomedical imaging capable of detecting live cellular processes. "These techniques differ from conventional medical imaging in that the information they show is function not form, which means that they are capable of showing the malfunctioning of an organ before the malfunction turns into an anatomical change", Juan JosГ© Vaquero explained. "In other words", he added, "they allow for earlier detection of a possible anomaly, which enormously facilitates treatment". In addition to making an earlier diagnosis possible these types of scanners are used in biomedical research and in pharmaceutical laboratories, for example, to speed up the development of new medicines
The growth of molecular imaging in recent years, according to experts, is chiefly due to the narrowing of the gap between molecular biology and imaging technologies, and it is expected that an acceleration of the transfer of these techniques to clinical practice will be produced. In fact, some of the characteristics of molecular imaging itself are already present in techniques for clinical use in humans such as nuclear medicine imaging or magnetic resonance imaging. "Computerized tomograhy by a sole photon emission, better known by its Anglo-Saxon acronym SPECT, is probably the most widespread molecular imagining technique in clinical practice, and from there stems the interest in having preclinical systems which allow the study of human illnesses to be carried out on animals", Professor Manuel Desco pointed out.
The Department of Bioengineering and Aerospace Engineering at UC3M focuses on the development of preclinical molecular imaging scanners used in research work on animals. Obtaining good quality in these applications constitutes a much more difficult technical challenge than with humans, due to the large difference in size (with animals being approximately 280 times smaller). The research group has completed the development of SPECT type of system for laboratory animals at University installation, which has features placing it among the top on an international scale in terms of facilities and cost.
This UC3M research group, in addition to carrying out research which leads to scientific publications, focuses a large part of its interest on technology transfer so that it can be commercialized. The company, SEDECAL, the largest domestic manufacturer and exporter of electro-medical imaging equipment, is going to commercialize the system in the immediate future. The research team from this Madrid public university continues to work on new developments in the area of technology, in close contact with national industry. Part of the developments are under the framework of the AMIT (Advanced Molecular Imaging Technologies) Project from the most recent CENIT public funding, whose scientific coordination oversees this equipment at the UC3M.
Further information:
Tittle: Data acquisition electronics for gamma ray emission tomography using width-modulated leading-edge discriminators
Authors: E. Lage, G. Tapias, J. Villena, M. Desco, J.J. Vaquero
Magazine: PHYSICS IN MEDICINE AND BIOLOGY
Vol. 55 (2010), pp 4291-4308
Tittle: Effects of the Super Bialkali Photocathode on the Performance Characteristics of a Position-Sensitive Depth-of-Interaction PET Detector Module
Authors: Juan J. Vaquero, JosГ© M. UdГas, Jurgen Seidel, Samuel EspaГ±a, Manuel Desco
Magazine: IEEE TRANSACTIONS ON NUCLEAR SCIENCE
Vol. 57, N. 5, OCTOBER 2010, pp 2437-2441
Tittle: A SPECT Scanner for Rodent Imaging Based on Small-Area Gamma Cameras
Authors: Eduardo Lage, JosГ© L. Villena, Gustavo Tapias, Naira P. MartГnez, Maria L. Soto-Montenegro, MГіnica Abella, Alejandro Sisniega, Francisco Pino, DomГЁnec Ros, Javier PavГa, Manuel Desco, Juan J. Vaquero
Magazine: IEEE TRANSACTIONS ON NUCLEAR SCIENCE
Vol. 57, N. 5, OCTOBER 2010, pp 2524-2531
Source:
Ana Herrera
Carlos III University of Madrid
New Culture Technique Could Lead To Drug Discoveries
A novel cell culture technique for a noninvasive breast malignancy known as ductal carcinoma in situ (DCIS) could facilitate the discovery of new drugs to prevent DCIS recurrence or progression.
Gillian Farnie, Ph.D, of the University of Manchester in England, and colleagues developed a novel method to culture DCIS cells, and using this method, they examined the role of the epidermal growth factor receptor and Notch signaling pathways in the growth of DCIS. They found that both pathways were involved in self-renewal of DCIS cells; the former was necessary for DCIS growth, and the latter was important for cell survival.
"To our knowledge, no culture technique for DCIS exists; thus, the nonadherent culture technique that we describe should be useful for isolating tumor-forming epithelial cells from their primary DCIS lesions to allow a better understanding of their growth," the authors write.
Contact: Gillian Farnie, Ph.D, of the University of Manchester
Other highlights from the April 18 Journal of the National Cancer Institute
Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jncicancerspectrum.oxfordjournals/.
Contact: Liz Savage
Journal of the National Cancer Institute
Gillian Farnie, Ph.D, of the University of Manchester in England, and colleagues developed a novel method to culture DCIS cells, and using this method, they examined the role of the epidermal growth factor receptor and Notch signaling pathways in the growth of DCIS. They found that both pathways were involved in self-renewal of DCIS cells; the former was necessary for DCIS growth, and the latter was important for cell survival.
"To our knowledge, no culture technique for DCIS exists; thus, the nonadherent culture technique that we describe should be useful for isolating tumor-forming epithelial cells from their primary DCIS lesions to allow a better understanding of their growth," the authors write.
Contact: Gillian Farnie, Ph.D, of the University of Manchester
Other highlights from the April 18 Journal of the National Cancer Institute
Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jncicancerspectrum.oxfordjournals/.
Contact: Liz Savage
Journal of the National Cancer Institute
IU Neuroscientists Tie Network Structure To Brain's Spontaneous Activity
Indiana University neuroscientists Olaf Sporns and Christopher Honey find the 98 percent of brain activity that other researchers consider just background noise to be fascinating and important.
Brains are always active, even when people are at rest. In this "resting state," waves of neural activity ripple through the brain, creating fluctuating and ever-changing patterns. Sporns and Honey's work on modeling this brain activity sheds new light on how and when these mysterious fluctuations occur and offers insights into what the brain does while idle.
"Some people see the brain in terms of inputs and outputs, like a computer. If you provide an input, you'll get a particular output," said Honey, a doctoral student in IU Bloomington's Department of Psychological and Brain Sciences. "We take a different view. We believe that even in the absence of an external stimulus, there are very important processes going on in the brain which affect the stimulus-responses that the brain will produce. We believe that ongoing spontaneous activity should be studied in itself. Other researchers consider this to be unimportant 'noise' that should be filtered out."
Honey and Sporns, associate professor in the Department of Psychological and Brain Sciences, took a close look at the spontaneous activity of the brain at rest. With their computational approach -- which involved creating a large-scale computer model of the brain of a macaque monkey -- they demonstrated that the shape and pattern of the fluctuations are determined by the brain's wiring diagram, its neuroanatomy.
Their model also can show how slow 5- to 10-second fluctuations of activity emerge naturally from much faster, chaotic neural interactions that typically last only a few milliseconds.
"Our model suggests that the cortical resting state is not time-invariant, but instead contains rich and interrelated temporal structure at multiple time scales that is shaped by the underlying structural topology," Sporns and Honey wrote in an article appearing this week in the Proceedings of the National Academy of Sciences early edition online.
The article, which will be available at pnas/cgi/doi/10.1073/pnas.0701519104, includes a link to a movie that visualizes what spontaneous fluctuations in the monkey's brain would look like. Coauthors of the article are Rolf Kötter, a neuroanatomist at Radboud University in Nijmegen in the Netherlands, and Michael Breakspear, a cognitive neuroscientist at the University of New South Wales in Australia.
When a person reads a book or talks with a friend, task-related neural activity occurs in different regions of the brain, but this activity only accounts for around 2 to 5 percent of the total activity of the brain. Fluctuations of similar magnitude -- the ones studied by Sporns and Honey -- occur when a person is at rest, doing nothing.
The nature of these "resting state fluctuations" is an active topic of research in cognitive neuroscience, with their mysterious origin prompting one prominent researcher to label them the "brain's dark energy," Sporns said. As yet, no one knows why these fluctuations occur or what their function might be.
Sporns and Honey suggest that a closer look at brain structure might provide a new perspective.
Despite the huge amount of work being done by neuroscientists, relatively little is known about how the human brain is structured -- how, for example the hundreds (the number is unknown) of regions in the human brain are connected. The computer model created by Sporns and Honey suggests that this very pattern of connectivity is crucial to generating and shaping brain activity in the resting and active brain.
Empirical work on the human brain is challenging due to the fact that the brain's intricacies cannot simply be manipulated and observed. Sporns and Honey compare studying the brain to studying other complex systems such as cellular metabolism, the economy or global climate change. Models must be used to test theories and generate new insights into how the system works as a whole.
And while technologies such as functional MRI allow scientists to measure some kinds of neural connectivity, neuroinformatics approaches, which use extensive anatomical and physiological data sets to describe the macacque's brain, allowed Sporns and Honey to collect data on all the activity that occurred during their simulations.
Sporns said he wants to create a similar large-scale computer model of the human brain that will allow them to study larger networks and connectivity, once the necessary data sets of how human neural networks are structured are available.
A computational model of the human brain would help researchers better understand where the observed resting state fluctuations come from. It also would let them tie neural activity to cognitive and behavioral performance and ask questions about differences in the brains of individual persons.
Sporns said this research could lead to clinical applications, offering new diagnostic tools for brain disorders such as Alzheimer's disease that are known to affect the brain's connections. It also could help explain why humans do not think alike.
"If fluctuations in brain activity are shaped by anatomy," Sporns said, "then individual differences in the way people think and what they think about could be rooted in differences in the way their brains are connected."
Contact: Olaf Sporns
Indiana University
Brains are always active, even when people are at rest. In this "resting state," waves of neural activity ripple through the brain, creating fluctuating and ever-changing patterns. Sporns and Honey's work on modeling this brain activity sheds new light on how and when these mysterious fluctuations occur and offers insights into what the brain does while idle.
"Some people see the brain in terms of inputs and outputs, like a computer. If you provide an input, you'll get a particular output," said Honey, a doctoral student in IU Bloomington's Department of Psychological and Brain Sciences. "We take a different view. We believe that even in the absence of an external stimulus, there are very important processes going on in the brain which affect the stimulus-responses that the brain will produce. We believe that ongoing spontaneous activity should be studied in itself. Other researchers consider this to be unimportant 'noise' that should be filtered out."
Honey and Sporns, associate professor in the Department of Psychological and Brain Sciences, took a close look at the spontaneous activity of the brain at rest. With their computational approach -- which involved creating a large-scale computer model of the brain of a macaque monkey -- they demonstrated that the shape and pattern of the fluctuations are determined by the brain's wiring diagram, its neuroanatomy.
Their model also can show how slow 5- to 10-second fluctuations of activity emerge naturally from much faster, chaotic neural interactions that typically last only a few milliseconds.
"Our model suggests that the cortical resting state is not time-invariant, but instead contains rich and interrelated temporal structure at multiple time scales that is shaped by the underlying structural topology," Sporns and Honey wrote in an article appearing this week in the Proceedings of the National Academy of Sciences early edition online.
The article, which will be available at pnas/cgi/doi/10.1073/pnas.0701519104, includes a link to a movie that visualizes what spontaneous fluctuations in the monkey's brain would look like. Coauthors of the article are Rolf Kötter, a neuroanatomist at Radboud University in Nijmegen in the Netherlands, and Michael Breakspear, a cognitive neuroscientist at the University of New South Wales in Australia.
When a person reads a book or talks with a friend, task-related neural activity occurs in different regions of the brain, but this activity only accounts for around 2 to 5 percent of the total activity of the brain. Fluctuations of similar magnitude -- the ones studied by Sporns and Honey -- occur when a person is at rest, doing nothing.
The nature of these "resting state fluctuations" is an active topic of research in cognitive neuroscience, with their mysterious origin prompting one prominent researcher to label them the "brain's dark energy," Sporns said. As yet, no one knows why these fluctuations occur or what their function might be.
Sporns and Honey suggest that a closer look at brain structure might provide a new perspective.
Despite the huge amount of work being done by neuroscientists, relatively little is known about how the human brain is structured -- how, for example the hundreds (the number is unknown) of regions in the human brain are connected. The computer model created by Sporns and Honey suggests that this very pattern of connectivity is crucial to generating and shaping brain activity in the resting and active brain.
Empirical work on the human brain is challenging due to the fact that the brain's intricacies cannot simply be manipulated and observed. Sporns and Honey compare studying the brain to studying other complex systems such as cellular metabolism, the economy or global climate change. Models must be used to test theories and generate new insights into how the system works as a whole.
And while technologies such as functional MRI allow scientists to measure some kinds of neural connectivity, neuroinformatics approaches, which use extensive anatomical and physiological data sets to describe the macacque's brain, allowed Sporns and Honey to collect data on all the activity that occurred during their simulations.
Sporns said he wants to create a similar large-scale computer model of the human brain that will allow them to study larger networks and connectivity, once the necessary data sets of how human neural networks are structured are available.
A computational model of the human brain would help researchers better understand where the observed resting state fluctuations come from. It also would let them tie neural activity to cognitive and behavioral performance and ask questions about differences in the brains of individual persons.
Sporns said this research could lead to clinical applications, offering new diagnostic tools for brain disorders such as Alzheimer's disease that are known to affect the brain's connections. It also could help explain why humans do not think alike.
"If fluctuations in brain activity are shaped by anatomy," Sporns said, "then individual differences in the way people think and what they think about could be rooted in differences in the way their brains are connected."
Contact: Olaf Sporns
Indiana University
Alzheimer's Disease Linked To Mitochondrial Damage
Investigators at the Burnham Institute for Medical Research (Burnham) have demonstrated that attacks on the mitochondrial protein Drp1 by the free radical nitric oxide which causes a chemical reaction called S-nitrosylation mediates neurodegeneration associated with Alzheimer's disease. Prior to this study, the mechanism by which beta-amyloid protein caused synaptic damage to neurons in Alzheimer's disease was unknown. These findings suggest that preventing S-nitrosylation of Drp1 may reduce or even prevent neurodegeneration in Alzheimer's patients. The paper was published in the April 3 issue of the journal Science.
The team of scientists, led by neuroscientist and clinical neurologist Stuart A. Lipton, M.D., Ph.D., director of the Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, showed that S-nitrosylated Drp1 (SNO-Drp1) facilitates mitochondrial fragmentation, damaging regions of nerve cell communication called synapses. Mitochondria are the energy storehouses of the cell, and their compromise by excessive fragmentation causes synaptic injury and eventual nerve cell death. Synapses are critical for learning and memory and their impairment leads to the dementia seen in Alzheimer's patients.
"We now have a better understanding of the mechanism by which beta-amyloid protein causes neurodegeneration in Alzheimer's disease," said Dr. Lipton. "We found that beta-amyloid can generate nitric oxide that reacts with Drp1. By identifying Drp1 as the protein responsible for synaptic injury, we now have a new target for developing drugs that may slow or stop the progression of Alzheimer's."
Drp1 is an enzyme that mediates fission or fragmentation of mitochondria. The Burnham researchers showed that excessive production of nitric oxide caused S-nitrosylation of Drp1 and induced excessive fragmentation of mitochondria in cultured nerve cells or neurons. The scientists also showed that beta-amyloid protein multimers, which had been previously implicated in Alzheimer's disease, induced formation of SNO-Drp1. Importantly, elevated SNO-Drp1 levels were also found in human brains of Alzheimer's patients, but not in those with Parkinson's disease or controls who didn't have neurodegenerative diseases.
Molecular modeling performed by the team suggested that S-nitrosylation of Drp1 causes dimerization of the protein and activation of enzymatic activity that induces mitochondrial fragmentation. To confirm this hypothesis, the scientists showed that RNA interference to knock down Drp1 or a mutation that prevented Drp1 activity inhibited excess mitochondrial fragmentation and protected the neurons. Finally, the researchers showed that a mutated Drp1, lacking the nitrosylation site, did not induce mitochondrial fragmentation and also prevented neuronal damage. Taken together, these findings suggest that multimers of beta-amyloid protein induce generation of nitric oxide, which reacts with Drp1 to cause excessive mitochondrial fragmentation and in turn neuronal damage.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Burnham Institute for Medical Research
10901 N Torrey Pines Rd.
La Jolla
CA 92029
United States
burnham
The team of scientists, led by neuroscientist and clinical neurologist Stuart A. Lipton, M.D., Ph.D., director of the Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, showed that S-nitrosylated Drp1 (SNO-Drp1) facilitates mitochondrial fragmentation, damaging regions of nerve cell communication called synapses. Mitochondria are the energy storehouses of the cell, and their compromise by excessive fragmentation causes synaptic injury and eventual nerve cell death. Synapses are critical for learning and memory and their impairment leads to the dementia seen in Alzheimer's patients.
"We now have a better understanding of the mechanism by which beta-amyloid protein causes neurodegeneration in Alzheimer's disease," said Dr. Lipton. "We found that beta-amyloid can generate nitric oxide that reacts with Drp1. By identifying Drp1 as the protein responsible for synaptic injury, we now have a new target for developing drugs that may slow or stop the progression of Alzheimer's."
Drp1 is an enzyme that mediates fission or fragmentation of mitochondria. The Burnham researchers showed that excessive production of nitric oxide caused S-nitrosylation of Drp1 and induced excessive fragmentation of mitochondria in cultured nerve cells or neurons. The scientists also showed that beta-amyloid protein multimers, which had been previously implicated in Alzheimer's disease, induced formation of SNO-Drp1. Importantly, elevated SNO-Drp1 levels were also found in human brains of Alzheimer's patients, but not in those with Parkinson's disease or controls who didn't have neurodegenerative diseases.
Molecular modeling performed by the team suggested that S-nitrosylation of Drp1 causes dimerization of the protein and activation of enzymatic activity that induces mitochondrial fragmentation. To confirm this hypothesis, the scientists showed that RNA interference to knock down Drp1 or a mutation that prevented Drp1 activity inhibited excess mitochondrial fragmentation and protected the neurons. Finally, the researchers showed that a mutated Drp1, lacking the nitrosylation site, did not induce mitochondrial fragmentation and also prevented neuronal damage. Taken together, these findings suggest that multimers of beta-amyloid protein induce generation of nitric oxide, which reacts with Drp1 to cause excessive mitochondrial fragmentation and in turn neuronal damage.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Burnham Institute for Medical Research
10901 N Torrey Pines Rd.
La Jolla
CA 92029
United States
burnham
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