Johns Hopkins Children's Center scientists have discovered that high blood levels of a protein commonly found in the central nervous system can predict brain injury and death in critically ill children on a form of life support called extra-corporeal membrane oxygenation or ECMO.
ECMO, used to temporarily oxygenate the blood of patients whose heart and lungs are too weak or damaged to do so on their own, is most often used as a last resort because it can increase the risk for brain bleeding, brain swelling, stroke and death in some patients.
A detailed report of the Hopkins team's findings is published ahead of print Nov. 4 in the journal Pediatric Critical Care Medicine.
Following 22 ECMO patients, ranging from two days to 9 years of age, the researchers found that those with abnormally high levels of glial fibrillary acidic protein (GFAP) were 13 times more likely to die and 11 times more likely to suffer brain injury than children with normal GFAP levels. GFAP levels are already used as a marker of neurologic damage in adults who suffer strokes and traumatic brain injuries.
Although preliminary, the team's findings may pave the way to a much-needed way to monitor the precarious neurologic status of children on ECMO without using imaging tests like ultrasounds or CT scans. Periodic blood tests measuring GFAP levels may be one such tool to monitor brain function and help ward off brain injury and death, the researchers say.
"A simple, fast and easy-to-use test has been needed to monitor, predict and prevent brain damage in children on ECMO because these children are unresponsive or heavily sedated, and doctors cannot easily gauge their neurologic function," says study lead investigator Melania Bembea, M.D., M.P. H., a pediatric critical-care specialist at Hopkins Children's.
"Early detection of brain injury can help us prevent further harm by changing medication doses and rapidly weaning the patient from ECMO support," she adds.
The findings may have implications beyond ECMO, the researchers say, as they offer a way to monitor brain damage in other high-risk situations, including heart surgery and severely premature birth.
"Our long-term goal is to make lifesaving therapies like ECMO and heart surgery safer and more effective by improving protection of the brain, and GFAP and other biomarkers can give us a much-needed benchmark around which we can make these therapies safer," says senior investigator Allen Everett, M.D., a cardiologist at Hopkins Children's.
In the study, seven of the 22 children on ECMO developed brain bleeding or brain swelling, five of whom died subsequently. These children had much higher peak levels of GFAP than children without brain injury 5.9 nanograms per milliliter of blood compared to 0.09 in children without brain injury. GFAP levels were also markedly higher among eight of the 22 children in the study who had poor neurologic outcomes after ECMO (3.6 ng/ml) than in those children who had good neurologic outcomes (0.09 ng/ml).
Researchers also measured GFAP levels among healthy children and among newborns without neurologic injuries. Their median GFAP level was 0.055 nanograms per milliliter of blood and as high as 0.436 in some cases. By comparison, overall GFAP levels in children with neurologic injuries were 13 times greater than GFAP levels in healthy children.
The researchers caution that their findings should be replicated in a larger trial with more patients and that future studies must clarify the relationship between a rise in GFAP levels and the onset of brain injury. In the current study, GFAP levels rose sharply in some patients one or two days before their brain damage was discovered on ultrasound.
ECMO is used in about 1,000 children each year. Between 10 percent and 60 percent of children who survive ECMO suffer neurologic damage either because of their underlying disease or complications during ECMO therapy, the researchers say.
Hopkins Children's is Maryland's only hospital providing pediatric ECMO service.
The research was funded by the National Institutes of Health.
Other investigators in the study included William Savage, M.D., John Strouse, M.D., Ph.D., Jamie Schwartz, M.D., Ernest Graham, Carol Thompson, M.B.A., M.S., all of Hopkins.
Related:
Source: Johns Hopkins Medicine
понедельник, 25 апреля 2011 г.
Cancer In Children And Young People Caused By Rearrangements Of Multifunctional Genes
A doctoral thesis presented at the Sahlgrenska Academy, University of Gothenburg, Sweden, shows that three genes that lie behind a number of malignant tumour diseases are normally involved in several fundamental processes in the cell. This may be the reason that the tumours arise early in life and principally affect children and young people.
A family of genes known as the "FET" genes has been investigated in the work presented in the thesis. This family contains three genes that are found in modified forms in several malignant soft-tissue tumours and several forms of leukaemia. The FET genes are found in these tumours in the form of what are known as "fusion genes" in which parts of two different genes have merged to form one gene. Fusion genes are translated into abnormal fusion proteins, which can in certain cases transform normal cells to cancer cells.
The human body consists of many different types of specialised cell types such as nerve cells, fat cells and intestinal cells. These are formed when stem cells multiply and mature gradually along different developmental pathways. Cancer may arise if something goes wrong in this process. The study has shown that the activities of the genes in the FET family fall as the cells mature, and scientists therefore believe that these genes play a role during the early stages of cell maturation, when the cells are not far from the stem cell stage. The normal maturation pathway of a cell becomes blocked when fusion genes that contain FET genes arise. The result is a cancer cell with properties similar to those of stem cells, and such a cell can multiply in an uncontrolled manner.
"We found that the FET genes are also involved in the response of the cell to external and internal stress, and when cells spread. Alterations of such processes are common in cancer cells", says Mattias Andersson.
It normally requires damage to several different genes before cancer cells develop, and this usually takes a long time. However, since the FET genes are involved in several of the normal cell processes, scientists believe that in their rearranged form they can affect in parallel several of the control systems that prevent a normal cell from becoming a cancer cell. This may give rise to rapid development of cancer, and it may be the reason that tumours with FET fusion genes are often found in children and young people.
"Studying normal FET genes has increased our understanding of what may go wrong in cancer cells having rearrangements of these genes. This may in the long term lead to new methods of treatment for tumour diseases that contain FET fusion genes", says Mattias Andersson.
Source: Ulrika Lundin
University of Gothenburg
A family of genes known as the "FET" genes has been investigated in the work presented in the thesis. This family contains three genes that are found in modified forms in several malignant soft-tissue tumours and several forms of leukaemia. The FET genes are found in these tumours in the form of what are known as "fusion genes" in which parts of two different genes have merged to form one gene. Fusion genes are translated into abnormal fusion proteins, which can in certain cases transform normal cells to cancer cells.
The human body consists of many different types of specialised cell types such as nerve cells, fat cells and intestinal cells. These are formed when stem cells multiply and mature gradually along different developmental pathways. Cancer may arise if something goes wrong in this process. The study has shown that the activities of the genes in the FET family fall as the cells mature, and scientists therefore believe that these genes play a role during the early stages of cell maturation, when the cells are not far from the stem cell stage. The normal maturation pathway of a cell becomes blocked when fusion genes that contain FET genes arise. The result is a cancer cell with properties similar to those of stem cells, and such a cell can multiply in an uncontrolled manner.
"We found that the FET genes are also involved in the response of the cell to external and internal stress, and when cells spread. Alterations of such processes are common in cancer cells", says Mattias Andersson.
It normally requires damage to several different genes before cancer cells develop, and this usually takes a long time. However, since the FET genes are involved in several of the normal cell processes, scientists believe that in their rearranged form they can affect in parallel several of the control systems that prevent a normal cell from becoming a cancer cell. This may give rise to rapid development of cancer, and it may be the reason that tumours with FET fusion genes are often found in children and young people.
"Studying normal FET genes has increased our understanding of what may go wrong in cancer cells having rearrangements of these genes. This may in the long term lead to new methods of treatment for tumour diseases that contain FET fusion genes", says Mattias Andersson.
Source: Ulrika Lundin
University of Gothenburg
News From The Journal Of Neuroscience
1. Polyhedral Cages Dock Vesicles at Active Zones
Guido A. Zampighi, Nick Fain, Lorenzo M. Zampighi, Francesca Cantele, Salvatore Lanzavecchia, and Ernest M. Wright
When looking at schematic illustrations of proteins found in presynaptic active zones, it is hard to imagine how all those proteins fit together in the cell. Even with electron microscopy, the organization of vesicle docking machinery is difficult to discriminate. But this week, Zampighi et al. present images of active zone complexes that were visualized using conical electron tomography. The authors used semiautomated volume-rendering techniques that colored individual voxels based on density thresholds and/or topology. The resulting images revealed that active zones of rat cortical synapses contain several units, each of which comprised a central polyhedral cage (which the authors call a syndesome) surrounded by synaptic vesicles. Some of these vesicles were partly or fully fused to the plasma membrane, suggesting that the polyhedral cages help mediate vesicle docking and fusion. Interestingly, the polyhedral cages resemble those of clathrin coats, which are normally associated with endocytosis rather than exocytosis.
2. Neurturin and Ret Influence Retinal Circuit Formation
Milam A. Brantley Jr, Sanjay Jain, Emily E. Barr, Eugene M. Johnson Jr, and Jeffrey Milbrandt
The receptor tyrosine kinase Ret, which is activated by glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), is essential for development of many tissues, and GDNF can slow retinal degeneration in animal models. Brantley et al. have detailed the role of this signaling pathway in retinal development. Mice with reduced Ret expression showed decreased light responses, as did mice lacking the GFL neurturin, but not other GFLs. Expression of fluorescent reporters under the control of Ret or neurturin receptor promoters indicated that both of these molecules are expressed in horizontal cells and some amacrine and ganglion cells. In neurturin knock-out mice, the outer plexiform layer (where photoreceptors synapse with horizontal and bipolar cells) was disorganized, horizontal cell axons and dendrites were sparse, bipolar and horizontal cell processes were abnormally long, and synapses were mislocalized to the outer nuclear layer. Therefore, neurturin-mediated Ret signaling appears necessary for normal circuit development in the retina.
3. Disinhibition Drives OFF Cell Depolarization
Michael B. Manookin, Deborah Langrill Beaudoin, Zachary Raymond Ernst, Leigh J. Flagel, and Jonathan B. Demb
It has been assumed that depolarization of retinal ganglion cells is driven by excitation from bipolar cells. Manookin et al. now report that OFF ganglion cells are also driven by reduced inhibition. Responses to light increments and decrements were recorded in guinea pig ON and OFF ganglion cells. At all increment levels, ON cells received both excitatory and inhibitory inputs; but at each decrement level, increased excitation of OFF cells was paired with decreased inhibition. By sequentially applying receptor agonists and antagonists to test each type of synapse (including gap junctions), it was determined that OFF cell inhibition is mediated by AII amacrine cells, which are electrically coupled to ON cone bipolar cells. When the light dims, ON cone bipolar cells hyperpolarize, which hyperpolarizes AII amacrine cells, thus reducing their inhibition of OFF ganglion cells. This disinhibition is the dominant driving force for OFF ganglion cells when light decrements are small.
4. Microglia Delimit Alzheimer Plaques
Tristan Bolmont, Florent Haiss, Daniel Eicke, Rebecca Radde, Chester A. Mathis, William E. Klunk, Shinichi Kohsaka, Mathias Jucker, and Michael E. Calhoun
Microglia play roles in many neurological diseases, including Alzheimer's disease (AD). In AD, microglia surround amyloid plaques, but it is not clear whether they are harmful (e.g., promoting inflammation) or beneficial (e.g., restricting plaque growth). To gain some insight into their function, Bolmont et al. imaged interactions occurring in vivo between microglia and amyloid plaques in a mouse model of AD. Microglia extended and retracted processes in all directions, but those that were near plaques extended more processes toward the plaque. Many nearby microglia migrated to the edge of a given plaque and remained there, but there was an upper limit to the number of microglia surrounding any plaque: larger plaques were associated with larger, not more, microglia. The total volume of microglia surrounding a plaque was predictive of whether the plaque grew over time, and microglia appeared to take up amyloid particles, suggesting the microglia may limit plaque growth.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
Guido A. Zampighi, Nick Fain, Lorenzo M. Zampighi, Francesca Cantele, Salvatore Lanzavecchia, and Ernest M. Wright
When looking at schematic illustrations of proteins found in presynaptic active zones, it is hard to imagine how all those proteins fit together in the cell. Even with electron microscopy, the organization of vesicle docking machinery is difficult to discriminate. But this week, Zampighi et al. present images of active zone complexes that were visualized using conical electron tomography. The authors used semiautomated volume-rendering techniques that colored individual voxels based on density thresholds and/or topology. The resulting images revealed that active zones of rat cortical synapses contain several units, each of which comprised a central polyhedral cage (which the authors call a syndesome) surrounded by synaptic vesicles. Some of these vesicles were partly or fully fused to the plasma membrane, suggesting that the polyhedral cages help mediate vesicle docking and fusion. Interestingly, the polyhedral cages resemble those of clathrin coats, which are normally associated with endocytosis rather than exocytosis.
2. Neurturin and Ret Influence Retinal Circuit Formation
Milam A. Brantley Jr, Sanjay Jain, Emily E. Barr, Eugene M. Johnson Jr, and Jeffrey Milbrandt
The receptor tyrosine kinase Ret, which is activated by glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), is essential for development of many tissues, and GDNF can slow retinal degeneration in animal models. Brantley et al. have detailed the role of this signaling pathway in retinal development. Mice with reduced Ret expression showed decreased light responses, as did mice lacking the GFL neurturin, but not other GFLs. Expression of fluorescent reporters under the control of Ret or neurturin receptor promoters indicated that both of these molecules are expressed in horizontal cells and some amacrine and ganglion cells. In neurturin knock-out mice, the outer plexiform layer (where photoreceptors synapse with horizontal and bipolar cells) was disorganized, horizontal cell axons and dendrites were sparse, bipolar and horizontal cell processes were abnormally long, and synapses were mislocalized to the outer nuclear layer. Therefore, neurturin-mediated Ret signaling appears necessary for normal circuit development in the retina.
3. Disinhibition Drives OFF Cell Depolarization
Michael B. Manookin, Deborah Langrill Beaudoin, Zachary Raymond Ernst, Leigh J. Flagel, and Jonathan B. Demb
It has been assumed that depolarization of retinal ganglion cells is driven by excitation from bipolar cells. Manookin et al. now report that OFF ganglion cells are also driven by reduced inhibition. Responses to light increments and decrements were recorded in guinea pig ON and OFF ganglion cells. At all increment levels, ON cells received both excitatory and inhibitory inputs; but at each decrement level, increased excitation of OFF cells was paired with decreased inhibition. By sequentially applying receptor agonists and antagonists to test each type of synapse (including gap junctions), it was determined that OFF cell inhibition is mediated by AII amacrine cells, which are electrically coupled to ON cone bipolar cells. When the light dims, ON cone bipolar cells hyperpolarize, which hyperpolarizes AII amacrine cells, thus reducing their inhibition of OFF ganglion cells. This disinhibition is the dominant driving force for OFF ganglion cells when light decrements are small.
4. Microglia Delimit Alzheimer Plaques
Tristan Bolmont, Florent Haiss, Daniel Eicke, Rebecca Radde, Chester A. Mathis, William E. Klunk, Shinichi Kohsaka, Mathias Jucker, and Michael E. Calhoun
Microglia play roles in many neurological diseases, including Alzheimer's disease (AD). In AD, microglia surround amyloid plaques, but it is not clear whether they are harmful (e.g., promoting inflammation) or beneficial (e.g., restricting plaque growth). To gain some insight into their function, Bolmont et al. imaged interactions occurring in vivo between microglia and amyloid plaques in a mouse model of AD. Microglia extended and retracted processes in all directions, but those that were near plaques extended more processes toward the plaque. Many nearby microglia migrated to the edge of a given plaque and remained there, but there was an upper limit to the number of microglia surrounding any plaque: larger plaques were associated with larger, not more, microglia. The total volume of microglia surrounding a plaque was predictive of whether the plaque grew over time, and microglia appeared to take up amyloid particles, suggesting the microglia may limit plaque growth.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
Mysteries Of Vitamin A Metabolism During Embryonic Development Unlocked By Rutgers Researchers
Researchers at Rutgers have unlocked some of the mysteries of how the developing embryo reacts to fluctuations in the amount of vitamin A present in the maternal blood stream. Their results are presented in the February 28 issue of the Journal of Biological Chemistry.
The researchers studied the role of LRAT, a protein that facilitates the formation of vitamin A stores in the body, during embryonic development. In particular, they showed how LRAT protects developing tissues from potentially toxic levels of vitamin A that have been ingested by the mother. Although this function of LRAT had previously been hypothesized in adults, this is the first time that its role has been demonstrated during embryonic development.
The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids, the vitamin A metabolites produced in the body. These are essential nutrients and they control the formation of the embryo's heart, central nervous system, eyes and other important organs and tissues. Malformations of the developing embryo can occur when too little, or too much, vitamin A is consumed by the mother.
"We were looking for the mechanisms that allow the fetus to maintain adequate amount of retinoids, whether the mother has over- or under-consumed vitamin A," said Dr. Loredana Quadro, an assistant professor in the Department of Food Science and member of the Center for Lipid Research at the Rutgers School of Environmental and Biological Sciences. "We also looked at the effects of different levels of vitamin A being transferred from the mother to the fetus."
When vitamin A is ingested, it is converted into retinyl ester (RE) in the intestine from where it is secreted in the bloodstream packaged with other dietary lipids into lipoprotein particles called chylomicrons. The majority of dietary RE reaches the liver, the main body storage site of vitamin A. Under insufficient dietary vitamin A intake, the liver transforms RE into retinol (ROH), which is then secreted into the bloodstream bound to retinol-binding protein (RBP), its sole specific serum carrier, to be delivered to the target tissues. Upon intake through a specific membrane receptor named Stra6, ROH is ultimately converted to retinoic acid (RA), which is the active form of vitamin A. If tissue RA is in excess, it is transformed into inactive forms, such as 4-hydroxy retinoic acid or 4-oxo retinoic acid (OXO-RA) by the action of a specific enzyme named Cyp26A1.
"When we think about vitamin A, we think about one compound," said Quadro. "But in reality, the term vitamin A comprises a family of different compounds. Each one has a slightly different action, and plays a different role."
The Rutgers researchers took a closer look at how ROH is metabolized into RE and RA to maintain an optimal balance of retinoids during the formation of the embryo. Mutant mice lacking both RBP and LRAT were generated to perform this study, so as to interfere with the two main pathways of maternal vitamin A delivery to the fetus (ROH-RBP from the liver stores and RE of dietary origin).
"We hypothesized that the lack of ROH-RBP and LRAT would make the embryo more vulnerable to changes in maternal dietary vitamin A intake," said Quadro "and our data proved this to be correct. Indeed, a severe embryonic vitamin A deficiency is readily attainable when the mothers are deprived of dietary vitamin A during pregnancy. Therefore, this strain turned out to be a very good model to study how embryonic development is affected by fluctuations in the amount of retinoids present in the maternal diet and hence in the maternal circulation".
The researchers identified LRAT, Cyp26A1 and Stra6 as the three key molecular players that act in coordination to protect the developing tissues from potentially detrimental levels of vitamin A ingested by the mother. "Understanding vitamin A metabolism in the developing fetus could have broad implications," said Quadro. "Consumption of large doses of dietary supplements and vitamins, including vitamin A, has become a very common practice in recent years, generating the necessity to investigate the effects of high doses of vitamin A intake at different stages of the lifecycle, including pregnancy and development. These studies expand our knowledge of maternal-fetal nutrition and dietary contribution to embryonic development and may ultimately provide new insight into appropriate dietary practices during pregnancy."
This research was lead by Quadro and carried out primarily by her lab members, Youn-Kyung Kim, a graduate assistant, and Dr. Lesley Wassef, a post-doctoral associate. Others contributing to the study were Leora Hamberger, a former research assistant in Quadro's laboratory, Dr. William Blaner and Roseann Piantedosi from Columbia University and Dr. Krzysztof Palczewski from Case Western Reserve.
The paper was previously published on the Journal of Biological Chemistry's web site on December 19, 2007.
Source: Michele Hujber
Rutgers University
The researchers studied the role of LRAT, a protein that facilitates the formation of vitamin A stores in the body, during embryonic development. In particular, they showed how LRAT protects developing tissues from potentially toxic levels of vitamin A that have been ingested by the mother. Although this function of LRAT had previously been hypothesized in adults, this is the first time that its role has been demonstrated during embryonic development.
The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids, the vitamin A metabolites produced in the body. These are essential nutrients and they control the formation of the embryo's heart, central nervous system, eyes and other important organs and tissues. Malformations of the developing embryo can occur when too little, or too much, vitamin A is consumed by the mother.
"We were looking for the mechanisms that allow the fetus to maintain adequate amount of retinoids, whether the mother has over- or under-consumed vitamin A," said Dr. Loredana Quadro, an assistant professor in the Department of Food Science and member of the Center for Lipid Research at the Rutgers School of Environmental and Biological Sciences. "We also looked at the effects of different levels of vitamin A being transferred from the mother to the fetus."
When vitamin A is ingested, it is converted into retinyl ester (RE) in the intestine from where it is secreted in the bloodstream packaged with other dietary lipids into lipoprotein particles called chylomicrons. The majority of dietary RE reaches the liver, the main body storage site of vitamin A. Under insufficient dietary vitamin A intake, the liver transforms RE into retinol (ROH), which is then secreted into the bloodstream bound to retinol-binding protein (RBP), its sole specific serum carrier, to be delivered to the target tissues. Upon intake through a specific membrane receptor named Stra6, ROH is ultimately converted to retinoic acid (RA), which is the active form of vitamin A. If tissue RA is in excess, it is transformed into inactive forms, such as 4-hydroxy retinoic acid or 4-oxo retinoic acid (OXO-RA) by the action of a specific enzyme named Cyp26A1.
"When we think about vitamin A, we think about one compound," said Quadro. "But in reality, the term vitamin A comprises a family of different compounds. Each one has a slightly different action, and plays a different role."
The Rutgers researchers took a closer look at how ROH is metabolized into RE and RA to maintain an optimal balance of retinoids during the formation of the embryo. Mutant mice lacking both RBP and LRAT were generated to perform this study, so as to interfere with the two main pathways of maternal vitamin A delivery to the fetus (ROH-RBP from the liver stores and RE of dietary origin).
"We hypothesized that the lack of ROH-RBP and LRAT would make the embryo more vulnerable to changes in maternal dietary vitamin A intake," said Quadro "and our data proved this to be correct. Indeed, a severe embryonic vitamin A deficiency is readily attainable when the mothers are deprived of dietary vitamin A during pregnancy. Therefore, this strain turned out to be a very good model to study how embryonic development is affected by fluctuations in the amount of retinoids present in the maternal diet and hence in the maternal circulation".
The researchers identified LRAT, Cyp26A1 and Stra6 as the three key molecular players that act in coordination to protect the developing tissues from potentially detrimental levels of vitamin A ingested by the mother. "Understanding vitamin A metabolism in the developing fetus could have broad implications," said Quadro. "Consumption of large doses of dietary supplements and vitamins, including vitamin A, has become a very common practice in recent years, generating the necessity to investigate the effects of high doses of vitamin A intake at different stages of the lifecycle, including pregnancy and development. These studies expand our knowledge of maternal-fetal nutrition and dietary contribution to embryonic development and may ultimately provide new insight into appropriate dietary practices during pregnancy."
This research was lead by Quadro and carried out primarily by her lab members, Youn-Kyung Kim, a graduate assistant, and Dr. Lesley Wassef, a post-doctoral associate. Others contributing to the study were Leora Hamberger, a former research assistant in Quadro's laboratory, Dr. William Blaner and Roseann Piantedosi from Columbia University and Dr. Krzysztof Palczewski from Case Western Reserve.
The paper was previously published on the Journal of Biological Chemistry's web site on December 19, 2007.
Source: Michele Hujber
Rutgers University
'Kiss Of Death' For Antibiotic-Resistant Germs With The Help Of Frog Skin
Kissing a frog won't turn it into a prince - except in fairy tales - but frogs may be hopping toward a real-world transformation into princely allies in humanity's battle with antibiotic-resistant infections that threaten millions of people worldwide. Scientists today reported that frog skin contains natural substances that could be the basis for a powerful new genre of antibiotics.
In a report at the 240th National Meeting of the American Chemical Society, the team of stalwart frog-fanciers described enlisting colleagues worldwide to ship secretions from hundreds of promising frog skins to their laboratory in the United Arab Emirates. Using that amphibious treasure trove, they identified more than 100 antibiotic substances in the skins of different frog species from around the world. One even fights "Iraqibacter," the bacterium responsible for drug-resistant infections in wounded soldiers returning from Iraq.
Michael Conlon, Ph.D., who reported on the research, noted that the emergence of drug-resistant bacteria, which have the ability to shrug off conventional antibiotics, is a growing problem worldwide. As a result, patients need new types of antibiotics to replace drugs that no longer work.
"Frog skin is an excellent potential source of such antibiotic agents," said Conlon, a biochemist at the United Arab Emirates University in Al-Ain, Abu Dhabi Emirate. "They've been around 300 million years, so they've had plenty of time to learn how to defend themselves against disease-causing microbes in the environment. Their own environment includes polluted waterways where strong defenses against pathogens are a must."
Scientists have known for years that the skin of frogs is a rich source of chemicals capable of killing bacteria, viruses, and fungi. Researchers have attempted to isolate those germ-fighting chemicals and make them suitable for development into new antibiotics. Success, however, has been elusive because froggy antibiotics tend to be toxic to human cells and certain chemicals in the bloodstream easily destroy them.
Conlon and colleagues described an approach to overcome these problems. They discovered a way to tweak the molecular structure of frog skin antibiotic substances, making them less toxic to human cells but more powerful germ killers. Similarly, the scientists also discovered other tweaks that enabled the frog skin secretions to shrug off attack by destructive enzymes in the blood. The result was antibiotics that last longer in the bloodstream and are more likely to be effective as infection fighters, Conlon noted.
The antibiotic substances work in an unusual way that makes it very difficult for disease-causing microbes to develop resistance, Conlon said.
The scientists are currently screening skin secretions from more than 6,000 species of frogs for antibiotic activity. So far, they have purified and determined the chemical structure of barely 200, leaving a potential bonanza of antibiotic substances awaiting discovery.
"Many people are working with me, giving me samples of frog skin secretions," said Conlon, who has a dozen research collaborators in Japan, France, the United States, and other countries. "We only actually use the frogs to get the chemical structure of the antibiotic, and then we make it in the lab. We take great care not to harm these delicate creatures, and scientists return them to the wild after swabbing their skin for the precious secretions."
One substance isolated from the skin secretions of the Foothill Yellow-legged Frog - a species once common in California and Oregon but now facing extinction - shows promise for killing methicillin-resistant Staphylococcus aureus (MRSA) bacteria. MRSA is a "superbug," infamous for causing deadly outbreaks of infection among hospitalized patients. Now it is occurring in settings outside hospitals, including schools, nursing homes, and day care centers.
The skin of the mink frog, likewise, contains secretions that show promise for fighting "Iraqibacter," caused by multidrug-resistant Acinetobacter baumanni.
Some of the substances could make their way into clinical trials within the next five years, Conlon predicted. He envisions that pharmaceutical companies could develop the chemicals as creams or ointments for treating skin infections or as injectable drugs for treating drug-resistant infections throughout the body. The United Arab Emirates University provided funding for the study.
"The research also is important because it underscores the importance of preserving biodiversity," Conlon pointed out. "Some frog species - including those that may contain potentially valuable medicinal substances - are in jeopardy worldwide due to loss of habitat, water pollution, and other problems."
The Skinny on Frog Skin
Frogs and toads have a "Lycra" type skin that protects them from injury and disease. It comes in a rainbow of color and patterns.
Frog skin is water permeable, letting water in and out. Frogs seldom drink with their mouths. Rather, they absorb water through their skin. A "seat pouch" on their bellies absorbs water.
Many species have skin glands that produce toxins and other substances to repel predators. Scientists are studying some as potential pain medications.
Skin colors and patterns are protective devices that warn predators that the frog may be poisonous. Some frogs change the color of their skin to absorb or reflect heat and thus control their body temperature. Patterned skin can help camouflage the frog, so it sinks into the background, hidden from predators.
Frogs regularly shed their skin. Most eat the shed skin.
Source:
Michael Bernstein
Michael Woods
American Chemical Society
In a report at the 240th National Meeting of the American Chemical Society, the team of stalwart frog-fanciers described enlisting colleagues worldwide to ship secretions from hundreds of promising frog skins to their laboratory in the United Arab Emirates. Using that amphibious treasure trove, they identified more than 100 antibiotic substances in the skins of different frog species from around the world. One even fights "Iraqibacter," the bacterium responsible for drug-resistant infections in wounded soldiers returning from Iraq.
Michael Conlon, Ph.D., who reported on the research, noted that the emergence of drug-resistant bacteria, which have the ability to shrug off conventional antibiotics, is a growing problem worldwide. As a result, patients need new types of antibiotics to replace drugs that no longer work.
"Frog skin is an excellent potential source of such antibiotic agents," said Conlon, a biochemist at the United Arab Emirates University in Al-Ain, Abu Dhabi Emirate. "They've been around 300 million years, so they've had plenty of time to learn how to defend themselves against disease-causing microbes in the environment. Their own environment includes polluted waterways where strong defenses against pathogens are a must."
Scientists have known for years that the skin of frogs is a rich source of chemicals capable of killing bacteria, viruses, and fungi. Researchers have attempted to isolate those germ-fighting chemicals and make them suitable for development into new antibiotics. Success, however, has been elusive because froggy antibiotics tend to be toxic to human cells and certain chemicals in the bloodstream easily destroy them.
Conlon and colleagues described an approach to overcome these problems. They discovered a way to tweak the molecular structure of frog skin antibiotic substances, making them less toxic to human cells but more powerful germ killers. Similarly, the scientists also discovered other tweaks that enabled the frog skin secretions to shrug off attack by destructive enzymes in the blood. The result was antibiotics that last longer in the bloodstream and are more likely to be effective as infection fighters, Conlon noted.
The antibiotic substances work in an unusual way that makes it very difficult for disease-causing microbes to develop resistance, Conlon said.
The scientists are currently screening skin secretions from more than 6,000 species of frogs for antibiotic activity. So far, they have purified and determined the chemical structure of barely 200, leaving a potential bonanza of antibiotic substances awaiting discovery.
"Many people are working with me, giving me samples of frog skin secretions," said Conlon, who has a dozen research collaborators in Japan, France, the United States, and other countries. "We only actually use the frogs to get the chemical structure of the antibiotic, and then we make it in the lab. We take great care not to harm these delicate creatures, and scientists return them to the wild after swabbing their skin for the precious secretions."
One substance isolated from the skin secretions of the Foothill Yellow-legged Frog - a species once common in California and Oregon but now facing extinction - shows promise for killing methicillin-resistant Staphylococcus aureus (MRSA) bacteria. MRSA is a "superbug," infamous for causing deadly outbreaks of infection among hospitalized patients. Now it is occurring in settings outside hospitals, including schools, nursing homes, and day care centers.
The skin of the mink frog, likewise, contains secretions that show promise for fighting "Iraqibacter," caused by multidrug-resistant Acinetobacter baumanni.
Some of the substances could make their way into clinical trials within the next five years, Conlon predicted. He envisions that pharmaceutical companies could develop the chemicals as creams or ointments for treating skin infections or as injectable drugs for treating drug-resistant infections throughout the body. The United Arab Emirates University provided funding for the study.
"The research also is important because it underscores the importance of preserving biodiversity," Conlon pointed out. "Some frog species - including those that may contain potentially valuable medicinal substances - are in jeopardy worldwide due to loss of habitat, water pollution, and other problems."
The Skinny on Frog Skin
Frogs and toads have a "Lycra" type skin that protects them from injury and disease. It comes in a rainbow of color and patterns.
Frog skin is water permeable, letting water in and out. Frogs seldom drink with their mouths. Rather, they absorb water through their skin. A "seat pouch" on their bellies absorbs water.
Many species have skin glands that produce toxins and other substances to repel predators. Scientists are studying some as potential pain medications.
Skin colors and patterns are protective devices that warn predators that the frog may be poisonous. Some frogs change the color of their skin to absorb or reflect heat and thus control their body temperature. Patterned skin can help camouflage the frog, so it sinks into the background, hidden from predators.
Frogs regularly shed their skin. Most eat the shed skin.
Source:
Michael Bernstein
Michael Woods
American Chemical Society
Discovery Of Circadian Rhythm-Metabolism Link
UC Irvine researchers have found a molecular link between circadian rhythms - our own body clock - and metabolism. The discovery reveals new possibilities for the treatment of diabetes, obesity and other related diseases.
Paolo Sassone-Corsi, Distinguished Professor and Chair of Pharmacology, and his colleagues have identified that an essential protein called CLOCK that regulates the body's circadian rhythms, works in balance with another protein called SIRT1 that modulates how much energy a cell uses.
"This interplay has far-reaching implications for human illness and aging, and it is likely vital for proper metabolism," said Sassone-Corsi, one of the world's leading researchers on circadian rhythms. The study appears in the July 25 issue of Cell.
Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day.
Disruption of these rhythms can profoundly influence human health and has been linked to metabolic disorders, insomnia, depression, coronary heart diseases and cancer.
It is estimated that up to 15 percent of our genes are regulated by these circadian clocks. Sassone-Corsi identified in 2006 that the protein CLOCK is an essential molecular gear of the circadian machinery.
Now, he and his colleagues have shown that the protein SIRT1 counterbalances the function of CLOCK. Even though SIRT1's function differs from CLOCK's, the two proteins interact, creating a bond that is finely regulated in the cell.
SIRT1 senses energy levels in the cell; its activity is modulated by how many nutrients a cell is consuming. It also helps cells resist oxidative and radiation-induced stress, and for this reason SIRT1 is known to help control the process of aging.
CLOCK and SIRT1 are both part of the epigenome, which consists of proteins existing in connection with a cell's DNA that take external environmental factors and make the cell's genes behave differently, even though those genes do not structurally change.
"When this balance between these two vital proteins is upset, normal cellular function can be disrupted," Sassone-Corsi said. "Because of the role these two enzymes play, changes in our sleep patterns or our diets can directly be translated into how our cells act."
The findings also suggest that proper sleep and diet could help maintain or rebuild the CLOCK-SIRT1 equilibrium and may help explain why lack of proper rest or disruption in our normal sleep patterns is known to increase hunger, which can lead to obesity and related illnesses and can accelerate the aging process.
The specific interaction between CLOCK and SIRT1 also could lead to the development of drugs aimed at facilitating healthy metabolism, thereby helping to solve major social and medical problems such as diabetes and obesity.
Yasukazu Nakahata, Milota Kaluzova, Benedetto Grimaldi, Saurabh Sahar and Jun Hirayama of UCI, and Danica Chen and Leonard P. Guarente of the Massachusetts Institute of Technology participated in the study, which was supported by the Cancer Research Coordinating Committee of the University of California and the National Institutes of Health.
About the University of California, Irvine:
The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 27,000 undergraduate and graduate students and nearly 2,000 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.6 billion. For more UCI news, visit today.uci/.
Source: Tom Vasich
University of California - Irvine
Paolo Sassone-Corsi, Distinguished Professor and Chair of Pharmacology, and his colleagues have identified that an essential protein called CLOCK that regulates the body's circadian rhythms, works in balance with another protein called SIRT1 that modulates how much energy a cell uses.
"This interplay has far-reaching implications for human illness and aging, and it is likely vital for proper metabolism," said Sassone-Corsi, one of the world's leading researchers on circadian rhythms. The study appears in the July 25 issue of Cell.
Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day.
Disruption of these rhythms can profoundly influence human health and has been linked to metabolic disorders, insomnia, depression, coronary heart diseases and cancer.
It is estimated that up to 15 percent of our genes are regulated by these circadian clocks. Sassone-Corsi identified in 2006 that the protein CLOCK is an essential molecular gear of the circadian machinery.
Now, he and his colleagues have shown that the protein SIRT1 counterbalances the function of CLOCK. Even though SIRT1's function differs from CLOCK's, the two proteins interact, creating a bond that is finely regulated in the cell.
SIRT1 senses energy levels in the cell; its activity is modulated by how many nutrients a cell is consuming. It also helps cells resist oxidative and radiation-induced stress, and for this reason SIRT1 is known to help control the process of aging.
CLOCK and SIRT1 are both part of the epigenome, which consists of proteins existing in connection with a cell's DNA that take external environmental factors and make the cell's genes behave differently, even though those genes do not structurally change.
"When this balance between these two vital proteins is upset, normal cellular function can be disrupted," Sassone-Corsi said. "Because of the role these two enzymes play, changes in our sleep patterns or our diets can directly be translated into how our cells act."
The findings also suggest that proper sleep and diet could help maintain or rebuild the CLOCK-SIRT1 equilibrium and may help explain why lack of proper rest or disruption in our normal sleep patterns is known to increase hunger, which can lead to obesity and related illnesses and can accelerate the aging process.
The specific interaction between CLOCK and SIRT1 also could lead to the development of drugs aimed at facilitating healthy metabolism, thereby helping to solve major social and medical problems such as diabetes and obesity.
Yasukazu Nakahata, Milota Kaluzova, Benedetto Grimaldi, Saurabh Sahar and Jun Hirayama of UCI, and Danica Chen and Leonard P. Guarente of the Massachusetts Institute of Technology participated in the study, which was supported by the Cancer Research Coordinating Committee of the University of California and the National Institutes of Health.
About the University of California, Irvine:
The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 27,000 undergraduate and graduate students and nearly 2,000 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.6 billion. For more UCI news, visit today.uci/.
Source: Tom Vasich
University of California - Irvine
MMR Information Systems Pursues International Patent Applications On Anti-CD20 Antibodies
MMR Information Systems, Inc. (OTCBB: MMRF) (the "Company"), which through its wholly-owned operating subsidiary, MyMedicalRecords, Inc. ("MMR") provides consumer-controlled Personal Health Records ("PHRs") (mymedicalrecords) and electronic safe deposit box storage solutions (myesafedepositbox), announced that it has taken the necessary steps to file for extensions of the Company's Patent Cooperation Treaty (PCT) patent application on anti-CD20 monoclonal antibodies to the national phase through filings in major European, Asian, North American, and South American markets.
Anti-CD20 antibodies are useful in treating B-Cell malignancies, including Non-Hodgkin Lymphoma (NHL) and additional B-Cell mediated conditions such as rheumatoid arthritis. The Company's anti-CD20 antibody asset is potentially a candidate for the next generation Rituximab. Rituximab, currently marketed under the trade name Rituxan® in the United States by Biogen Idec and Genentech (wholly owned member of the Roche Group) and under the name MabThera® by Roche in the rest of the world except Japan, where it is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd., is one of the world's most successful monoclonal antibodies with reported total sales in 2008 in excess of USD $5.4 billion.
MMR Information Systems, Inc. acquired the technology through its reverse merger with Favrille, Inc., which was completed in January 2009. Favrille had previously acquired the technology from Diversa Corporation (now Verenium Corporation). According to consultants to the Company and former science executives of Favrille, Inc., and based on Diversa's pre-clinical research and testing of the scientific evidence, the next generation of Rituximab and further applications of the anti-CD20 antibodies may make the treatment of B-Cell malignancies even more effective in the future.
This second generation technology includes a series of optimized anti-CD20 monoclonal antibodies and provides potential future treatment options for various autoimmune and B-Cell mediated diseases, including lupus nephritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, respiratory distress syndrome, chronic lymphocytic leukemia, multiple sclerosis and vaculitis.
Because of its interest in maximizing shareholder value, MMR Information Systems is working with independent consultants to attempt to monetize these anti-CD20 antibody assets around the world, and will attend meetings at the Drug Information Association's (DIA) Annual Meeting being held in San Diego this week. However, the Company's focus will continue to be on its primary products, the MyMedicalRecords Personal Health Record, MyMedicalRecords Pro for physicians and healthcare professionals, and MyEsafeDepositBox electronic safe deposit box storage solutions.
Source
MMR Information Systems, Inc.
View drug information on Rituxan.
Anti-CD20 antibodies are useful in treating B-Cell malignancies, including Non-Hodgkin Lymphoma (NHL) and additional B-Cell mediated conditions such as rheumatoid arthritis. The Company's anti-CD20 antibody asset is potentially a candidate for the next generation Rituximab. Rituximab, currently marketed under the trade name Rituxan® in the United States by Biogen Idec and Genentech (wholly owned member of the Roche Group) and under the name MabThera® by Roche in the rest of the world except Japan, where it is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd., is one of the world's most successful monoclonal antibodies with reported total sales in 2008 in excess of USD $5.4 billion.
MMR Information Systems, Inc. acquired the technology through its reverse merger with Favrille, Inc., which was completed in January 2009. Favrille had previously acquired the technology from Diversa Corporation (now Verenium Corporation). According to consultants to the Company and former science executives of Favrille, Inc., and based on Diversa's pre-clinical research and testing of the scientific evidence, the next generation of Rituximab and further applications of the anti-CD20 antibodies may make the treatment of B-Cell malignancies even more effective in the future.
This second generation technology includes a series of optimized anti-CD20 monoclonal antibodies and provides potential future treatment options for various autoimmune and B-Cell mediated diseases, including lupus nephritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, respiratory distress syndrome, chronic lymphocytic leukemia, multiple sclerosis and vaculitis.
Because of its interest in maximizing shareholder value, MMR Information Systems is working with independent consultants to attempt to monetize these anti-CD20 antibody assets around the world, and will attend meetings at the Drug Information Association's (DIA) Annual Meeting being held in San Diego this week. However, the Company's focus will continue to be on its primary products, the MyMedicalRecords Personal Health Record, MyMedicalRecords Pro for physicians and healthcare professionals, and MyEsafeDepositBox electronic safe deposit box storage solutions.
Source
MMR Information Systems, Inc.
View drug information on Rituxan.
Study Of Firefly Flashes May Shed Light On The Evolution Of Communication
A new study by biologists at Tufts University has discovered a dark side lurking behind the magical light shows put on by fireflies each summer. Using both laboratory and field experiments to explore the potential costs of firefly courtship displays, the biologists have uncovered some surprising answers.
The research, to be published in the November 2007 issue of American Naturalist and now available online (here), revealed that it's energetically cheap for fireflies to produce their distinctive flash signals, but that flashier males are more likely to end up on the dinner table.
On summer evenings, male Photinus fireflies lift off into the air to broadcast their bioluminescent flashes in search of females. Females perched in the grass sit and admire passing males and, if they're interested, will flash in response. Previous research on many different firefly species has shown that females respond more readily to males that give longer flashes, as well as those with faster flash rhythms. This female choice favors firefly males that produce more conspicuous flashes.
"Since females so clearly prefer the flashier males, one thing that's been puzzling scientists is what's keeping these males from evolving longer and longer, faster and faster flashes," says Sara Lewis, professor of biology at Tufts and leader of the research team that included postdoctoral researcher William Woods and two undergraduate students. In theory, there might be some hidden costs to more conspicuous flashes, but what are they"
To answer this question, the researchers set out to look at two potential costs of firefly flash signals. First they measured the energy that fireflies expend while they're producing their bioluminescent flashes. In carefully controlled laboratory experiments, the team used tiny respirometry chambers to measure how much carbon dioxide each firefly produced when they were flashing compared with when they were resting. "Basically, we're in the business of measuring bug breath," notes Woods. These respirometry results demonstrated that fireflies require surprisingly little energy to produce their magical flashes, even less than what it takes them just to walk around.
Evolutionary Balancing Act Could Generate New Species
Once the Tufts team established that flashing had such a low energy cost, they tried a simple field experiment to measure the potential predation costs of firefly flash signals. Photinus fireflies are known to produce noxious chemicals that deter most predators, yet make them the top menu choice for the larger predatory fireflies known as Photuris. Using basic materials that included electronic fake fireflies (manufactured by Firefly Magic), plastic toy-dispensing capsules designed for vending machines, and sticky glue, the researchers made two startling discoveries.
In the field, predatory fireflies were attracted significantly more often to the fake firefly signals compared with non-flashing but otherwise identical controls. In addition, when flash signals were more frequent, they were much more likely to attract predators. So even though more conspicuous flash signals provide male fireflies with an evolutionary leg up in terms of attracting females, they also have a potentially fatal downside because they are more likely to attract predators in search of their next meal.
"Every single night, male fireflies are out there flying a fine line between sex and death. For us, it definitely rivals the most exciting television thriller!" says Lewis. "So, next time you're outside on a summer night take a moment to admire the firefly romance and risk that's playing out all around you."
According to Lewis, the importance of these two conflicting forces could easily shift in different firefly populations. Therefore, it's possible that this evolutionary balancing act might generate entirely new firefly species with their own distinctive flash codes.
Funded by a National Science Foundation program called Research Experiences for Undergraduates, the Tufts research could ultimately help us to better understand the evolution of communication in many organisms, including humans.
Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives spanning all Tufts campuses and joint degree programs are available for both undergraduate and graduate school students in liberal arts, sciences and engineering, and the university's graduate and professional schools.
Source: Kim Thurler
Tufts University
The research, to be published in the November 2007 issue of American Naturalist and now available online (here), revealed that it's energetically cheap for fireflies to produce their distinctive flash signals, but that flashier males are more likely to end up on the dinner table.
On summer evenings, male Photinus fireflies lift off into the air to broadcast their bioluminescent flashes in search of females. Females perched in the grass sit and admire passing males and, if they're interested, will flash in response. Previous research on many different firefly species has shown that females respond more readily to males that give longer flashes, as well as those with faster flash rhythms. This female choice favors firefly males that produce more conspicuous flashes.
"Since females so clearly prefer the flashier males, one thing that's been puzzling scientists is what's keeping these males from evolving longer and longer, faster and faster flashes," says Sara Lewis, professor of biology at Tufts and leader of the research team that included postdoctoral researcher William Woods and two undergraduate students. In theory, there might be some hidden costs to more conspicuous flashes, but what are they"
To answer this question, the researchers set out to look at two potential costs of firefly flash signals. First they measured the energy that fireflies expend while they're producing their bioluminescent flashes. In carefully controlled laboratory experiments, the team used tiny respirometry chambers to measure how much carbon dioxide each firefly produced when they were flashing compared with when they were resting. "Basically, we're in the business of measuring bug breath," notes Woods. These respirometry results demonstrated that fireflies require surprisingly little energy to produce their magical flashes, even less than what it takes them just to walk around.
Evolutionary Balancing Act Could Generate New Species
Once the Tufts team established that flashing had such a low energy cost, they tried a simple field experiment to measure the potential predation costs of firefly flash signals. Photinus fireflies are known to produce noxious chemicals that deter most predators, yet make them the top menu choice for the larger predatory fireflies known as Photuris. Using basic materials that included electronic fake fireflies (manufactured by Firefly Magic), plastic toy-dispensing capsules designed for vending machines, and sticky glue, the researchers made two startling discoveries.
In the field, predatory fireflies were attracted significantly more often to the fake firefly signals compared with non-flashing but otherwise identical controls. In addition, when flash signals were more frequent, they were much more likely to attract predators. So even though more conspicuous flash signals provide male fireflies with an evolutionary leg up in terms of attracting females, they also have a potentially fatal downside because they are more likely to attract predators in search of their next meal.
"Every single night, male fireflies are out there flying a fine line between sex and death. For us, it definitely rivals the most exciting television thriller!" says Lewis. "So, next time you're outside on a summer night take a moment to admire the firefly romance and risk that's playing out all around you."
According to Lewis, the importance of these two conflicting forces could easily shift in different firefly populations. Therefore, it's possible that this evolutionary balancing act might generate entirely new firefly species with their own distinctive flash codes.
Funded by a National Science Foundation program called Research Experiences for Undergraduates, the Tufts research could ultimately help us to better understand the evolution of communication in many organisms, including humans.
Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives spanning all Tufts campuses and joint degree programs are available for both undergraduate and graduate school students in liberal arts, sciences and engineering, and the university's graduate and professional schools.
Source: Kim Thurler
Tufts University
New Fruit Fly Protein Illuminates Circadian Response To Light
Researchers at the University of Pennsylvania School of Medicine have identified a new protein required for the circadian response to light in fruit flies. The discovery of this protein - named JET - brings investigators one step closer to understanding the process by which the body's internal clock synchronizes to light. Understanding how light affects circadian (24-hour) rhythms will likely open doors to future treatments of jetlag.
The body's 24-hour clock controls a multitude of internal functions such as periods of sleep and wakefulness, body temperature, and metabolism. Although circadian function produces a stable rhythm in the body, the biological clock will reset in response to light. The human condition known as jet lag takes place during the period when the body is attempting to resynchronize to the environmental light changes brought on by travel, namely from one time zone to another.
A mutant fruit fly that possesses jetlag-like behaviors enabled senior author Amita Sehgal, PhD, Professor of Neuroscience at Penn and a Howard Hughes Medical Institute (HHMI) Investigator, and colleagues to identify the gene and subsequent protein that aids in the response of the internal biological clock to light. The researchers report their findings in most recent issue of Science.
To test the circadian rhythm of fruit flies, Sehgal and others exposed wild type (control) and mutant flies to several light and dark settings вЂ" constant darkness, constant light, and equal periods of light and darkness (a light-dark cycle). During exposure to constant light for one week, the controls developed a disrupted sleep pattern after a few days, while the mutants maintained a regular circadian rhythm. The mutant and control flies displayed no behavioral differences during their exposure to constant darkness and the light-dark cycle. However, when the fruit flies were shifted from one light-dark cycle to another, the mutant flies took two days longer to adjust their sleep-wake cycle to the new light-dark schedule.
"The behavior of the mutant flies is similar to that displayed in a person who has prolonged jetlag," notes Sehgal. In search of answers to the mutant's defective circadian response to light, Sehgal and colleagues looked to the molecular details of the clock cells in the jetlag flies.
When a fruit fly is exposed to light, a photoreceptor called cryptochrome (CRY) transduces the light signal and kicks off a series of reactions within the clock cells of the brain. Under normal conditions, CRY will respond to light by binding to a protein called timeless (TIM). A second protein, a member of the F-box protein family, also binds to TIM, signaling TIM for cellular destruction.
Genetic analysis revealed that the jetlag flies possess a mutation in a gene that encodes a member of the F-box protein family. A closer examination of the protein produced by the mutated sequence led researchers to JET, a new protein within the F-box protein family.
"Since the degradation of TIM always happens in the presence of light, the animal associates the absence of TIM with daytime hours," explains Sehgal. The mutated JET protein reduces the light-dependent degradation of TIM and the circadian response to light.
Sehgal and others were able to reverse the behaviors in the jetlag flies by genetically replacing the mutated gene sequence with the normal sequence, which led to the production of the wild-type (control) JET protein. When the jetlag flies acquired the normal JET protein, regular TIM degradation took place and the fruit fly was better able to adjust to shifts in the light-dark cycle.
Future studies in the Sehgal lab will focus on continuing to identify other molecules required for the circadian response to light. "Some of the molecules required for the circadian light response in flies may be conserved in humans. Over time, we will have a better understanding of how the human clock responds to light and may be able to design drugs to treat jetlag," concludes Sehgal.
Study co-authors are Kyunghee Koh and Xiangzhong Zheng, both from Penn. These studies were funded by the National Institutes of Health and HHMI.
Penn Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Contact: Karen Kreeger
University of Pennsylvania School of Medicine
The body's 24-hour clock controls a multitude of internal functions such as periods of sleep and wakefulness, body temperature, and metabolism. Although circadian function produces a stable rhythm in the body, the biological clock will reset in response to light. The human condition known as jet lag takes place during the period when the body is attempting to resynchronize to the environmental light changes brought on by travel, namely from one time zone to another.
A mutant fruit fly that possesses jetlag-like behaviors enabled senior author Amita Sehgal, PhD, Professor of Neuroscience at Penn and a Howard Hughes Medical Institute (HHMI) Investigator, and colleagues to identify the gene and subsequent protein that aids in the response of the internal biological clock to light. The researchers report their findings in most recent issue of Science.
To test the circadian rhythm of fruit flies, Sehgal and others exposed wild type (control) and mutant flies to several light and dark settings вЂ" constant darkness, constant light, and equal periods of light and darkness (a light-dark cycle). During exposure to constant light for one week, the controls developed a disrupted sleep pattern after a few days, while the mutants maintained a regular circadian rhythm. The mutant and control flies displayed no behavioral differences during their exposure to constant darkness and the light-dark cycle. However, when the fruit flies were shifted from one light-dark cycle to another, the mutant flies took two days longer to adjust their sleep-wake cycle to the new light-dark schedule.
"The behavior of the mutant flies is similar to that displayed in a person who has prolonged jetlag," notes Sehgal. In search of answers to the mutant's defective circadian response to light, Sehgal and colleagues looked to the molecular details of the clock cells in the jetlag flies.
When a fruit fly is exposed to light, a photoreceptor called cryptochrome (CRY) transduces the light signal and kicks off a series of reactions within the clock cells of the brain. Under normal conditions, CRY will respond to light by binding to a protein called timeless (TIM). A second protein, a member of the F-box protein family, also binds to TIM, signaling TIM for cellular destruction.
Genetic analysis revealed that the jetlag flies possess a mutation in a gene that encodes a member of the F-box protein family. A closer examination of the protein produced by the mutated sequence led researchers to JET, a new protein within the F-box protein family.
"Since the degradation of TIM always happens in the presence of light, the animal associates the absence of TIM with daytime hours," explains Sehgal. The mutated JET protein reduces the light-dependent degradation of TIM and the circadian response to light.
Sehgal and others were able to reverse the behaviors in the jetlag flies by genetically replacing the mutated gene sequence with the normal sequence, which led to the production of the wild-type (control) JET protein. When the jetlag flies acquired the normal JET protein, regular TIM degradation took place and the fruit fly was better able to adjust to shifts in the light-dark cycle.
Future studies in the Sehgal lab will focus on continuing to identify other molecules required for the circadian response to light. "Some of the molecules required for the circadian light response in flies may be conserved in humans. Over time, we will have a better understanding of how the human clock responds to light and may be able to design drugs to treat jetlag," concludes Sehgal.
Study co-authors are Kyunghee Koh and Xiangzhong Zheng, both from Penn. These studies were funded by the National Institutes of Health and HHMI.
Penn Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Contact: Karen Kreeger
University of Pennsylvania School of Medicine
New Leads For Treating Parasitic Worm Disease Identifed
A research team supported by the National Institutes of Health (NIH) Roadmap and the National Institute of Allergy and Infectious Diseases (NIAID) has identified chemical compounds that hold promise as potential therapies for schistosomiasis, a parasitic disease that afflicts more than 200 million people worldwide. The findings were reported in the advance online publication of the journal Nature Medicine.
In their paper, researchers from Illinois State University (ISU) in Normal, Ill., and NIH's Chemical Genomics Center (NCGC) report that chemical compounds known as oxadiazoles can inhibit an enzyme vital to survival of Schistosoma, a group of parasitic flatworms that cause schistosomiasis. The NCGC, established in 2004 by the NIH Roadmap for Medical Research, includes a set of strategic initiatives drawing collectively from the agency-wide research resources of NIH.
"New therapeutic agents are sorely needed if we hope to ease the burden of schistosomiasis on the world's health," said NIH Director Elias A. Zerhouni, M.D. "These findings exemplify what academic researchers can accomplish with access to translational infrastructure and technologies that have previously been beyond their reach."
Schistosomiasis, also known as bilharzia or snail fever, affects an estimated 207 million people, most of whom live in developing nations in tropical areas. About 20 million of those people are seriously disabled due to severe anemia, diarrhea, internal bleeding and/or organ damage. In addition, another 280,000 die of the disease each year.
People become infected with Schistosoma when they wade, swim or bathe in fresh water inhabited by snails, which serve as the worms' intermediate hosts. The microscopic worms enter the human body by boring through the skin and migrate into the blood vessels that supply the intestinal and urinary systems. After the worms mature and reproduce, their eggs are eliminated in human urine and feces. If human waste contaminated by worm eggs finds its way into fresh water, the cycle begins again.
Currently, people living in more than 70 tropical nations require annual or semi-annual drug treatment to rid their bodies of the parasite. Since the 1980s, praziquantel has effectively been the sole drug used for this purpose. Public health experts are concerned that the Schistosoma parasites will become resistant to praziquantel and the drug will lose its effectiveness, as has been the case for agents used to combat many other infectious diseases such as malaria and tuberculosis.
"The search for new drugs for schistosomiasis is imperative if we are to control this devastating disease that exacts an enormous toll, both in terms of human suffering and economic development," said NIAID Director Anthony S. Fauci, M.D.
The new research, which was conducted with Schistosoma maintained in laboratory conditions, shows that an oxadiazole compound was effective in inhibiting a crucial worm enzyme, called thioredoxin glutathione reductase (TGR). Furthermore, in tests of laboratory mice infected with Schistosoma, this compound killed the parasite in all of its stages, from larva to adult. The results exceeded all benchmarks set by the World Health Organization for potential new compounds to treat schistosomiasis. Importantly, the researchers also showed that the compound was active against all three major species of Schistosoma worms that infect humans.
"This builds upon my lab's previous findings that Schistosoma worms survive in the host due to a protective enzyme TGR. By teaming with NCGC, we were able to move our research one step closer to the clinic by identifying a class of compounds that specifically target that enzyme," said the study's lead researcher, David L. Williams, Ph.D., a professor of biology at ISU and NIAID grantee. "Still, much remains to be done. Our ultimate goal is to see our basic biological findings translated into help for people with schistosomiasis."
The TGR project submitted to NCGC by Dr. Williams' group was the first one officially accepted for screening by the NIH Roadmap Molecular Libraries Initiative. The results of that collaboration underscore the value of a new paradigm established by the NCGC, which is administered by the National Human Genome Research Institute (NHGRI). The high-tech center offers academic researchers, such as the ISU team, the opportunity to tap into a robotic system for quickly screening large numbers of chemical compounds for biological activity.
"Chemical genomic advances are being used to develop a new approach to a parasite that has afflicted countless generations of humankind," said NHGRI Director Francis S. Collins, M.D., Ph.D. "This study showcases the beauty of high-throughput chemical screening for biomedical applications."
NCGC Director Christopher P. Austin, M.D., who is a co-author of the Nature Medicine paper, said "Our center has brought pharmaceutical-scale chemical screening, informatics and medicinal chemistry to bear on neglected diseases that affect millions globally, but are not worked on by the pharmaceutical industry since they cannot generate the needed financial returns. This study demonstrates the wonderful things that can happen when the NCGC's scientific capabilities and infrastructure are combined with the biological expertise of individual academic investigators."
Click here for more information on schistosomiasis.
A diagram depicting the life cycle of the Schistosoma parasite can be found at genome/pressDisplay.cfm?photoID=20042.
Micrographs of Schistosoma parasites can be found at:
genome/pressDisplay.cfm?photoID=20041
genome/pressDisplay.cfm?photoID=20043
and
genome/pressDisplay.cfm?photoID=20044
Full-resolution video clips of NCGC's chemical screening facility in action are available at genome/pressDisplay.cfm?photoID=20030.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, genome/.
NIAID is a component of the NIH. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site niaid.nih/.
NCGC is an ultra-high-throughput screening center that generates chemical probes of gene and cell functions in health and disease, and catalyzes drug development for neglected rare and orphan diseases. It is part of the NIH Roadmap for Medical Research. The Roadmap is a series of initiatives designed to pursue major opportunities and gaps in biomedical research that no single NIH institute could tackle alone, but which the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Roadmap can be found at nihroadmap.nih/.
The National Institutes of Health - "The Nation's Medical Research Agency" - includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit nih/.
Source: Raymond MacDougall
NIH/National Human Genome Research Institute
In their paper, researchers from Illinois State University (ISU) in Normal, Ill., and NIH's Chemical Genomics Center (NCGC) report that chemical compounds known as oxadiazoles can inhibit an enzyme vital to survival of Schistosoma, a group of parasitic flatworms that cause schistosomiasis. The NCGC, established in 2004 by the NIH Roadmap for Medical Research, includes a set of strategic initiatives drawing collectively from the agency-wide research resources of NIH.
"New therapeutic agents are sorely needed if we hope to ease the burden of schistosomiasis on the world's health," said NIH Director Elias A. Zerhouni, M.D. "These findings exemplify what academic researchers can accomplish with access to translational infrastructure and technologies that have previously been beyond their reach."
Schistosomiasis, also known as bilharzia or snail fever, affects an estimated 207 million people, most of whom live in developing nations in tropical areas. About 20 million of those people are seriously disabled due to severe anemia, diarrhea, internal bleeding and/or organ damage. In addition, another 280,000 die of the disease each year.
People become infected with Schistosoma when they wade, swim or bathe in fresh water inhabited by snails, which serve as the worms' intermediate hosts. The microscopic worms enter the human body by boring through the skin and migrate into the blood vessels that supply the intestinal and urinary systems. After the worms mature and reproduce, their eggs are eliminated in human urine and feces. If human waste contaminated by worm eggs finds its way into fresh water, the cycle begins again.
Currently, people living in more than 70 tropical nations require annual or semi-annual drug treatment to rid their bodies of the parasite. Since the 1980s, praziquantel has effectively been the sole drug used for this purpose. Public health experts are concerned that the Schistosoma parasites will become resistant to praziquantel and the drug will lose its effectiveness, as has been the case for agents used to combat many other infectious diseases such as malaria and tuberculosis.
"The search for new drugs for schistosomiasis is imperative if we are to control this devastating disease that exacts an enormous toll, both in terms of human suffering and economic development," said NIAID Director Anthony S. Fauci, M.D.
The new research, which was conducted with Schistosoma maintained in laboratory conditions, shows that an oxadiazole compound was effective in inhibiting a crucial worm enzyme, called thioredoxin glutathione reductase (TGR). Furthermore, in tests of laboratory mice infected with Schistosoma, this compound killed the parasite in all of its stages, from larva to adult. The results exceeded all benchmarks set by the World Health Organization for potential new compounds to treat schistosomiasis. Importantly, the researchers also showed that the compound was active against all three major species of Schistosoma worms that infect humans.
"This builds upon my lab's previous findings that Schistosoma worms survive in the host due to a protective enzyme TGR. By teaming with NCGC, we were able to move our research one step closer to the clinic by identifying a class of compounds that specifically target that enzyme," said the study's lead researcher, David L. Williams, Ph.D., a professor of biology at ISU and NIAID grantee. "Still, much remains to be done. Our ultimate goal is to see our basic biological findings translated into help for people with schistosomiasis."
The TGR project submitted to NCGC by Dr. Williams' group was the first one officially accepted for screening by the NIH Roadmap Molecular Libraries Initiative. The results of that collaboration underscore the value of a new paradigm established by the NCGC, which is administered by the National Human Genome Research Institute (NHGRI). The high-tech center offers academic researchers, such as the ISU team, the opportunity to tap into a robotic system for quickly screening large numbers of chemical compounds for biological activity.
"Chemical genomic advances are being used to develop a new approach to a parasite that has afflicted countless generations of humankind," said NHGRI Director Francis S. Collins, M.D., Ph.D. "This study showcases the beauty of high-throughput chemical screening for biomedical applications."
NCGC Director Christopher P. Austin, M.D., who is a co-author of the Nature Medicine paper, said "Our center has brought pharmaceutical-scale chemical screening, informatics and medicinal chemistry to bear on neglected diseases that affect millions globally, but are not worked on by the pharmaceutical industry since they cannot generate the needed financial returns. This study demonstrates the wonderful things that can happen when the NCGC's scientific capabilities and infrastructure are combined with the biological expertise of individual academic investigators."
Click here for more information on schistosomiasis.
A diagram depicting the life cycle of the Schistosoma parasite can be found at genome/pressDisplay.cfm?photoID=20042.
Micrographs of Schistosoma parasites can be found at:
genome/pressDisplay.cfm?photoID=20041
genome/pressDisplay.cfm?photoID=20043
and
genome/pressDisplay.cfm?photoID=20044
Full-resolution video clips of NCGC's chemical screening facility in action are available at genome/pressDisplay.cfm?photoID=20030.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, genome/.
NIAID is a component of the NIH. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site niaid.nih/.
NCGC is an ultra-high-throughput screening center that generates chemical probes of gene and cell functions in health and disease, and catalyzes drug development for neglected rare and orphan diseases. It is part of the NIH Roadmap for Medical Research. The Roadmap is a series of initiatives designed to pursue major opportunities and gaps in biomedical research that no single NIH institute could tackle alone, but which the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Roadmap can be found at nihroadmap.nih/.
The National Institutes of Health - "The Nation's Medical Research Agency" - includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit nih/.
Source: Raymond MacDougall
NIH/National Human Genome Research Institute
Nurtured Chimps Rake It In
Human interaction and stimulation enhance chimpanzees' cognitive abilities, according to new research from the Chimpanzee Cognition Center at The Ohio State University. The study (1) is the first to demonstrate that raising chimpanzees in a human cultural environment enhances their cognitive abilities, as measured by their ability to understand how tools work. The findings have just been published online in the Springer journal Animal Cognition.
The scientists compared three groups of chimpanzees: one with a history of long-term stable, social interaction with humans ('enculturated'); a group raised in a sanctuary setting, with only caretaker contact with humans ('semi-enculturated'); and another group raised under more austere captive conditions (laboratory chimpanzees). The experiments looked at how the chimpanzees used rakes in order to retrieve a fruit yoghurt reward. The overall study examined not only whether the chimpanzees understood the properties of the tool, but also whether they understood the reasons why the tool worked.
The researchers gave the animals access to small rakes with either a rigid wooden head or a flimsy fabric head. Both enculturated and semi-enculturated chimpanzees correctly chose the rigid rake which enabled them to obtain the reward, indicating that both of these groups understood the physical properties of the two different rakes.
The researchers then presented the same two groups with two identical 'hybrid' rakes. Each rake head had a rigid side made of wood (functional) and another side made of flimsy cloth (non-functional). The reward was placed in front of the rigid side of one rake, and in front of the flimsy side of the second rake. The animals who picked the rake with the food reward on the rigid side demonstrated that they understood the causal principles behind the functionality of the rake.
The enculturated chimpanzees successfully selected the functional rake, while the sanctuary chimpanzees chose randomly between the two hybrid tools. The captive laboratory chimpanzees failed both tests, as demonstrated in previously published work (2).
According to Dr. Sarah Boysen, who led the study, "We think our findings mean that the conditions under which chimpanzees are raised, housed, and maintained have long-term effects on their cognitive development, and offer direct comparisons with early experience, issues of attachment, and preschool education for human infants and children,"
The authors conclude that the differences in performance between the three groups are directly attributable to the significant effect of level of enculturation. They add that "enculturated chimpanzees may be better at learning within a highly social, interactive context because they have heightened attention to the actions of others."
1. Furlong EE, Boose KJ, Boysen ST (2007). Raking it in: the impact of enculturation on chimpanzee tool use. Animal Cognition DOI 10.1007/s10071-007-0091-6
2. Povinelli DJ (2000). Folk physics for apes: the chimpanzee's theory of how the world works. Oxford University Press, New York.
Contact: Joan Robinson
Springer
The scientists compared three groups of chimpanzees: one with a history of long-term stable, social interaction with humans ('enculturated'); a group raised in a sanctuary setting, with only caretaker contact with humans ('semi-enculturated'); and another group raised under more austere captive conditions (laboratory chimpanzees). The experiments looked at how the chimpanzees used rakes in order to retrieve a fruit yoghurt reward. The overall study examined not only whether the chimpanzees understood the properties of the tool, but also whether they understood the reasons why the tool worked.
The researchers gave the animals access to small rakes with either a rigid wooden head or a flimsy fabric head. Both enculturated and semi-enculturated chimpanzees correctly chose the rigid rake which enabled them to obtain the reward, indicating that both of these groups understood the physical properties of the two different rakes.
The researchers then presented the same two groups with two identical 'hybrid' rakes. Each rake head had a rigid side made of wood (functional) and another side made of flimsy cloth (non-functional). The reward was placed in front of the rigid side of one rake, and in front of the flimsy side of the second rake. The animals who picked the rake with the food reward on the rigid side demonstrated that they understood the causal principles behind the functionality of the rake.
The enculturated chimpanzees successfully selected the functional rake, while the sanctuary chimpanzees chose randomly between the two hybrid tools. The captive laboratory chimpanzees failed both tests, as demonstrated in previously published work (2).
According to Dr. Sarah Boysen, who led the study, "We think our findings mean that the conditions under which chimpanzees are raised, housed, and maintained have long-term effects on their cognitive development, and offer direct comparisons with early experience, issues of attachment, and preschool education for human infants and children,"
The authors conclude that the differences in performance between the three groups are directly attributable to the significant effect of level of enculturation. They add that "enculturated chimpanzees may be better at learning within a highly social, interactive context because they have heightened attention to the actions of others."
1. Furlong EE, Boose KJ, Boysen ST (2007). Raking it in: the impact of enculturation on chimpanzee tool use. Animal Cognition DOI 10.1007/s10071-007-0091-6
2. Povinelli DJ (2000). Folk physics for apes: the chimpanzee's theory of how the world works. Oxford University Press, New York.
Contact: Joan Robinson
Springer
New Centre To Fight Infectious Diseases - China-Australia Centre For Phenomics Research
The fight against infectious diseases such as Avian influenza will receive a boost today with the official opening of the China-Australia Centre for Phenomics Research at The Australian National University.
The centre will be opened by ANU Vice-Chancellor Professor Ian Chubb and Professor Lu Yongxiang, President of the Chinese Academy of Sciences. The centre, funded by the Chinese and Australian Governments, will be located in the John Curtin School for Medical Research at the ANU. The opening will be marked by a plaque unveiling and speeches from Professor Chubb, Professor Lu, His Excellency Ambassador Zhang Junsai, Chinese Ambassador to Australia and Professor Frances Shannon, Director of the ANU John Curtin School of Medical Research.
"The centre will study alterations in the genome code that lead to increased resistance or susceptibility to a range of infectious diseases including Avian Influenza," said Dr Edward Bertram, the University's Program Manager for the China-Australia Centre for Phenomics Research. "It's hoped that this work will help us to identify targets for designing new treatments to boost the immune system against these diseases."
The centre brings together some of Australia and China's high performing immunologists and virologists to work towards new discoveries in this field of research. The Australian program will be lead by ANU researchers Dr Edward Bertram, Professor Chris Goodnow and Dr Steve Winslade, but will also involve some of Australia's top immunologists including Nobel Prize winner Professor Peter Doherty, Dr Stephen Turner from the University of Melbourne, Professor Doug Hilton from The Walter and Eliza Hall Institute of Medical Research and Professor Paul Hertzog from Monash Institute of Medical Research.
The Chinese team will be led by Professor Hong Tang, Director of the Centre for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences in Beijing.
WHAT:Opening of the China-Australia Centre for Phenomics Research
WHEN: Monday 24 November, 2pm - 3pm
WHERE: Finkel Theatre, John Curtin School of Medical Research, Garran Road
Source
Martyn Pearce
Media Officer
Communications and External Liaison Office
Office of the Vice-Chancellor
The Australian National University
anu.au
The centre will be opened by ANU Vice-Chancellor Professor Ian Chubb and Professor Lu Yongxiang, President of the Chinese Academy of Sciences. The centre, funded by the Chinese and Australian Governments, will be located in the John Curtin School for Medical Research at the ANU. The opening will be marked by a plaque unveiling and speeches from Professor Chubb, Professor Lu, His Excellency Ambassador Zhang Junsai, Chinese Ambassador to Australia and Professor Frances Shannon, Director of the ANU John Curtin School of Medical Research.
"The centre will study alterations in the genome code that lead to increased resistance or susceptibility to a range of infectious diseases including Avian Influenza," said Dr Edward Bertram, the University's Program Manager for the China-Australia Centre for Phenomics Research. "It's hoped that this work will help us to identify targets for designing new treatments to boost the immune system against these diseases."
The centre brings together some of Australia and China's high performing immunologists and virologists to work towards new discoveries in this field of research. The Australian program will be lead by ANU researchers Dr Edward Bertram, Professor Chris Goodnow and Dr Steve Winslade, but will also involve some of Australia's top immunologists including Nobel Prize winner Professor Peter Doherty, Dr Stephen Turner from the University of Melbourne, Professor Doug Hilton from The Walter and Eliza Hall Institute of Medical Research and Professor Paul Hertzog from Monash Institute of Medical Research.
The Chinese team will be led by Professor Hong Tang, Director of the Centre for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences in Beijing.
WHAT:Opening of the China-Australia Centre for Phenomics Research
WHEN: Monday 24 November, 2pm - 3pm
WHERE: Finkel Theatre, John Curtin School of Medical Research, Garran Road
Source
Martyn Pearce
Media Officer
Communications and External Liaison Office
Office of the Vice-Chancellor
The Australian National University
anu.au
Can Monkeys Choose Optimally When Faced With Noisy Stimuli And Unequal Rewards?
Even when faced with distractions, monkeys are able to consistently choose the path of greatest reward, according to a study conducted by researchers
from Princeton and Stanford Universities. The study, published February 13th in the open-access journal PLoS Computational Biology, adds to the
growing evidence that animal foraging behavior can approach optimality, and could provide a basis for understanding the computations involved in this
and related tasks.
In the article, Feng and colleagues address ongoing experiments relating to monkeys' abilities to distinguish among moving stimuli. Monkeys were
trained to identify the direction of motion of a field of randomly-moving dots, a fraction of which move coherently in one of two possible directions.
But unlike most previous studies in which all correct choices were equally rewarded, different sized rewards were now associated with different
stimuli, and the researchers developed a mathematical model to predict how the animals should balance sensory information and prior expectations
regarding rewards, in order to maximize their net returns. The study is unique in that it assesses not only the accuracy of decisions, but also the
overall harvesting efficiency.
Remarkably, the monkeys devised a near-optimal strategy. Across the course of several hundred choices in each daily session, with randomly
interspersed coherence and reward conditions, their typical harvesting efficiency fell within 1-2% of the theoretical maximum. These findings reveal
impressive decision-making ability, and raise important questions about the neural mechanisms that underlie it.
CITATION
"Can Monkeys Choose Optimally When Faced with Noisy Stimuli and Unequal Rewards?"
Feng S, Holmes P, Rorie A, Newsome WT (2009)
PLoS Comput
Biol 5(2): e1000284. doi:10.1371/journal.pcbi.1000284
Click here to view article online
About PLoS Computational Biology
PLoS Computational Biology features works of exceptional significance that further our understanding of living systems at all
scales through the application of computational methods. All works published in PLoS Computational Biology are open access. Everything is immediately
available subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The
Public Library of Science uses the Creative Commons Attribution License.
PLoS Computational Biology
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.
Public Library of Science
from Princeton and Stanford Universities. The study, published February 13th in the open-access journal PLoS Computational Biology, adds to the
growing evidence that animal foraging behavior can approach optimality, and could provide a basis for understanding the computations involved in this
and related tasks.
In the article, Feng and colleagues address ongoing experiments relating to monkeys' abilities to distinguish among moving stimuli. Monkeys were
trained to identify the direction of motion of a field of randomly-moving dots, a fraction of which move coherently in one of two possible directions.
But unlike most previous studies in which all correct choices were equally rewarded, different sized rewards were now associated with different
stimuli, and the researchers developed a mathematical model to predict how the animals should balance sensory information and prior expectations
regarding rewards, in order to maximize their net returns. The study is unique in that it assesses not only the accuracy of decisions, but also the
overall harvesting efficiency.
Remarkably, the monkeys devised a near-optimal strategy. Across the course of several hundred choices in each daily session, with randomly
interspersed coherence and reward conditions, their typical harvesting efficiency fell within 1-2% of the theoretical maximum. These findings reveal
impressive decision-making ability, and raise important questions about the neural mechanisms that underlie it.
CITATION
"Can Monkeys Choose Optimally When Faced with Noisy Stimuli and Unequal Rewards?"
Feng S, Holmes P, Rorie A, Newsome WT (2009)
PLoS Comput
Biol 5(2): e1000284. doi:10.1371/journal.pcbi.1000284
Click here to view article online
About PLoS Computational Biology
PLoS Computational Biology features works of exceptional significance that further our understanding of living systems at all
scales through the application of computational methods. All works published in PLoS Computational Biology are open access. Everything is immediately
available subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The
Public Library of Science uses the Creative Commons Attribution License.
PLoS Computational Biology
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.
Public Library of Science
Rebuilding Immunoreceptors Reveals Their Mode Of Activation
Just 110 years ago in 1900, Paul Ehrlich, one of the founding fathers of modern immunology, gave the Croonian Lecture to the Royal Society in London "On Immunity with Special Reference to Cell Life". In this lecture he explained his "side-chain theory" proposing for the first time a receptor-ligand interaction as the basis for the immune reaction against bacterial toxins. This theory fell in discredit when it was found that our immune system does not only react against toxins but against a diverse universe of different molecular structures that are foreign to our body. Since then, immunologists have made many important discoveries better describing the cells and molecules of our immune system. It is now known that B lymphocytes are the cells that produce antibodies once they are activated by the binding of a foreign molecule (called antigen) to the antigen receptor. Antigens can be a virus, a bacterial molecule or any higher-structured molecule foreign to our body. Other receptors on the cell surface are only activated when they bind to a specific ligand molecule that brings the receptor into the proper conformation required for signalling. How then can the B cell antigen receptor (BCR) achieve this by binding to thousands of different structures?
Dr. Jianying Yang and Prof. Dr. Michael Reth, two members of the Centre for Biological Signalling Studies BIOSS of the University of Freiburg and of the Max-Planck-Institute of Immunobiology, have now found a solution to this longstanding puzzle. Using methods of synthetic biology, namely the rebuilding of the BCR in its native and altered form, they demonstrated that on resting B lymphocytes the antigen receptors form tight oligomeric structures inhibiting the signalling of this receptor. Exposure of the cell to antigen results in the dissociation of these tight oligomers and to signalling. Interestingly, this dissociation process is independent of the ligand's structural input and therefore explains why these receptors can be activated by thousands of structurally different ligands. The new model of BCR activation is diametrically opposed to the currently accepted model suggesting that the antigen receptors on B lymphocytes are dispersed monomers that are activated when two receptors are cross-linked by an antigen. "Our new model suggests that it is the dissociation rather than the formation of a defined BCR complex that activates B cells and this can be done by many different antigens," explains Michael Reth.
The discovery of an ordered oligomeric structure of the antigen receptor has many implications for future research on new vaccination strategies or new treatments against B cell tumors such as leukemia or lymphomas. Indeed, dysregulated signals from the antigen receptor are associated with the development of B cell tumors. It is likely that the oligomeric antigen receptor on resting B cells is surrounded by other molecules helping it to keep silent. The search for this silencing complex is now ongoing and the two investigators are hoping that the synthetic biology tools developed by BIOSS will allow scientists to find these components of the BCR complex.
Sources: Albert-Ludwigs-Universität Freiburg, AlphaGalileo Foundation.
Dr. Jianying Yang and Prof. Dr. Michael Reth, two members of the Centre for Biological Signalling Studies BIOSS of the University of Freiburg and of the Max-Planck-Institute of Immunobiology, have now found a solution to this longstanding puzzle. Using methods of synthetic biology, namely the rebuilding of the BCR in its native and altered form, they demonstrated that on resting B lymphocytes the antigen receptors form tight oligomeric structures inhibiting the signalling of this receptor. Exposure of the cell to antigen results in the dissociation of these tight oligomers and to signalling. Interestingly, this dissociation process is independent of the ligand's structural input and therefore explains why these receptors can be activated by thousands of structurally different ligands. The new model of BCR activation is diametrically opposed to the currently accepted model suggesting that the antigen receptors on B lymphocytes are dispersed monomers that are activated when two receptors are cross-linked by an antigen. "Our new model suggests that it is the dissociation rather than the formation of a defined BCR complex that activates B cells and this can be done by many different antigens," explains Michael Reth.
The discovery of an ordered oligomeric structure of the antigen receptor has many implications for future research on new vaccination strategies or new treatments against B cell tumors such as leukemia or lymphomas. Indeed, dysregulated signals from the antigen receptor are associated with the development of B cell tumors. It is likely that the oligomeric antigen receptor on resting B cells is surrounded by other molecules helping it to keep silent. The search for this silencing complex is now ongoing and the two investigators are hoping that the synthetic biology tools developed by BIOSS will allow scientists to find these components of the BCR complex.
Sources: Albert-Ludwigs-Universität Freiburg, AlphaGalileo Foundation.
Protein Behind Development Of Immune System Sentinels Identified
A protein called PU.1 is essential for the development of dendritic cells, the sentinels of the immune system, Walter and Eliza Hall Institute researchers in Melbourne, Australia, have shown.
Dendritic cells (DC) are immune cells that present proteins from foreign invaders, such as viruses, to the killer T cells of the immune system, allowing a full immune response to be mounted against the invaders.
Researchers from the Immunology division have been studying dendritic cells and how different molecules regulate their development.
Dr Li Wu said one of the molecules that is known to be important to this development is a protein called Flt3 which is a cytokine receptor found on the surface of blood stem cells and the parent cells that give rise to DC.
"Despite its importance in early blood cell development and dendritic cell development, there is surprisingly little known about how Flt3 expression is controlled," Dr Wu said.
The team of Dr Sebastian Carotta, Dr Aleksandar Dakic, Ms Angela D'Amico, Mr Milon Pang and Dr Kylie Greig, led by Dr Stephen Nutt and Dr Li Wu, has shown the transcription factor PU.1 can directly bind to the Flt3 gene to regulate its expression. "PU.1 can therefore control DC development through regulating Flt3," Dr Wu said.
Dr Carotta said PU.1 was already known to be important to the development of blood cells and immune cells. "If PU.1 is poorly regulated there is a deficiency in the development of blood cells and leukaemia can result," he said.
"To study the role of PU.1 and look at how it's regulated we developed an animal model and a new in vitro system for tracing DC development from their precursors. These systems make it possible to switch off PU.1 in the precursor cells to DC. From that we determined that loss of PU.1 completely abolished DC development," Dr Carotta said.
Dr Wu said this study revealed PU.1 to be a master regulator of DC development. "Although a growing number of transcription factors have been implicated in the development of specific dendritic cell populations, this is the first time a single transcription factor has been shown to be required for all DC lineages," she said.
The study has been published in the journal Immunity.
Dr Wu said the findings had potential to improve DC-based therapies, such as those given to cancer patients who have suppressed DC function. "The problem is people don't know how to develop good DC for these therapies," she said. "By understanding how DC development is regulated it should be possible to create different types of DC populations for therapeutic use."
The study was supported by the National Health and Medical Research Council of Australia, the Australian Research Council, the Leukaemia Foundation and Pfizer Australia.
Source:
Penny Fannin
Walter and Eliza Hall Institute
Dendritic cells (DC) are immune cells that present proteins from foreign invaders, such as viruses, to the killer T cells of the immune system, allowing a full immune response to be mounted against the invaders.
Researchers from the Immunology division have been studying dendritic cells and how different molecules regulate their development.
Dr Li Wu said one of the molecules that is known to be important to this development is a protein called Flt3 which is a cytokine receptor found on the surface of blood stem cells and the parent cells that give rise to DC.
"Despite its importance in early blood cell development and dendritic cell development, there is surprisingly little known about how Flt3 expression is controlled," Dr Wu said.
The team of Dr Sebastian Carotta, Dr Aleksandar Dakic, Ms Angela D'Amico, Mr Milon Pang and Dr Kylie Greig, led by Dr Stephen Nutt and Dr Li Wu, has shown the transcription factor PU.1 can directly bind to the Flt3 gene to regulate its expression. "PU.1 can therefore control DC development through regulating Flt3," Dr Wu said.
Dr Carotta said PU.1 was already known to be important to the development of blood cells and immune cells. "If PU.1 is poorly regulated there is a deficiency in the development of blood cells and leukaemia can result," he said.
"To study the role of PU.1 and look at how it's regulated we developed an animal model and a new in vitro system for tracing DC development from their precursors. These systems make it possible to switch off PU.1 in the precursor cells to DC. From that we determined that loss of PU.1 completely abolished DC development," Dr Carotta said.
Dr Wu said this study revealed PU.1 to be a master regulator of DC development. "Although a growing number of transcription factors have been implicated in the development of specific dendritic cell populations, this is the first time a single transcription factor has been shown to be required for all DC lineages," she said.
The study has been published in the journal Immunity.
Dr Wu said the findings had potential to improve DC-based therapies, such as those given to cancer patients who have suppressed DC function. "The problem is people don't know how to develop good DC for these therapies," she said. "By understanding how DC development is regulated it should be possible to create different types of DC populations for therapeutic use."
The study was supported by the National Health and Medical Research Council of Australia, the Australian Research Council, the Leukaemia Foundation and Pfizer Australia.
Source:
Penny Fannin
Walter and Eliza Hall Institute
Research May Lead To Improved Therapeutics Against Asthma
Researchers at Karolinska Institutet in Sweden have managed to elucidate the crystal structure of a human membrane protein -- LTC4 synthase -- which has a major influence on the development of asthma. LTC4 synthase is extremely difficult to analyze, and previously only low resolution information has been available on two membrane protein structures from human. The scientists now believe that their work will enable the development of new and better therapeutics against inflammations in the pulmonary tract.
Asthma attacks are caused by an acute inflammatory reaction in the airways, a reaction that is largely due to actions of LTC4 synthase. For this reason asthma medicines often aim at blocking the downstream effects of LTC4 synthase. However, there is a need for new pharmaceutical alternatives, since not all patients respond to the existing medicines.
Scientists at the Department of Medical Biochemistry and Biophysics have now, with the help of the two EU networks 'EICOSANOX' and 'E-Mep', elucidated the three dimensional structure of the LTC4 synthase at 2.0 -- resolution (1 - = 1 Angstrom = 10-10 m = 0,000 000 000 1 m). It is clear from the structure that the protein has three identical subunits, each of them consisting of four spiral structures that span the nuclear membrane. Also the exact position and characteristics of the active sites, where activating or blocking molecules can bind, have been identified. With this knowledge it is now possible to tailor new molecules that can block the LTC4 synthase.
The new results are also very important as they can lead the way for the development of new and more effective therapeutics against other diseases. Some 40 % of the proteins of interest for pharmaceutical developments are membrane proteins. Until now detailed structural information on these proteins has been absent, and therefore it has been difficult to fully understand their function. The present study is likely to lead the way for the determination of structures of other human membrane proteins. The elucidation of more membrane protein structures will help us understand fundamental processes that take place in the cell membranes.
Facts: Proteins consist of a chain of amino acids. The length of this chain can range from a few to thousands of amino acids. The chain is then folded in a characteristic way and the 3-D structure can bind different molecules. Determining a protein structure and its biochemical characteristics helps us understand its function, and to design blocking or activating molecules which can serve as medicines. A known protein structure therefore makes it easier and faster to develop new pharmaceuticals.
The EU network EICOSANOX brings together leading scientists from Europe and Canada, and is coordinated by Karolinska Institutet.
Publication:
"Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase"
Martinez Molina D, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggstrom JZ, Nordlund P.
Nature, AOP 15 July 2007
For more information, please contact:
Professor Jesper Z. Haeggstrom, coordinator for EICOSANOX
Karolinska Institutet is one of the leading medical universities in Europe. Through research, education and information, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine. For more information, visit ki.se/
Source: Professor Par Nordlund
Karolinska Institutet
Asthma attacks are caused by an acute inflammatory reaction in the airways, a reaction that is largely due to actions of LTC4 synthase. For this reason asthma medicines often aim at blocking the downstream effects of LTC4 synthase. However, there is a need for new pharmaceutical alternatives, since not all patients respond to the existing medicines.
Scientists at the Department of Medical Biochemistry and Biophysics have now, with the help of the two EU networks 'EICOSANOX' and 'E-Mep', elucidated the three dimensional structure of the LTC4 synthase at 2.0 -- resolution (1 - = 1 Angstrom = 10-10 m = 0,000 000 000 1 m). It is clear from the structure that the protein has three identical subunits, each of them consisting of four spiral structures that span the nuclear membrane. Also the exact position and characteristics of the active sites, where activating or blocking molecules can bind, have been identified. With this knowledge it is now possible to tailor new molecules that can block the LTC4 synthase.
The new results are also very important as they can lead the way for the development of new and more effective therapeutics against other diseases. Some 40 % of the proteins of interest for pharmaceutical developments are membrane proteins. Until now detailed structural information on these proteins has been absent, and therefore it has been difficult to fully understand their function. The present study is likely to lead the way for the determination of structures of other human membrane proteins. The elucidation of more membrane protein structures will help us understand fundamental processes that take place in the cell membranes.
Facts: Proteins consist of a chain of amino acids. The length of this chain can range from a few to thousands of amino acids. The chain is then folded in a characteristic way and the 3-D structure can bind different molecules. Determining a protein structure and its biochemical characteristics helps us understand its function, and to design blocking or activating molecules which can serve as medicines. A known protein structure therefore makes it easier and faster to develop new pharmaceuticals.
The EU network EICOSANOX brings together leading scientists from Europe and Canada, and is coordinated by Karolinska Institutet.
Publication:
"Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase"
Martinez Molina D, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggstrom JZ, Nordlund P.
Nature, AOP 15 July 2007
For more information, please contact:
Professor Jesper Z. Haeggstrom, coordinator for EICOSANOX
Karolinska Institutet is one of the leading medical universities in Europe. Through research, education and information, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine. For more information, visit ki.se/
Source: Professor Par Nordlund
Karolinska Institutet
Spores Breaking Out Of Dormant State, Tracked By Researchers
Tapping into the unknown world of awakening dormant bacterial spores, researchers have revealed through atomic force microscopy (AFM) the alterations of spore coat and germ cell wall that accompany the transformation from a spore to a vegetative cell.
When starved of nutrients Bacillus (rod-shaped bacteria) cells initiate a series of genetic, biochemical and structural events that result in the formation of metabolically dormant spores. They can remain dormant for extended periods and, partly because of their tough spore coat, have a significant resistance to extreme environmental factors including heat, radiation and toxic chemicals. However, once in favorable conditions, spores break the dormant state through germination and reenter the vegetative mode of replication.
Although significant progress has been made in understanding the biochemical and genetic bases of the spore germination process, it is still unclear how a spore breaks out of its dormant state.
But a new in vitro study of single germinating Bacillus atrophaeus spores details how the spore coat structures break down, and it shows with unprecedented resolution how the new bacterium emerges from the disintegrating spore. The new research, led by Lawrence Livermore National Laboratory scientists, appeared in the early online edition of the Proceedings of the National Academy of Sciences. The research appears in the June 4 issue of PNAS.
"A thorough understanding of spore germination is important for the development of new countermeasures that identify the earliest stages of a wide range of spore mediated diseases, including botulism, gas gangrene and pulmonary anthrax," said Alexander Malkin, senior author from LLNL's Biosciences and Biotechnology Division. "But it's also important to gain fundamental insights into the key events in bacterial cell development."
The researchers, including Marco Plomp, lead author at LLNL, and those from Children's Hospital Oakland Research Institute and Northwestern University, used AFM to identify disassembly of the outer spore coat rodlet structures, which appear to be structurally similar to amyloid fibrils that have been associated with neural degenerative diseases, such as Alzheimer's and prion diseases. "The extreme physical and chemical resistance of Bacillus spores suggests that evolutionary forces have captured the mechanical rigidity and resistance of these amyloid self-assembling biomaterials to structure the protective outer spore surface," Plomp said.
When exposed to a solution that triggers germination, nanometer sized etch pits were seen developing in the rodlet layer. These etch pits evolved into ever widening fissures, leaving narrow strips of remaining rodlet structure. In the end, 1- to 3- nm-wide fibrils remained. The in vitro AFM imaging also revealed the porous fibrous cell wall structure of newly emerging and mature vegetative cells, consisting of a network of nanometer-wide peptidoglycan fibers. "These results show that dynamic AFM is a promising tool to investigate the formation and evolution of the bacterial cell wall," Malkin said.
The research is funded by LLNL's Laboratory Directed Research and Development program, the Defense Advanced Research Project Agency (DARPA) and the Federal Bureau of Investigation.
Founded in 1952, Lawrence Livermore National Laboratory is a national security laboratory, with a mission to ensure national security and apply science and technology to the important issues of our time. Lawrence Livermore National Laboratory is managed by the University of California for the U.S. Department of Energy's National Nuclear Security Administration.
Contact: Anne Stark
DOE/Lawrence Livermore National Laboratory
When starved of nutrients Bacillus (rod-shaped bacteria) cells initiate a series of genetic, biochemical and structural events that result in the formation of metabolically dormant spores. They can remain dormant for extended periods and, partly because of their tough spore coat, have a significant resistance to extreme environmental factors including heat, radiation and toxic chemicals. However, once in favorable conditions, spores break the dormant state through germination and reenter the vegetative mode of replication.
Although significant progress has been made in understanding the biochemical and genetic bases of the spore germination process, it is still unclear how a spore breaks out of its dormant state.
But a new in vitro study of single germinating Bacillus atrophaeus spores details how the spore coat structures break down, and it shows with unprecedented resolution how the new bacterium emerges from the disintegrating spore. The new research, led by Lawrence Livermore National Laboratory scientists, appeared in the early online edition of the Proceedings of the National Academy of Sciences. The research appears in the June 4 issue of PNAS.
"A thorough understanding of spore germination is important for the development of new countermeasures that identify the earliest stages of a wide range of spore mediated diseases, including botulism, gas gangrene and pulmonary anthrax," said Alexander Malkin, senior author from LLNL's Biosciences and Biotechnology Division. "But it's also important to gain fundamental insights into the key events in bacterial cell development."
The researchers, including Marco Plomp, lead author at LLNL, and those from Children's Hospital Oakland Research Institute and Northwestern University, used AFM to identify disassembly of the outer spore coat rodlet structures, which appear to be structurally similar to amyloid fibrils that have been associated with neural degenerative diseases, such as Alzheimer's and prion diseases. "The extreme physical and chemical resistance of Bacillus spores suggests that evolutionary forces have captured the mechanical rigidity and resistance of these amyloid self-assembling biomaterials to structure the protective outer spore surface," Plomp said.
When exposed to a solution that triggers germination, nanometer sized etch pits were seen developing in the rodlet layer. These etch pits evolved into ever widening fissures, leaving narrow strips of remaining rodlet structure. In the end, 1- to 3- nm-wide fibrils remained. The in vitro AFM imaging also revealed the porous fibrous cell wall structure of newly emerging and mature vegetative cells, consisting of a network of nanometer-wide peptidoglycan fibers. "These results show that dynamic AFM is a promising tool to investigate the formation and evolution of the bacterial cell wall," Malkin said.
The research is funded by LLNL's Laboratory Directed Research and Development program, the Defense Advanced Research Project Agency (DARPA) and the Federal Bureau of Investigation.
Founded in 1952, Lawrence Livermore National Laboratory is a national security laboratory, with a mission to ensure national security and apply science and technology to the important issues of our time. Lawrence Livermore National Laboratory is managed by the University of California for the U.S. Department of Energy's National Nuclear Security Administration.
Contact: Anne Stark
DOE/Lawrence Livermore National Laboratory
Animal Research Uncovers Another Mechanism Of Cholesterol Lowering Drug
New research in animals suggests why the commonly prescribed cholesterol-lowering drug ezetimibe (Zetia®) is so potent. The research, reported by scientists at Wake Forest University School of Medicine, is reported online by the Journal of Clinical Investigation and will appear in the July 2 print issue.
It had previously been thought that the drug works by preventing cells in the intestine from absorbing cholesterol. The new research suggests that Zetia also works in the liver. In both locations, the drug's target is a protein known as NPC1L1 that moves cholesterol into the body's cells. Zetia blocks the protein's actions so cholesterol cannot be absorbed.
Cholesterol comes not only from the foods we eat, but is also produced by the liver. The organ is involved in making cholesterol, as well as in taking up cholesterol and packaging it for the body's use.
"We know that this protein that the drug targets is expressed not only in the intestine, but is abundant in the human liver," said Ryan E. Temel, Ph.D., lead author.
The scientists made the discovery about Zetia's dual action by studying mice that were specially engineered to produce NPC1L1 in the liver. When there were high levels of the protein in the liver, which enhanced cholesterol absorption by the cells, there was a drastic reduction in cholesterol levels in the bile. But when the mice were treated with Zetia, the cholesterol levels returned to normal, suggesting that the drug targets NPC1L1 in the liver.
"These findings suggest that in humans, the drug may reduce cholesterol levels in the blood by inhibiting NPC1L1 function in both the intestine and liver," said Liqing Yu, M.D., Ph.D., senior researcher and an assistant professor of pathology, Section on Lipid Sciences.
The researchers theorize that when Zetia blocks this process in the liver, the cholesterol that cannot be absorbed is secreted into bile, the digestive juices that are stored in the gallbladder. Normally, most of biliary cholesterol is secreted from the body in the feces. However, when the bile contains too much cholesterol, gallstones can result. These hardened pieces of cholesterol can block the passageway from the gallbladder to the intestine, resulting in severe abdominal pain, liver damage and nutrient malabsorption.
"The fact that Zetia works in two locations is positive because it makes it more effective as a cholesterol-lowering drug," said Temel. "But our research suggests the potential for having too much cholesterol in the bile, which could possibly cause gallstones."
The researchers hope to study the question in monkeys and said more research is needed to see if the drug increases gallstone formation in some people.
"Until more research is done in animal models that naturally express the protein, it is difficult to say whether this would apply to humans," said Yu.
Co-researchers were Weiqing Tang, M.D., Yinyan Ma, B.S., Lawrence Rudel, Ph.D., and Mark Willingham, M.D., all with Wake Forest, Yiannis Ioannou, Ph.D., and Joanna Davies, Ph.D., both from Mount Sinai School of Medicine, and Lisa-Mari Nilsson, M.D., from Karolinska University Hospital Huddinge in Stockholm, Sweden.
Contacts: Shannon Koontz,Bonnie Davis.
About Wake Forest University Baptist Medical Center: Wake Forest Baptist is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. The system comprises 1,282 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.
Contact: Karen Richardson
Wake Forest University Baptist Medical Center
It had previously been thought that the drug works by preventing cells in the intestine from absorbing cholesterol. The new research suggests that Zetia also works in the liver. In both locations, the drug's target is a protein known as NPC1L1 that moves cholesterol into the body's cells. Zetia blocks the protein's actions so cholesterol cannot be absorbed.
Cholesterol comes not only from the foods we eat, but is also produced by the liver. The organ is involved in making cholesterol, as well as in taking up cholesterol and packaging it for the body's use.
"We know that this protein that the drug targets is expressed not only in the intestine, but is abundant in the human liver," said Ryan E. Temel, Ph.D., lead author.
The scientists made the discovery about Zetia's dual action by studying mice that were specially engineered to produce NPC1L1 in the liver. When there were high levels of the protein in the liver, which enhanced cholesterol absorption by the cells, there was a drastic reduction in cholesterol levels in the bile. But when the mice were treated with Zetia, the cholesterol levels returned to normal, suggesting that the drug targets NPC1L1 in the liver.
"These findings suggest that in humans, the drug may reduce cholesterol levels in the blood by inhibiting NPC1L1 function in both the intestine and liver," said Liqing Yu, M.D., Ph.D., senior researcher and an assistant professor of pathology, Section on Lipid Sciences.
The researchers theorize that when Zetia blocks this process in the liver, the cholesterol that cannot be absorbed is secreted into bile, the digestive juices that are stored in the gallbladder. Normally, most of biliary cholesterol is secreted from the body in the feces. However, when the bile contains too much cholesterol, gallstones can result. These hardened pieces of cholesterol can block the passageway from the gallbladder to the intestine, resulting in severe abdominal pain, liver damage and nutrient malabsorption.
"The fact that Zetia works in two locations is positive because it makes it more effective as a cholesterol-lowering drug," said Temel. "But our research suggests the potential for having too much cholesterol in the bile, which could possibly cause gallstones."
The researchers hope to study the question in monkeys and said more research is needed to see if the drug increases gallstone formation in some people.
"Until more research is done in animal models that naturally express the protein, it is difficult to say whether this would apply to humans," said Yu.
Co-researchers were Weiqing Tang, M.D., Yinyan Ma, B.S., Lawrence Rudel, Ph.D., and Mark Willingham, M.D., all with Wake Forest, Yiannis Ioannou, Ph.D., and Joanna Davies, Ph.D., both from Mount Sinai School of Medicine, and Lisa-Mari Nilsson, M.D., from Karolinska University Hospital Huddinge in Stockholm, Sweden.
Contacts: Shannon Koontz,Bonnie Davis.
About Wake Forest University Baptist Medical Center: Wake Forest Baptist is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. The system comprises 1,282 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.
Contact: Karen Richardson
Wake Forest University Baptist Medical Center
Odd energy mechanism in bacteria analyzed
Scientists at Oregon State University have successfully cultured in a laboratory a microorganism with a gene for an alternate form of photochemistry - an advance that may ultimately help shed light on the ecology of the world's oceans.
The microorganism is SAR11, the smallest free living cell known and probably the most abundant organism in the seas. By being able for the first time to study the SAR11 "proteorhodopsin" gene in a laboratory, researchers will be able to better understand how it is activated, its role in the life and survival of SAR11, and how it affects ocean ecology. The findings are being published today in the journal Nature.
Surprisingly, the SAR11 bacteria continued to grow normally whether or not there was light available - indicating to OSU researchers that the cell does not require this energy producing mechanism in normal conditions. It's possible, they said, that this alternate form of photochemistry serves as a "backup" system to provide energy to the cells when they face starvation in the open ocean, which often has very limited nutrients.
"It's exciting to learn more about another form of photochemistry that does not use chlorophyll", said Stephen Giovannoni, a professor of microbiology at OSU. "This proteorhodopsin gene, however, seems to have a subtle role in the life and survival of SAR11, and appears to be an auxiliary system to aid cell survival."
The level of interest in SAR11 is high, researchers say, because it dominates microbial life in the oceans, survives where most other cells would die, and plays a major role in the cycling of carbon on Earth. These bacteria may have been thriving for a billion years or more, but they have the smallest genetic structure of any independent cell and were only first discovered by OSU scientists in 1990.
Although tiny, because of their huge numbers SAR11 plays a major role in the planet's carbon cycle as a consumer of organic carbon. Its main energy generating system is the respiration of organic carbon, producing carbon dioxide and water in the process.
Oxygen in the Earth's atmosphere was largely created and is maintained by photosynthesis, in which plants convert sunlight into biological energy through a process that requires chlorophyll. In the oceans, SAR11 is a partner in this process, recycling organic carbon and producing the nutrients needed for the algae that produce about half of the oxygen that enters Earth's atmosphere every day.
The carbon cycle ultimately affects all plant and animal life on Earth.
However, it's now clear that SAR11 has its own mechanism to use sunlight energy that does not involve chlorophyll. Rather, it uses retinal, the same protein used by the eyes of animals and humans to detect light, and serves as a "proton pump" to energize the cell membrane. Proteorhodopsin was only discovered in 2000, but until now, it had not been found in a living organism. It's still not totally clear, Giovannoni said, how this energy producing mechanism benefits the cell.
"When we turned the lights off, there was no mechanism for the proteorhodopsin gene to produce energy, but that didn't seem to make any difference in the growth rate of SAR11," Giovannoni said. "So we know that under normal conditions this alternate form of energy production is not required. This system may be there for emergencies. But it may still be very important to ocean life, and that's what we need to find out more about."
By David Stauth
Steve Giovannoni
steve.giovannonioregonstate
Oregon State University
orst
The microorganism is SAR11, the smallest free living cell known and probably the most abundant organism in the seas. By being able for the first time to study the SAR11 "proteorhodopsin" gene in a laboratory, researchers will be able to better understand how it is activated, its role in the life and survival of SAR11, and how it affects ocean ecology. The findings are being published today in the journal Nature.
Surprisingly, the SAR11 bacteria continued to grow normally whether or not there was light available - indicating to OSU researchers that the cell does not require this energy producing mechanism in normal conditions. It's possible, they said, that this alternate form of photochemistry serves as a "backup" system to provide energy to the cells when they face starvation in the open ocean, which often has very limited nutrients.
"It's exciting to learn more about another form of photochemistry that does not use chlorophyll", said Stephen Giovannoni, a professor of microbiology at OSU. "This proteorhodopsin gene, however, seems to have a subtle role in the life and survival of SAR11, and appears to be an auxiliary system to aid cell survival."
The level of interest in SAR11 is high, researchers say, because it dominates microbial life in the oceans, survives where most other cells would die, and plays a major role in the cycling of carbon on Earth. These bacteria may have been thriving for a billion years or more, but they have the smallest genetic structure of any independent cell and were only first discovered by OSU scientists in 1990.
Although tiny, because of their huge numbers SAR11 plays a major role in the planet's carbon cycle as a consumer of organic carbon. Its main energy generating system is the respiration of organic carbon, producing carbon dioxide and water in the process.
Oxygen in the Earth's atmosphere was largely created and is maintained by photosynthesis, in which plants convert sunlight into biological energy through a process that requires chlorophyll. In the oceans, SAR11 is a partner in this process, recycling organic carbon and producing the nutrients needed for the algae that produce about half of the oxygen that enters Earth's atmosphere every day.
The carbon cycle ultimately affects all plant and animal life on Earth.
However, it's now clear that SAR11 has its own mechanism to use sunlight energy that does not involve chlorophyll. Rather, it uses retinal, the same protein used by the eyes of animals and humans to detect light, and serves as a "proton pump" to energize the cell membrane. Proteorhodopsin was only discovered in 2000, but until now, it had not been found in a living organism. It's still not totally clear, Giovannoni said, how this energy producing mechanism benefits the cell.
"When we turned the lights off, there was no mechanism for the proteorhodopsin gene to produce energy, but that didn't seem to make any difference in the growth rate of SAR11," Giovannoni said. "So we know that under normal conditions this alternate form of energy production is not required. This system may be there for emergencies. But it may still be very important to ocean life, and that's what we need to find out more about."
By David Stauth
Steve Giovannoni
steve.giovannonioregonstate
Oregon State University
orst
Schmidt-Nielsen Mentor/Scientist Award Won By Joey P. Granger, Ph.D.
The American Physiological Society (APS; the-aps/) has announced that it has presented its prestigious Bodil M. Schmidt-Nielsen Distinguished Mentor and Scientist Award to Joey P. Granger, Ph.D., of the University of Mississippi Medical Center. The honor, now in its fifth year, is bestowed upon members of the APS who have made outstanding contributions to physiological research and demonstrated the highest level of dedication and commitment to excellence in training the next generation of young physiologists.
Dr. Granger's research involves the investigation into how thin layers of cells inside the blood vessels alter kidney function and induce high blood pressure (hypertension) during a pregnancy related disease called preeclampsia. This form of hypertension affects nearly 5-7 percent of all pregnancies in the U.S. and is one of the leading causes of maternal death and perinatal morbidity. The valuable research Dr. Granger has done on this subject may lead to better diagnosis, treatment and prevention of preeclampsia.
As a physiologist Dr. Granger has mentored five visiting scientists, including 13 postdoctoral fellows and 10 pre-doctoral students. He is the founder of a mentoring group for junior faculty, which assists in obtaining departmental funding and has also established a summer research internship program. Since being named dean of the school of Graduate Studies in the Health Sciences in 2007, Granger has improved graduate education by providing superior stipend and health insurance support for all graduate students at the University of Mississippi Medical Center. Dr. Granger also participates in his local community by serving as a judge for local science fairs and frequently speaking at area high schools.
Dr. Granger received his Ph. D. from the University of Mississippi Medical Center, while completing his post doctoral work at the Mayo Clinic. He was named the Associate Director of the Center for Excellence in Cardiovascular-Renal Research at the University of Mississippi Medical Center, in 1996. Dr. Granger was also honored, in 2004 as the Billy S. Guyton Distinguished Professor. In 2007, Dr. Granger was appointed Dean of the School of Graduate Studies in the Health Sciences, at the University of Mississippi Medical Center in Jackson.
About the Bodil Schmidt-Nielsen Award
Bodil Schmidt-Nielsen was elected the first woman president of APS in 1975. She was not only a distinguished physiologist, but also made significant contributions to her field. Her election was a historical moment for APS and representation of the growing importance of women in the field of physiology. She once said, "I think the best way I can represent women in physiology is to do my best possible job as president," a true reflection of her legacy.
As the 2008 Schmidt-Nielsen Awardee, Dr. Granger will be recognized at the APS's 2008 Experimental Biology meeting, and present his remarks on mentoring.
Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS) has been an integral part of this scientific discovery process since it was established in 1887.
Source: Melinda Lowy
American Physiological Society
Dr. Granger's research involves the investigation into how thin layers of cells inside the blood vessels alter kidney function and induce high blood pressure (hypertension) during a pregnancy related disease called preeclampsia. This form of hypertension affects nearly 5-7 percent of all pregnancies in the U.S. and is one of the leading causes of maternal death and perinatal morbidity. The valuable research Dr. Granger has done on this subject may lead to better diagnosis, treatment and prevention of preeclampsia.
As a physiologist Dr. Granger has mentored five visiting scientists, including 13 postdoctoral fellows and 10 pre-doctoral students. He is the founder of a mentoring group for junior faculty, which assists in obtaining departmental funding and has also established a summer research internship program. Since being named dean of the school of Graduate Studies in the Health Sciences in 2007, Granger has improved graduate education by providing superior stipend and health insurance support for all graduate students at the University of Mississippi Medical Center. Dr. Granger also participates in his local community by serving as a judge for local science fairs and frequently speaking at area high schools.
Dr. Granger received his Ph. D. from the University of Mississippi Medical Center, while completing his post doctoral work at the Mayo Clinic. He was named the Associate Director of the Center for Excellence in Cardiovascular-Renal Research at the University of Mississippi Medical Center, in 1996. Dr. Granger was also honored, in 2004 as the Billy S. Guyton Distinguished Professor. In 2007, Dr. Granger was appointed Dean of the School of Graduate Studies in the Health Sciences, at the University of Mississippi Medical Center in Jackson.
About the Bodil Schmidt-Nielsen Award
Bodil Schmidt-Nielsen was elected the first woman president of APS in 1975. She was not only a distinguished physiologist, but also made significant contributions to her field. Her election was a historical moment for APS and representation of the growing importance of women in the field of physiology. She once said, "I think the best way I can represent women in physiology is to do my best possible job as president," a true reflection of her legacy.
As the 2008 Schmidt-Nielsen Awardee, Dr. Granger will be recognized at the APS's 2008 Experimental Biology meeting, and present his remarks on mentoring.
Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS) has been an integral part of this scientific discovery process since it was established in 1887.
Source: Melinda Lowy
American Physiological Society
No getting around RET
Researchers find no role for RET-independent GFR-alpha in development or regeneration -
Neurons depend on external molecular signals for their very survival. These molecules, collectively referred to as neurotrophic factors, include a family of
four GDNF Family Ligands (GFLs) that bind to specific receptor sites on the surfaces of neural cells. These sites allow GFLs to signal through a receptor
complex composed of the RET tyrosine kinase and a GFRб-family receptor. Tyrosine kinases, such as RET, are well-known for their function in
phosphorylation cascades that span the cell membrane. The role of the GFRб co-receptors in these complexes was long thought to be limited to as a co
-receptor for RET, but GFRs have recently been suggested to play other roles as well.
The individual functions of the RET and GFRб subunits in these receptor complexes, which are important in developmental milieux from peripheral
neurogenesis to the developing kidney, remains a thorny question complicated by the fact that GFRб is much more widely expressed in the body than is
RET and that, in vitro, cells expressing GFRб1 without RET have been shown to respond to GDNF signals. A report by Hideki Enomoto (Team Leader,
Laboratory for Neuronal Differentiation and Regeneration) and colleagues at the RIKEN Center for Developmental Biology and the Washington University
School of Medicine published in the November 18 issue of Neuron now challenges the view that RET-independent GFRб1 signaling plays a significant
physiological role in either development or regeneration.
Enomoto first devised an elegant experimental system to make it possible to generate mice specifically lacking RET-independent GFRб1. The study of
GFRб deficiencies in vivo is dogged by the lethality of the phenotype, in which the absence of enteric neurons and functioning kidneys results in death
soon after birth. In vitro studies and the proximity of RET-independent GFRб and RET-expressing cells in some developmental regions, however, have
prompted strong speculation that GFRб might be able to operate even in the absence of RET indigenous to the cell. It has been suggested that this might
take the form of either trans signaling, in which the GFRб receptor captures diffusible GFLs and presents them to a neighboring RET-expressing cell, or
through a separate signaling mechanism mediated by GFL-activated neural cell adhesion molecules (NCAMs).
Given this body of work showing the likelihood of a physiological role for RET-independent GFRб1 activity, Enomoto et al. decided to test whether the in
vitro evidence would be borne out in living mice. The team first showed that mice homozygous for a transgene deleting an important segment of the GFR
б1 gene died in the perinatal period, while heterozygotes (which carried only a single copy of the transgene) were healthy and fertile. On comparing
specific embryonic regions in hetero- and homozygous mice, they found associations between RET-expressing and RET-independent GFRб1 cells in
kidney, enteric and motor neurons, as well as the expected disturbances in development. However, when they next generated mice that were only capable
of expressing GFRб1 only in the RET-expressing cells (by cloning GFRб1 cDNA into a region under the control of the Ret promoter and crossbreeding
the resulting animals with GFRб1 heterozygotes), they were surprised to discover the mice were born healthy and free of any evident developmental
defects in the kidney or nervous system. They found no trace of GFRб1 mRNA in non-Ret-expressing cells in these mice (which they named Cis-only
mice, for their lack of trans signaling), while GFRб1 transcripts were detected as expected in RET-positive cells, proving that the conditional expression
scheme had worked.
Analysis of individual regions known to be susceptible developmental failure on loss of GFRб1 function, such as the kidneys, motor and enteric neurons
and certain parts of the central nervous system during development and following injury, showed that Cis-only mice develop and regenerate structures
that are both morphologically normal and fully functional.
Investigating the second question of a possible alternate RET-independent GDNF receptor complex thought to involve neural cell adhesion molecules,
they next examined Cis-only mouse olfactory bulbs. These bulbs are reduced in size in NCAM-deficient mice as the result of impaired migration of neural
precursors through a zone called the rostral migratory stream and swell with cells that have failed to reach their normal destination; this phenotype is seen
in mice only weakly lacking GFRб1 (which is thought by some to regulate NCAM-mediated cell adhesion), but not in mice lacking RET. Again, the Cis-only
mice showed no discernible differences from wild type.
This comprehensive series of experiments makes a convincing case against any essential physiological role for RET-independent GFRб1, but leaves the
question of why GFRб1 would be more widely expressed if it indeed plays no role without RET. It may be the case that GFRб receptors associate with
other partners that have yet to be identified. Whatever the answer, by laying to rest a theory that had been strongly supported by in vitro evidence, the
Enomoto report serves to underscore the importance of differences between the behavior of cells in the body and cells in a dish.
Contact: Doug Sipp
sippcdb.riken.jp
RIKEN Center for Developmental Biology
Neurons depend on external molecular signals for their very survival. These molecules, collectively referred to as neurotrophic factors, include a family of
four GDNF Family Ligands (GFLs) that bind to specific receptor sites on the surfaces of neural cells. These sites allow GFLs to signal through a receptor
complex composed of the RET tyrosine kinase and a GFRб-family receptor. Tyrosine kinases, such as RET, are well-known for their function in
phosphorylation cascades that span the cell membrane. The role of the GFRб co-receptors in these complexes was long thought to be limited to as a co
-receptor for RET, but GFRs have recently been suggested to play other roles as well.
The individual functions of the RET and GFRб subunits in these receptor complexes, which are important in developmental milieux from peripheral
neurogenesis to the developing kidney, remains a thorny question complicated by the fact that GFRб is much more widely expressed in the body than is
RET and that, in vitro, cells expressing GFRб1 without RET have been shown to respond to GDNF signals. A report by Hideki Enomoto (Team Leader,
Laboratory for Neuronal Differentiation and Regeneration) and colleagues at the RIKEN Center for Developmental Biology and the Washington University
School of Medicine published in the November 18 issue of Neuron now challenges the view that RET-independent GFRб1 signaling plays a significant
physiological role in either development or regeneration.
Enomoto first devised an elegant experimental system to make it possible to generate mice specifically lacking RET-independent GFRб1. The study of
GFRб deficiencies in vivo is dogged by the lethality of the phenotype, in which the absence of enteric neurons and functioning kidneys results in death
soon after birth. In vitro studies and the proximity of RET-independent GFRб and RET-expressing cells in some developmental regions, however, have
prompted strong speculation that GFRб might be able to operate even in the absence of RET indigenous to the cell. It has been suggested that this might
take the form of either trans signaling, in which the GFRб receptor captures diffusible GFLs and presents them to a neighboring RET-expressing cell, or
through a separate signaling mechanism mediated by GFL-activated neural cell adhesion molecules (NCAMs).
Given this body of work showing the likelihood of a physiological role for RET-independent GFRб1 activity, Enomoto et al. decided to test whether the in
vitro evidence would be borne out in living mice. The team first showed that mice homozygous for a transgene deleting an important segment of the GFR
б1 gene died in the perinatal period, while heterozygotes (which carried only a single copy of the transgene) were healthy and fertile. On comparing
specific embryonic regions in hetero- and homozygous mice, they found associations between RET-expressing and RET-independent GFRб1 cells in
kidney, enteric and motor neurons, as well as the expected disturbances in development. However, when they next generated mice that were only capable
of expressing GFRб1 only in the RET-expressing cells (by cloning GFRб1 cDNA into a region under the control of the Ret promoter and crossbreeding
the resulting animals with GFRб1 heterozygotes), they were surprised to discover the mice were born healthy and free of any evident developmental
defects in the kidney or nervous system. They found no trace of GFRб1 mRNA in non-Ret-expressing cells in these mice (which they named Cis-only
mice, for their lack of trans signaling), while GFRб1 transcripts were detected as expected in RET-positive cells, proving that the conditional expression
scheme had worked.
Analysis of individual regions known to be susceptible developmental failure on loss of GFRб1 function, such as the kidneys, motor and enteric neurons
and certain parts of the central nervous system during development and following injury, showed that Cis-only mice develop and regenerate structures
that are both morphologically normal and fully functional.
Investigating the second question of a possible alternate RET-independent GDNF receptor complex thought to involve neural cell adhesion molecules,
they next examined Cis-only mouse olfactory bulbs. These bulbs are reduced in size in NCAM-deficient mice as the result of impaired migration of neural
precursors through a zone called the rostral migratory stream and swell with cells that have failed to reach their normal destination; this phenotype is seen
in mice only weakly lacking GFRб1 (which is thought by some to regulate NCAM-mediated cell adhesion), but not in mice lacking RET. Again, the Cis-only
mice showed no discernible differences from wild type.
This comprehensive series of experiments makes a convincing case against any essential physiological role for RET-independent GFRб1, but leaves the
question of why GFRб1 would be more widely expressed if it indeed plays no role without RET. It may be the case that GFRб receptors associate with
other partners that have yet to be identified. Whatever the answer, by laying to rest a theory that had been strongly supported by in vitro evidence, the
Enomoto report serves to underscore the importance of differences between the behavior of cells in the body and cells in a dish.
Contact: Doug Sipp
sippcdb.riken.jp
RIKEN Center for Developmental Biology
Multidisciplinary Team Researching Advanced Light Microscopy At UCLA To Be Funded By $1.1 Million NSF Grant
The National Science Foundation has awarded a $1.1 million Major Research Instrumentation grant for the Advanced Light Microscopy core laboratory at the California NanoSystems Institute at UCLA. The award will facilitate the acquisition of the first commercially available super-resolution stimulated emission depletion (STED) confocal laser scanning microscope for nanoscopic resolution of biological samples.
The device will be used by a multidisciplinary research team with expertise in physics, chemistry, imaging, genetics and molecular biology led by principal investigator Shimon Weiss, UCLA professor of chemistry and biochemistry, and co-principal investigators Michael Grunstein, UCLA professor of biological chemistry, and Dr. Laurent Bentolila, UCLA senior researcher in chemistry and biochemistry. The team will collaborate with Stefan W. Hell, director of the Max Planck Institute for Biophysical Chemistry in Germany.
Researchers will use the microscope to investigate molecular assemblies at the nanoscale -- including deciphering the structure of chromatin and its packaging into chromosomes in the cell -- and to study cell signaling, viral and bacterial infection pathways, neural plasticity and many other important biological questions. They will also develop a new family of STED probes based on semiconductor nanocrystals.
"We have assembled a group of multidisciplinary UCLA users who will significantly advance their research by making use of this instrument," said Weiss, who is also a member of the California NanoSystems Institute (CNSI) at UCLA.
Developed by Leica Microsystems, the microscope is uniquely designed for nanoscopic resolution of biological and artificial samples. Despite using regular lenses and visible light, the microscope is not limited by diffraction and diplays a x10 resolution improvement over conventional light microscopes.
STED microscopy provides an alternative to electron microscopy because it capitalizes on the well-established advantages of fluorescence microscopy -- including sensitivity, molecular specificity, genetically encoded probes, live cells and ease of operation.
The STED concept relies on stimulated emission, coupled with smart optics, to sharpen the confocal excitation spot, resulting in more detailed, nanometer-resolved images. Bridging the gap between electron and diffraction-limited light microscopy, the STED microscope promises to be a powerful tool for unraveling the relationship between structure and function in cell biology.
The CNSI Advanced Light Microscopy/Spectroscopy shared facility currently provides training to more than 250 research students at the undergraduate, graduate and postdoctoral levels. The new microscope will be used in the education and training of students and researchers through a series of courses offered by the facility. The instrument will also be made available to a large network of researchers throughout Southern California and the United States.
Super-resolution STED microscopy holds great promise because it is expected to lead to significant new discoveries across the fields of biology, chemistry, materials sciences, engineering, medicine and physics.
"Super-resolution fluorescence microscopy will be decisive in solving long-lasting fundamental scientific questions which lie in this intermediate scale of tens of nanometers," said Bentolila, director of the Advanced Light Microscopy core lab at the CNSI.
Leica Microsystems is a leading global designer and producer of innovative high-tech precision optics systems for the analysis of microstructures. It is a market leader in the fields microscopy, confocal laser scanning microscopy, imaging systems, specimen preparation and medical equipment. The company manufactures a broad range of products for numerous applications requiring microscopic imaging, measurement and analysis. It also offers system solutions in the areas of biotechnology and medicine, as well as in the science of raw materials and industrial quality assurance. Comprising nine manufacturing facilities in seven countries, sales and service companies in 20 countries, and an international network of dealers, the company is represented in more than 100 countries. Its international headquarters are in Wetzlar, Germany.
The California NanoSystems Institute is a multidisciplinary research center at UCLA whose mission is to encourage university-industry collaboration and enable the rapid commercialization of discoveries in nanosystems. CNSI members include some of the world's preeminent scientists, and the work conducted at the institute represents world-class expertise in five targeted areas of nanosystems-related research: renewable energy; environmental nanotechnology and nanotoxicology; nanobiotechnology and biomaterials; nanomechanical and nanofluidic systems; and nanoelectronics, photonics and architectonics. For additional information on the institute, visit cnsi.ucla/.
UCLA is California's largest university, with an enrollment of nearly 37,000 undergraduate and graduate students. The UCLA College of Letters and Science and the university's 11 professional schools feature renowned faculty and offer more than 300 degree programs and majors. UCLA is a national and international leader in the breadth and quality of its academic, research, health care, cultural, continuing education and athletic programs. Four alumni and five faculty have been awarded the Nobel Prize.
Source: Jennifer Marcus
University of California - Los Angeles
The device will be used by a multidisciplinary research team with expertise in physics, chemistry, imaging, genetics and molecular biology led by principal investigator Shimon Weiss, UCLA professor of chemistry and biochemistry, and co-principal investigators Michael Grunstein, UCLA professor of biological chemistry, and Dr. Laurent Bentolila, UCLA senior researcher in chemistry and biochemistry. The team will collaborate with Stefan W. Hell, director of the Max Planck Institute for Biophysical Chemistry in Germany.
Researchers will use the microscope to investigate molecular assemblies at the nanoscale -- including deciphering the structure of chromatin and its packaging into chromosomes in the cell -- and to study cell signaling, viral and bacterial infection pathways, neural plasticity and many other important biological questions. They will also develop a new family of STED probes based on semiconductor nanocrystals.
"We have assembled a group of multidisciplinary UCLA users who will significantly advance their research by making use of this instrument," said Weiss, who is also a member of the California NanoSystems Institute (CNSI) at UCLA.
Developed by Leica Microsystems, the microscope is uniquely designed for nanoscopic resolution of biological and artificial samples. Despite using regular lenses and visible light, the microscope is not limited by diffraction and diplays a x10 resolution improvement over conventional light microscopes.
STED microscopy provides an alternative to electron microscopy because it capitalizes on the well-established advantages of fluorescence microscopy -- including sensitivity, molecular specificity, genetically encoded probes, live cells and ease of operation.
The STED concept relies on stimulated emission, coupled with smart optics, to sharpen the confocal excitation spot, resulting in more detailed, nanometer-resolved images. Bridging the gap between electron and diffraction-limited light microscopy, the STED microscope promises to be a powerful tool for unraveling the relationship between structure and function in cell biology.
The CNSI Advanced Light Microscopy/Spectroscopy shared facility currently provides training to more than 250 research students at the undergraduate, graduate and postdoctoral levels. The new microscope will be used in the education and training of students and researchers through a series of courses offered by the facility. The instrument will also be made available to a large network of researchers throughout Southern California and the United States.
Super-resolution STED microscopy holds great promise because it is expected to lead to significant new discoveries across the fields of biology, chemistry, materials sciences, engineering, medicine and physics.
"Super-resolution fluorescence microscopy will be decisive in solving long-lasting fundamental scientific questions which lie in this intermediate scale of tens of nanometers," said Bentolila, director of the Advanced Light Microscopy core lab at the CNSI.
Leica Microsystems is a leading global designer and producer of innovative high-tech precision optics systems for the analysis of microstructures. It is a market leader in the fields microscopy, confocal laser scanning microscopy, imaging systems, specimen preparation and medical equipment. The company manufactures a broad range of products for numerous applications requiring microscopic imaging, measurement and analysis. It also offers system solutions in the areas of biotechnology and medicine, as well as in the science of raw materials and industrial quality assurance. Comprising nine manufacturing facilities in seven countries, sales and service companies in 20 countries, and an international network of dealers, the company is represented in more than 100 countries. Its international headquarters are in Wetzlar, Germany.
The California NanoSystems Institute is a multidisciplinary research center at UCLA whose mission is to encourage university-industry collaboration and enable the rapid commercialization of discoveries in nanosystems. CNSI members include some of the world's preeminent scientists, and the work conducted at the institute represents world-class expertise in five targeted areas of nanosystems-related research: renewable energy; environmental nanotechnology and nanotoxicology; nanobiotechnology and biomaterials; nanomechanical and nanofluidic systems; and nanoelectronics, photonics and architectonics. For additional information on the institute, visit cnsi.ucla/.
UCLA is California's largest university, with an enrollment of nearly 37,000 undergraduate and graduate students. The UCLA College of Letters and Science and the university's 11 professional schools feature renowned faculty and offer more than 300 degree programs and majors. UCLA is a national and international leader in the breadth and quality of its academic, research, health care, cultural, continuing education and athletic programs. Four alumni and five faculty have been awarded the Nobel Prize.
Source: Jennifer Marcus
University of California - Los Angeles
Tracing The History, Genetic Makeup Of Workhorse Laboratory Bacteria
An international team of researchers from the United States, Korea, and France has sequenced and analyzed the genomes of two important laboratory strains of E. coli bacteria, one used to study evolution and the other to produce proteins for basic research or practical applications. The findings will help guide future research and will also open a window to a deeper understanding of classical research that is the foundation of our understanding of basic molecular biology and genetics.
The team, which includes two researchers from the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, published its results online on October 17, 2009, in three papers in the Journal of Molecular Biology.
E. coli has been associated with recent outbreaks of food-borne illnesses, but the two most important laboratory types, named K-12 and B, were isolated from benign E. coli that are normal inhabitants of the human intestine. Both have been indispensable tools for biomedical research and biotechnology.
K-12 was isolated in 1922 in Palo Alto, California. Its genome sequence - the series of nucleotide bases (labeled A, T, G, and C) that make up the source code for running the machinery of the cell - has been known since 1997. The early history of B, however, was unknown until the current collaboration combed through historical scientific papers and personal recollections to trace it back to a strain at the Institut Pasteur, in Paris, in 1918. Adding to this historical reconstruction, the newly sequenced genomes of two different B strains allow the complete genomes of these laboratory workhorses to be compared for the first time.
"Although the B and K-12 strains came into the laboratory half a world apart, their genome sequences show that they are closely related," said Brookhaven biophysicist William Studier, who, along with Brookhaven physicist Sergei Maslov helped analyze the genome sequences.
The genomes of the two B strains were sequenced at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) and at Genoscope, the French center for genome sequencing. Like K-12, the two B genomes each contain about 4.6 million nucleotide base pairs (Ts linked with As or Gs linked with Cs).
"One of the most striking observations in comparing the B and K-12 genomes is the seemingly non-random distribution of single base-pair differences between them," said Maslov, a physicist who studies computationally intensive biological problems. "We are pursuing further analysis to try to understand the evolutionary mechanisms that produced this distribution."
The genome comparisons also turned up some interesting differences between the two B strains. Like identical twins separated at birth, the two B strains have had separate laboratory histories since 1959. One became REL606, a strain used by Richard Lenski at Michigan State University and his collaborators to study long-term evolution in the laboratory. The other became BL21(DE3), a strain developed by Studier and colleagues at Brookhaven Lab to be used as a "factory" for producing proteins for basic research and for medical and industrial use.
"Detailed information about these two strains is useful for future laboratory studies but is also important for companies who are using proteins made from E. coli B strains for medical purposes," Studier said. "They want to know as much as possible about the bacterial strain, including where it came from."
Some detective work was required before the differences between the two B genomes could be understood. Although scientific papers told one story, information in the genome sequences told another, Studier said. The researchers pinpointed the discrepancy to a period in the 1960s, as scientists at different labs shared strains for their research. Apparently, one sample was mislabeled in one of these exchanges. The current detailed genomic analysis uncovered this long-buried mix-up.
Once this mystery was solved, every difference between the two B genome sequences could be understood in terms of the different laboratory manipulations used on the ancestral strains, Studier said. This information provided new insights into the types of changes to the genome caused by standard laboratory treatments, including exposure to chemicals, irradiation with ultraviolet light, and transfer of DNA between genomes.
"It's amazing how much valuable information can be revealed by looking in detail at genome sequences," Studier said.
This work was supported by the 21C Frontier Microbial Genomics and Applications Center Program of the Korean Ministry of Education, Science and Technology; the KRIBB Research Initiative Program; the Consortium National de Recherche en GГ©nomique; the GTL Program of the Office of Biological and Environmental Sciences and the Division of Materials Science within the DOE Office of Science; the National Science Foundation; the Defense Advanced Research Projects Agency; and internal research funding from Brookhaven National Laboratory.
Source:
Kendra Snyder
DOE/Brookhaven National Laboratory
The team, which includes two researchers from the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, published its results online on October 17, 2009, in three papers in the Journal of Molecular Biology.
E. coli has been associated with recent outbreaks of food-borne illnesses, but the two most important laboratory types, named K-12 and B, were isolated from benign E. coli that are normal inhabitants of the human intestine. Both have been indispensable tools for biomedical research and biotechnology.
K-12 was isolated in 1922 in Palo Alto, California. Its genome sequence - the series of nucleotide bases (labeled A, T, G, and C) that make up the source code for running the machinery of the cell - has been known since 1997. The early history of B, however, was unknown until the current collaboration combed through historical scientific papers and personal recollections to trace it back to a strain at the Institut Pasteur, in Paris, in 1918. Adding to this historical reconstruction, the newly sequenced genomes of two different B strains allow the complete genomes of these laboratory workhorses to be compared for the first time.
"Although the B and K-12 strains came into the laboratory half a world apart, their genome sequences show that they are closely related," said Brookhaven biophysicist William Studier, who, along with Brookhaven physicist Sergei Maslov helped analyze the genome sequences.
The genomes of the two B strains were sequenced at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) and at Genoscope, the French center for genome sequencing. Like K-12, the two B genomes each contain about 4.6 million nucleotide base pairs (Ts linked with As or Gs linked with Cs).
"One of the most striking observations in comparing the B and K-12 genomes is the seemingly non-random distribution of single base-pair differences between them," said Maslov, a physicist who studies computationally intensive biological problems. "We are pursuing further analysis to try to understand the evolutionary mechanisms that produced this distribution."
The genome comparisons also turned up some interesting differences between the two B strains. Like identical twins separated at birth, the two B strains have had separate laboratory histories since 1959. One became REL606, a strain used by Richard Lenski at Michigan State University and his collaborators to study long-term evolution in the laboratory. The other became BL21(DE3), a strain developed by Studier and colleagues at Brookhaven Lab to be used as a "factory" for producing proteins for basic research and for medical and industrial use.
"Detailed information about these two strains is useful for future laboratory studies but is also important for companies who are using proteins made from E. coli B strains for medical purposes," Studier said. "They want to know as much as possible about the bacterial strain, including where it came from."
Some detective work was required before the differences between the two B genomes could be understood. Although scientific papers told one story, information in the genome sequences told another, Studier said. The researchers pinpointed the discrepancy to a period in the 1960s, as scientists at different labs shared strains for their research. Apparently, one sample was mislabeled in one of these exchanges. The current detailed genomic analysis uncovered this long-buried mix-up.
Once this mystery was solved, every difference between the two B genome sequences could be understood in terms of the different laboratory manipulations used on the ancestral strains, Studier said. This information provided new insights into the types of changes to the genome caused by standard laboratory treatments, including exposure to chemicals, irradiation with ultraviolet light, and transfer of DNA between genomes.
"It's amazing how much valuable information can be revealed by looking in detail at genome sequences," Studier said.
This work was supported by the 21C Frontier Microbial Genomics and Applications Center Program of the Korean Ministry of Education, Science and Technology; the KRIBB Research Initiative Program; the Consortium National de Recherche en GГ©nomique; the GTL Program of the Office of Biological and Environmental Sciences and the Division of Materials Science within the DOE Office of Science; the National Science Foundation; the Defense Advanced Research Projects Agency; and internal research funding from Brookhaven National Laboratory.
Source:
Kendra Snyder
DOE/Brookhaven National Laboratory
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