Sleep onset and duration uncoupled
Receptors producing synaptic inhibition regulate the time it takes to get to sleep. This work begins to dissect the biological mechanisms underlying the differences between various types of insomnia.
Drosophila are used as a model for understanding sleep because flies replicate many of the behavioral characteristics of mammalian sleep. This research has not yet produced evidence that the pathways targeted by insomnia drugs in humans are necessary for sleep in flies, however, casting doubt of the relevance of fly sleep as a model for human sleep.
Using genetics and pharmacology, Leslie Griffith and colleagues demonstrate that the biophysical properties of a particular inhibitory receptor influenced both falling and staying asleep in flies, but in different ways. Manipulating receptor desensitization only affected sleep onset, uncoupling the control of sleep initiation and maintenance.
This work further confirms the validity of Drosophila as a model of mammalian sleep and provides a biological explanation for a specific type of insomnia. Future studies exploring other aspects of sleep regulation involving inhibitory receptors may assist in better targeting of drugs designed to specifically influence one particular aspect of sleep without unnecessarily affecting other aspects.
Author contact:
Leslie Griffith (Brandeis University, Waltham, MA, USA)
Tel: +1 781 736 3125; E-mail: griffith@brandeis.edu
Monday, January 28, 2008
Mother knows best
Breast feeding may help protect babies against allergic asthma reports a paper in this week’s Nature Medicine. Airborne allergen is able to pass from mother to child through breast milk, which creates a tolerance to the allergen.
Allergic asthma affects 300 million people worldwide and is characterized by obstruction of the respiratory pathways in response to allergen exposure. Its prevalence has increased in recent decades, probably due to changes in environmental factors. Indeed, exposure to environmental antigens during infancy reduces the likelihood of developing asthma.
Valerie Julia and her colleagues investigated whether exposing lactating mice to an airborne allergen—ovalbumin—affected asthma development in the offspring. They found that ovalbumin was efficiently transferred from the mother to the neonate through the milk, leading to the development of immunological tolerance. Tolerance induction relied on the presence of transforming growth factor-beta and was mediated by regulatory CD4+ T lymphocytes, but did not require the transfer of immunoglobulins through the milk.
Breast milk-mediated transfer of an antigen to the neonate can result in oral tolerance induction, leading to antigen-specific protection from allergic asthma. These observations may pave the way for the design of new strategies to prevent the development of allergic diseases.
Author contact:
Valerie Julia (INSERM-UNSA, Valbonne, France)
Tel. +33 4 93 95 77 85;E-mail: vjulia@unice.fr
Breast feeding may help protect babies against allergic asthma reports a paper in this week’s Nature Medicine. Airborne allergen is able to pass from mother to child through breast milk, which creates a tolerance to the allergen.
Allergic asthma affects 300 million people worldwide and is characterized by obstruction of the respiratory pathways in response to allergen exposure. Its prevalence has increased in recent decades, probably due to changes in environmental factors. Indeed, exposure to environmental antigens during infancy reduces the likelihood of developing asthma.
Valerie Julia and her colleagues investigated whether exposing lactating mice to an airborne allergen—ovalbumin—affected asthma development in the offspring. They found that ovalbumin was efficiently transferred from the mother to the neonate through the milk, leading to the development of immunological tolerance. Tolerance induction relied on the presence of transforming growth factor-beta and was mediated by regulatory CD4+ T lymphocytes, but did not require the transfer of immunoglobulins through the milk.
Breast milk-mediated transfer of an antigen to the neonate can result in oral tolerance induction, leading to antigen-specific protection from allergic asthma. These observations may pave the way for the design of new strategies to prevent the development of allergic diseases.
Author contact:
Valerie Julia (INSERM-UNSA, Valbonne, France)
Tel. +33 4 93 95 77 85;E-mail: vjulia@unice.fr
An amicable separation
Graphene — a carbon-based nanomaterial known for its unique electronic, thermal and mechanical properties — can form stable dispersions in water without the need for additional chemical stabilizers. The research has practical implications for the development of coatings to reduce static build-up on materials.
Graphene is the name given to the individual sheets of carbon, just one atom thick, that stack together to form graphite. Keeping graphene sheets separate from one another is a difficult task because they tend to stick together, forming larger structures that are not particularly useful. Now, however, using a sequence of chemical reactions, a team led by Gordon Wallace and Dan Li have shown how aqueous dispersions of well-separated graphene sheets can be made from graphite — an abundant and inexpensive starting material.
Rather than relying on either polymer or surfactant stabilizers, their approach maximizes the electrostatic charge on the graphene sheets, ensuring that they repel one another instead of clumping together. This low-cost approach offers the potential for large-scale production of stable graphene colloids that can be processed using well-established solution-based techniques — such as filtration or spraying — to make conductive films. In addition to antistatic coatings, these materials are expected to have applications in flexible transparent electronics, high-performance composites and nanomedicine.
Author contact:
Gordon Wallace (University of Wollongong, New South Wales, Australia)
Tel: +61 2 4221 3127; E-mail: gwallace@uow.edu.au
Dan Li (University of Wollongong, New South Wales, Australia)
Tel: +61 2 4221 3319; E-mail: danli@uow.edu.au
Graphene — a carbon-based nanomaterial known for its unique electronic, thermal and mechanical properties — can form stable dispersions in water without the need for additional chemical stabilizers. The research has practical implications for the development of coatings to reduce static build-up on materials.
Graphene is the name given to the individual sheets of carbon, just one atom thick, that stack together to form graphite. Keeping graphene sheets separate from one another is a difficult task because they tend to stick together, forming larger structures that are not particularly useful. Now, however, using a sequence of chemical reactions, a team led by Gordon Wallace and Dan Li have shown how aqueous dispersions of well-separated graphene sheets can be made from graphite — an abundant and inexpensive starting material.
Rather than relying on either polymer or surfactant stabilizers, their approach maximizes the electrostatic charge on the graphene sheets, ensuring that they repel one another instead of clumping together. This low-cost approach offers the potential for large-scale production of stable graphene colloids that can be processed using well-established solution-based techniques — such as filtration or spraying — to make conductive films. In addition to antistatic coatings, these materials are expected to have applications in flexible transparent electronics, high-performance composites and nanomedicine.
Author contact:
Gordon Wallace (University of Wollongong, New South Wales, Australia)
Tel: +61 2 4221 3127; E-mail: gwallace@uow.edu.au
Dan Li (University of Wollongong, New South Wales, Australia)
Tel: +61 2 4221 3319; E-mail: danli@uow.edu.au
Amyloid inhibitors are aggregates too
A new understanding of the way protein inhibitors work may have major implications in the development of drugs for Alzheimer’s and other neurodegenerative diseases. Scientists have discovered a significant feature in the way that known amyloid inhibitors work, according to a paper to be published online this week in Nature Chemical Biology.
Several neurodegenerative diseases may be caused by the collection of various proteins into large clumps of disordered proteins, known as fibrils. A common strategy to try to find cures for these diseases is to search for molecules that can prevent formation of these fibrils or even cause them to break apart.
Brian Shoichet and colleagues demonstrate that the molecules that have been identified so far in this search act in an unusual manner: the compounds themselves form large groups, known as aggregates, which then act on the proteins to prevent the undesired clumping. The authors also found that other compounds not previously identified as amyloid inhibitors but known to form aggregates also stop the proteins from clumping up. This result will require a significant re-evaluation of the way in which drug developers approach Alzheimer’s disease.
Author contact:
Brian Shoichet (University of California San Francisco, San Francisco, CA. USA)
Tel: +1 415 514 4126; E-mail: shoichet@cgl.ucsf.edu
A new understanding of the way protein inhibitors work may have major implications in the development of drugs for Alzheimer’s and other neurodegenerative diseases. Scientists have discovered a significant feature in the way that known amyloid inhibitors work, according to a paper to be published online this week in Nature Chemical Biology.
Several neurodegenerative diseases may be caused by the collection of various proteins into large clumps of disordered proteins, known as fibrils. A common strategy to try to find cures for these diseases is to search for molecules that can prevent formation of these fibrils or even cause them to break apart.
Brian Shoichet and colleagues demonstrate that the molecules that have been identified so far in this search act in an unusual manner: the compounds themselves form large groups, known as aggregates, which then act on the proteins to prevent the undesired clumping. The authors also found that other compounds not previously identified as amyloid inhibitors but known to form aggregates also stop the proteins from clumping up. This result will require a significant re-evaluation of the way in which drug developers approach Alzheimer’s disease.
Author contact:
Brian Shoichet (University of California San Francisco, San Francisco, CA. USA)
Tel: +1 415 514 4126; E-mail: shoichet@cgl.ucsf.edu
Sunday, January 27, 2008
Genes Linked to Parkinson's Protection Identified
University of Alabama researchers have identified five genes within animal models displaying protective capabilities against a hallmark trait of Parkinson’s disease.
The research, publishing Jan. 8 in the Proceedings of the National Academy of Sciences’ Early Edition, is a possible step toward identifying both new targets for drug treatment development and genetic factors which make some people more susceptible to the disease, the researchers said.
“We’ve found five genes so far that significantly protect dopamine neurons from dying within our animal models,” said Dr. Guy Caldwell, associate professor of biological sciences at UA and co-author of the research.
The UA researchers’ efforts, Caldwell said, represents one of the largest functional analyses of genes ever reported for Parkinson's disease. Shusei Hamamichi, a UA doctoral student, is lead author of the research paper and led the University’s effort, along with Renee Rivas and Adam Knight, two UA undergraduates, Songsong Cao, a former doctoral student, Dr. Kim Caldwell, assistant professor of biological sciences, and Guy Caldwell.
Hamamichi’s role represents a “heroic effort,” Guy Caldwell said.
UA researchers used specific strains of tiny nematode worms as animal models for the research. These genetically engineered worms contain a human protein, alpha-synuclein, within their cells. Scientists have learned that people with too many copies of the code for alpha-synuclein within their DNA will contract Parkinson’s.
Extra copies of alpha-synuclein can lead to repeated protein misfolding and death of the dopamine producing neurons in the brain. In Parkinson’s patients, the death of these neurons leads to rigid and tremoring limbs, difficulty in movement and impaired reflexes. More than 1 million Americans are estimated to have Parkinson’s.
Utilizing bioinformatic databases – which contain an abundance of information related to various genes and their genetic associations – the UA researchers first mined the data, prioritizing 867 genes for testing.
Using a revolutionary technique known as RNA interference, or RNAi, Hamamichi removed, one at a time, the functions of each of the 867 genes from the tiny nematodes. This, Caldwell said, enabled the research team to investigate the impact the missing function would have on cellular processes.
“Of these approximate 900 genes, we narrowed it down to 20 top candidates that seemed to have the most significant affect on alpha-synuclein aggregation as the animals aged,” Caldwell said.
Importantly, secondary screening of the 20 genes has thus far revealed five that offer dopamine neurons protection from dying, Caldwell said. The gene identified as offering the most statistically significant protection is a subject of a Michael J. Fox Foundation Target Validation initiative. In that effort, the Caldwells, with foundation funding, are teaming with UAB’s Dr. David Standaert for additional research in mammalian models.
“Even though our functional analysis was done in a worm, worms have dopamine neurons, worms have many of the features in their cells that are shared with us,” said Guy Caldwell, a faculty member in UA’s College of Arts and Sciences. “There’s good reason to believe that things functionally discovered in worms will still have meaning in higher systems.”
More than 50 percent of all human hereditary diseases have been linked to genetic components also found in the worm, so it’s frequently used by scientists as a model on which to study human diseases. “The power of the animal is that we can screen through large numbers of genes very rapidly, and it’s inexpensive. While worms are wonderful, in order to identify a target for true therapeutic development, the best way is to go forward by validating in mammalian models of Parkinson’s.”
The UA effort was supported by the Bachmann-Strauss Dystonia & Parkinson Foundation, the United Parkinson Foundation, the American Parkinson Disease Association, the Parkinson Association of Alabama Inc., the Michael J. Fox Foundation for Parkinson’s Research and an Undergraduate Research Science Program Grant from the Howard Hughes Medical Institute.
University of Alabama researchers have identified five genes within animal models displaying protective capabilities against a hallmark trait of Parkinson’s disease.
The research, publishing Jan. 8 in the Proceedings of the National Academy of Sciences’ Early Edition, is a possible step toward identifying both new targets for drug treatment development and genetic factors which make some people more susceptible to the disease, the researchers said.
“We’ve found five genes so far that significantly protect dopamine neurons from dying within our animal models,” said Dr. Guy Caldwell, associate professor of biological sciences at UA and co-author of the research.
The UA researchers’ efforts, Caldwell said, represents one of the largest functional analyses of genes ever reported for Parkinson's disease. Shusei Hamamichi, a UA doctoral student, is lead author of the research paper and led the University’s effort, along with Renee Rivas and Adam Knight, two UA undergraduates, Songsong Cao, a former doctoral student, Dr. Kim Caldwell, assistant professor of biological sciences, and Guy Caldwell.
Hamamichi’s role represents a “heroic effort,” Guy Caldwell said.
UA researchers used specific strains of tiny nematode worms as animal models for the research. These genetically engineered worms contain a human protein, alpha-synuclein, within their cells. Scientists have learned that people with too many copies of the code for alpha-synuclein within their DNA will contract Parkinson’s.
Extra copies of alpha-synuclein can lead to repeated protein misfolding and death of the dopamine producing neurons in the brain. In Parkinson’s patients, the death of these neurons leads to rigid and tremoring limbs, difficulty in movement and impaired reflexes. More than 1 million Americans are estimated to have Parkinson’s.
Utilizing bioinformatic databases – which contain an abundance of information related to various genes and their genetic associations – the UA researchers first mined the data, prioritizing 867 genes for testing.
Using a revolutionary technique known as RNA interference, or RNAi, Hamamichi removed, one at a time, the functions of each of the 867 genes from the tiny nematodes. This, Caldwell said, enabled the research team to investigate the impact the missing function would have on cellular processes.
“Of these approximate 900 genes, we narrowed it down to 20 top candidates that seemed to have the most significant affect on alpha-synuclein aggregation as the animals aged,” Caldwell said.
Importantly, secondary screening of the 20 genes has thus far revealed five that offer dopamine neurons protection from dying, Caldwell said. The gene identified as offering the most statistically significant protection is a subject of a Michael J. Fox Foundation Target Validation initiative. In that effort, the Caldwells, with foundation funding, are teaming with UAB’s Dr. David Standaert for additional research in mammalian models.
“Even though our functional analysis was done in a worm, worms have dopamine neurons, worms have many of the features in their cells that are shared with us,” said Guy Caldwell, a faculty member in UA’s College of Arts and Sciences. “There’s good reason to believe that things functionally discovered in worms will still have meaning in higher systems.”
More than 50 percent of all human hereditary diseases have been linked to genetic components also found in the worm, so it’s frequently used by scientists as a model on which to study human diseases. “The power of the animal is that we can screen through large numbers of genes very rapidly, and it’s inexpensive. While worms are wonderful, in order to identify a target for true therapeutic development, the best way is to go forward by validating in mammalian models of Parkinson’s.”
The UA effort was supported by the Bachmann-Strauss Dystonia & Parkinson Foundation, the United Parkinson Foundation, the American Parkinson Disease Association, the Parkinson Association of Alabama Inc., the Michael J. Fox Foundation for Parkinson’s Research and an Undergraduate Research Science Program Grant from the Howard Hughes Medical Institute.
Small changes, big impacts
Molecular-scale rearrangements influence how receptors transmit their message, adding another layer of complexity to the regulation of cell signaling
The pathways by which signals are transmitted within cells are extremely convoluted, involving sequential interactions between large numbers of individual proteins. Modeling these pathways is a daunting enough challenge, but recent studies designed to actively monitor individual protein molecules have hinted at additional levels of complexity.
“Single-molecule studies suggest that proteins [undergo] complex structural and reaction dynamics,” explains Yasushi Sako, a biophysics specialist at the Discovery Research Institute in Wako who specializes in biomolecular imaging. “We wanted to investigate the possibility that complex protein dynamics are involved in molecular-level signal processing.” Sako and colleagues focused on epidermal growth factor receptor (EGFR), a membrane protein that transmits signals responsible for cell division. Several proteins bind to EGFR following activation, including Grb2, which serves as an ‘adaptor’ that enables other signaling proteins to associate with the receptor.
Sako and colleagues took advantage of sophisticated new imaging methods that made it possible for the first time to examine the interaction of Grb2 with full-length, intact EGFR, yielding valuable insights into the kinetics of association between these two proteins1. The group attached individual receptor molecules to a solid support, and then exposed the receptor molecules to different amounts of fluorescently tagged Grb2; by monitoring the appearance and disappearance of fluorescence at individual receptor locations, they were able to quantitatively measure Grb2 binding and release.
Instead of a basic on–off interaction between the two proteins, the interaction data suggested a far more complex picture, where the rate of association with EGFR is strongly dependent on the concentration of Grb2. “This means that the protein EGFR can sense the concentration of its association partner,” says Sako. Their findings further suggested the receptor does not constantly maintain a single fixed structure, but instead transitions through multiple structural ‘substates’, and that these fluctuations in turn affect the kinetics of subsequent interactions between receptor molecules and Grb2 (Fig. 1).
The resulting model reveals an additional level of fine control over the process of signal transduction at the molecular scale, and Sako suggests that a better understanding of the structural changes involved could be a boon for future bioengineering projects. “If we know the mechanism of the molecular-level signal processing and can design the reaction behavior of proteins at will,” he says, “that would be big progress toward realizing sophisticated protein nanomachines.”
Reference
1. Morimatsu, M., Takagi, H., Ota, K., Iwamoto, R., Yanagida, T. & Sako, Y. Multiple-state reactions between the epidermal growth factor receptor and Grb2 as observed by using single-molecule analysis. Proceedings of the National Academy of Sciences USA 104, 18013–18018 (2007).
Molecular-scale rearrangements influence how receptors transmit their message, adding another layer of complexity to the regulation of cell signaling
The pathways by which signals are transmitted within cells are extremely convoluted, involving sequential interactions between large numbers of individual proteins. Modeling these pathways is a daunting enough challenge, but recent studies designed to actively monitor individual protein molecules have hinted at additional levels of complexity.
“Single-molecule studies suggest that proteins [undergo] complex structural and reaction dynamics,” explains Yasushi Sako, a biophysics specialist at the Discovery Research Institute in Wako who specializes in biomolecular imaging. “We wanted to investigate the possibility that complex protein dynamics are involved in molecular-level signal processing.” Sako and colleagues focused on epidermal growth factor receptor (EGFR), a membrane protein that transmits signals responsible for cell division. Several proteins bind to EGFR following activation, including Grb2, which serves as an ‘adaptor’ that enables other signaling proteins to associate with the receptor.
Sako and colleagues took advantage of sophisticated new imaging methods that made it possible for the first time to examine the interaction of Grb2 with full-length, intact EGFR, yielding valuable insights into the kinetics of association between these two proteins1. The group attached individual receptor molecules to a solid support, and then exposed the receptor molecules to different amounts of fluorescently tagged Grb2; by monitoring the appearance and disappearance of fluorescence at individual receptor locations, they were able to quantitatively measure Grb2 binding and release.
Instead of a basic on–off interaction between the two proteins, the interaction data suggested a far more complex picture, where the rate of association with EGFR is strongly dependent on the concentration of Grb2. “This means that the protein EGFR can sense the concentration of its association partner,” says Sako. Their findings further suggested the receptor does not constantly maintain a single fixed structure, but instead transitions through multiple structural ‘substates’, and that these fluctuations in turn affect the kinetics of subsequent interactions between receptor molecules and Grb2 (Fig. 1).
The resulting model reveals an additional level of fine control over the process of signal transduction at the molecular scale, and Sako suggests that a better understanding of the structural changes involved could be a boon for future bioengineering projects. “If we know the mechanism of the molecular-level signal processing and can design the reaction behavior of proteins at will,” he says, “that would be big progress toward realizing sophisticated protein nanomachines.”
Reference
1. Morimatsu, M., Takagi, H., Ota, K., Iwamoto, R., Yanagida, T. & Sako, Y. Multiple-state reactions between the epidermal growth factor receptor and Grb2 as observed by using single-molecule analysis. Proceedings of the National Academy of Sciences USA 104, 18013–18018 (2007).
Quasi-crystals avoid repetition
X-rays, neutrons and theoretical modeling are used to explore the physics of quasi-crystals
In a crystal, the same atom or group of atoms is repeated with perfect periodicity. Quasi-crystals, on the other hand, are materials without periodicity. Whether the absence of periodicity in a quasi-crystalline material fundamentally affects its properties, however, is still an open question.
Now, as reported recently in Nature Materials(1), an international team of scientists, including Alfred Baron of RIKEN’s SPring-8 Center in Harima, has combined high-resolution neutron and x-ray scattering experiments with theoretical calculations to better understand the physics of quasi-crystals.
Most of the physics of solids rests on a simplifying assumption, known as Bloch’s Theorem, that can only be applied to crystalline materials. This theorem reduces the task of calculating the properties of macroscopic materials with approximately 1021 atoms to calculating the properties of one repeating unit of atoms. Baron explains: “When Bloch’s theorem no longer applies, the problem becomes much more complex. Quasi-crystals are then interesting both intrinsically, and as a first step away from periodic crystalline order.”
To tackle the question of how the properties of quasi-crystals may differ from perfect crystals, the researchers focused on a material called i-ZnMgSc. This material consists of ‘triacontrahedral’ clusters (Fig. 1, center) each containing 158 atoms and arranged on a quasi-periodic network. i-ZnMgSc is of interest because it has a nearly identical counterpart,or ‘approximant’, made up of similar clusters arranged on a periodic lattice. Thus, comparing the two structures allows researchers to isolate the effects of periodicity—or the lack of it—on materials properties.
Baron and co-workers used specialized techniques to measure atomic vibrations in i-ZnMgSc and its approximant. The atoms in a material vibrate around their equilibrium positions with patterns and frequencies that are intimately related to the material’s atomic structure, and in particular, the periodicity of this structure. With neutrons, and more recently with x-rays, these vibrations can be measured with very high accuracy.
The team mapped out the energy of the atomic vibrations for the quasi-crystal and the approximant and compared their results with atomic-scale calculations (Fig. 1). Both the calculations and the experiments show important, though subtle, differences between the two materials. In particular, certain vibrations that are well defined in the approximant have a different energy—or do not even appear—in the quasi-crystal. These results could have relevance to the use of quasi-crystals in several fields, including photonic crystals and thermoelectrics.
Reference
1. de Boissieu, M., Francoual, S., Mihalkovi, M., Shibata, K., Baron, A. Q. R., Sidis, Y., Ishimasa, T., Wu, D., Lograsso, T., Regnault, L-P., et al. Lattice dynamics of the Zn–Mg–Sc icosahedral quasicrystal and its Zn–Sc periodic 1/1 approximant. Nature Materials 6, 977–984 (2007)
X-rays, neutrons and theoretical modeling are used to explore the physics of quasi-crystals
In a crystal, the same atom or group of atoms is repeated with perfect periodicity. Quasi-crystals, on the other hand, are materials without periodicity. Whether the absence of periodicity in a quasi-crystalline material fundamentally affects its properties, however, is still an open question.
Now, as reported recently in Nature Materials(1), an international team of scientists, including Alfred Baron of RIKEN’s SPring-8 Center in Harima, has combined high-resolution neutron and x-ray scattering experiments with theoretical calculations to better understand the physics of quasi-crystals.
Most of the physics of solids rests on a simplifying assumption, known as Bloch’s Theorem, that can only be applied to crystalline materials. This theorem reduces the task of calculating the properties of macroscopic materials with approximately 1021 atoms to calculating the properties of one repeating unit of atoms. Baron explains: “When Bloch’s theorem no longer applies, the problem becomes much more complex. Quasi-crystals are then interesting both intrinsically, and as a first step away from periodic crystalline order.”
To tackle the question of how the properties of quasi-crystals may differ from perfect crystals, the researchers focused on a material called i-ZnMgSc. This material consists of ‘triacontrahedral’ clusters (Fig. 1, center) each containing 158 atoms and arranged on a quasi-periodic network. i-ZnMgSc is of interest because it has a nearly identical counterpart,or ‘approximant’, made up of similar clusters arranged on a periodic lattice. Thus, comparing the two structures allows researchers to isolate the effects of periodicity—or the lack of it—on materials properties.
Baron and co-workers used specialized techniques to measure atomic vibrations in i-ZnMgSc and its approximant. The atoms in a material vibrate around their equilibrium positions with patterns and frequencies that are intimately related to the material’s atomic structure, and in particular, the periodicity of this structure. With neutrons, and more recently with x-rays, these vibrations can be measured with very high accuracy.
The team mapped out the energy of the atomic vibrations for the quasi-crystal and the approximant and compared their results with atomic-scale calculations (Fig. 1). Both the calculations and the experiments show important, though subtle, differences between the two materials. In particular, certain vibrations that are well defined in the approximant have a different energy—or do not even appear—in the quasi-crystal. These results could have relevance to the use of quasi-crystals in several fields, including photonic crystals and thermoelectrics.
Reference
1. de Boissieu, M., Francoual, S., Mihalkovi, M., Shibata, K., Baron, A. Q. R., Sidis, Y., Ishimasa, T., Wu, D., Lograsso, T., Regnault, L-P., et al. Lattice dynamics of the Zn–Mg–Sc icosahedral quasicrystal and its Zn–Sc periodic 1/1 approximant. Nature Materials 6, 977–984 (2007)
Nucleus demonstrates its independence
Japanese researchers unravel how cells move to form the brain
A RIKEN-led research team has shown that the nuclei of migrating nerve cells in the mouse brain move independently of the centrosomes, the organelles previously thought to pull them along. The work is important because disruption to nerve-cell migration during brain development, can impact the positioning and integration of cells. This can lead to neurological disorders, and has been implicated in conditions such as epilepsy, schizophrenia and bipolar disease.
Nerve cells or neurons are generated on the brain’s inner surface and migrate outwards to where they operate. Although neural migration is most evident during brain development, it continues throughout the animal’s adult life.
Neurons have long, thin projections called ‘processes’ extending from their cell bodies. During migration, a process extends in the direction of movement and the cell body with its organelles, of which the nucleus is the largest, then moves down that leading process.
The centrosome is the main organizing center for microtubules—strings of structural proteins, bundles of which form the dynamic skeleton in the cell. In many previous studies, researchers observed that the centrosome was nearly always positioned ahead of the nucleus during migration. It was thus thought that the nucleus was connected via microtubules through the centrosome to the leading process and was thereby dragged along.
Now, in a paper published recently in the Proceedings of the National Academy of Sciences (1), researchers from Kyoto University and the RIKEN Brain Science Institute in Wako show otherwise. Using time-lapse photography under a confocal microscope, they observed the movement of stained mouse neurons during migration. The nuclei exhibited a jumping motion—an alternating fast and slow movement—at times moving ahead of the centrosome.
When the researchers stained for bundles of stable and dynamic microtubules, they found the nucleus was connected to the leading process directly (Fig. 1); there was no intervening link to the centrosome, which is separately bound to the leading process. Stable microtubules, in particular, appear to be critical to nuclear movement, which is disrupted by the formation of too many or too few of them. The researchers also found that inhibiting LIS1, the product of a gene associated with a neural migration disorder, specifically affects nuclear movement, but not that of the centrosome.
“We now want to uncover the complete mechanism of nuclear and centrosomal movement,” says the project coordinator, Mineko Kengaku of the Brain Science Institute.
Reference
1. Umeshima, H., Hirano, T. & Kengaku, M. Microtubule-based nuclear movement occurs independently of centrosome positioning in migrating neurons. Proceedings of the National Academy of Sciences USA 104, 16182–16187 (2007).
Japanese researchers unravel how cells move to form the brain
A RIKEN-led research team has shown that the nuclei of migrating nerve cells in the mouse brain move independently of the centrosomes, the organelles previously thought to pull them along. The work is important because disruption to nerve-cell migration during brain development, can impact the positioning and integration of cells. This can lead to neurological disorders, and has been implicated in conditions such as epilepsy, schizophrenia and bipolar disease.
Nerve cells or neurons are generated on the brain’s inner surface and migrate outwards to where they operate. Although neural migration is most evident during brain development, it continues throughout the animal’s adult life.
Neurons have long, thin projections called ‘processes’ extending from their cell bodies. During migration, a process extends in the direction of movement and the cell body with its organelles, of which the nucleus is the largest, then moves down that leading process.
The centrosome is the main organizing center for microtubules—strings of structural proteins, bundles of which form the dynamic skeleton in the cell. In many previous studies, researchers observed that the centrosome was nearly always positioned ahead of the nucleus during migration. It was thus thought that the nucleus was connected via microtubules through the centrosome to the leading process and was thereby dragged along.
Now, in a paper published recently in the Proceedings of the National Academy of Sciences (1), researchers from Kyoto University and the RIKEN Brain Science Institute in Wako show otherwise. Using time-lapse photography under a confocal microscope, they observed the movement of stained mouse neurons during migration. The nuclei exhibited a jumping motion—an alternating fast and slow movement—at times moving ahead of the centrosome.
When the researchers stained for bundles of stable and dynamic microtubules, they found the nucleus was connected to the leading process directly (Fig. 1); there was no intervening link to the centrosome, which is separately bound to the leading process. Stable microtubules, in particular, appear to be critical to nuclear movement, which is disrupted by the formation of too many or too few of them. The researchers also found that inhibiting LIS1, the product of a gene associated with a neural migration disorder, specifically affects nuclear movement, but not that of the centrosome.
“We now want to uncover the complete mechanism of nuclear and centrosomal movement,” says the project coordinator, Mineko Kengaku of the Brain Science Institute.
Reference
1. Umeshima, H., Hirano, T. & Kengaku, M. Microtubule-based nuclear movement occurs independently of centrosome positioning in migrating neurons. Proceedings of the National Academy of Sciences USA 104, 16182–16187 (2007).
Friday, January 25, 2008
Allergic Disease Linked to Irritable Bowel Syndrome
Adults with allergy symptoms report a high incidence of Irritable Bowel Syndrome (IBS), suggesting a link between atopic disorders and IBS according to a study published this month in Annals of Allergy, Asthma & Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI).
In a study of 125 adults, Mary C. Tobin, M.D, Department of Immunology/Microbiology at Rush University Medical Center, Chicago, and colleagues found the likelihood of IBS was significantly higher in patients with seasonal allergic rhinitis (2.67 times), patients with allergic eczema (3.85 times), and patients with depression (2.56 times).
Irritable Bowel Syndrome, affecting 15 percent of the general population, is a cluster of symptoms including abdominal pain for 12 weeks within the past year, change in stool consistency or frequency, and relief of abdominal pain with defecation. Various findings suggest indirectly that allergen exposure may lead to IBS symptoms in some patients, but the frequency has not been studied.
“The reported presence of allergic dermatitis was highly correlated to the presence of IBS in our population,” investigators noted. “In atopic disease, allergic dermatitis is the first step of the ‘atopic march.’ In early childhood, AE (allergic eczema) is frequently associated with gastrointestinal dysfunction and food allergy. A clinical history of AE may be a useful marker for patients with gut hypersensitivity and atopic IBS.”
Asthma and Irritable Bowel Syndrome was reported by 12 of 41 patients (29 percent), which is similar to findings in a previous report. Authors propose that “this subgroup of IBS (atopic IBS) be considered separately from patients with IBS without atopic symptoms, because they may have distinct pathophysiologic features and may benefit from specific therapeutic interventions.”
Patient information on allergic diseases is available by calling the ACAAI toll free number at (800) 842-7777 or visiting its Web site at http://www.acaai.org.
An allergist-immunologist is a physician who specializes in the diagnosis and treatment of asthma and other allergic diseases. The allergist is specially trained to identify the allergic and non-allergic factors that trigger asthma and other allergic diseases. Allergists help people treat or prevent their allergy problems. After earning a medical degree, the allergist-immunologist completes a three-year residency training program in either internal medicine or pediatrics. Next the allergist completes two or three more years of study in the field of allergy-immunology in order to prepare for certification by the American Board of Allergy and Immunology.
The American College of Allergy, Asthma and Immunology (ACAAI) is a professional medical organization headquartered in Arlington Heights, Ill., that promotes excellence in the practice of the subspecialty of allergy and immunology. The College, comprising more than 5,000 allergists-immunologists and related health care professionals, fosters a culture of collaboration and congeniality in which its members work together and with others toward the common goals of patient care, education, advocacy and research.
Citation: Tobin MC, et al. Atopic irritable bowel syndrome: a novel subgroup of irritable bowel syndrome with allergic manifestations. Ann Allergy Asthma Immunol 2008;100:49-53.
Adults with allergy symptoms report a high incidence of Irritable Bowel Syndrome (IBS), suggesting a link between atopic disorders and IBS according to a study published this month in Annals of Allergy, Asthma & Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI).
In a study of 125 adults, Mary C. Tobin, M.D, Department of Immunology/Microbiology at Rush University Medical Center, Chicago, and colleagues found the likelihood of IBS was significantly higher in patients with seasonal allergic rhinitis (2.67 times), patients with allergic eczema (3.85 times), and patients with depression (2.56 times).
Irritable Bowel Syndrome, affecting 15 percent of the general population, is a cluster of symptoms including abdominal pain for 12 weeks within the past year, change in stool consistency or frequency, and relief of abdominal pain with defecation. Various findings suggest indirectly that allergen exposure may lead to IBS symptoms in some patients, but the frequency has not been studied.
“The reported presence of allergic dermatitis was highly correlated to the presence of IBS in our population,” investigators noted. “In atopic disease, allergic dermatitis is the first step of the ‘atopic march.’ In early childhood, AE (allergic eczema) is frequently associated with gastrointestinal dysfunction and food allergy. A clinical history of AE may be a useful marker for patients with gut hypersensitivity and atopic IBS.”
Asthma and Irritable Bowel Syndrome was reported by 12 of 41 patients (29 percent), which is similar to findings in a previous report. Authors propose that “this subgroup of IBS (atopic IBS) be considered separately from patients with IBS without atopic symptoms, because they may have distinct pathophysiologic features and may benefit from specific therapeutic interventions.”
Patient information on allergic diseases is available by calling the ACAAI toll free number at (800) 842-7777 or visiting its Web site at http://www.acaai.org.
An allergist-immunologist is a physician who specializes in the diagnosis and treatment of asthma and other allergic diseases. The allergist is specially trained to identify the allergic and non-allergic factors that trigger asthma and other allergic diseases. Allergists help people treat or prevent their allergy problems. After earning a medical degree, the allergist-immunologist completes a three-year residency training program in either internal medicine or pediatrics. Next the allergist completes two or three more years of study in the field of allergy-immunology in order to prepare for certification by the American Board of Allergy and Immunology.
The American College of Allergy, Asthma and Immunology (ACAAI) is a professional medical organization headquartered in Arlington Heights, Ill., that promotes excellence in the practice of the subspecialty of allergy and immunology. The College, comprising more than 5,000 allergists-immunologists and related health care professionals, fosters a culture of collaboration and congeniality in which its members work together and with others toward the common goals of patient care, education, advocacy and research.
Citation: Tobin MC, et al. Atopic irritable bowel syndrome: a novel subgroup of irritable bowel syndrome with allergic manifestations. Ann Allergy Asthma Immunol 2008;100:49-53.
Tuesday, January 22, 2008
Genetic variants associated with susceptibility to lupus
Newly discovered genetic variants in at least six different regions of the genome are associated with increased risk of developing lupus, according to three studies. Lupus is a complex autoimmune disorder, more common in women than men, that causes inflammation and damage to a wide range of tissues.
An international consortium (SLEGEN) led by John Harley and Carl Langefeld carried out a genome-wide association scan of more than 1,800 women with lupus, and identify variants in or near the genes ITGAM, KIAA1542, PXK, as well in a so-called ‘gene desert’ on chromosome 1, and a possible association with BLK amongst others. They also confirmed the association of several previously identified variants with susceptibility to lupus.
In a separate study, Swapan Nath and colleagues reported association with a variant in ITGAM. In a third study, Marta Alarcón-Riquelme and colleagues demonstrate association with the gene BANK1.
Finally, a study to be published simultaneously in the New England Journal of Medicine by Timothy Behrens and colleagues reports association with variants in ITGAM and BLK. The proteins encoded by ITGAM, BLK, and BANK1 all function in cells of the immune system, and their association with susceptibility to lupus provides new insight into the mechanisms underlying the disease.
Author contacts:
Swapan Nath (Oklahoma Medical Research Foundation, Oklahoma City, OK, USA)
Tel: +1 405 271 7765; E-mail: Swapan-Nath@omrf.org Author paper [17]
Newly discovered genetic variants in at least six different regions of the genome are associated with increased risk of developing lupus, according to three studies. Lupus is a complex autoimmune disorder, more common in women than men, that causes inflammation and damage to a wide range of tissues.
An international consortium (SLEGEN) led by John Harley and Carl Langefeld carried out a genome-wide association scan of more than 1,800 women with lupus, and identify variants in or near the genes ITGAM, KIAA1542, PXK, as well in a so-called ‘gene desert’ on chromosome 1, and a possible association with BLK amongst others. They also confirmed the association of several previously identified variants with susceptibility to lupus.
In a separate study, Swapan Nath and colleagues reported association with a variant in ITGAM. In a third study, Marta Alarcón-Riquelme and colleagues demonstrate association with the gene BANK1.
Finally, a study to be published simultaneously in the New England Journal of Medicine by Timothy Behrens and colleagues reports association with variants in ITGAM and BLK. The proteins encoded by ITGAM, BLK, and BANK1 all function in cells of the immune system, and their association with susceptibility to lupus provides new insight into the mechanisms underlying the disease.
Author contacts:
Swapan Nath (Oklahoma Medical Research Foundation, Oklahoma City, OK, USA)
Tel: +1 405 271 7765; E-mail: Swapan-Nath@omrf.org Author paper [17]
A stem cell-based therapy to treat muscular dystrophy
A new way to manipulate embryonic stem cells (ESCs) in mice offers hope for an eventual cell-based therapy to treat muscular dystrophies.
Muscular dystrophies, such as Duchenne’s muscular dystrophy (DMD), are caused by genetic mutations that lead to a loss of expression of dystrophin, a key structural protein of muscle cells, which results in cell dysfunction. When this occurs the cells can no longer regenerate after injury, resulting in progressive muscle weakness and eventual death. One hope for therapy has been to replenish these defective cells with ESCs that produce normal dystrophin. However, this approach has been hampered by an inability to get ESCs to form muscle cells at appreciable levels.
Rita Perlingeiro and colleagues have overcome this hurdle and show functional recovery after injection of ESCs into a mouse model of DMD. The key to their success was to take advantage of the facts that almost all skeletal muscles have a similar embryonic origin and that muscle development depends on the transcription factor Pax3. As ESCs grown in a culture dish are not exposed to the embryonic environmental milieu that induces muscle differentiation, it might be possible to bypass this requirement by directly expressing Pax3, which orchestrates muscle development in the embryo, through genetic manipulations. This manipulation allows a muscle progenitor cell population to arise and in sufficient quantities to then use therapeutically in mice. The team was able to deliver these cells through the circulation, targeting many more muscle locations than by intramuscular injection, resulting in significantly improved muscle function. Finally, the use of the isolated muscle progenitor cells, owing to their partially differentiated state, did not result in tumor formation, which has previously hampered the therapeutic use of ESCs.
While the genetic manipulation of the ESCs disallows this technique to be used in the clinic at this point, future studies may point to ways of inducing Pax3 expression in human ESCs without the need of genetically modifying the cells.
Author contact:
Rita Perlingeiro (University of Texas Southwestern, TX, USA)
Tel: +1 214 645 5913; E-mail: Rita.Perlingeiro@UTSouthwestern.edu
A new way to manipulate embryonic stem cells (ESCs) in mice offers hope for an eventual cell-based therapy to treat muscular dystrophies.
Muscular dystrophies, such as Duchenne’s muscular dystrophy (DMD), are caused by genetic mutations that lead to a loss of expression of dystrophin, a key structural protein of muscle cells, which results in cell dysfunction. When this occurs the cells can no longer regenerate after injury, resulting in progressive muscle weakness and eventual death. One hope for therapy has been to replenish these defective cells with ESCs that produce normal dystrophin. However, this approach has been hampered by an inability to get ESCs to form muscle cells at appreciable levels.
Rita Perlingeiro and colleagues have overcome this hurdle and show functional recovery after injection of ESCs into a mouse model of DMD. The key to their success was to take advantage of the facts that almost all skeletal muscles have a similar embryonic origin and that muscle development depends on the transcription factor Pax3. As ESCs grown in a culture dish are not exposed to the embryonic environmental milieu that induces muscle differentiation, it might be possible to bypass this requirement by directly expressing Pax3, which orchestrates muscle development in the embryo, through genetic manipulations. This manipulation allows a muscle progenitor cell population to arise and in sufficient quantities to then use therapeutically in mice. The team was able to deliver these cells through the circulation, targeting many more muscle locations than by intramuscular injection, resulting in significantly improved muscle function. Finally, the use of the isolated muscle progenitor cells, owing to their partially differentiated state, did not result in tumor formation, which has previously hampered the therapeutic use of ESCs.
While the genetic manipulation of the ESCs disallows this technique to be used in the clinic at this point, future studies may point to ways of inducing Pax3 expression in human ESCs without the need of genetically modifying the cells.
Author contact:
Rita Perlingeiro (University of Texas Southwestern, TX, USA)
Tel: +1 214 645 5913; E-mail: Rita.Perlingeiro@UTSouthwestern.edu
Animals: Turn up the heat on sex determination
A thirty-year-old model of sex determination is finally proven in the Jacky dragon (Amphibolurus muricatus), a short-lived species of lizard found in Australia. The results provide the first unequivocal demonstration that incubation temperature affects male or female fitness and optimises reproductive success.
In mammals and birds, sex is determined by genotype at fertilization. Many reptiles, however, hedge their bets, determining the sex of an individual by interaction with the environment, typically temperature. A model, published by Charnov and Bull in 1977, speculates that environmental sex determination will be favoured by selection, if it could be shown that different temperature regimes maximized reproductive fitness for each sex. However, until now it has been difficult to set up the ‘control’ experiment and produce the ‘wrong’ sex at a given temperature.
Using hormone treatments, Daniel Warner and Richard Shine have overcome previous difficulties and, using the short-lived Jacky dragon, they show that the Charnov–Bull model is correct.
Author contact:
Daniel Warner (Iowa State University, Ames, IA, USA)
Tel: +1 515 294 1968; E-mail: dwarner@iastate.edu
A thirty-year-old model of sex determination is finally proven in the Jacky dragon (Amphibolurus muricatus), a short-lived species of lizard found in Australia. The results provide the first unequivocal demonstration that incubation temperature affects male or female fitness and optimises reproductive success.
In mammals and birds, sex is determined by genotype at fertilization. Many reptiles, however, hedge their bets, determining the sex of an individual by interaction with the environment, typically temperature. A model, published by Charnov and Bull in 1977, speculates that environmental sex determination will be favoured by selection, if it could be shown that different temperature regimes maximized reproductive fitness for each sex. However, until now it has been difficult to set up the ‘control’ experiment and produce the ‘wrong’ sex at a given temperature.
Using hormone treatments, Daniel Warner and Richard Shine have overcome previous difficulties and, using the short-lived Jacky dragon, they show that the Charnov–Bull model is correct.
Author contact:
Daniel Warner (Iowa State University, Ames, IA, USA)
Tel: +1 515 294 1968; E-mail: dwarner@iastate.edu
Sensor System Helps Understand Causes of Asthma Attacks
Researchers at the Georgia Tech Research Institute (GTRI) have developed a sensor system that continuously monitors the air around persons prone to asthma attacks. Worn in the pockets of a vest, the new system could help researchers understand the causes of asthma attacks.
“We are investigating whether we can go back after an asthma attack and see what was going on environmentally when the attack started,” said Charlene Bayer, a GTRI principal research scientist.
This research was supported by the U.S. Department of Housing and Urban Development and initial funding from the GTRI Independent Research and Development (IRAD) program.
Although no one fully understands why certain people get asthma, doctors know that once a person has it, his/her lungs can overreact to environmental stimuli causing chest tightness or breathlessness, known as an asthma attack.
The new sensor system measures airborne exposure to formaldehyde, carbon dioxide, ozone, nitrogen dioxide, temperature, relative humidity and total volatile organic compounds (VOCs). VOCs are emitted as gases from products such as paints, cleaning supplies, pesticide formulations, building materials and furnishings, office equipment and craft materials.
In addition to detecting the seven environmental stimuli mentioned above, a special mesh filter collects particles. A pump pulls air through the filter so that the quantity of particles can be measured at the end of the sampling period. The composition of the collected particulate can also be analyzed in the laboratory.
The battery-powered system fits into the pocket of a vest and contains commercially available sensors that were integrated into a single system by Mark Jones, chief executive officer of Keehi Technologies.
“The device weighs less than one pound including batteries and it takes a measurement of air every two minutes, stores the data in on-board memory and then sleeps to conserve battery power,” said Jones.
Bayer and GTRI Research Scientist Robert Hendry calibrated and tested the sensors in a large room-sized chamber that simulates real-world environmental conditions inside buildings. Coupled with sensitive mass spectrometers, the chamber allows the changing indoor air chemistry to be studied in detail.
The sensor system is designed to be comfortably worn in the pockets of a vest throughout the day and kept at the bedside while sleeping at night. Another vest pocket contains an electronic peak flow meter to periodically measure pulmonary function. When experiencing an asthma attack, the vest wearer notes what time it occurred and Bayer can examine the levels of the chemical compounds at that time.
Six adult volunteers have tested the vest for comfort and the effectiveness of the sensor system under actual use conditions. And that has already brought benefits for one volunteer, whose vest detected higher volatile organic exposures in his home than anywhere else. That led researchers to discover a pollutant pathway from the volunteer’s basement garage into the living areas that was allowing automobile exhaust and gasoline fumes to invade the house.
With future funding, Bayer hopes to develop a smaller and more sensitive sensor system, test the current vest in population studies of asthmatic children and develop software to process the population studies data as it is collected.
“With this system we can determine what children are exposed to at home, at school and outside where they play,” said Bayer. “Chances are there are some overreaching compounds that seem to trigger asthma attacks in more children.”
Queen’s Immunologists Find Better Way to Boost the Immune System
Queen’s University immunologists in Kingston Ontario have discovered how to manipulate the immune system to increase its power and protect the body from successive viral infections.
Published in the current edition of Viral Immunology, these findings may point the way toward developing new and more effective vaccines against diseases like influenza or HIV and enhance new developments in immunology.
The study suggests that scientists can boost the body’s resistance and fend off successive viral infections by taking components of the virus and indirectly activating specific populations of killer T cells – the body’s virus-killing cells. The virus components are introduced through a process known as “cross priming” whereby virus molecules are engulfed by immune cells to activate killer T cells.
“With this mechanism in mind, we can develop better tools to make more successful and effective vaccines,” says Sam Basta, Queen’s professor of Microbiology and Immunology, and the principal investigator of the study. The other members of the research team are master’s students Attiya Alatery and Erin Dunbar.
The researchers hope to build on their findings by next studying which immune cells do a better job of protecting the body while using this mechanism.
“The answer to this question is like having the Holy Grail of immunotherapy and vaccine design within our grasp,” says Dr. Basta.
Dr. Basta suggests that by fully understanding this new mechanism, researchers should be able to shuttle the appropriate viral components to the right immune cells.
The study was funded by Natural Sciences and Engineering Research Council of Canada and the Franklin Bracken Fellowship program.
Queen’s University immunologists in Kingston Ontario have discovered how to manipulate the immune system to increase its power and protect the body from successive viral infections.
Published in the current edition of Viral Immunology, these findings may point the way toward developing new and more effective vaccines against diseases like influenza or HIV and enhance new developments in immunology.
The study suggests that scientists can boost the body’s resistance and fend off successive viral infections by taking components of the virus and indirectly activating specific populations of killer T cells – the body’s virus-killing cells. The virus components are introduced through a process known as “cross priming” whereby virus molecules are engulfed by immune cells to activate killer T cells.
“With this mechanism in mind, we can develop better tools to make more successful and effective vaccines,” says Sam Basta, Queen’s professor of Microbiology and Immunology, and the principal investigator of the study. The other members of the research team are master’s students Attiya Alatery and Erin Dunbar.
The researchers hope to build on their findings by next studying which immune cells do a better job of protecting the body while using this mechanism.
“The answer to this question is like having the Holy Grail of immunotherapy and vaccine design within our grasp,” says Dr. Basta.
Dr. Basta suggests that by fully understanding this new mechanism, researchers should be able to shuttle the appropriate viral components to the right immune cells.
The study was funded by Natural Sciences and Engineering Research Council of Canada and the Franklin Bracken Fellowship program.
Tuesday, January 08, 2008
Scientists capture vital DNA images during cell division
Houston, Jan 8 - Researchers have for the first
time captured detailed images of life's essence and revealed
the structure of a DNA-protein complex that is crucial in the
spread of antibiotic resistance among bacteria.
The dazzling pictures reveal a key step in the process
of cell division, which all organisms must undergo to survive.
The moment occurs deep within a cell, as two proteins work in
concert to unzip a strand of DNA to create two new cells.
Until now, scientists seeking to directly observe this
essential process could only view fuzzy images taken by an
electron microscope.
A scientist at the University of Texas M.D. Anderson
Cancer Center has changed that by perfecting a technique
employed by biophysicist Rosalind Franklin more than half a
century ago to gather the first images of DNA.
The research focuses on how DNA separates and maintains
its integrity when a cell divides. Using X-ray
crystallography, the team led by structural biologists Maria
Schumacher, with colleagues at the University of Sydney,
Australia, produced clear 3-D images of the structure that
results when two proteins connect with a DNA site to
"segregate" DNA during cell division.
"We solve structures to answer questions about how
molecules carry out their biological functions. Without
knowing the structure, you can't understand molecular
mechanisms at a detailed level," says Schumacher, associate
professor.
In this case, Schumacher and colleagues answer a basic
science question and flag a possible target for clinical
attack on antibiotic-resistant Staphlococcus Aureas, a
tenacious and often lethal staph infection.
By understanding the precise mechanism by which a cancer
cell divides, for instance, it might be possible for
scientists to develop a better drug to stop the process.
"The plasmid segregation system we are working on,
called pSK41, is found in S. aureus and confers resistance to
multiple antibiotics, including the drug of last resort,
vancomycin," Schumacher says.
"Because the segregation systems are essential for the
retention of these multidrug resistant plasmids, they
represent wonderful drug targets."
Plasmids are additional strips or circles of DNA found
in bacteria that provide the bacterium with some mechanism of
defence -- in this case, protection against antibiotics.
Plasmids can be transferred from one type of bacteria
to another through a number of mechanisms.
Plasmids are also a great model for understanding cell
division and segregation, Schumacher says, because plasmid
segregation is relatively simple: two proteins connect to one
DNA site to launch the process. Cells divide to multiply and
it's crucial for this split to go smoothly so each daughter
cell ends up with the DNA it needs to function.
"If these plasmids don't divide and go to the next
generation of cells, those bacteria cells lose their drug
resistance," Schumacher notes.
In the Nature paper, the scientists capture the first
structure ever solved of a segrosome complex that partitions
and divides DNA.
A protein called ParR connects with a centromere DNA
site, a round string of DNA repeats in the plasmid, to form
the segrosome complex, which then completes itself by
attracting filaments of another protein called ParM.
Houston, Jan 8 - Researchers have for the first
time captured detailed images of life's essence and revealed
the structure of a DNA-protein complex that is crucial in the
spread of antibiotic resistance among bacteria.
The dazzling pictures reveal a key step in the process
of cell division, which all organisms must undergo to survive.
The moment occurs deep within a cell, as two proteins work in
concert to unzip a strand of DNA to create two new cells.
Until now, scientists seeking to directly observe this
essential process could only view fuzzy images taken by an
electron microscope.
A scientist at the University of Texas M.D. Anderson
Cancer Center has changed that by perfecting a technique
employed by biophysicist Rosalind Franklin more than half a
century ago to gather the first images of DNA.
The research focuses on how DNA separates and maintains
its integrity when a cell divides. Using X-ray
crystallography, the team led by structural biologists Maria
Schumacher, with colleagues at the University of Sydney,
Australia, produced clear 3-D images of the structure that
results when two proteins connect with a DNA site to
"segregate" DNA during cell division.
"We solve structures to answer questions about how
molecules carry out their biological functions. Without
knowing the structure, you can't understand molecular
mechanisms at a detailed level," says Schumacher, associate
professor.
In this case, Schumacher and colleagues answer a basic
science question and flag a possible target for clinical
attack on antibiotic-resistant Staphlococcus Aureas, a
tenacious and often lethal staph infection.
By understanding the precise mechanism by which a cancer
cell divides, for instance, it might be possible for
scientists to develop a better drug to stop the process.
"The plasmid segregation system we are working on,
called pSK41, is found in S. aureus and confers resistance to
multiple antibiotics, including the drug of last resort,
vancomycin," Schumacher says.
"Because the segregation systems are essential for the
retention of these multidrug resistant plasmids, they
represent wonderful drug targets."
Plasmids are additional strips or circles of DNA found
in bacteria that provide the bacterium with some mechanism of
defence -- in this case, protection against antibiotics.
Plasmids can be transferred from one type of bacteria
to another through a number of mechanisms.
Plasmids are also a great model for understanding cell
division and segregation, Schumacher says, because plasmid
segregation is relatively simple: two proteins connect to one
DNA site to launch the process. Cells divide to multiply and
it's crucial for this split to go smoothly so each daughter
cell ends up with the DNA it needs to function.
"If these plasmids don't divide and go to the next
generation of cells, those bacteria cells lose their drug
resistance," Schumacher notes.
In the Nature paper, the scientists capture the first
structure ever solved of a segrosome complex that partitions
and divides DNA.
A protein called ParR connects with a centromere DNA
site, a round string of DNA repeats in the plasmid, to form
the segrosome complex, which then completes itself by
attracting filaments of another protein called ParM.
Sunlight 'can prevent' skin and non-skin cancers
New York, Jan 8 - It's definitely a puzzle to
scientists, but a new study has suggested that the main cause
of skin cancer -- sunlight -- may also help protect against
the deadly disease as well as other malignant tumours.
A team of international researchers has carried out
the study and found moderately increased exposure to sunlight
not only reduces the risk of getting skin cancer but can also
prevent breast, colon and lung cancers.
"Since vitamin D has been shown to play a protective
role in a number of internal cancers and possibly a range of
other diseases, it is important to study the relative risks to
determine whether advice to avoid sun exposure may be causing
more harm than good in some populations," according to lead
researcher Richard Setlow of Brookhaven National Laboratory.
According to the researchers, solar radiation is a
major, if not the main, source of vitamin D in humans. In the
presence of sunlight, the body converts certain precursor
chemicals to active vitamin D.
But, the researchers have cautioned that too much
exposure to sunlight can cause other skin diseases. "As far as
skin cancer goes, we need to be most worried about melanoma, a
serious disease with significant mortality," Setlow was quoted
by the 'ScienceDaily' as saying.
For the study, Setlow and his colleagues in the
United States and Norway used a special model to calculate the
relative production of vitamin D via sunlight on a group of
people depending on how far they live from the Equator.
According to their findings, people residing in
Australia (just below the equator) produce 3.4 times more
Vitamin D as a result of sun exposure than people in Britain,
and 4.8 times more than people in Scandinavia.
"There is a clear north-south gradient in vitamin D
production with people in the northern latitudes producing
significantly less than people nearer the equator," according
to Setlow.
In populations with similar skin types, there is also
a clear increase in the incidence of all forms of skin cancer
from north to south. "This gradient in skin cancer rates
indicates that there is a true north-south gradient in real
sun exposure," he said.
The scientists also found that the incidence rates of
major internal cancers such as colon cancer, lung cancer, and
cancers of the breast and prostate also increased from north
to south.
However, when the scientists examined the survival
rates for these cancers, they found that people from the
southern latitudes were significantly less likely to die from
these internal cancers than people in the north.
"In previous work, we have shown that survival rates
for these cancers improve when the diagnosis coincides with
the season of maximum sun exposure, indicating a positive role
for sun-induced vitamin D in prognosis.
"The current data provide a further indication
of the beneficial role of sun-induced vitamin D for cancer
prognosis," Setlow said.
New York, Jan 8 - It's definitely a puzzle to
scientists, but a new study has suggested that the main cause
of skin cancer -- sunlight -- may also help protect against
the deadly disease as well as other malignant tumours.
A team of international researchers has carried out
the study and found moderately increased exposure to sunlight
not only reduces the risk of getting skin cancer but can also
prevent breast, colon and lung cancers.
"Since vitamin D has been shown to play a protective
role in a number of internal cancers and possibly a range of
other diseases, it is important to study the relative risks to
determine whether advice to avoid sun exposure may be causing
more harm than good in some populations," according to lead
researcher Richard Setlow of Brookhaven National Laboratory.
According to the researchers, solar radiation is a
major, if not the main, source of vitamin D in humans. In the
presence of sunlight, the body converts certain precursor
chemicals to active vitamin D.
But, the researchers have cautioned that too much
exposure to sunlight can cause other skin diseases. "As far as
skin cancer goes, we need to be most worried about melanoma, a
serious disease with significant mortality," Setlow was quoted
by the 'ScienceDaily' as saying.
For the study, Setlow and his colleagues in the
United States and Norway used a special model to calculate the
relative production of vitamin D via sunlight on a group of
people depending on how far they live from the Equator.
According to their findings, people residing in
Australia (just below the equator) produce 3.4 times more
Vitamin D as a result of sun exposure than people in Britain,
and 4.8 times more than people in Scandinavia.
"There is a clear north-south gradient in vitamin D
production with people in the northern latitudes producing
significantly less than people nearer the equator," according
to Setlow.
In populations with similar skin types, there is also
a clear increase in the incidence of all forms of skin cancer
from north to south. "This gradient in skin cancer rates
indicates that there is a true north-south gradient in real
sun exposure," he said.
The scientists also found that the incidence rates of
major internal cancers such as colon cancer, lung cancer, and
cancers of the breast and prostate also increased from north
to south.
However, when the scientists examined the survival
rates for these cancers, they found that people from the
southern latitudes were significantly less likely to die from
these internal cancers than people in the north.
"In previous work, we have shown that survival rates
for these cancers improve when the diagnosis coincides with
the season of maximum sun exposure, indicating a positive role
for sun-induced vitamin D in prognosis.
"The current data provide a further indication
of the beneficial role of sun-induced vitamin D for cancer
prognosis," Setlow said.
Sunday, January 06, 2008
Regulating a regulator
Researchers identify a mechanism controlling the function of an important cellular protein
New work designates the protein RCN1 as a harness responsible for restraining the protein calcineurin, whose activity is essential for proper regulation of immune, muscle and brain cells. However, as evidenced by links to osteoporosis and Down’s syndrome, unleashed or excessive calcineurin function can result in devastating biological consequences. Thus, calcineurin acts as a delicate pivot point on which physiological homeostasis rests.
Prior work aligned calcium ‘upstream’ of calcineurin, and RCN proteins ‘downstream’ of calcineurin in intracellular signaling pathways. However, confusing data indicating that RCN proteins can both inhibit and enhance calcineurin activity remained unresolved.
A group led by Tsutomu Kishi, a scientist at the RIKEN Frontier Research System in Wako, set out to understand the molecular process through which RCN proteins influence calcineurin activity. Their findings were published in a recent issue of the Proceedings of the National Academy of Sciences of the USA1.
The researchers hypothesized that RCN proteins might be controlled by SCFCdc4, a protein complex that binds to and routes substrate proteins for destruction. Conducted in yeast cells, an unbiased screen for proteins interacting with SCFCdc4 confirmed their suspicions. Experiments using mutant yeast cells firmly designated SCFCdc4 as essential for destabilization and degradation of RCN1, and showed that RCN1 destruction is required for calcineurin activation.
As RCN1 is degraded in a dynamic rather than constitutive manner, the team sought to identify the mechanism responsible for ‘tagging’ RCN1 for destruction. Their focus on Mck1, a protein already established as capable of phosphorylating RCN1, proved fruitful. Mutant RCN1 proteins lacking the serine residues phosphorylated by Mck1 were resistant to SCFCdc4-mediated degradation.
Adding to the complexity of calcineurin control mechanisms, the researchers noted that calcineurin, a phosphatase capable of dephosphorylating proteins, effectively counteracted Mck1-mediated RCN1 phosphorylation.
Thus it appears that a ‘feedback loop’ regulates calcineurin activity (Fig. 1). Calcium flux stimulates Mck1-mediated phosphorylation of RCN1. SCFCdc4 targets phosphorylated RCN1 for destruction and releases calcineurin function. By synthesizing, dephosphorylating and stabilizing RCN1, activated calcineurin then suppresses its own activation.
Additional work is needed to understand the factors capable of influencing the direction in which this regulatory cycle spins. “We believe that cellular regulation by this feedback loop and the selective degradation of feedback inhibitors might be a fundamental strategy to control cellular signals,” says Kishi.
1. Kishi, T., Ikeda, A., Nagao, R. & Koyama, N. The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proceedings of the National Academy of Sciences USA 104, 17418–17423 (2007).
Researchers identify a mechanism controlling the function of an important cellular protein
New work designates the protein RCN1 as a harness responsible for restraining the protein calcineurin, whose activity is essential for proper regulation of immune, muscle and brain cells. However, as evidenced by links to osteoporosis and Down’s syndrome, unleashed or excessive calcineurin function can result in devastating biological consequences. Thus, calcineurin acts as a delicate pivot point on which physiological homeostasis rests.
Prior work aligned calcium ‘upstream’ of calcineurin, and RCN proteins ‘downstream’ of calcineurin in intracellular signaling pathways. However, confusing data indicating that RCN proteins can both inhibit and enhance calcineurin activity remained unresolved.
A group led by Tsutomu Kishi, a scientist at the RIKEN Frontier Research System in Wako, set out to understand the molecular process through which RCN proteins influence calcineurin activity. Their findings were published in a recent issue of the Proceedings of the National Academy of Sciences of the USA1.
The researchers hypothesized that RCN proteins might be controlled by SCFCdc4, a protein complex that binds to and routes substrate proteins for destruction. Conducted in yeast cells, an unbiased screen for proteins interacting with SCFCdc4 confirmed their suspicions. Experiments using mutant yeast cells firmly designated SCFCdc4 as essential for destabilization and degradation of RCN1, and showed that RCN1 destruction is required for calcineurin activation.
As RCN1 is degraded in a dynamic rather than constitutive manner, the team sought to identify the mechanism responsible for ‘tagging’ RCN1 for destruction. Their focus on Mck1, a protein already established as capable of phosphorylating RCN1, proved fruitful. Mutant RCN1 proteins lacking the serine residues phosphorylated by Mck1 were resistant to SCFCdc4-mediated degradation.
Adding to the complexity of calcineurin control mechanisms, the researchers noted that calcineurin, a phosphatase capable of dephosphorylating proteins, effectively counteracted Mck1-mediated RCN1 phosphorylation.
Thus it appears that a ‘feedback loop’ regulates calcineurin activity (Fig. 1). Calcium flux stimulates Mck1-mediated phosphorylation of RCN1. SCFCdc4 targets phosphorylated RCN1 for destruction and releases calcineurin function. By synthesizing, dephosphorylating and stabilizing RCN1, activated calcineurin then suppresses its own activation.
Additional work is needed to understand the factors capable of influencing the direction in which this regulatory cycle spins. “We believe that cellular regulation by this feedback loop and the selective degradation of feedback inhibitors might be a fundamental strategy to control cellular signals,” says Kishi.
1. Kishi, T., Ikeda, A., Nagao, R. & Koyama, N. The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proceedings of the National Academy of Sciences USA 104, 17418–17423 (2007).
Electron’s magnetism pinned down precisely
Development of a computation system that can accurately predict electron magnetism provides a test of quantum theory
The most precise theoretical calculation of the electron’s magnetism to date has been made by RIKEN scientists, providing them with a powerful test of quantum theory.
The electron’s magnetic strength is represented by its ‘g-factor’, which theoretical physicist Paul Dirac—who developed the mathematical foundations of quantum theory in the 1920s—valued at precisely 2.
But experiments have shown that the real value of g is slightly larger. This so-called magnetic moment anomaly is caused by quantum phenomena not included in Dirac’s original theory. In an attempt to pin down exactly why the difference arises, physicists improved theoretical predictions that agreed precisely with experimental results—and the g-factor has consequently become one of the most studied quantities in physics both theoretically and experimentally.
Tatsumi Aoyama and colleagues of RIKEN’s Nishina Center, Wako, have now developed a computation system that can predict g with an accuracy exceeding that of the latest experimental results1.
Much of the discrepancy in g is caused by the electron’s virtual emission and absorption of photons—a process where the electron behaves as if fleeting packets of light are bouncing between it and its surroundings. This process is described by the theory of quantum electrodynamics (QED).
The RIKEN team has established the effects of four virtual photons around the electron, known as the eighth-order contribution. The photons’ effects can be depicted by Feynman diagrams. The researchers’ automated computation system has calculated 518 of 891 Feynman diagrams involved in the eighth-order term of the g-factor (Fig. 1), refining the number to astonishing levels of precision. The other 373 diagrams were obtained previously.
A more precise g-factor allows scientists to determine a more accurate value of the fine structure constant, α. This fundamental constant of nature characterizes the strength of the electromagnetic force that governs the interaction between light and matter. Determining α provides a stringent test of QED, and also has strong impact on determining units of electric charge, mass, electric resistance, and many others.
The RIKEN team is now working to calculate the tenth-order contribution to the g-factor anomaly. “The measurement uncertainty has been reduced to less than one in a trillion, so we are now at the stage where a reliable estimate of the tenth-order contribution is needed,” says Aoyama.
The tenth-order term involves 12,672 diagrams, he adds, estimating that the new computer program for integrating these diagrams will need about one hundred million lines of FORTRAN source code.
1. Aoyama, T., Hayakawa, M., Kinoshita, T. & Nio, M. Revised value of the eighth-order contribution to the electron g – 2. Physical Review Letters 99, 110406 (2007).
Development of a computation system that can accurately predict electron magnetism provides a test of quantum theory
The most precise theoretical calculation of the electron’s magnetism to date has been made by RIKEN scientists, providing them with a powerful test of quantum theory.
The electron’s magnetic strength is represented by its ‘g-factor’, which theoretical physicist Paul Dirac—who developed the mathematical foundations of quantum theory in the 1920s—valued at precisely 2.
But experiments have shown that the real value of g is slightly larger. This so-called magnetic moment anomaly is caused by quantum phenomena not included in Dirac’s original theory. In an attempt to pin down exactly why the difference arises, physicists improved theoretical predictions that agreed precisely with experimental results—and the g-factor has consequently become one of the most studied quantities in physics both theoretically and experimentally.
Tatsumi Aoyama and colleagues of RIKEN’s Nishina Center, Wako, have now developed a computation system that can predict g with an accuracy exceeding that of the latest experimental results1.
Much of the discrepancy in g is caused by the electron’s virtual emission and absorption of photons—a process where the electron behaves as if fleeting packets of light are bouncing between it and its surroundings. This process is described by the theory of quantum electrodynamics (QED).
The RIKEN team has established the effects of four virtual photons around the electron, known as the eighth-order contribution. The photons’ effects can be depicted by Feynman diagrams. The researchers’ automated computation system has calculated 518 of 891 Feynman diagrams involved in the eighth-order term of the g-factor (Fig. 1), refining the number to astonishing levels of precision. The other 373 diagrams were obtained previously.
A more precise g-factor allows scientists to determine a more accurate value of the fine structure constant, α. This fundamental constant of nature characterizes the strength of the electromagnetic force that governs the interaction between light and matter. Determining α provides a stringent test of QED, and also has strong impact on determining units of electric charge, mass, electric resistance, and many others.
The RIKEN team is now working to calculate the tenth-order contribution to the g-factor anomaly. “The measurement uncertainty has been reduced to less than one in a trillion, so we are now at the stage where a reliable estimate of the tenth-order contribution is needed,” says Aoyama.
The tenth-order term involves 12,672 diagrams, he adds, estimating that the new computer program for integrating these diagrams will need about one hundred million lines of FORTRAN source code.
1. Aoyama, T., Hayakawa, M., Kinoshita, T. & Nio, M. Revised value of the eighth-order contribution to the electron g – 2. Physical Review Letters 99, 110406 (2007).
The indecisive insulator
Researchers are applying relativistic quantum theory to explain how graphene could switch from a metal to an insulator
Graphene, which consists of single sheets of carbon atoms peeled off graphite, has recently been fabricated for the first time. Graphene has unusual electrical properties that originate from the unconventional manner in which its electrons behave. A team from the University of California, the Paul Scherrer Institute in Switzerland and the RIKEN Discovery Research Institute in Wako are gaining insight into graphene by expanding the quantum theory for relativistic particles1.
Electron transport in solids is usually non-relativistic and governed by the Schrödinger equation. However the electrons in graphene effectively behave like massless relativistic particles, which are described by a Dirac equation. This means that in two dimensions the electronic energy band is cone-shaped (Fig. 1), and gives graphene the potential to switch from a conducting metal to an insulator.
“Electrons are scattered randomly by impurities and defects in a solid,” explains project-member Akira Furusaki from RIKEN. “When such scattering happens sufficiently frequently, electrons become localized in a finite region and cannot propagate over a distance. This phenomenon is called Anderson localization.”
During Anderson localization, the wavefunction—or probability distribution of different states—of an electron is very narrow in space. If all the electrons in a solid are Anderson localized, the solid is an insulator. In contrast, electrons in a conducting metal are free to move, having wavefunctions extended over the entire system.
Furusaki and co-workers extended an aspect of quantum field theory called the nonlinear sigma model to examine Anderson localizations in graphene. The model is defined whenever electrons move by diffusion, and has been a standard tool to describe transport properties of electrons in disordered solids.
The researchers discovered that when the nonlinear sigma model is used to describe the transport of two-dimensional Dirac electrons in a random electrostatic potential, a topological term is required in the mathematical formulation (at the same time, a German and Russian team reached a similar conclusion independently(2).
The topological term arises from Majorana fermions—theoretical particles that are their own antiparticles—originating in the theory of the Anderson localization in graphene. “The presence of a topological term can change low-energy (long-distance) properties of the model drastically and is responsible for metallic transport in graphene,” says Furusaki.
In future the researchers hope to generalize their theory to three dimensions. “We also plan to examine other systems such as disordered superconductors,” says Furusaki, “in which the transport of low-energy quasiparticles may be highly complex.”
1. Ryu, S., Mudry, C., Obuse, H. & Furusaki, A. Z2 topological term, the global anomaly, and the two-dimensional symplectic symmetry class of Anderson localization. Physical Review Letters 99, 116601 (2007).
2. Ostrovsky, P.M., Gornyi, I.V. & Mirlin, A.D. Quantum criticality and minimal conductivity in graphene with long-range disorder. Physical Review Letters 98, 256801 (2007).
Researchers are applying relativistic quantum theory to explain how graphene could switch from a metal to an insulator
Graphene, which consists of single sheets of carbon atoms peeled off graphite, has recently been fabricated for the first time. Graphene has unusual electrical properties that originate from the unconventional manner in which its electrons behave. A team from the University of California, the Paul Scherrer Institute in Switzerland and the RIKEN Discovery Research Institute in Wako are gaining insight into graphene by expanding the quantum theory for relativistic particles1.
Electron transport in solids is usually non-relativistic and governed by the Schrödinger equation. However the electrons in graphene effectively behave like massless relativistic particles, which are described by a Dirac equation. This means that in two dimensions the electronic energy band is cone-shaped (Fig. 1), and gives graphene the potential to switch from a conducting metal to an insulator.
“Electrons are scattered randomly by impurities and defects in a solid,” explains project-member Akira Furusaki from RIKEN. “When such scattering happens sufficiently frequently, electrons become localized in a finite region and cannot propagate over a distance. This phenomenon is called Anderson localization.”
During Anderson localization, the wavefunction—or probability distribution of different states—of an electron is very narrow in space. If all the electrons in a solid are Anderson localized, the solid is an insulator. In contrast, electrons in a conducting metal are free to move, having wavefunctions extended over the entire system.
Furusaki and co-workers extended an aspect of quantum field theory called the nonlinear sigma model to examine Anderson localizations in graphene. The model is defined whenever electrons move by diffusion, and has been a standard tool to describe transport properties of electrons in disordered solids.
The researchers discovered that when the nonlinear sigma model is used to describe the transport of two-dimensional Dirac electrons in a random electrostatic potential, a topological term is required in the mathematical formulation (at the same time, a German and Russian team reached a similar conclusion independently(2).
The topological term arises from Majorana fermions—theoretical particles that are their own antiparticles—originating in the theory of the Anderson localization in graphene. “The presence of a topological term can change low-energy (long-distance) properties of the model drastically and is responsible for metallic transport in graphene,” says Furusaki.
In future the researchers hope to generalize their theory to three dimensions. “We also plan to examine other systems such as disordered superconductors,” says Furusaki, “in which the transport of low-energy quasiparticles may be highly complex.”
1. Ryu, S., Mudry, C., Obuse, H. & Furusaki, A. Z2 topological term, the global anomaly, and the two-dimensional symplectic symmetry class of Anderson localization. Physical Review Letters 99, 116601 (2007).
2. Ostrovsky, P.M., Gornyi, I.V. & Mirlin, A.D. Quantum criticality and minimal conductivity in graphene with long-range disorder. Physical Review Letters 98, 256801 (2007).
Friday, January 04, 2008
Protein a Possible Key to Allergy and Asthma Control
Description
Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.
Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.
Previous studies by Bruce Bochner and his colleagues at the Johns Hopkins Asthma and Allergy Center had zeroed in on the protein, Siglec-8, as an important player in allergic reactions. This protein is found on the surfaces of some types of immune cells, namely eosinophils, basophils and mast cells, which have diverse but cooperative roles in normal immune function and allergic diseases. Eosinophils directly combat foreign invaders, such as parasites. Basophils and mast cells store and release substances such as histamine, prostaglandins and cytokines, which signal other immune system cells to ready for battle.
When functioning correctly, these cells are a valuable aid to keeping the body healthy and infection-free. However, in allergic reactions and asthma attacks, the cells unleash an overwhelming response that typically harms the body more than it helps.
The researchers found in previous studies that when they activated Siglec-8 on the surface of eosinophils, the cells promptly died. Expecting the same suicidal response in mast cells, the scientists tested their theory in a new study on human mast cells and mast-cell-containing tissues.
Using mast cells grown in a lab, the researchers used antibodies to activate Siglec-8. “We were surprised to see that these cells just sat there happily in their petri dishes and lived on,” says Bochner, director of the Division of Allergy and Clinical Immunology at the Johns Hopkins University School of Medicine.
With their initial theory disproven, Bochner and his colleagues suspected that Siglec-8 might be slowing down other cellular processes based on the protein’s distinctive structure. To investigate what else Siglec-8 might inhibit, the scientists activated the protein in mast cells once again with antibodies. Then, they attempted to trigger an allergic response from these cells.
Normally, mast cells respond with an outpouring of histamine, prostaglandins and other substances that spur allergic reactions in other cells. However, Bochner and his colleagues found that cells with activated Siglec-8 released less than half the typical amount of these substances.
Extending their experiment from cells to whole tissues, Bochner and his colleagues used antibodies to activate mast cells’ Siglec-8 in small pieces of human lung saved from autopsies. When the researchers triggered the cells to release their payloads-an act that typically causes airways to sharply constrict-the contractions were about 25 percent weaker than in lung tissue where the mast cells’ Siglec-8 wasn’t activated.
The researchers are still unsure exactly how Siglec-8 inhibits mast cells from releasing their immune-triggering chemicals. However, follow-up experiments suggested that activating the protein keeps calcium from moving efficiently into the cells. Mast cells need this calcium signal to release their contents.
Bochner notes that researchers might eventually use these results, published in the February Journal of Allergy and Clinical Immunology, to develop a drug with this same effect. Such a drug would have the dual effect of blocking or reducing allergic reactions by killing eosinophils and preventing mast cells from releasing their substances.
“Both of these effects could make allergic diseases and asthma less severe,” he says. “It’s an intriguing approach because there are no drugs that specifically target both these cell types.”
Though drugs exist that affect either eosinophils or mast cells, Bochner says developing a single drug that takes aim at both types of cells could be even more effective than existing therapies and may also have a reduced risk of side effects. He and his colleagues are also searching for natural molecules in the body that activate Siglec-8, which could bring researchers a step closer to developing pharmaceuticals that target this protein.
Additional Hopkins researchers who contributed to this paper include Hidenori Yokoi, M.D., Oksoon H. Choi, Ph.D., Walter Hubbard, Ph.D., Hyun-Sil Lee, Ph.D., Brendan J. Canning, Ph.D., Hyun H. Lee, M.D., Seung-Duk Ryu, Ph.D., Stephan von Gunten, Ph.D., Carol A. Bickel, M.S., Sherry A. Hudson, M.S.B., and Donald W. MacGlashan Jr., M.D., Ph.D.
(Newswise)
Description
Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.
Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.
Previous studies by Bruce Bochner and his colleagues at the Johns Hopkins Asthma and Allergy Center had zeroed in on the protein, Siglec-8, as an important player in allergic reactions. This protein is found on the surfaces of some types of immune cells, namely eosinophils, basophils and mast cells, which have diverse but cooperative roles in normal immune function and allergic diseases. Eosinophils directly combat foreign invaders, such as parasites. Basophils and mast cells store and release substances such as histamine, prostaglandins and cytokines, which signal other immune system cells to ready for battle.
When functioning correctly, these cells are a valuable aid to keeping the body healthy and infection-free. However, in allergic reactions and asthma attacks, the cells unleash an overwhelming response that typically harms the body more than it helps.
The researchers found in previous studies that when they activated Siglec-8 on the surface of eosinophils, the cells promptly died. Expecting the same suicidal response in mast cells, the scientists tested their theory in a new study on human mast cells and mast-cell-containing tissues.
Using mast cells grown in a lab, the researchers used antibodies to activate Siglec-8. “We were surprised to see that these cells just sat there happily in their petri dishes and lived on,” says Bochner, director of the Division of Allergy and Clinical Immunology at the Johns Hopkins University School of Medicine.
With their initial theory disproven, Bochner and his colleagues suspected that Siglec-8 might be slowing down other cellular processes based on the protein’s distinctive structure. To investigate what else Siglec-8 might inhibit, the scientists activated the protein in mast cells once again with antibodies. Then, they attempted to trigger an allergic response from these cells.
Normally, mast cells respond with an outpouring of histamine, prostaglandins and other substances that spur allergic reactions in other cells. However, Bochner and his colleagues found that cells with activated Siglec-8 released less than half the typical amount of these substances.
Extending their experiment from cells to whole tissues, Bochner and his colleagues used antibodies to activate mast cells’ Siglec-8 in small pieces of human lung saved from autopsies. When the researchers triggered the cells to release their payloads-an act that typically causes airways to sharply constrict-the contractions were about 25 percent weaker than in lung tissue where the mast cells’ Siglec-8 wasn’t activated.
The researchers are still unsure exactly how Siglec-8 inhibits mast cells from releasing their immune-triggering chemicals. However, follow-up experiments suggested that activating the protein keeps calcium from moving efficiently into the cells. Mast cells need this calcium signal to release their contents.
Bochner notes that researchers might eventually use these results, published in the February Journal of Allergy and Clinical Immunology, to develop a drug with this same effect. Such a drug would have the dual effect of blocking or reducing allergic reactions by killing eosinophils and preventing mast cells from releasing their substances.
“Both of these effects could make allergic diseases and asthma less severe,” he says. “It’s an intriguing approach because there are no drugs that specifically target both these cell types.”
Though drugs exist that affect either eosinophils or mast cells, Bochner says developing a single drug that takes aim at both types of cells could be even more effective than existing therapies and may also have a reduced risk of side effects. He and his colleagues are also searching for natural molecules in the body that activate Siglec-8, which could bring researchers a step closer to developing pharmaceuticals that target this protein.
Additional Hopkins researchers who contributed to this paper include Hidenori Yokoi, M.D., Oksoon H. Choi, Ph.D., Walter Hubbard, Ph.D., Hyun-Sil Lee, Ph.D., Brendan J. Canning, Ph.D., Hyun H. Lee, M.D., Seung-Duk Ryu, Ph.D., Stephan von Gunten, Ph.D., Carol A. Bickel, M.S., Sherry A. Hudson, M.S.B., and Donald W. MacGlashan Jr., M.D., Ph.D.
(Newswise)
Fellowships offer
The Centre for Science and Technology of the Non-Aligned and Other Developing Countries is offering three Fellowship schemes aimed at supporting deserving young scientists and researchers in developing countries. Applications are invited for the year 2008.
In line with its resolute efforts to promote the South-South and North-South cooperation in science and technology, the Centre for Science and Technology of the Non-Aligned and Other Developing Countries (NAM S&T Centre; www.namstct.org) is currently executing the below-mentioned three Fellowship schemes that aim at supporting the deserving young scientists and researchers in the developing countries to upgrade their academic and research skills and invites applications from suitable candidates for the year 2008.
We request you to please forward / disseminate this information to your concerned scientist colleagues and also, if possible, display the same on your Notice Board.
I. Joint NAM S&T Centre – ZMT Bremen (Germany) Fellowship in Ecology and Biogeochemistry of Tropical Coastal Marine Systems
This is a new Fellowship scheme being started from January 2008 for affiliation of the scientists from the developing countries for a period of up to 3 months with the Centre for Tropical Marine Ecology (ZMT), Bremen, Germany [www.zmt-bremen.de] to work with its senior researchers and faculty members for upgrading research skills in the fields related to Ecology and Biogeochemistry of Tropical Coastal Marine Systems and undertaking short-term joint research projects. Depending on the research topic, the Fellows can also benefit from the ZMT’s association with the Marine Science Institute of Bremen University, Max Plank Institute for Marine Microbiology and the MARUM Research Center in Bremen. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given calendar year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. ZMT provides a subsistence monthly allowance of 1000 Euros for accommodation and other expenses in Bremen. Selection is strictly on competitive basis based on the applicant’s academic and professional background, the plan of work and mutual research interests of the applicant and ZMT. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
II. Joint NAM S&T Centre - ICCBS (Karachi, Pakistan) Fellowship in Natural Products Chemistry, Drugs and Pharmaceuticals
This Fellowship is available for affiliation of the scientists from the developing countries for a period of up to 3 months with the International Centre for Chemical and Biological Sciences (ICCBS) of the H.E.J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research, Karachi, Pakistan [http://www.iccs.edu/] to work in the areas of Natural Products Chemistry, Herbal Medicines, Drugs, Pharmaceuticals and Neutraceuticals, Molecular Medicine, Drug Research, Clinical Research etc. in order to enhance their research skills, facilitate exchange of information and contacts and create a network between the scientists and researchers from Pakistan and other countries. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. The ICCBS provides free furnished accommodation and a monthly allowance of US$130 for meals and out of pocket expenses to the selected Fellows. The selection is strictly based on the professional details of the applicant, plan of work to be carried out and mutual research interests of the applicant and ICCBS. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. Scientists from Pakistan are not eligible to apply for this Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
III. NAM S&T Centre Research Fellowship in Any Scientific Field (for Scientists exclusively from the Member Countries of the NAM S&T Centre)
This Fellowship has been instituted by the NAM S&T Centre to facilitate the international travel of the scientists and researchers of its member countries to the scientific institutions located in another member country for capacity building, enhancing research skills, undertaking short-term joint scientific projects, delivering lectures and developing further linkages (not for attending workshops and conferences). All the 41 member countries of the NAM S&T Centre are listed at the Centre’s website www.namstct.org. Under this scheme, the Centre covers the expense on the international airfare of one scientist each from each of its member countries in any given year, subject to the host country providing free furnished accommodation, meals and/or a per diem allowance to the Fellow during the period of his/her affiliation with the institute(s). The selection is strictly based on the professional details of the applicant, the plan of work to be carried out and the mutual scientific and academic interests of the applicant and the host institution. A precondition for considering an application is that the applicant should first approach the host institution(s) to obtain their consent to accept him/her for working in the institution for a specified period with necessary facilities and for providing total hospitality for such period. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s website, which also gives the detailed guidelines for the Fellowship. Up to 5 fellowships are available for award during the current year. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
For more information, please contact:
M. Bandyopadhyay
Senior Expert & Administrative Officer,
Centre for Science & Technology of Non-Aligned and Other Developing Countries
(NAM S&T Centre),
Core 6A, 2nd Floor,
India Habitat Centre, Lodhi Road,
NEW DELHI - 110 003 (INDIA)
Ph.:(+91)(11) 24645134/24644974 (O)
Fax: (+91)(11) 24644973
E-mail: namstct@gmail.com, namstct@vsnl.com
The Centre for Science and Technology of the Non-Aligned and Other Developing Countries is offering three Fellowship schemes aimed at supporting deserving young scientists and researchers in developing countries. Applications are invited for the year 2008.
In line with its resolute efforts to promote the South-South and North-South cooperation in science and technology, the Centre for Science and Technology of the Non-Aligned and Other Developing Countries (NAM S&T Centre; www.namstct.org) is currently executing the below-mentioned three Fellowship schemes that aim at supporting the deserving young scientists and researchers in the developing countries to upgrade their academic and research skills and invites applications from suitable candidates for the year 2008.
We request you to please forward / disseminate this information to your concerned scientist colleagues and also, if possible, display the same on your Notice Board.
I. Joint NAM S&T Centre – ZMT Bremen (Germany) Fellowship in Ecology and Biogeochemistry of Tropical Coastal Marine Systems
This is a new Fellowship scheme being started from January 2008 for affiliation of the scientists from the developing countries for a period of up to 3 months with the Centre for Tropical Marine Ecology (ZMT), Bremen, Germany [www.zmt-bremen.de] to work with its senior researchers and faculty members for upgrading research skills in the fields related to Ecology and Biogeochemistry of Tropical Coastal Marine Systems and undertaking short-term joint research projects. Depending on the research topic, the Fellows can also benefit from the ZMT’s association with the Marine Science Institute of Bremen University, Max Plank Institute for Marine Microbiology and the MARUM Research Center in Bremen. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given calendar year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. ZMT provides a subsistence monthly allowance of 1000 Euros for accommodation and other expenses in Bremen. Selection is strictly on competitive basis based on the applicant’s academic and professional background, the plan of work and mutual research interests of the applicant and ZMT. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
II. Joint NAM S&T Centre - ICCBS (Karachi, Pakistan) Fellowship in Natural Products Chemistry, Drugs and Pharmaceuticals
This Fellowship is available for affiliation of the scientists from the developing countries for a period of up to 3 months with the International Centre for Chemical and Biological Sciences (ICCBS) of the H.E.J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research, Karachi, Pakistan [http://www.iccs.edu/] to work in the areas of Natural Products Chemistry, Herbal Medicines, Drugs, Pharmaceuticals and Neutraceuticals, Molecular Medicine, Drug Research, Clinical Research etc. in order to enhance their research skills, facilitate exchange of information and contacts and create a network between the scientists and researchers from Pakistan and other countries. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. The ICCBS provides free furnished accommodation and a monthly allowance of US$130 for meals and out of pocket expenses to the selected Fellows. The selection is strictly based on the professional details of the applicant, plan of work to be carried out and mutual research interests of the applicant and ICCBS. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. Scientists from Pakistan are not eligible to apply for this Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
III. NAM S&T Centre Research Fellowship in Any Scientific Field (for Scientists exclusively from the Member Countries of the NAM S&T Centre)
This Fellowship has been instituted by the NAM S&T Centre to facilitate the international travel of the scientists and researchers of its member countries to the scientific institutions located in another member country for capacity building, enhancing research skills, undertaking short-term joint scientific projects, delivering lectures and developing further linkages (not for attending workshops and conferences). All the 41 member countries of the NAM S&T Centre are listed at the Centre’s website www.namstct.org. Under this scheme, the Centre covers the expense on the international airfare of one scientist each from each of its member countries in any given year, subject to the host country providing free furnished accommodation, meals and/or a per diem allowance to the Fellow during the period of his/her affiliation with the institute(s). The selection is strictly based on the professional details of the applicant, the plan of work to be carried out and the mutual scientific and academic interests of the applicant and the host institution. A precondition for considering an application is that the applicant should first approach the host institution(s) to obtain their consent to accept him/her for working in the institution for a specified period with necessary facilities and for providing total hospitality for such period. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s website, which also gives the detailed guidelines for the Fellowship. Up to 5 fellowships are available for award during the current year. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.
For more information, please contact:
M. Bandyopadhyay
Senior Expert & Administrative Officer,
Centre for Science & Technology of Non-Aligned and Other Developing Countries
(NAM S&T Centre),
Core 6A, 2nd Floor,
India Habitat Centre, Lodhi Road,
NEW DELHI - 110 003 (INDIA)
Ph.:(+91)(11) 24645134/24644974 (O)
Fax: (+91)(11) 24644973
E-mail: namstct@gmail.com, namstct@vsnl.com
Announcement: International Conference on Biotechnology 2008
Event dates: Wednesday, 6th February 2008 09:00 AM to Friday, 8th February 2008 17:00PM
Location: Vellore, India
Vellore, India - This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.
The interaction among different sectors such as Universities, Research Institutions and Industries should help to disseminate state of the art knowledge in various fields and topics related to biotechnology. This should also serve as forum for young researchers to present their work and interact with more experienced experts in the field. This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.
The conference will encompass the following topics. However, these topics are not exclusive and papers can be submitted on current issues in allied areas in the field of Biotechnology.
Agricultural Biotechnology
Animal Biotechnology
Plant Biotechnology
Biomedical Engineering
Genetic Engineering
Microbiology & Microbial Technology
Bio-processing and Chemical Engineering
Nano-Biotechnology
Bioinformatics
Cell & Tissue Culture
Industrial & Environmental Biotechnology
Biodiversity and Bioethics
Bio-safety and Patenting
Contact Information:
School of Biotechnology
Chemical and Biomedical Engineering(SBCBE)
Vit University
Vellore-632 014
Tamilnadu
India
Email prasad@vit.ac.in
Event dates: Wednesday, 6th February 2008 09:00 AM to Friday, 8th February 2008 17:00PM
Location: Vellore, India
Vellore, India - This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.
The interaction among different sectors such as Universities, Research Institutions and Industries should help to disseminate state of the art knowledge in various fields and topics related to biotechnology. This should also serve as forum for young researchers to present their work and interact with more experienced experts in the field. This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.
The conference will encompass the following topics. However, these topics are not exclusive and papers can be submitted on current issues in allied areas in the field of Biotechnology.
Agricultural Biotechnology
Animal Biotechnology
Plant Biotechnology
Biomedical Engineering
Genetic Engineering
Microbiology & Microbial Technology
Bio-processing and Chemical Engineering
Nano-Biotechnology
Bioinformatics
Cell & Tissue Culture
Industrial & Environmental Biotechnology
Biodiversity and Bioethics
Bio-safety and Patenting
Contact Information:
School of Biotechnology
Chemical and Biomedical Engineering(SBCBE)
Vit University
Vellore-632 014
Tamilnadu
India
Email prasad@vit.ac.in
Cancer: Breast cancer goes NUMB
A protein called NUMB has a crucial role in keeping breast cancer at bay. New research shows how this protein acts to preserve the function of p53, another protein that is known to protect against cancer.
It is already known that many cases of breast cancer are characterized by the loss of the NUMB protein, which normally functions to help determine how different cell types develop. Now, researchers led by Pier Paolo Di Fiore describe how NUMB helps to stave off cancer by binding to p53 and a third protein, HDM2, which usually degrades p53 and prevents its cancer-busting activity.
By protecting p53 in this way, NUMB is itself acting as an anti-cancer protein, say the researchers, who made their discovery by studying a range of different cells in the test tube, including human breast cells. This is highlighted by the fact that cancers that feature abnormally low levels of NUMB tend to be particularly aggressive, they add.
CONTACT
Pier Paolo Di Fiore (The FIRC Institute for Molecular Oncology, Milan, Italy)
Tel: +39 02 5743 03257; E-mail: pierpaolo.difiore@ifom-ieo-campus.it
A protein called NUMB has a crucial role in keeping breast cancer at bay. New research shows how this protein acts to preserve the function of p53, another protein that is known to protect against cancer.
It is already known that many cases of breast cancer are characterized by the loss of the NUMB protein, which normally functions to help determine how different cell types develop. Now, researchers led by Pier Paolo Di Fiore describe how NUMB helps to stave off cancer by binding to p53 and a third protein, HDM2, which usually degrades p53 and prevents its cancer-busting activity.
By protecting p53 in this way, NUMB is itself acting as an anti-cancer protein, say the researchers, who made their discovery by studying a range of different cells in the test tube, including human breast cells. This is highlighted by the fact that cancers that feature abnormally low levels of NUMB tend to be particularly aggressive, they add.
CONTACT
Pier Paolo Di Fiore (The FIRC Institute for Molecular Oncology, Milan, Italy)
Tel: +39 02 5743 03257; E-mail: pierpaolo.difiore@ifom-ieo-campus.it
Tumour incidence: When three is better than two
People with Down’s syndrome seem to be less susceptible to cancers - an observation that may at least partly derive from their having an extra copy of the chromosome responsible for the syndrome, chromosome 21. This idea to the test in mouse models of Down’s syndrome and finds that the animals are indeed less likely to develop colon cancer.
Roger Reeves and colleagues pinpoint a gene, known as Ets2, on chromosome 21 that seems to confer protection in these mice. The authors explain their finding as a ‘dosage’ effect: having three copies of chromosome 21 instead of the normal two means that more Ets2 protein is produced. This came as a surprise, because Ets2 is generally thought to encourage tumours to grow.
The discovery could be exploited in developing a drug to promote cancer resistance, suggest the authors.
CONTACT
Roger Reeves (The Johns Hopkins University, Baltimore, MD, USA)
Tel: +1 410 955 6621; E-mail: rreeves@jhmi.edu
David Threadgill (University of North Carolina, Chapel Hill, NC, USA) N&V Author
Tel: +1 919 843 6472; E-mail: dwt@med.unc.edu
People with Down’s syndrome seem to be less susceptible to cancers - an observation that may at least partly derive from their having an extra copy of the chromosome responsible for the syndrome, chromosome 21. This idea to the test in mouse models of Down’s syndrome and finds that the animals are indeed less likely to develop colon cancer.
Roger Reeves and colleagues pinpoint a gene, known as Ets2, on chromosome 21 that seems to confer protection in these mice. The authors explain their finding as a ‘dosage’ effect: having three copies of chromosome 21 instead of the normal two means that more Ets2 protein is produced. This came as a surprise, because Ets2 is generally thought to encourage tumours to grow.
The discovery could be exploited in developing a drug to promote cancer resistance, suggest the authors.
CONTACT
Roger Reeves (The Johns Hopkins University, Baltimore, MD, USA)
Tel: +1 410 955 6621; E-mail: rreeves@jhmi.edu
David Threadgill (University of North Carolina, Chapel Hill, NC, USA) N&V Author
Tel: +1 919 843 6472; E-mail: dwt@med.unc.edu
Carbon balance: Autumn warming boosts carbon loss
A warm spring in the Northern Hemisphere means that plants absorb more carbon as their growing season gets off to an early start, but what happens as autumn becomes steadily warmer as well? Not what you might expect, although a balmy autumn allows plants’ greenery to flourish for longer, carbon uptake tails off and instead escapes into the atmosphere as carbon dioxide.
Shilong Piao and colleagues found a trend over the past twenty years towards an earlier autumn-to-winter build-up of carbon dioxide in northern ecosystems, suggesting that the period of net carbon uptake is becoming shorter. They use satellite observations of vegetation greenery and biosphere modelling to explain this response to autumnal warming: although plants’ respiration (emitting carbon dioxide) and photosynthesis (storing carbon dioxide) are both stepped up, the former outstrips the latter to give a net loss of carbon.
What’s more, this loss may offset much of the increased uptake of carbon dioxide during spring. Eastern Asia and North America are both experiencing strong autumn warming, which may account for Eurasia’s larger carbon sink, suggest the authors.
CONTACT
Shilong Piao (Laboratoire des Sciences du Climat et de l'Environnement, CEA/CNRS, Paris, France)
Tel: +33 1 6908 3876; Tel: slpiao@lsce.ipsl.fr
John Miller (National Oceanic and Atmospheric Administration, Boulder, CO, USA) N&V Author
Tel: +1 303 497 7739; E-mail: john.b.miller@noaa.gov
A warm spring in the Northern Hemisphere means that plants absorb more carbon as their growing season gets off to an early start, but what happens as autumn becomes steadily warmer as well? Not what you might expect, although a balmy autumn allows plants’ greenery to flourish for longer, carbon uptake tails off and instead escapes into the atmosphere as carbon dioxide.
Shilong Piao and colleagues found a trend over the past twenty years towards an earlier autumn-to-winter build-up of carbon dioxide in northern ecosystems, suggesting that the period of net carbon uptake is becoming shorter. They use satellite observations of vegetation greenery and biosphere modelling to explain this response to autumnal warming: although plants’ respiration (emitting carbon dioxide) and photosynthesis (storing carbon dioxide) are both stepped up, the former outstrips the latter to give a net loss of carbon.
What’s more, this loss may offset much of the increased uptake of carbon dioxide during spring. Eastern Asia and North America are both experiencing strong autumn warming, which may account for Eurasia’s larger carbon sink, suggest the authors.
CONTACT
Shilong Piao (Laboratoire des Sciences du Climat et de l'Environnement, CEA/CNRS, Paris, France)
Tel: +33 1 6908 3876; Tel: slpiao@lsce.ipsl.fr
John Miller (National Oceanic and Atmospheric Administration, Boulder, CO, USA) N&V Author
Tel: +1 303 497 7739; E-mail: john.b.miller@noaa.gov
Wednesday, January 02, 2008
Two Genes Are Important Key to Regulating Immune Response
Description
A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).
A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).
The discovery fills in an important "missing link" in a biochemical pathway that's long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.
"IL-10 production has to be kept in a delicate balance for health," explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. "Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and -- potentially -- how to better treat them," he says.
The findings are reported in this month's issue of Immunity (vol. 27).
Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.
Every second, millions of the body's cells undergo naturally programmed cell death -- a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system "scavenger" cells such as macrophages.
However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.
IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.
"That can be a good thing, of course," he says. "But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy."
All of this means that "anything that we can learn about IL-10 production -- and related T-cell suppression -- is a boon to medical research," Dr. Ma explains.
Prior studies had already shown that CD36 -- a protein receptor lying on the surface of the macrophage -- was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.
The team then asked a deeper question: "What signals lead to IL-10 production from CD36 present at the cell surface?"
To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.
"We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells," Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.
These genes -- pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) -- are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.
"In that sense, their presence as immune system transcription factors came as a big surprise to us," Dr. Ma says. "In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered."
The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.
"Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward," Dr. Ma explains. "It's these types of breakthroughs in the lab that -- step by step -- will end up bringing real hope to patients down the line."
This work was supported by the U.S. National Institutes of Health and the Mary Kirkland Foundation for Lupus Research.
Co-researchers include Dr. Yoichiro Homma, Yunhua Zhang, Dr. Andrea Brendolan, Dr. Matilde Saggese, Dr. Jihong Han and Dr. Licia Selleri -- all of Weill Cornell Medical College; and Dr. Roy Silverstein of the Cleveland Clinic Foundation.
Weill Cornell Medical College
Weill Cornell Medical College -- Cornell University's Medical School located in New York City -- is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College -- in its commitment to global health and education -- has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. (Newswise)
Description
A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).
A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).
The discovery fills in an important "missing link" in a biochemical pathway that's long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.
"IL-10 production has to be kept in a delicate balance for health," explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. "Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and -- potentially -- how to better treat them," he says.
The findings are reported in this month's issue of Immunity (vol. 27).
Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.
Every second, millions of the body's cells undergo naturally programmed cell death -- a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system "scavenger" cells such as macrophages.
However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.
IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.
"That can be a good thing, of course," he says. "But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy."
All of this means that "anything that we can learn about IL-10 production -- and related T-cell suppression -- is a boon to medical research," Dr. Ma explains.
Prior studies had already shown that CD36 -- a protein receptor lying on the surface of the macrophage -- was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.
The team then asked a deeper question: "What signals lead to IL-10 production from CD36 present at the cell surface?"
To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.
"We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells," Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.
These genes -- pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) -- are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.
"In that sense, their presence as immune system transcription factors came as a big surprise to us," Dr. Ma says. "In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered."
The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.
"Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward," Dr. Ma explains. "It's these types of breakthroughs in the lab that -- step by step -- will end up bringing real hope to patients down the line."
This work was supported by the U.S. National Institutes of Health and the Mary Kirkland Foundation for Lupus Research.
Co-researchers include Dr. Yoichiro Homma, Yunhua Zhang, Dr. Andrea Brendolan, Dr. Matilde Saggese, Dr. Jihong Han and Dr. Licia Selleri -- all of Weill Cornell Medical College; and Dr. Roy Silverstein of the Cleveland Clinic Foundation.
Weill Cornell Medical College
Weill Cornell Medical College -- Cornell University's Medical School located in New York City -- is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College -- in its commitment to global health and education -- has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. (Newswise)
Image: Courtesy of Dr. Gray Pearson, Salk Institute for Biological Studies
The colored lines track selected cells over a time period of 12 hours in a tissue culture model that recreates the ducts of the mammary gland.
Breast Cancer Cells Have to Learn to Walk Before They Can Run
Description
Early-stage breast cancer that has not yet invaded the surrounding tissues may already contain highly motile cells, bringing the tumor one step closer to metastasis, report researchers at the Salk Institute for Biological Studies.
Early-stage breast cancer that has not yet invaded the surrounding tissues may already contain highly motile cells, bringing the tumor one step closer to metastasis, report researchers at the Salk Institute for Biological Studies.
Their study, published in the Dec. 30 issue of the Journal of Cell Biology, suggests that these cells, although not yet invasive, could wander off along milk ducts and seed new tumors within the same breast. “A lack of invasion suggested a lack of motility,” says lead author Gray Pearson, Ph.D, a postdoctoral researcher in the Molecular and Cell Biology Laboratory at the Salk, “but that’s not so.”
“This is an exciting finding because it suggests that cells might acquire migratory properties much earlier than expected,” says senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory.
Due to improved screening programs, most breast tumors are discovered at an early stage when they are still small and confined. In such cases, cancer cells have not grown into the surrounding tissues and remain within the borders of a duct, the most common site where invasive breast cancer arises. These tumors are known as DCIS (ductal carcinoma in situ).
The standard treatment for DCIS is lumpectomy, the surgical removal of the tumor and surrounding tissue. Approximately 16% of DCIS patients treated with lumpectomy alone develop recurrent breast cancer growth within 5 years of treatment. One of the questions faced by oncologists and patients is whether they should add gamma radiation after undergoing surgery to catch straying tumor cells and reduce the risk of recurrent breast cancer. Currently, the decision is based solely on the size of the tumor.
“Our findings suggest that, if a DCIS contains these highly motile cells, the patient may have an increased risk for recurrent growth,” says Pearson. “Under these circumstances you would consider adding radiation treatment regardless of tumor size.”
While the presence of highly motile cells may guide treatment decisions in the future, the researchers have yet to show that wandering cells do indeed influence a patient’s outcome, cautions Pearson.
In their study, the Salk researchers used a tissue culture model that recreates the duct of the mammary gland. They embedded human cells, isolated from breast tissue, in a three-dimensional matrix that mimics their natural surroundings. These cells spontaneously develop into so called acini, hollow structures resembling tiny milk ducts.
Then they turned on the ERK1/2 MAP kinase pathway, a signaling cascade frequently activated during the development of tumors, and watched in real time as breast cancer cells learned how to walk. “We quickly realized that there was a significant cell movement, which was quite surprising,” recounts Pearson. “Within 24 hours, a large number of these spheres had lost their organization, and the cells started to dance around.” (see movie)
While dangerously invasive cells can squeeze through the basement membrane and make a run for the surrounding tissue, motile cells still could not escape the confines of the ERK-activated acini. “But the acquisition of motility prior to invasion presumably lowers the barrier for future invasive growth,” explains Pearson.
“The advent of live-cell imaging allows us to watch labeled cells move around in tissues and learn a lot about their behavior, which wouldn’t be revealed in cultured cells,” says Hunter.
With the next step, Pearson hopes to identify molecular markers for breast cancer cell motility that will help oncologists to diagnose patients who are at higher risk of metastasis.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
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