MEDICINE : New drug to treat schizophrenia
A drug that works effectively in people with schizophrenia by targeting glutamate-mediated neurotransmission.
Altered glutamate-mediated neurotransmission has repeatedly been linked to schizophrenia, but compelling evidence for its involvement has been lacking, and all commonly prescribed antipsychotic drugs act on dopamine receptors. Sandeep Patil and colleagues now report that a selective agonist of a specific subtype of glutamate receptors known as mGlu2/3 has antipsychotic effects in patients with the disease.
They evaluated their drug—LY2140023—in a double-blind, placebo-controlled trial in patients with schizophrenia, and compared how well it worked versus olanzapine, a commonly used antipsychotic compound that targets dopamine receptors. The authors found that patients treated with LY2140023 showed improvements in both positive (hallucinations, delusions and thought disorder) and negative (social withdrawal, apathy and emotional blunting) symptoms of schizophrenia compared to placebo after four weeks of treatment.
The results from this study indicate that mGlu2/3 receptor agonists have antipsychotic properties and represent the first credible alternative treatment for schizophrenia that does not target dopamine.
Author contacts:
Sandeep Patil (Takeda Global Research & Development Center, Deerfield, IL, USA)Development Tel: +1 224 554 5403; E-mail: spatil@tgrd.com
James Monn (Eli Lilly and Company, Indianapolis, IN, USA)
Tel: +1 317 276 9101; E-mail: Monn_James_A@lilly.com
Monday, September 03, 2007
BIOTECHNOLOGY : Adult stem cell with muscle
A ready source of muscle progenitor cells might be useful for treating diseases that involve muscle atrophy, such as muscular dystrophy. Johnny Huard and colleagues describe a type of cell in human adult skeletal muscle with a greater capacity to regenerate muscle tissue than progenitor cells (or ‘satellite cells’) previously isolated from muscles.
The new progenitors, called myoendothelial cells, express cell-surface markers of both satellite cells and endothelial (blood vessel) cells. They are easily isolated using fluorescently labelled antibodies against the markers and a fluorescence-activated cell sorting machine. They can be differentiated in culture dishes towards muscle, bone and cartilage. Studies in mice indicate that myoendothelial cells are much more efficient at forming muscle fibres in the body than both satellite and endothelial cells: 1000 myoendothelial cells transplanted into the injured skeletal muscle of immunodeficient animals produce on average 89 muscle fibres, whereas the same number of endothelial or satellite cells generate only 9 and 5 muscle fibres, respectively. Tests to investigate the safety of myoendothelial cells suggest that they have no propensity to form tumours.
Author contact:
Johnny Huard (University of Pittsburgh, PA, USA)
Tel: +1 412 692 7807; E-mail: jhuard@pitt.edu
A ready source of muscle progenitor cells might be useful for treating diseases that involve muscle atrophy, such as muscular dystrophy. Johnny Huard and colleagues describe a type of cell in human adult skeletal muscle with a greater capacity to regenerate muscle tissue than progenitor cells (or ‘satellite cells’) previously isolated from muscles.
The new progenitors, called myoendothelial cells, express cell-surface markers of both satellite cells and endothelial (blood vessel) cells. They are easily isolated using fluorescently labelled antibodies against the markers and a fluorescence-activated cell sorting machine. They can be differentiated in culture dishes towards muscle, bone and cartilage. Studies in mice indicate that myoendothelial cells are much more efficient at forming muscle fibres in the body than both satellite and endothelial cells: 1000 myoendothelial cells transplanted into the injured skeletal muscle of immunodeficient animals produce on average 89 muscle fibres, whereas the same number of endothelial or satellite cells generate only 9 and 5 muscle fibres, respectively. Tests to investigate the safety of myoendothelial cells suggest that they have no propensity to form tumours.
Author contact:
Johnny Huard (University of Pittsburgh, PA, USA)
Tel: +1 412 692 7807; E-mail: jhuard@pitt.edu
GENETICS : The genetics of human height
A variant in a gene called HMGA2 is associated with differences in adult and childhood height in the general population. This is the first such common variant to be reproducibly associated with human stature, and likely heralds a new wave of studies associating genetic variation with non–disease-related complex traits in humans.
Studies of twins have shown that up to 90% of the normal variation in human height is due to genetic variation, with such variants likely to be distributed among a large number of genes. A large consortium of investigators led by Timothy Frayling, Joel Hirschhorn, and Mark McCarthy carried out a genome-wide association study of nearly 5,000 individuals, and found two variants very close to HMGA2 to be associated with variation in height. A follow-up study of more then 19,000 individuals confirmed the association.
HMGA2 is an excellent candidate to be associated with height, as rare, severe mutations in the gene cause dramatic alterations of body size in mice and humans. Although the effect of these common HMGA2 variants is small—explaining approximately 0.3% of population variation in height, or approximately 0.4 cm increased height per copy in an individual—the success of the study suggests that additional genes will soon be associated with height and other visible traits in humans.
Author contact:
Timothy Frayling (Peninsula Medical School, Exeter, UK)
Tel: +44 1392 262 935; E-mail: tim.frayling@pms.ac.uk
A variant in a gene called HMGA2 is associated with differences in adult and childhood height in the general population. This is the first such common variant to be reproducibly associated with human stature, and likely heralds a new wave of studies associating genetic variation with non–disease-related complex traits in humans.
Studies of twins have shown that up to 90% of the normal variation in human height is due to genetic variation, with such variants likely to be distributed among a large number of genes. A large consortium of investigators led by Timothy Frayling, Joel Hirschhorn, and Mark McCarthy carried out a genome-wide association study of nearly 5,000 individuals, and found two variants very close to HMGA2 to be associated with variation in height. A follow-up study of more then 19,000 individuals confirmed the association.
HMGA2 is an excellent candidate to be associated with height, as rare, severe mutations in the gene cause dramatic alterations of body size in mice and humans. Although the effect of these common HMGA2 variants is small—explaining approximately 0.3% of population variation in height, or approximately 0.4 cm increased height per copy in an individual—the success of the study suggests that additional genes will soon be associated with height and other visible traits in humans.
Author contact:
Timothy Frayling (Peninsula Medical School, Exeter, UK)
Tel: +44 1392 262 935; E-mail: tim.frayling@pms.ac.uk
IMMUNOLOGY : Stop that itch!
Immune cells in the skin secrete a chemical that limits the inflammatory response to poison ivy and sunburn.
Stephen Galli and colleagues look at how the immune system responds to irritants such poison ivy and poison oak or to sunburn, all of which can lead to blistering of the skin. Their research identifies mast cells, a form of immune cell that resides in the skin, as the source of interleukin 10 (IL-10), a molecule known to suppress immune responses. Mice that lack mast cells or have mutant mast cells that are unable to make IL-10 develop larger skin lesions, which last much longer, than those of normal mice upon exposure to the irritant found in poisonous plants. The mutant mice also display higher numbers of T cells recruited to the affected skin lesions.
The work identifies a new role for mast cells, which have been previously associated with releasing mediators of allergic reactions. The authors utilize these findings to manipulate mast cell release of IL-10 in settings of skin inflammation and irritation to limit further damage. These findings might lead to new therapies for skin damage.
Author contact:
Stephen Galli (Stanford University School of Medicine, Stanford, CA, USA)
Tel: +1 650 723 7975; E-mail: sgalli@Stanford.edu
Restraining allergic responses
A cellular process crucial for preventing allergy.
Certain varieties of immune cells release interleukin 4, a protein that, upon binding to its receptor, triggers signals that promote hallmark features of allergy. Yoshinori Fukui and colleagues show that interleukin 4 receptors expressed on the surface of immune cells called T cells are quickly internalized, directed along the complex network of protein ‘fibres’ that support T cell structure and shape, and ultimately routed into cellular compartments for degradation. This ‘harness’ on interleukin 4 expression is interrupted in T cells lacking Dock2, a protein responsible for regulating the ‘trafficking’ of internalized cargo. As a result Dock2-deficient T cells display excessive amounts of interleukin-4 receptors and Dock2-deficient mice suffer from spontaneous allergic inflammation. Whether Dock2 regulates the intracellular fate of other T cell surface proteins remains for future investigations.
Author contact:
Yoshinori Fukui (Kyushu University, Fukuoka, Japan)
Tel: +81 92 642 6828; E-mail: fukui@bioreg.kyushu-u.ac.jp
Immune cells in the skin secrete a chemical that limits the inflammatory response to poison ivy and sunburn.
Stephen Galli and colleagues look at how the immune system responds to irritants such poison ivy and poison oak or to sunburn, all of which can lead to blistering of the skin. Their research identifies mast cells, a form of immune cell that resides in the skin, as the source of interleukin 10 (IL-10), a molecule known to suppress immune responses. Mice that lack mast cells or have mutant mast cells that are unable to make IL-10 develop larger skin lesions, which last much longer, than those of normal mice upon exposure to the irritant found in poisonous plants. The mutant mice also display higher numbers of T cells recruited to the affected skin lesions.
The work identifies a new role for mast cells, which have been previously associated with releasing mediators of allergic reactions. The authors utilize these findings to manipulate mast cell release of IL-10 in settings of skin inflammation and irritation to limit further damage. These findings might lead to new therapies for skin damage.
Author contact:
Stephen Galli (Stanford University School of Medicine, Stanford, CA, USA)
Tel: +1 650 723 7975; E-mail: sgalli@Stanford.edu
Restraining allergic responses
A cellular process crucial for preventing allergy.
Certain varieties of immune cells release interleukin 4, a protein that, upon binding to its receptor, triggers signals that promote hallmark features of allergy. Yoshinori Fukui and colleagues show that interleukin 4 receptors expressed on the surface of immune cells called T cells are quickly internalized, directed along the complex network of protein ‘fibres’ that support T cell structure and shape, and ultimately routed into cellular compartments for degradation. This ‘harness’ on interleukin 4 expression is interrupted in T cells lacking Dock2, a protein responsible for regulating the ‘trafficking’ of internalized cargo. As a result Dock2-deficient T cells display excessive amounts of interleukin-4 receptors and Dock2-deficient mice suffer from spontaneous allergic inflammation. Whether Dock2 regulates the intracellular fate of other T cell surface proteins remains for future investigations.
Author contact:
Yoshinori Fukui (Kyushu University, Fukuoka, Japan)
Tel: +81 92 642 6828; E-mail: fukui@bioreg.kyushu-u.ac.jp
Sunday, September 02, 2007
Surviving separation
Japanese researchers may have found a simple solution to the problem of keeping human embryonic stem (hES) cells alive after dissociation of the embryo into individual cells.
ROCK-blocked human embryonic stem cells survive dissociation to grow in culture
Inhibition of the enzyme rho-associated coiled-coil kinase (ROCK), which is believed to play a role in the initiation of apoptosis or programmed cell death, results in a marked reduction in dissociation-induced apoptosis, and an increase in cloning efficiency.
Human embryonic stem (hES) cells hold much potential for the treatment of many diseases, but the cells have proven far more difficult to grow in culture than murine embryonic stem (mES) cells. The poor survival of dissociated cells in culture has hindered efforts to isolate or subclone specific populations of cells after the induction of differentiation or gene transfer.
The researchers, at the RIKEN Center for Developmental Biology, Kobe, Japan’s National Center for Geriatrics and Gerontology and Kyoto University, have recently published their findings in Nature Biotechnology1. They showed that the cloning efficiency of cells treated with the compound Y-27632, which selectively inhibits ROCK, increased from around 1% in untreated cells to 27% in the treated cells (Fig. 1 - Click on link below).
The cells treated with Y-27632 could also be grown in a serum-free suspension culture and induced to differentiate into precursor cells that resemble the cells of the embryonic brain and neural system.
Team leader Yoshiki Sasai says while it isn’t well understood why hES cells are so prone to apoptosis after dissociation, a better understanding of the role of ROCK in triggering apoptotic cell death may provide some answers.
“This is one of the most interesting questions for future study: why hES cells, but not mouse ones, are so prone to go apoptotic upon dissociation,” he says. “We have no answer for it, and are currently comparing these two systems both upstream and downstream of ROCK.”
In the meantime, the use of Y-27632 to improve cell survival and cloning efficiency will enable researchers to manipulate hES cells with greater ease, allowing large-scale dissociation culture, and easier isolation of genetically modified cells after gene transfer as well as the ability to establish cell lines of hES cells from a single cell.
Ultimately, Sasai says, the use of hES cells may lead to new therapies for degenerative diseases and intractable conditions including Lou Gehrig’s disease (amyotrophic lateral sclerosis (ALS)) and other neurological diseases.
Reference
1. Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J.B., Nishikawa, S., Nishikawa, S., Muguruma, K. & Sasai, Y. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nature Biotechnology 25, 681–686 (2007).
Japanese researchers may have found a simple solution to the problem of keeping human embryonic stem (hES) cells alive after dissociation of the embryo into individual cells.
ROCK-blocked human embryonic stem cells survive dissociation to grow in culture
Inhibition of the enzyme rho-associated coiled-coil kinase (ROCK), which is believed to play a role in the initiation of apoptosis or programmed cell death, results in a marked reduction in dissociation-induced apoptosis, and an increase in cloning efficiency.
Human embryonic stem (hES) cells hold much potential for the treatment of many diseases, but the cells have proven far more difficult to grow in culture than murine embryonic stem (mES) cells. The poor survival of dissociated cells in culture has hindered efforts to isolate or subclone specific populations of cells after the induction of differentiation or gene transfer.
The researchers, at the RIKEN Center for Developmental Biology, Kobe, Japan’s National Center for Geriatrics and Gerontology and Kyoto University, have recently published their findings in Nature Biotechnology1. They showed that the cloning efficiency of cells treated with the compound Y-27632, which selectively inhibits ROCK, increased from around 1% in untreated cells to 27% in the treated cells (Fig. 1 - Click on link below).
The cells treated with Y-27632 could also be grown in a serum-free suspension culture and induced to differentiate into precursor cells that resemble the cells of the embryonic brain and neural system.
Team leader Yoshiki Sasai says while it isn’t well understood why hES cells are so prone to apoptosis after dissociation, a better understanding of the role of ROCK in triggering apoptotic cell death may provide some answers.
“This is one of the most interesting questions for future study: why hES cells, but not mouse ones, are so prone to go apoptotic upon dissociation,” he says. “We have no answer for it, and are currently comparing these two systems both upstream and downstream of ROCK.”
In the meantime, the use of Y-27632 to improve cell survival and cloning efficiency will enable researchers to manipulate hES cells with greater ease, allowing large-scale dissociation culture, and easier isolation of genetically modified cells after gene transfer as well as the ability to establish cell lines of hES cells from a single cell.
Ultimately, Sasai says, the use of hES cells may lead to new therapies for degenerative diseases and intractable conditions including Lou Gehrig’s disease (amyotrophic lateral sclerosis (ALS)) and other neurological diseases.
Reference
1. Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J.B., Nishikawa, S., Nishikawa, S., Muguruma, K. & Sasai, Y. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nature Biotechnology 25, 681–686 (2007).
Laser light switches molecular bonds
Laser irradiation switches the magnetic and structural properties of a molecular complex
Researchers from the RIKEN SPring-8 Center in Harima and from the universities of Tsukuba and Tokyo have demonstrated that laser light of a single wavelength can induce reversible transformations in the molecular bond, leading to changes in a material’s magnetic properties.
Reversible magnetic transformation by laser light is a promising path towards optical telecommunications applications, as “this process can be used as a fast and efficient optical switching technique,” explains Kenichi Kato from the RIKEN team. One candidate material for use in such applications is the Fe(phen)2(NCS)2 complex (Fig. 1 - Click on link below). This compound shows no magnetism at low temperatures, but is magnetic above 176 K.
In their study, published in the journal Applied Physics Letters (1), the researchers demonstrate that illumination with laser light of the material in its low-temperature phase can induce an almost complete transformation from the non-magnetic to the magnetic state. As long as the laser light remains on, the magnetic phase is stable for more than eleven hours without any signs of deterioration. After the light is turned off, however, the relaxation speed is of the order of 10 seconds, which is several hours faster than previously observed at low temperatures. The team also found the magnitude of the switching can be controlled via the intensity of the laser light.
To elucidate the origin of the switching process, the researchers studied the material’s crystal structure at the SPring-8 synchrotron x-ray light source. They showed that the molecular bonds between the iron and nitrogen atoms are important for the magnetism of the compound. In the crystal structure, the iron atom is surrounded by six nitrogen atoms, which form an octahedron—a structure formed by two pyramids attached to each other at their respective bases. The experiments show that the iron–nitrogen bonds in the octahedra are modified in the ‘on’ state under laser illumination. This peculiar change is the origin of the reversible magnetic properties of the complex.
To improve the switching properties of the molecules, the details and dynamics of this re-arrangement need to be understood. “Our next target is to see the switching process as moving pictures of the electron distribution using the high-time resolution possible with SPring-8,” says Kato. When complete, these experiments could lead to the design of improved molecules for even faster switching and for operation temperatures closer to room temperature.
Reference
1. Kato, K., Takata, M., Moritomo, Y., Nakamoto, A. & Kojima, N. On-off optical switching of the magnetic and structural properties in a spin-crossover complex. Applied Physics Letters 90, 201902 (2007).
Laser irradiation switches the magnetic and structural properties of a molecular complex
Researchers from the RIKEN SPring-8 Center in Harima and from the universities of Tsukuba and Tokyo have demonstrated that laser light of a single wavelength can induce reversible transformations in the molecular bond, leading to changes in a material’s magnetic properties.
Reversible magnetic transformation by laser light is a promising path towards optical telecommunications applications, as “this process can be used as a fast and efficient optical switching technique,” explains Kenichi Kato from the RIKEN team. One candidate material for use in such applications is the Fe(phen)2(NCS)2 complex (Fig. 1 - Click on link below). This compound shows no magnetism at low temperatures, but is magnetic above 176 K.
In their study, published in the journal Applied Physics Letters (1), the researchers demonstrate that illumination with laser light of the material in its low-temperature phase can induce an almost complete transformation from the non-magnetic to the magnetic state. As long as the laser light remains on, the magnetic phase is stable for more than eleven hours without any signs of deterioration. After the light is turned off, however, the relaxation speed is of the order of 10 seconds, which is several hours faster than previously observed at low temperatures. The team also found the magnitude of the switching can be controlled via the intensity of the laser light.
To elucidate the origin of the switching process, the researchers studied the material’s crystal structure at the SPring-8 synchrotron x-ray light source. They showed that the molecular bonds between the iron and nitrogen atoms are important for the magnetism of the compound. In the crystal structure, the iron atom is surrounded by six nitrogen atoms, which form an octahedron—a structure formed by two pyramids attached to each other at their respective bases. The experiments show that the iron–nitrogen bonds in the octahedra are modified in the ‘on’ state under laser illumination. This peculiar change is the origin of the reversible magnetic properties of the complex.
To improve the switching properties of the molecules, the details and dynamics of this re-arrangement need to be understood. “Our next target is to see the switching process as moving pictures of the electron distribution using the high-time resolution possible with SPring-8,” says Kato. When complete, these experiments could lead to the design of improved molecules for even faster switching and for operation temperatures closer to room temperature.
Reference
1. Kato, K., Takata, M., Moritomo, Y., Nakamoto, A. & Kojima, N. On-off optical switching of the magnetic and structural properties in a spin-crossover complex. Applied Physics Letters 90, 201902 (2007).
On the scent of how a sense of smell develops
Neurobiologists from Japan and the US have identified a signaling system functioning during vertebrate development that controls the proper positioning of cells giving rise to future olfactory neurons, and their eventual correct wiring to the brain.
Researchers identify factors needed for proper olfactory developmentDuring development many cells originate in one place but then migrate to another before they mature into their final functional cell type. One example of this process is the development of the placodes—areas of thickening along the embryonic epithelia that gives rise to organs for hearing, seeing and smelling. This last one—the nasal placode—contains the future nasal epithelia and olfactory neurons. To better understand how these placodes form, scientists have focused their attention recently on a family of small, secreted proteins, the so-called chemokines, which were originally identified as controlling immune cell migration.
Using zebrafish, the team led by Nobuhiko Miyasaka from the RIKEN Brain Science Institute in Wako, has now identified the chemokine Cxcl12a and its receptor, Cxcr4b, as key molecules necessary for the correct positioning of the nasal placode (1).
The team showed that in mutant fish lacking either Cxcl12a or Cxcr4b function some cells failed to join this placode. They further showed that in both types of mutant fish the olfactory neurons developed in the placode, though in most instances they subsequently failed to project axons to the olfactory bulb, a region in the brain some distance from the placode that transmit a sense of smell to higher olfactory centers (Fig. 1 - Click on link below).
The researchers confirmed these findings by showing that experimentally-induced mis-expression of Cxcl12a also perturbed the placode assembly, but unlike loss of its expression (or that of Cxcr4b), it did not affect olfactory axon outgrowth towards the olfactory bulb. Importantly, this suggests that Cxcl12a is not acting as a guidance factor for olfactory axons because ubiquitous mis-expression would have ‘confused’ the axons if it was acting in this way. Rather, Cxcl12a is acting as a ‘permissive factor’ that allows these axons to navigate the local environment.
Previous studies have shown that Cxcl12/Cxcr4 signaling regulates retinal axon projections in zebrafish (2) and motor axon projections in mice (3). Miyasaka therefore says that “Cxcl12/Cxcr4 signaling might be a general, evolutionary conserved molecular tool that allows for and shapes the initial trajectory needed by various growing axons to properly innervate their respective targets.” Insight from future studies could illuminate the molecular mechanisms downstream of these chemokines, which one day may be manipulated to regrow axons on demand.
1. Miyasaka, N., Knaut, H. & Yoshihara, Y. Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development 134, 2459–2468 (2007).
2. Li, Q., Shirabe, K., Thisse, C., Thisse, B., Okamoto, H., Masai, I. & Kuwada J.Y. Chemokine signaling guides axons within the retina in zebrafish. Journal of Neuroscience 25, 1711–1717 (2005).
3. Lieberam, I., Agalliu, D., Nagasawa, T., Ericson, J. & Jessell, T.M. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47, 667–679 (2005).
Neurobiologists from Japan and the US have identified a signaling system functioning during vertebrate development that controls the proper positioning of cells giving rise to future olfactory neurons, and their eventual correct wiring to the brain.
Researchers identify factors needed for proper olfactory developmentDuring development many cells originate in one place but then migrate to another before they mature into their final functional cell type. One example of this process is the development of the placodes—areas of thickening along the embryonic epithelia that gives rise to organs for hearing, seeing and smelling. This last one—the nasal placode—contains the future nasal epithelia and olfactory neurons. To better understand how these placodes form, scientists have focused their attention recently on a family of small, secreted proteins, the so-called chemokines, which were originally identified as controlling immune cell migration.
Using zebrafish, the team led by Nobuhiko Miyasaka from the RIKEN Brain Science Institute in Wako, has now identified the chemokine Cxcl12a and its receptor, Cxcr4b, as key molecules necessary for the correct positioning of the nasal placode (1).
The team showed that in mutant fish lacking either Cxcl12a or Cxcr4b function some cells failed to join this placode. They further showed that in both types of mutant fish the olfactory neurons developed in the placode, though in most instances they subsequently failed to project axons to the olfactory bulb, a region in the brain some distance from the placode that transmit a sense of smell to higher olfactory centers (Fig. 1 - Click on link below).
The researchers confirmed these findings by showing that experimentally-induced mis-expression of Cxcl12a also perturbed the placode assembly, but unlike loss of its expression (or that of Cxcr4b), it did not affect olfactory axon outgrowth towards the olfactory bulb. Importantly, this suggests that Cxcl12a is not acting as a guidance factor for olfactory axons because ubiquitous mis-expression would have ‘confused’ the axons if it was acting in this way. Rather, Cxcl12a is acting as a ‘permissive factor’ that allows these axons to navigate the local environment.
Previous studies have shown that Cxcl12/Cxcr4 signaling regulates retinal axon projections in zebrafish (2) and motor axon projections in mice (3). Miyasaka therefore says that “Cxcl12/Cxcr4 signaling might be a general, evolutionary conserved molecular tool that allows for and shapes the initial trajectory needed by various growing axons to properly innervate their respective targets.” Insight from future studies could illuminate the molecular mechanisms downstream of these chemokines, which one day may be manipulated to regrow axons on demand.
1. Miyasaka, N., Knaut, H. & Yoshihara, Y. Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development 134, 2459–2468 (2007).
2. Li, Q., Shirabe, K., Thisse, C., Thisse, B., Okamoto, H., Masai, I. & Kuwada J.Y. Chemokine signaling guides axons within the retina in zebrafish. Journal of Neuroscience 25, 1711–1717 (2005).
3. Lieberam, I., Agalliu, D., Nagasawa, T., Ericson, J. & Jessell, T.M. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47, 667–679 (2005).
Wednesday, August 29, 2007
Bio-Coat for Reinforced Earth Material
Researchers in Universiti Sains Malaysia developed Bio-Coat from oil palm empty fruit bunches as an alternative to commercial geosynthetic and geotextile materials for slope protection, reinforced earth wall and other soil improvement uses.
Project title: Bio-Coat for Reinforced Earth Material
Researchers: Assoc. Prof. Dr. Fauziah Ahmad, Assoc. Prof. Dr. Abdul Khalil Shawkataly, Ahmad Halmi Ghazalli, Dziauddin Zainol Abidin, Azhar Mohamad Noor
In this project, oil palm empty fruit bunches (EFB) mat fibres were impregnated with Acrylonitrile Butadienne Styrene (ABS). The resulting material also popularly known as "Bio-Coat" were then used as reinforced material for geotechnical applications such as reinforced earth wall, slope protection and other geotechnical soil improvement techniques.
Just like the oil palm, the Bio-Coat has many uses in engineering and construction including that of (1)Reinforcement, (2)Drainage, (3)Filtration, (4)Separator and (5)Barrier.
It can also be used in household applications such as; reinforced plants, garden drainage, unpaved road on soft ground, flower pot, garden mat and other landscaping applications. It was found that, the Load-Strain for the Bio-Coat material increased more than 100% compared to commercial geotextiles and geosynthetics material. The Bio-Coat will be a welcome alternative to the construction, geotechnical and landscaping industries. It not only makes good use of material that would have otherwise been discarded as waste, the Bio-Coat strengthens and improves the soil while remaining highly cost effective.
contact with researcher:
Dr. Fauziah Ahmad
Address:
School of Civil Engineering
Engineering Campus
Universiti Sains Malaysia
Penang
Malaysia
Institution:Universiti Sains Malaysia
Telephone:604-5996268
Email:cefahmad@usm.my
Areas of expertise:civil engineering; erosion control
Researchers in Universiti Sains Malaysia developed Bio-Coat from oil palm empty fruit bunches as an alternative to commercial geosynthetic and geotextile materials for slope protection, reinforced earth wall and other soil improvement uses.
Project title: Bio-Coat for Reinforced Earth Material
Researchers: Assoc. Prof. Dr. Fauziah Ahmad, Assoc. Prof. Dr. Abdul Khalil Shawkataly, Ahmad Halmi Ghazalli, Dziauddin Zainol Abidin, Azhar Mohamad Noor
In this project, oil palm empty fruit bunches (EFB) mat fibres were impregnated with Acrylonitrile Butadienne Styrene (ABS). The resulting material also popularly known as "Bio-Coat" were then used as reinforced material for geotechnical applications such as reinforced earth wall, slope protection and other geotechnical soil improvement techniques.
Just like the oil palm, the Bio-Coat has many uses in engineering and construction including that of (1)Reinforcement, (2)Drainage, (3)Filtration, (4)Separator and (5)Barrier.
It can also be used in household applications such as; reinforced plants, garden drainage, unpaved road on soft ground, flower pot, garden mat and other landscaping applications. It was found that, the Load-Strain for the Bio-Coat material increased more than 100% compared to commercial geotextiles and geosynthetics material. The Bio-Coat will be a welcome alternative to the construction, geotechnical and landscaping industries. It not only makes good use of material that would have otherwise been discarded as waste, the Bio-Coat strengthens and improves the soil while remaining highly cost effective.
contact with researcher:
Dr. Fauziah Ahmad
Address:
School of Civil Engineering
Engineering Campus
Universiti Sains Malaysia
Penang
Malaysia
Institution:Universiti Sains Malaysia
Telephone:604-5996268
Email:cefahmad@usm.my
Areas of expertise:civil engineering; erosion control
Tuesday, August 28, 2007
Plant genetics: A vintage genome sequence
A high-quality draft of the grapevine genome sequence is reported in Nature. The analysis of a grapevine line originally derived from Pinot Noir reveals that it contains twice as many enzymes contributing to essential oil and aroma than other sequenced plants, suggesting that it might eventually be possible to trace the diversity of wine flavours down to the genome level.
The French–Italian Public Consortium for Grapevine Genome Characterization sequenced the genome of Vitis vinifera, the fourth sequence produced for a flowering plant and the first for a fruit crop. The authors selected grapevine for their analysis because of its important place in the cultural heritage of humanity, beginning during the Neolithic period. They report that the genes involved in the metabolism of tannins and terpenes – which contribute to a wine’s aromatic features – have been selectively amplified in this genome. They also found an expansion in the family of genes driving the production of resveratrol, the chemical associated with the proposed health benefits of drinking moderate amounts of red wine.
Public access to the grapevine genome sequence should help identify the genes underlying particular agricultural features and domestication traits. This could be of use for not only recognizing which genes are responsible for the characteristic flavours of a wine, but also in speeding up the process of introducing disease-resistant genes, thereby decreasing the need for pesticides.
Author contact:
Patrick Wincker (Genoscope-Centre National de Sequencage and CNRS, Evry, France)
Tel: +33 1 60 87 25 68; E-mail: pwincker@genoscope.cns.fr
A high-quality draft of the grapevine genome sequence is reported in Nature. The analysis of a grapevine line originally derived from Pinot Noir reveals that it contains twice as many enzymes contributing to essential oil and aroma than other sequenced plants, suggesting that it might eventually be possible to trace the diversity of wine flavours down to the genome level.
The French–Italian Public Consortium for Grapevine Genome Characterization sequenced the genome of Vitis vinifera, the fourth sequence produced for a flowering plant and the first for a fruit crop. The authors selected grapevine for their analysis because of its important place in the cultural heritage of humanity, beginning during the Neolithic period. They report that the genes involved in the metabolism of tannins and terpenes – which contribute to a wine’s aromatic features – have been selectively amplified in this genome. They also found an expansion in the family of genes driving the production of resveratrol, the chemical associated with the proposed health benefits of drinking moderate amounts of red wine.
Public access to the grapevine genome sequence should help identify the genes underlying particular agricultural features and domestication traits. This could be of use for not only recognizing which genes are responsible for the characteristic flavours of a wine, but also in speeding up the process of introducing disease-resistant genes, thereby decreasing the need for pesticides.
Author contact:
Patrick Wincker (Genoscope-Centre National de Sequencage and CNRS, Evry, France)
Tel: +33 1 60 87 25 68; E-mail: pwincker@genoscope.cns.fr
Developmental biology: New method sets stem cells apart
Researchers have devised a way to distinguish between two similar, yet vitally different, proliferative cell types found in the developing brain. Their findings should prove useful in stem cell research.
The developing brain contains many different proliferative cell types including neural stem cells (NSCs), which can give rise to many different types of mature brain cell, and neuroblasts, which are more restricted in their fate. But the signalling differences between these two populations are poorly understood.
Nicholas Gaiano and colleagues now show that differences in the Notch signalling pathway — a highly conserved system known to influence cell fate decisions during embryonic and adult life — may account for the variation between the two cell types. The discovery has yielded a method for separating these two cell types in a dish, a feat that should help researchers to characterise them further.
Author contact:
Nicholas Gaiano (Johns Hopkins School of Medicine, Baltimore, MD, USA)
Tel: +1 443 287 4866; E-mail: gaiano@jhmi.edu
Researchers have devised a way to distinguish between two similar, yet vitally different, proliferative cell types found in the developing brain. Their findings should prove useful in stem cell research.
The developing brain contains many different proliferative cell types including neural stem cells (NSCs), which can give rise to many different types of mature brain cell, and neuroblasts, which are more restricted in their fate. But the signalling differences between these two populations are poorly understood.
Nicholas Gaiano and colleagues now show that differences in the Notch signalling pathway — a highly conserved system known to influence cell fate decisions during embryonic and adult life — may account for the variation between the two cell types. The discovery has yielded a method for separating these two cell types in a dish, a feat that should help researchers to characterise them further.
Author contact:
Nicholas Gaiano (Johns Hopkins School of Medicine, Baltimore, MD, USA)
Tel: +1 443 287 4866; E-mail: gaiano@jhmi.edu
BIOTECHNOLOGY : Human embryonic stem cells do a heart good
Heart attacks may respond to treatment with cells derived from human embryonic stem (ES) cells. Charles Murry and colleagues find that rats subjected to experimental heart attacks show improved cardiac function four weeks after receiving a transplant of heart muscle cells generated in a dish from human ES cells.
Human ES cells are considered a promising source of cells for regenerative medicine because, in theory, they can be taken off the laboratory shelf, coaxed into becoming any kind of specialized cell for repairing damaged organs and given to any patient. But many problems must be solved before this vision is reduced to practice.
Murry and colleagues address two critical problems in heart regeneration. First, they improve the efficiency with which ES cells are converted into heart cells. Second, they improve the survival of such heart cells after transplantation into damaged animal hearts using a ‘survival cocktail’—a mixture of chemicals that blocks various causes of cell death. By combining these techniques, they succeeded in slowing the progression of heart failure in the treated animals.
Author contact:
Charles Murry (University of Washington, Seattle, WA, USA)
Tel: +1 206 616 8685; E-mail: murry@u.washington.edu
Heart attacks may respond to treatment with cells derived from human embryonic stem (ES) cells. Charles Murry and colleagues find that rats subjected to experimental heart attacks show improved cardiac function four weeks after receiving a transplant of heart muscle cells generated in a dish from human ES cells.
Human ES cells are considered a promising source of cells for regenerative medicine because, in theory, they can be taken off the laboratory shelf, coaxed into becoming any kind of specialized cell for repairing damaged organs and given to any patient. But many problems must be solved before this vision is reduced to practice.
Murry and colleagues address two critical problems in heart regeneration. First, they improve the efficiency with which ES cells are converted into heart cells. Second, they improve the survival of such heart cells after transplantation into damaged animal hearts using a ‘survival cocktail’—a mixture of chemicals that blocks various causes of cell death. By combining these techniques, they succeeded in slowing the progression of heart failure in the treated animals.
Author contact:
Charles Murry (University of Washington, Seattle, WA, USA)
Tel: +1 206 616 8685; E-mail: murry@u.washington.edu
METHODS : Shedding light on animals’ interiors
Bright far-red fluorescent proteins that emit light at longer wavelengths than typical red fluorescent proteins, improving their usefulness for deep imaging in living animals.
Fluorescent proteins are invaluable tools for many types of biological investigation. The light from the best performing fluorescent proteins, however, has a difficult time penetrating living tissue due to the relatively short wavelengths emitted. This has limited the usefulness of these proteins for in vivo fluorescence imaging of whole animals. But fluorescent proteins that emit longer wavelength light, in the far-red and infrared regions of the spectrum, have so far been difficult to develop.
Dmitriy Chudakov and colleagues previously cloned a bright red fluorescent protein from a sea anemone. They engineered this protein to increase the wavelength of the emitted light while retaining its brightness. These longer wavelengths of light penetrate tissue more efficiently making detection of fluorescence emanating from deep inside an animal easier than with existing fluorescent proteins. The researchers developed two versions of the protein that are best suited for different applications. These will aid many researchers in different fields of biology who can benefit from the improved in vivo imaging performance the proteins offer.
Author contact:
Dmitriy Chudakov (Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia)
Tel: +7 495 429 8020; E-mail: ChudakovDM@mail.ru
Bright far-red fluorescent proteins that emit light at longer wavelengths than typical red fluorescent proteins, improving their usefulness for deep imaging in living animals.
Fluorescent proteins are invaluable tools for many types of biological investigation. The light from the best performing fluorescent proteins, however, has a difficult time penetrating living tissue due to the relatively short wavelengths emitted. This has limited the usefulness of these proteins for in vivo fluorescence imaging of whole animals. But fluorescent proteins that emit longer wavelength light, in the far-red and infrared regions of the spectrum, have so far been difficult to develop.
Dmitriy Chudakov and colleagues previously cloned a bright red fluorescent protein from a sea anemone. They engineered this protein to increase the wavelength of the emitted light while retaining its brightness. These longer wavelengths of light penetrate tissue more efficiently making detection of fluorescence emanating from deep inside an animal easier than with existing fluorescent proteins. The researchers developed two versions of the protein that are best suited for different applications. These will aid many researchers in different fields of biology who can benefit from the improved in vivo imaging performance the proteins offer.
Author contact:
Dmitriy Chudakov (Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia)
Tel: +7 495 429 8020; E-mail: ChudakovDM@mail.ru
New method of immobilising enzyme helps tell left from right
Researchers from Universiti Putra Malaysia have discovered a simple technique to immobilise the enzyme lipase onto a support providing a derivatised enzyme that shows a high capacity to resolve between chiral pairs. This ability aids in the synthesis of specific compounds in its pure form which is very much sought after by the chemical industry
Chirazim™ — a highly enantioselective enzyme
Researchers: Abu Bakar Salleh, Siti Salhah Othman, Mahiran Basri, Mohd Zobir Hussein, Mohd. Basyaruddin Abd. Rahman and Raja Noor Zaliha Abdul Rahman
If we face our hand right towards our hand left, we can say that each is the mirror image of the other. Although they look similar they are not exactly the same as they cannot overlap on top of each other. In the world of compounds, these are known as chiral compounds.
In nature, we have many such chiral pairs designated as the R and S isomer. Of importance, each member of a chiral pair can exhibit different biological properties. The differential effect is caused by the presence of enzymes (biocatalysts) in living cells that are able to recognize and thus react with specific compounds (i.e. even either member of a chiral pair).
The ability to synthesis specific compounds in its pure form is very much sought after by the chemical industry. Pure isomer has specific applications in the medical and agrichemical industry. Mixed products may diminish the effect required, or worse still may lead to detrimental results. Specific examples of isomer in industrial applications include S-ibuprofen, an analgesic agent, R- chlorophenoxy propanoate, a type of herbicide, and a number of R menthol esters that are used as flavour additives in the food and beverage industry.
However, not all enzymes have the capacity to resolve enantiomers. The ability to recognize each compound depends a lot on the shape and conformation of the enzyme molecules, especially that of the active or catalytic site. One way of modifying the conformation of the enzyme is through the process of immobilisation, where an enzyme is attached to a solid support.
There are different types of supports and techniques to immobilize enzymes. These are selected in accordance to the property of the enzymes as well as the ultimate applications. Immobilised enzymes are easy to handle and can be reused.
Chirazim (TM) is a new discovery where lipase, the enzyme was immobilised onto a support via a simple method. The support used was a multi layered hydroxide that can also be easily produced.
Immobilisation resulted in a derivatised enzyme that showed high capacity to resolve S and R isomers. Apart from that the immobilized enzyme is stable to organic solvents and high temperature, suitable characteristics in the synthesis of chiral compounds.
Researchers from Universiti Putra Malaysia have discovered a simple technique to immobilise the enzyme lipase onto a support providing a derivatised enzyme that shows a high capacity to resolve between chiral pairs. This ability aids in the synthesis of specific compounds in its pure form which is very much sought after by the chemical industry
Chirazim™ — a highly enantioselective enzyme
Researchers: Abu Bakar Salleh, Siti Salhah Othman, Mahiran Basri, Mohd Zobir Hussein, Mohd. Basyaruddin Abd. Rahman and Raja Noor Zaliha Abdul Rahman
If we face our hand right towards our hand left, we can say that each is the mirror image of the other. Although they look similar they are not exactly the same as they cannot overlap on top of each other. In the world of compounds, these are known as chiral compounds.
In nature, we have many such chiral pairs designated as the R and S isomer. Of importance, each member of a chiral pair can exhibit different biological properties. The differential effect is caused by the presence of enzymes (biocatalysts) in living cells that are able to recognize and thus react with specific compounds (i.e. even either member of a chiral pair).
The ability to synthesis specific compounds in its pure form is very much sought after by the chemical industry. Pure isomer has specific applications in the medical and agrichemical industry. Mixed products may diminish the effect required, or worse still may lead to detrimental results. Specific examples of isomer in industrial applications include S-ibuprofen, an analgesic agent, R- chlorophenoxy propanoate, a type of herbicide, and a number of R menthol esters that are used as flavour additives in the food and beverage industry.
However, not all enzymes have the capacity to resolve enantiomers. The ability to recognize each compound depends a lot on the shape and conformation of the enzyme molecules, especially that of the active or catalytic site. One way of modifying the conformation of the enzyme is through the process of immobilisation, where an enzyme is attached to a solid support.
There are different types of supports and techniques to immobilize enzymes. These are selected in accordance to the property of the enzymes as well as the ultimate applications. Immobilised enzymes are easy to handle and can be reused.
Chirazim (TM) is a new discovery where lipase, the enzyme was immobilised onto a support via a simple method. The support used was a multi layered hydroxide that can also be easily produced.
Immobilisation resulted in a derivatised enzyme that showed high capacity to resolve S and R isomers. Apart from that the immobilized enzyme is stable to organic solvents and high temperature, suitable characteristics in the synthesis of chiral compounds.
Monday, August 27, 2007
New scaffold supporting our molecular understanding of psychiatric disorders
Researchers establish a causative link between mutations in a single gene and the pathology of psychiatric illnesses
New work in mice indicates that defective function of the molecular ‘scaffold’ protein Disc1 results in behaviors resembling human schizophrenia and depression. Current treatments for these devastating diseases are palliative but not curative.
Prior work hints at a link between Disc1 and psychiatric illness. Some mood disorders in humans are ameliorated by drugs suppressing the function of PDE4B: a protein that binds to molecular scaffolds including Disc1 and metabolizes cAMP, a compound essential for transmission of cellular signals. From studies in humans, scientists are also aware of associations between Disc1 mutations and the incidence of psychiatric illnesses. However, whether these mutations altered Disc1 function, and thus whether Disc1 dysfunction actually contributed to brain pathology, was not determined.
An international group led by Yoichi Gondo, a scientist at RIKEN Genomic Sciences Center in Yokohama, used a mouse model to forge a causative link between alterations in Disc1 function and the pathology of psychiatric disorders. This work was published in a recent issue of Neuron (1).
The researchers used a chemical mutagen to scatter random infrequent mutations throughout the genome of laboratory mice, and extensive DNA sequencing to identify two mice that each contained a distinct mutation predicted to change the sequence of the PDE4B-binding region of Disc1.
Like brains of some patients with mood disorders, brains in mice expressing mutated versions of Disc1 were of small volume (Fig. 1 - Click on link below). However, although both mutated Disc1 proteins exhibited impaired binding to PDE4B, only one Disc1 mutant reduced PDE4B activity.
Mice expressing this Disc1 mutant exhibited behaviour characteristic of depression; these mice displayed reduced sociability and disinterest in pleasurable activities. In contrast, mice expressing the Disc1 mutant that left PDE4B function intact failed to process and respond to distracting stimuli; this behaviour is more reminiscent of humans with schizophrenia. PDE4B inhibitors ameliorated the behaviour only of mice expressing the latter mutant.
Whether mutations having similar consequences on Disc1 function arise naturally in humans is unknown. Nevertheless, these findings reveal a complex role of Disc1 in brain function, and suggest that psychiatric disorders caused by distinct lesions of Disc1 may require different treatments.
“Studies in mouse models should lead to precise molecular diagnostics for psychiatric illness and allow us to develop preventive and therapeutic medicines. The RIKEN mutant mouse library, from where these Disc1 mutant mice were obtained, provides mouse models for the study of many human diseases,” says Gondo.
Reference
1. Clapcote, S.J., Lipina, T.V., Millar, J.K., Mackie, S., Christie, S., Ogawa, F., Lerch, J.P., Trimble, K., Uchiyama, M., Sakuraba, Y., et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54, 387–402 (2007).
Researchers establish a causative link between mutations in a single gene and the pathology of psychiatric illnesses
New work in mice indicates that defective function of the molecular ‘scaffold’ protein Disc1 results in behaviors resembling human schizophrenia and depression. Current treatments for these devastating diseases are palliative but not curative.
Prior work hints at a link between Disc1 and psychiatric illness. Some mood disorders in humans are ameliorated by drugs suppressing the function of PDE4B: a protein that binds to molecular scaffolds including Disc1 and metabolizes cAMP, a compound essential for transmission of cellular signals. From studies in humans, scientists are also aware of associations between Disc1 mutations and the incidence of psychiatric illnesses. However, whether these mutations altered Disc1 function, and thus whether Disc1 dysfunction actually contributed to brain pathology, was not determined.
An international group led by Yoichi Gondo, a scientist at RIKEN Genomic Sciences Center in Yokohama, used a mouse model to forge a causative link between alterations in Disc1 function and the pathology of psychiatric disorders. This work was published in a recent issue of Neuron (1).
The researchers used a chemical mutagen to scatter random infrequent mutations throughout the genome of laboratory mice, and extensive DNA sequencing to identify two mice that each contained a distinct mutation predicted to change the sequence of the PDE4B-binding region of Disc1.
Like brains of some patients with mood disorders, brains in mice expressing mutated versions of Disc1 were of small volume (Fig. 1 - Click on link below). However, although both mutated Disc1 proteins exhibited impaired binding to PDE4B, only one Disc1 mutant reduced PDE4B activity.
Mice expressing this Disc1 mutant exhibited behaviour characteristic of depression; these mice displayed reduced sociability and disinterest in pleasurable activities. In contrast, mice expressing the Disc1 mutant that left PDE4B function intact failed to process and respond to distracting stimuli; this behaviour is more reminiscent of humans with schizophrenia. PDE4B inhibitors ameliorated the behaviour only of mice expressing the latter mutant.
Whether mutations having similar consequences on Disc1 function arise naturally in humans is unknown. Nevertheless, these findings reveal a complex role of Disc1 in brain function, and suggest that psychiatric disorders caused by distinct lesions of Disc1 may require different treatments.
“Studies in mouse models should lead to precise molecular diagnostics for psychiatric illness and allow us to develop preventive and therapeutic medicines. The RIKEN mutant mouse library, from where these Disc1 mutant mice were obtained, provides mouse models for the study of many human diseases,” says Gondo.
Reference
1. Clapcote, S.J., Lipina, T.V., Millar, J.K., Mackie, S., Christie, S., Ogawa, F., Lerch, J.P., Trimble, K., Uchiyama, M., Sakuraba, Y., et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54, 387–402 (2007).
Enzymes lead the way
A protease enzyme called MIG-17 points cells in the right direction during the development of organ
During the growth and development of organs, proteins act from outside the organs to direct the movements of cells. Researchers at the RIKEN Centre for Developmental Biology in Kobe have identified one such protein that is essential for the development of gonads in the nematode roundworm Caenorhabditis elegans (1).
In C. elegans, the gonads grow along the body wall and then turn through 180°, making two U-shaped gonad arms. The movement is directed by two specialized leader cells called ‘distal tip cells’ (DTCs). The researchers found that when they inhibited the activity of a proteolytic enzyme called MIG-17, the DTCs failed to function properly, resulting in misshapen gonads.
”We mutagenized wild-type worms with [a] chemical mutagen and isolated many mutant worms with misshapen gonads,” says group leader Kiyoji Nishiwaki. “The MIG-17 mutant is one of these isolates and was found to encode a protein of the ADAMTS protease family.”
The MIG-17 enzyme is secreted from muscle cells, and is initially folded over to hide an active zinc ion (Fig. 1). The researchers discovered that actions in part of the MIG-17 molecule called the prodomain are essential for moving the molecule to the gonad. However, the prodomain must first be modified by another protein, MIG-23, in a process called glycosylation.
Previous studies had indicated a role for the prodomain in protein folding and secretion, but this is the first time it has been shown to be crucial for targeting the whole MIG-17 molecule to the gonad. “It is possible that prodomain targeting is one of the key strategies employed by ADAMTS proteins to localize to specific tissues,” says Nishiwaki.
Once the MIG-17 molecule reaches the gonadal membrane, an unknown stimulus initiates autocatalytic cleavage of the molecule. The prodomain falls off, leaving the active zinc ion exposed (Fig. 1). “The zinc ion probably degrades a specific substrate in the gonadal membrane and thereby acts in directing DTCs,” explains Nishiwaki.
In humans, mutations in ADAMTS proteins cause various hereditary diseases related to disorders in connective tissues. MIG-17 is most similar to an enzyme called ADAMTS-10 that may have a role in organ development in humans.
“ADAMTS-10 is a causative gene for Weill–Marchesani syndrome [in humans], characterized by short stature, shortness of fingers and toes and eye abnormalities,” says Nishiwaki. “Abnormalities of internal organs may also occur, although this is not examined yet.”
Reference
1. Ihara, S. & Nishiwaki, K. Prodomain-dependent tissue targeting of an ADAMTS protease controls cell migration in Caenorhabditis elegans. The EMBO Journal 26, 2607–2620 (2007).
A protease enzyme called MIG-17 points cells in the right direction during the development of organ
During the growth and development of organs, proteins act from outside the organs to direct the movements of cells. Researchers at the RIKEN Centre for Developmental Biology in Kobe have identified one such protein that is essential for the development of gonads in the nematode roundworm Caenorhabditis elegans (1).
In C. elegans, the gonads grow along the body wall and then turn through 180°, making two U-shaped gonad arms. The movement is directed by two specialized leader cells called ‘distal tip cells’ (DTCs). The researchers found that when they inhibited the activity of a proteolytic enzyme called MIG-17, the DTCs failed to function properly, resulting in misshapen gonads.
”We mutagenized wild-type worms with [a] chemical mutagen and isolated many mutant worms with misshapen gonads,” says group leader Kiyoji Nishiwaki. “The MIG-17 mutant is one of these isolates and was found to encode a protein of the ADAMTS protease family.”
The MIG-17 enzyme is secreted from muscle cells, and is initially folded over to hide an active zinc ion (Fig. 1). The researchers discovered that actions in part of the MIG-17 molecule called the prodomain are essential for moving the molecule to the gonad. However, the prodomain must first be modified by another protein, MIG-23, in a process called glycosylation.
Previous studies had indicated a role for the prodomain in protein folding and secretion, but this is the first time it has been shown to be crucial for targeting the whole MIG-17 molecule to the gonad. “It is possible that prodomain targeting is one of the key strategies employed by ADAMTS proteins to localize to specific tissues,” says Nishiwaki.
Once the MIG-17 molecule reaches the gonadal membrane, an unknown stimulus initiates autocatalytic cleavage of the molecule. The prodomain falls off, leaving the active zinc ion exposed (Fig. 1). “The zinc ion probably degrades a specific substrate in the gonadal membrane and thereby acts in directing DTCs,” explains Nishiwaki.
In humans, mutations in ADAMTS proteins cause various hereditary diseases related to disorders in connective tissues. MIG-17 is most similar to an enzyme called ADAMTS-10 that may have a role in organ development in humans.
“ADAMTS-10 is a causative gene for Weill–Marchesani syndrome [in humans], characterized by short stature, shortness of fingers and toes and eye abnormalities,” says Nishiwaki. “Abnormalities of internal organs may also occur, although this is not examined yet.”
Reference
1. Ihara, S. & Nishiwaki, K. Prodomain-dependent tissue targeting of an ADAMTS protease controls cell migration in Caenorhabditis elegans. The EMBO Journal 26, 2607–2620 (2007).
Observing single cells on the move
Researchers hold a key to studying cancer, wound healing and development
A team of researchers from RIKEN and other Japanese research institutions has developed a flexible technique for studying migration behavior of single cells. It relies on guiding cell movement by creating adhesive pathways through a non-adhesive environment using a light-driven reaction.
With their technique, the researchers are able to study details of the mechanics of how individual cells move. Already, for example, the team has been able to determine that cells which move by extending a broad front known as a lamellipodium travel faster than cells which can only use the much narrower filopodium.
The study is significant as migration of cells is fundamental to important medical processes such as growth and development, wound healing and the spread of cancer. In addition, the new technique allows researchers to guide individual cells into position, thus engineering nerve networks, for instance.
In the past, migration has been investigated using methods involving monolayers of cells. But cells within layers are unavoidably squeezed into different shapes and orientations and contact variable numbers of other cells, all of which affect movement. So the research team from RIKEN’s Discovery Research Institute in Wako, the Japan Science and Technology Agency, and Waseda and Kanagawa universities set about developing a way of studying the motion of individual cells in isolation, free from these influences.
In a recent paper, the researchers describe coating a glass coverslip with a compound to which cells cannot stick1. The chemical nature of this surface can be changed into one to which cells can adhere by exposure to ultraviolet light. And this can be done with great precision.
The team then prepared coverslips with adhesive patches just big enough for a single fibroblast cell (Fig.1). Leading from those cells they created pathways of adhesive surface in two forms—a broad form, the same width as the patch, which could accommodate lamellipodia, and a narrow pathway, one fifth the width, only fit for filopodia.
Movement of the cells could be followed under a conventional fluorescent microscope. When presented with a broad pathway, less than 10% of the cells extended filopodia. And those cells which used filopodia for movement traveled only about 80% as fast as those employing lamellipodia.
“We now want to combine this technique with advanced fluorescent microscope technologies to observe the molecular events in migrating cells,” says one of the project leaders, Jun Nakanishi. “We are also hoping to engineer neuronal networks by applying our technique to control the movement of single cells.”
Reference
1. Nakanishi, J., Kikuchi, Y., Inoue, S., Yamaguchi, K., Takarada, T. & Maeda, M. Spatiotemporal control of migration of single cells on a photoactivatable cell microarray. Journal of the American Chemical Society 129, 6694–6695 (2007).
Researchers hold a key to studying cancer, wound healing and development
A team of researchers from RIKEN and other Japanese research institutions has developed a flexible technique for studying migration behavior of single cells. It relies on guiding cell movement by creating adhesive pathways through a non-adhesive environment using a light-driven reaction.
With their technique, the researchers are able to study details of the mechanics of how individual cells move. Already, for example, the team has been able to determine that cells which move by extending a broad front known as a lamellipodium travel faster than cells which can only use the much narrower filopodium.
The study is significant as migration of cells is fundamental to important medical processes such as growth and development, wound healing and the spread of cancer. In addition, the new technique allows researchers to guide individual cells into position, thus engineering nerve networks, for instance.
In the past, migration has been investigated using methods involving monolayers of cells. But cells within layers are unavoidably squeezed into different shapes and orientations and contact variable numbers of other cells, all of which affect movement. So the research team from RIKEN’s Discovery Research Institute in Wako, the Japan Science and Technology Agency, and Waseda and Kanagawa universities set about developing a way of studying the motion of individual cells in isolation, free from these influences.
In a recent paper, the researchers describe coating a glass coverslip with a compound to which cells cannot stick1. The chemical nature of this surface can be changed into one to which cells can adhere by exposure to ultraviolet light. And this can be done with great precision.
The team then prepared coverslips with adhesive patches just big enough for a single fibroblast cell (Fig.1). Leading from those cells they created pathways of adhesive surface in two forms—a broad form, the same width as the patch, which could accommodate lamellipodia, and a narrow pathway, one fifth the width, only fit for filopodia.
Movement of the cells could be followed under a conventional fluorescent microscope. When presented with a broad pathway, less than 10% of the cells extended filopodia. And those cells which used filopodia for movement traveled only about 80% as fast as those employing lamellipodia.
“We now want to combine this technique with advanced fluorescent microscope technologies to observe the molecular events in migrating cells,” says one of the project leaders, Jun Nakanishi. “We are also hoping to engineer neuronal networks by applying our technique to control the movement of single cells.”
Reference
1. Nakanishi, J., Kikuchi, Y., Inoue, S., Yamaguchi, K., Takarada, T. & Maeda, M. Spatiotemporal control of migration of single cells on a photoactivatable cell microarray. Journal of the American Chemical Society 129, 6694–6695 (2007).
Investigating a perplexing mystery
Ultrahigh-energy cosmic particles are an intriguing puzzle in high-energy physics, and RIKEN is involved in a project to solve it. On May 16, the RIKEN proposal for the second utilization plan of the Japanese Experiment Module (JEM) on board the International Space Station was accepted, and its kickoff meeting was held on June 6 to 8 at RIKEN, Wako.
The particles have extremely high kinetic energies, as much as 1020 electronvolts, far greater than other cosmic-ray particles. They are also extremely rare—only 11 have been observed in 13 years of searching with the Akeno Giant Air Shower Array (AGASA), which has an effective area as large as the area enclosed by the Yamanote line in the Tokyo Metro. No one knows where they come from, or how they could have that much energy left over after the long journey through intergalactic and interstellar space.
To observe these rare phenomena, a telescope with an extremely wide field of view is needed, and it is being provided by the Extreme Universe Space Observatory (EUSO), to be installed on the JEM on the International Space Station, after JEM is launched in 2008.
Instead of looking out into space like a conventional telescope, EUSO will look down at the Earth from space, searching for streaks of ultraviolet fluorescence and Cerenkov radiation, which cosmic particles produce when they interact with the Earth's atmosphere.
EUSO incorporates a Fresnel lens, a very thin, wide-aperture lens made up of concentric rings, which provides a 60 ° field of view. The lens was made using ultraprecise grinding technology at the RIKEN Ohmori laboratory.
To detect the faint streaks of ultraviolet fluorescence and Cerenkov radiation that the particles produce as they enter the Earth’s atmosphere, EUSO contains 6,000 photomultiplier tubes, which were developed and built in Japan.
EUSO is said to be launched by a Japanese H-IIB rocket and transferred by H-II transfer vehicle (HTV), and it is expected to detect about 1,000 ultrahigh-energy cosmic particles in the five years of its operation. From this data researchers hope to determine whether the particles originated from a single source or occur throughout the universe.
Ultrahigh-energy cosmic particles are an intriguing puzzle in high-energy physics, and RIKEN is involved in a project to solve it. On May 16, the RIKEN proposal for the second utilization plan of the Japanese Experiment Module (JEM) on board the International Space Station was accepted, and its kickoff meeting was held on June 6 to 8 at RIKEN, Wako.
The particles have extremely high kinetic energies, as much as 1020 electronvolts, far greater than other cosmic-ray particles. They are also extremely rare—only 11 have been observed in 13 years of searching with the Akeno Giant Air Shower Array (AGASA), which has an effective area as large as the area enclosed by the Yamanote line in the Tokyo Metro. No one knows where they come from, or how they could have that much energy left over after the long journey through intergalactic and interstellar space.
To observe these rare phenomena, a telescope with an extremely wide field of view is needed, and it is being provided by the Extreme Universe Space Observatory (EUSO), to be installed on the JEM on the International Space Station, after JEM is launched in 2008.
Instead of looking out into space like a conventional telescope, EUSO will look down at the Earth from space, searching for streaks of ultraviolet fluorescence and Cerenkov radiation, which cosmic particles produce when they interact with the Earth's atmosphere.
EUSO incorporates a Fresnel lens, a very thin, wide-aperture lens made up of concentric rings, which provides a 60 ° field of view. The lens was made using ultraprecise grinding technology at the RIKEN Ohmori laboratory.
To detect the faint streaks of ultraviolet fluorescence and Cerenkov radiation that the particles produce as they enter the Earth’s atmosphere, EUSO contains 6,000 photomultiplier tubes, which were developed and built in Japan.
EUSO is said to be launched by a Japanese H-IIB rocket and transferred by H-II transfer vehicle (HTV), and it is expected to detect about 1,000 ultrahigh-energy cosmic particles in the five years of its operation. From this data researchers hope to determine whether the particles originated from a single source or occur throughout the universe.
Friday, August 24, 2007
Australia research links obesity, infertility
Australian researchers have found
a fatty diet damages eggs in the ovaries and prevents them
from becoming healthy embryos, a finding they say may explain
why obese women are often infertile.
While obesity has long been suspected of hampering a
woman's ability to conceive, the University of Adelaide
research is said to be the first to find a direct scientific
link.
Researcher Cadence Minge said experiments on female
mice showed that fat has an impact on the egg before it is
even fertilised.
"Consuming a diet of high fat causes damage to eggs
stored in female ovaries," Minge said. "As a result, when
fertilised, these eggs are not able to undergo normal, healthy
development into embryos."
Minge said a protein called peroxisome
proliferator-activated receptor gamma found in the cells that
nourish the egg was the main reason for diet-induced
infertility.
"The behaviour of this protein helps to determine the
way in which the ovaries sense and respond to fats," she said.
"Being able to control this protein will be very
important in the quest to reverse infertility caused by poor
diets."
Minge found that an anti-diabetes drug called
rosglitazone helped counter the protein's impact, resulting in
higher birth weights and better rates of foetal survival in
the mice being studies.
However, she said the drug had side effects and could
not be seen as a "quick-fix" for infertile obese women.
Australian researchers have found
a fatty diet damages eggs in the ovaries and prevents them
from becoming healthy embryos, a finding they say may explain
why obese women are often infertile.
While obesity has long been suspected of hampering a
woman's ability to conceive, the University of Adelaide
research is said to be the first to find a direct scientific
link.
Researcher Cadence Minge said experiments on female
mice showed that fat has an impact on the egg before it is
even fertilised.
"Consuming a diet of high fat causes damage to eggs
stored in female ovaries," Minge said. "As a result, when
fertilised, these eggs are not able to undergo normal, healthy
development into embryos."
Minge said a protein called peroxisome
proliferator-activated receptor gamma found in the cells that
nourish the egg was the main reason for diet-induced
infertility.
"The behaviour of this protein helps to determine the
way in which the ovaries sense and respond to fats," she said.
"Being able to control this protein will be very
important in the quest to reverse infertility caused by poor
diets."
Minge found that an anti-diabetes drug called
rosglitazone helped counter the protein's impact, resulting in
higher birth weights and better rates of foetal survival in
the mice being studies.
However, she said the drug had side effects and could
not be seen as a "quick-fix" for infertile obese women.
Titanium Oxide to keep dress fresh for ever!
Coimbatore (India): Believe it or not! people would
require only one pair of dress, if Titanium Oxide was applied
in its molecular form on it.
The cloth would not absorb sweat or any external particle
and would retain an everlasting shine.
"Man would require only one pair of T Shirt or any other
dress material, since it would not get dirtied by dust or any
other particle, if the chemical was used by applying
nanotechnology", Dr A Sivathanu Pillai, Chief Controller, R
and D, DRDO, said during an interaction with college students
here.
"You can just wipe off, if tea falls on the shirt. It will
not be absorbed by the shirt. Shining would remain", Pillai,
said, much to the surprise of over 800 students and faculty
members assembled at the function.
Applying of titanium oxide would not cause any harm to the
human skin also, he assured.
DRDO has been conducting researches in nano technology for
quite some time.
However, he jokingly remarked that the revenue of the
textile industry would dip, since people would be happy
with one or two pairs of dresses.
Coimbatore (India): Believe it or not! people would
require only one pair of dress, if Titanium Oxide was applied
in its molecular form on it.
The cloth would not absorb sweat or any external particle
and would retain an everlasting shine.
"Man would require only one pair of T Shirt or any other
dress material, since it would not get dirtied by dust or any
other particle, if the chemical was used by applying
nanotechnology", Dr A Sivathanu Pillai, Chief Controller, R
and D, DRDO, said during an interaction with college students
here.
"You can just wipe off, if tea falls on the shirt. It will
not be absorbed by the shirt. Shining would remain", Pillai,
said, much to the surprise of over 800 students and faculty
members assembled at the function.
Applying of titanium oxide would not cause any harm to the
human skin also, he assured.
DRDO has been conducting researches in nano technology for
quite some time.
However, he jokingly remarked that the revenue of the
textile industry would dip, since people would be happy
with one or two pairs of dresses.
Thursday, August 23, 2007
Cholesterol synthesis: Regulation by destruction
-Dangsheng Li
AbstractScientists have found that the degradation of a key enzyme involved in cholesterol synthesis is regulated by a cofactor known as Ufd1
The endoplasmic reticulum (ER) is an organelle responsible for several specialized functions, including the synthesis of some proteins. As a quality control, ER destroys misfolded proteins through a process known as ER-associated degradation. Cells also use this process to degrade the key enzyme, HMG-CoA reductase (HMGCR), which is involved in cholesterol synthesis. Baoliang Song, Boliang Li at the Chinese Academy of Sciences in Shanghai and co-workers1 have found that the degradation of HMGCR is regulated by a cofactor, Ufd1.
An important step in HMGCR degradation is the attachment of a regulatory protein called ubiquitin — a unique tag which marks the HMGCR for destruction. This ubiquitin attachment is catalysed by an ER-residing enzyme. The researchers discovered that Ufd1 binds directly to this enzyme, enhances its ability to tag ubiquitin onto HMGCR, and consequently helps HMGCR degradation. As a result, cells with higher levels of Ufd1 produce less cholesterol and, to compensate, are able to take up more cholesterol from outside the cell.
A high cholesterol level is associated with medical conditions such as heart disease. The finding provides new strategies to lower cholesterol through regulating HMGCR degradation.
The authors of this work are from:
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
-Dangsheng Li
AbstractScientists have found that the degradation of a key enzyme involved in cholesterol synthesis is regulated by a cofactor known as Ufd1
The endoplasmic reticulum (ER) is an organelle responsible for several specialized functions, including the synthesis of some proteins. As a quality control, ER destroys misfolded proteins through a process known as ER-associated degradation. Cells also use this process to degrade the key enzyme, HMG-CoA reductase (HMGCR), which is involved in cholesterol synthesis. Baoliang Song, Boliang Li at the Chinese Academy of Sciences in Shanghai and co-workers1 have found that the degradation of HMGCR is regulated by a cofactor, Ufd1.
An important step in HMGCR degradation is the attachment of a regulatory protein called ubiquitin — a unique tag which marks the HMGCR for destruction. This ubiquitin attachment is catalysed by an ER-residing enzyme. The researchers discovered that Ufd1 binds directly to this enzyme, enhances its ability to tag ubiquitin onto HMGCR, and consequently helps HMGCR degradation. As a result, cells with higher levels of Ufd1 produce less cholesterol and, to compensate, are able to take up more cholesterol from outside the cell.
A high cholesterol level is associated with medical conditions such as heart disease. The finding provides new strategies to lower cholesterol through regulating HMGCR degradation.
The authors of this work are from:
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Monday, August 20, 2007
Controlling basal stem rot disease in palm oil
TrichoGreen is a Trichoderma-infused compost which is also an effective biological control agent against the basal stem rot disease for palm oil. The production process is entirely organic, eliminates the need for burning, and is an excellent form of environmentally-friendly waste management.
Trichogreen, the Biocontrol Agent and Growth Enhancer for the Oil Palm Industry
Faridah Abdullah
The production of TrichoGreen is a recycling process, turning agricultural waste into useful products.
The production process is entirely organic, eliminates the need for burning, and is an excellent form of
environmentally-friendly waste management. The industry is sustainable and can generate downstream activities.
The product was later found to be a good plant growth enhancer as well. The biocontrol property of
Trichoderma is isolate-specific and from extensive in vitro screening, isolate FA 1132 (T. harzianum) was
selected as the best candidate for biocontrol purposes. From nursery trials, TrichoGreen can save as
much as 95% of plants if treatment is given simultaneously to the infected seedlings; the success rate
decreases with increased severity of tissue damage caused to the palm.
The product has been successfully upscaled using a bioreactor, producing x107 propagules/ml within 96
hours, which was then used to prepare inocula and subsequently in its mass production, using palm
pressed fibres (PPF) agrowaste as the feedstock. The PPF were piled into windrows at 50 mt feedstock
per row of 80m x 4m. Together with intermittent supplies of POME (palm oil mill effluents) and scheduled
turnovers in a solid substrate fermentation, the final product of 22mt per windrow at x1011
propagules/kg material, was achieved over 12 to 15 weeks. Field trials over 8 weeks’ treatment thus far
showed that it significantly enhanced growth of the oil palm, followed only by organic compost and
thirdly the routinely-used fertiliser application. Field applications of TrichoGreen on Ganoderma-infected fields are currently on trial and the results are estimated in 2 to 3 years.
Dr. Nayan KANWAL
Email: ndeeps@admin.upm.edu.my
TrichoGreen is a Trichoderma-infused compost which is also an effective biological control agent against the basal stem rot disease for palm oil. The production process is entirely organic, eliminates the need for burning, and is an excellent form of environmentally-friendly waste management.
Trichogreen, the Biocontrol Agent and Growth Enhancer for the Oil Palm Industry
Faridah Abdullah
The production of TrichoGreen is a recycling process, turning agricultural waste into useful products.
The production process is entirely organic, eliminates the need for burning, and is an excellent form of
environmentally-friendly waste management. The industry is sustainable and can generate downstream activities.
The product was later found to be a good plant growth enhancer as well. The biocontrol property of
Trichoderma is isolate-specific and from extensive in vitro screening, isolate FA 1132 (T. harzianum) was
selected as the best candidate for biocontrol purposes. From nursery trials, TrichoGreen can save as
much as 95% of plants if treatment is given simultaneously to the infected seedlings; the success rate
decreases with increased severity of tissue damage caused to the palm.
The product has been successfully upscaled using a bioreactor, producing x107 propagules/ml within 96
hours, which was then used to prepare inocula and subsequently in its mass production, using palm
pressed fibres (PPF) agrowaste as the feedstock. The PPF were piled into windrows at 50 mt feedstock
per row of 80m x 4m. Together with intermittent supplies of POME (palm oil mill effluents) and scheduled
turnovers in a solid substrate fermentation, the final product of 22mt per windrow at x1011
propagules/kg material, was achieved over 12 to 15 weeks. Field trials over 8 weeks’ treatment thus far
showed that it significantly enhanced growth of the oil palm, followed only by organic compost and
thirdly the routinely-used fertiliser application. Field applications of TrichoGreen on Ganoderma-infected fields are currently on trial and the results are estimated in 2 to 3 years.
Dr. Nayan KANWAL
Email: ndeeps@admin.upm.edu.my
Getting on worms’ nerves
Two devices that help researchers correlate nerve cell activity with behaviour in the living worm.
The microscopic worm C. elegans has a very simple nervous system, with only 302 neurons. However, it is difficult to monitor neuronal activity in worms without either using invasive methods or restraining them in an unphysiological way. Nikos Chronis and colleagues present devices which make it possible to use a microscope to monitor nerve activity in intact, live worms. The key is that the worms are enclosed in tiny channels only slightly bigger than the animals, so that they are free to move to some extent, but restrained sufficiently to allow for imaging of the neurons. The trapped worms can also be stimulated in a very controlled fashion by substances delivered at the tip of the animal’s nose, so that their effect on nerve activity can be recorded.
The researchers used these devices to uncover new information about particular neurons involved in movement and sensation in the worm. This may very well pave the way to ever more sophisticated devices, as well as to devices for monitoring other small organisms in physiological and precisely controlled environments.
Author contact:
Nikos Chronis (University of Michigan, Ann Arbor, MI, USA)
Tel: +1 734 763 0154; E-mail: chronis@umich.edu
Two devices that help researchers correlate nerve cell activity with behaviour in the living worm.
The microscopic worm C. elegans has a very simple nervous system, with only 302 neurons. However, it is difficult to monitor neuronal activity in worms without either using invasive methods or restraining them in an unphysiological way. Nikos Chronis and colleagues present devices which make it possible to use a microscope to monitor nerve activity in intact, live worms. The key is that the worms are enclosed in tiny channels only slightly bigger than the animals, so that they are free to move to some extent, but restrained sufficiently to allow for imaging of the neurons. The trapped worms can also be stimulated in a very controlled fashion by substances delivered at the tip of the animal’s nose, so that their effect on nerve activity can be recorded.
The researchers used these devices to uncover new information about particular neurons involved in movement and sensation in the worm. This may very well pave the way to ever more sophisticated devices, as well as to devices for monitoring other small organisms in physiological and precisely controlled environments.
Author contact:
Nikos Chronis (University of Michigan, Ann Arbor, MI, USA)
Tel: +1 734 763 0154; E-mail: chronis@umich.edu
Sunday, August 19, 2007
A very sociable brain
Brain activity in primates is directly influenced by social context
Human society puts heavy demands on the brain. Neurons must adapt rapidly to contextual changes in the social environment. Researchers at the RIKEN Brain Science Institute in Wako are gaining insight into this ‘social brain function’ by observing Japanese macaque monkeys (1).
“We can understand how our brain recognizes and adapts to social environments by expanding research in primates,” says cognitive neuroscientist Naotaka Fujii, “because the social behavior of monkeys is very similar to that of human children.”
Fujii’s team placed two male monkeys around a square table in chairs that restricted their necks and lower bodies but arms and head free to move. Food was placed in random positions on the table, and the monkeys’ arm and head movements were closely monitored using a 3D motion capture system. Individual neuron activity was measured by inserting electrodes into the parietal cortex, a region of the brain that processes sensory information to determine the locations and movements of objects. In total, 174 neurons were isolated of which 91 were related to specific actions.
When the monkeys were seated opposite one another, they could only reach half the table each, so could not compete with one another. They effectively behaved as if no other monkey was present, and most activated neurons were associated with the monkeys’ own right-arm motion.
However, when the monkeys were seated on adjacent edges of the table, they shared a corner and could fight over food items that were placed there. One monkey appeared to be dominant, taking the food about 90% of the time. The dominant monkey frequently watched the submissive monkey, and became aggressive on the rare occasions that the submissive monkey managed to grab the food “When the monkeys are placed in a conflict situation, they tend to be more active to get the reward, even when they are not hungry,” says Fujii.
Brain activity changed dramatically when this social conflict was introduced. The researchers saw decreased activity in neurons related to the monkeys’ own right-arm movements, and increased activity in neurons related to other stimuli, such as the actions of their competitor’s arms.
“This is the first evidence that neurons are manipulating activity depending on social context at a single cell level,” says Fujii. “However, the parietal cortex may not be the only structure that implements the function. We have to expand recording areas to obtain an entire view of social brain functions.”
Reference
1. Fujii, N., Hihara, S. & Iriki, A. Dynamic social adaptation of motion-related neurons in primate parietal cortex. PLoS ONE [online] 4, e397 (2007) (doi: 10.1371/journal.pone.0000397).
Agriculture:Putting a STOP to acid stress
A transcription protein called STOP1 helps plants to tolerate aluminum ions and protons
Plant growth can be badly stunted by excess ions in the soil. This effect, called acid soil syndrome, can cause severe agricultural yield losses, especially in areas prone to drought. For this reason, a team of researchers from RIKEN and two Japanese universities are working to identify genes that regulate a plant’s tolerance of ions (1).
Much work has been done on aluminum toxicity in plants, but little is known about the genes that control direct tolerance to acid in the form of hydrogen ions, or protons. The researchers prepared thale cress, Arabidopsis thaliana, from seeds treated with ethyl methanesulfonate to introduce random point mutations in their genome. The seeds were cultivated in an acidic (proton-rich) environment, and the researchers looked for seedlings that failed to grow roots.
“We carried out screening using 25,000 seedlings,” says project leader Satoshi Iuchi from the RIKEN BioResources Center in Tsukuba. “Finally we obtained one mutant that had an acid sensitive phenotype.”
The mutant plant, named stop1 (Sensitive TO Proton), was cloned and subjected to DNA sequencing. The sequencing revealed mutations in a part of the genome that encodes a protein called STOP1, consisting of 499 amino acids. The protein contains four ‘zinc-finger’ domains that regulate DNA transcription in the cell nucleus.
The researchers next investigated whether the stop1 mutant strain was sensitive to other toxic ions. It showed no particular sensitivity to cadmium, copper, sodium, lanthanum or manganese, but was extra sensitive to aluminum ions—stop1 plants showed 80–90% reduced root growth when exposed to aluminum, compared to only 30% in control plants.
Arabidopsis is known to tolerate aluminum by excreting malate, an ionized form of malic acid that is regulated by a gene called AtALMT1. This new study confirmed the link—stop1 mutants failed to express AtALMT1 in the toxic aluminum, and did not excrete any malate.
However, when AtALMT1 was deliberately disrupted in the control plants, the proton sensitivity was not affected. Therefore STOP1 must regulate different genes related to proton sensitivity (Fig. 1).
This work puts STOP1 on the expanding list of transcriptional factors that respond to stress and regulate genes to ensure a plant’s survival. Iuchi believes genetic modification of proteins such as STOP1 is the best way to improve farming efficiency. “Large amounts of chemical fertilizer are used in agriculture, which causes problems,” he says. “If enhanced-tolerance plants can be used, chemical fertilizer usage can be reduced.”
Reference1. Iuchi, S., Koyama, H., Iuchi, A., Kobayashi, Y., Kitabayashi, S., Kobayashi, Y., Ikka, T., Hirayama, T., Shinozaki, K. & Kobayashi, M. Zinc finger protein STOP1 is critical for proton tolerance in Arabidopsis and coregulates a key gene in aluminum tolerance. Proceedings of the National Academy of Sciences USA 104, 9900–9905 (2007).
A transcription protein called STOP1 helps plants to tolerate aluminum ions and protons
Plant growth can be badly stunted by excess ions in the soil. This effect, called acid soil syndrome, can cause severe agricultural yield losses, especially in areas prone to drought. For this reason, a team of researchers from RIKEN and two Japanese universities are working to identify genes that regulate a plant’s tolerance of ions (1).
Much work has been done on aluminum toxicity in plants, but little is known about the genes that control direct tolerance to acid in the form of hydrogen ions, or protons. The researchers prepared thale cress, Arabidopsis thaliana, from seeds treated with ethyl methanesulfonate to introduce random point mutations in their genome. The seeds were cultivated in an acidic (proton-rich) environment, and the researchers looked for seedlings that failed to grow roots.
“We carried out screening using 25,000 seedlings,” says project leader Satoshi Iuchi from the RIKEN BioResources Center in Tsukuba. “Finally we obtained one mutant that had an acid sensitive phenotype.”
The mutant plant, named stop1 (Sensitive TO Proton), was cloned and subjected to DNA sequencing. The sequencing revealed mutations in a part of the genome that encodes a protein called STOP1, consisting of 499 amino acids. The protein contains four ‘zinc-finger’ domains that regulate DNA transcription in the cell nucleus.
The researchers next investigated whether the stop1 mutant strain was sensitive to other toxic ions. It showed no particular sensitivity to cadmium, copper, sodium, lanthanum or manganese, but was extra sensitive to aluminum ions—stop1 plants showed 80–90% reduced root growth when exposed to aluminum, compared to only 30% in control plants.
Arabidopsis is known to tolerate aluminum by excreting malate, an ionized form of malic acid that is regulated by a gene called AtALMT1. This new study confirmed the link—stop1 mutants failed to express AtALMT1 in the toxic aluminum, and did not excrete any malate.
However, when AtALMT1 was deliberately disrupted in the control plants, the proton sensitivity was not affected. Therefore STOP1 must regulate different genes related to proton sensitivity (Fig. 1).
This work puts STOP1 on the expanding list of transcriptional factors that respond to stress and regulate genes to ensure a plant’s survival. Iuchi believes genetic modification of proteins such as STOP1 is the best way to improve farming efficiency. “Large amounts of chemical fertilizer are used in agriculture, which causes problems,” he says. “If enhanced-tolerance plants can be used, chemical fertilizer usage can be reduced.”
Reference1. Iuchi, S., Koyama, H., Iuchi, A., Kobayashi, Y., Kitabayashi, S., Kobayashi, Y., Ikka, T., Hirayama, T., Shinozaki, K. & Kobayashi, M. Zinc finger protein STOP1 is critical for proton tolerance in Arabidopsis and coregulates a key gene in aluminum tolerance. Proceedings of the National Academy of Sciences USA 104, 9900–9905 (2007).
Thursday, August 16, 2007
Stellar science: A turbulent wake
A stunning ultraviolet image of a turbulent wind wake produced by the binary star Mira offers a new, unprecedented direct measure of the star’s mass loss history.
Stars such as Mira — in the late stages of stellar evolution and with low-to-intermediate mass — return a large fraction of their original mass to the interstellar medium through the dusty, molecular winds they send out. This means they have a direct affect on subsequent star and planet formation in their host galaxy.
D. Christopher Martin and colleagues report the discovery of an ultraviolet-emitting bow shock and turbulent wake extending over 2 degrees on the sky, produced by the interaction of Mira’s stellar wind and the ambient interstellar medium.
The wind wake is a tracer of the last 30,000 years of Mira’s mass loss history. In the past, observations of interactions between Mira-type stellar winds and the interstellar medium have been in the infrared.
CONTACT
D. Christopher Martin (California Institute of Technology, Pasadena, CA, USA)
Tel: +1 626 395 4243; E-mail: cmartin@srl.caltech.edu
A stunning ultraviolet image of a turbulent wind wake produced by the binary star Mira offers a new, unprecedented direct measure of the star’s mass loss history.
Stars such as Mira — in the late stages of stellar evolution and with low-to-intermediate mass — return a large fraction of their original mass to the interstellar medium through the dusty, molecular winds they send out. This means they have a direct affect on subsequent star and planet formation in their host galaxy.
D. Christopher Martin and colleagues report the discovery of an ultraviolet-emitting bow shock and turbulent wake extending over 2 degrees on the sky, produced by the interaction of Mira’s stellar wind and the ambient interstellar medium.
The wind wake is a tracer of the last 30,000 years of Mira’s mass loss history. In the past, observations of interactions between Mira-type stellar winds and the interstellar medium have been in the infrared.
CONTACT
D. Christopher Martin (California Institute of Technology, Pasadena, CA, USA)
Tel: +1 626 395 4243; E-mail: cmartin@srl.caltech.edu
Ageing and cancer: Henrietta's legacy
Over fifty years ago, a 31-year-old woman underwent a biopsy for a suspicious cervical mass. Part of the sample went for pathological analysis, but another went to the research laboratory of George and Martha Gey. The patient died from her cancer just 8 months later, and on that day George Gey appeared on American TV announcing the dawn of a new era in medical research. For the first time, he explained, it was possible to grow human cells continuously in culture. And he called the biopsy-derived cell line 'HeLa', in memory of Henrietta Lacks, the unfortunate young mother whose tumour made it all possible.
Since then, researchers have been slowly stripping away the many secrets that endow cancer cells with the gift of immortality. In a review Toren Finkel and colleagues not only offer a historical perspective, but also describe the more recent research linking cancer biology to normal ageing.
CONTACT
Toren Finkel (National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA)
Tel: +1 301 402 4081; E-mail: finkelt@nih.gov
Over fifty years ago, a 31-year-old woman underwent a biopsy for a suspicious cervical mass. Part of the sample went for pathological analysis, but another went to the research laboratory of George and Martha Gey. The patient died from her cancer just 8 months later, and on that day George Gey appeared on American TV announcing the dawn of a new era in medical research. For the first time, he explained, it was possible to grow human cells continuously in culture. And he called the biopsy-derived cell line 'HeLa', in memory of Henrietta Lacks, the unfortunate young mother whose tumour made it all possible.
Since then, researchers have been slowly stripping away the many secrets that endow cancer cells with the gift of immortality. In a review Toren Finkel and colleagues not only offer a historical perspective, but also describe the more recent research linking cancer biology to normal ageing.
CONTACT
Toren Finkel (National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA)
Tel: +1 301 402 4081; E-mail: finkelt@nih.gov
Geology: The creeping San Andreas
Scientists have discovered talc in rock samples drilled through the San Andreas fault, which could explain why this segment of the tectonic boundary experiences such a high rate of creep. The central Californian part of the San Andreas fault very slowly moves or ‘creeps’ along at a rate of up to 28 millimetres a year and is thought to be the weakest zone of the 1,300-kilometre plate boundary between North America and the Pacific. This weakness was proposed to be due to the presence of the metamorphic rock serpentinite, but recent pressure and temperature measurements have shown that serpentinite is actually too strong and unstable to produce the observed conditions.
Diane Moore and Michael Rymer report the discovery of talc in cuttings collected during drilling of the fault zone. This three-kilometre-deep drill hole — part of the San Andreas Fault Observatory at Depth (SAFOD) — is located near Parkfield in central California. Instruments have been installed across the fault to record data near the source of earthquakes, and rock and fluid samples have been collected to help scientists evaluate the geological properties that control the seismological behaviour of the fault in the region.
The authors examined the mineral composition of grains of serpentinite collected at three-metre intervals. They found that talc of recent origin had replaced the serpentinite along veins and foliations. The presence of talc in the active trace of the San Andreas fault is significant because talc has a very low shear strength in the temperature range found in the fault. They conclude that talc may therefore provide the connection between serpentinite and creep in the San Andreas fault.
CONTACT
Diane Moore (US Geological Survey, Menlo Park, CA, USA)
Tel: +1 650 329 4825; E-mail: dmoore@usgs.gov
Christopher Wibberley (Universite de Nice - Sophia Antipolis, Valbonne, France) N&V author
Tel: +33 4 92 94 26 32; E-mail: wibbs@geoazur.unice.fr
Scientists have discovered talc in rock samples drilled through the San Andreas fault, which could explain why this segment of the tectonic boundary experiences such a high rate of creep. The central Californian part of the San Andreas fault very slowly moves or ‘creeps’ along at a rate of up to 28 millimetres a year and is thought to be the weakest zone of the 1,300-kilometre plate boundary between North America and the Pacific. This weakness was proposed to be due to the presence of the metamorphic rock serpentinite, but recent pressure and temperature measurements have shown that serpentinite is actually too strong and unstable to produce the observed conditions.
Diane Moore and Michael Rymer report the discovery of talc in cuttings collected during drilling of the fault zone. This three-kilometre-deep drill hole — part of the San Andreas Fault Observatory at Depth (SAFOD) — is located near Parkfield in central California. Instruments have been installed across the fault to record data near the source of earthquakes, and rock and fluid samples have been collected to help scientists evaluate the geological properties that control the seismological behaviour of the fault in the region.
The authors examined the mineral composition of grains of serpentinite collected at three-metre intervals. They found that talc of recent origin had replaced the serpentinite along veins and foliations. The presence of talc in the active trace of the San Andreas fault is significant because talc has a very low shear strength in the temperature range found in the fault. They conclude that talc may therefore provide the connection between serpentinite and creep in the San Andreas fault.
CONTACT
Diane Moore (US Geological Survey, Menlo Park, CA, USA)
Tel: +1 650 329 4825; E-mail: dmoore@usgs.gov
Christopher Wibberley (Universite de Nice - Sophia Antipolis, Valbonne, France) N&V author
Tel: +33 4 92 94 26 32; E-mail: wibbs@geoazur.unice.fr
Social mammals: Drive him away or let him stay
Female spotted hyaenas are the determining force behind building a healthy clan. Research shows that female mate-choice is the main factor behind which group males begin their sexual career. Males that responded best to the female preferences had the highest long-term reproductive success.
Dispersal has a significant impact on lifetime reproductive success, and in group-living animals it is usually male biased. Oliver Höner and colleagues use microsatellite DNA profiling in their study and show that the responses of male hyaenas to female mate-choice rules mean that there are no specific kin discrimination mechanisms needed to avoid inbreeding. This is the first empirical study to demonstrate that male dispersal is the result of an adaptive response to female mate-choice.
CONTACT
Oliver Höner (Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany)
Tel: +49 30 5168 516; E-mail: hoener@izw-berlin.de
Female spotted hyaenas are the determining force behind building a healthy clan. Research shows that female mate-choice is the main factor behind which group males begin their sexual career. Males that responded best to the female preferences had the highest long-term reproductive success.
Dispersal has a significant impact on lifetime reproductive success, and in group-living animals it is usually male biased. Oliver Höner and colleagues use microsatellite DNA profiling in their study and show that the responses of male hyaenas to female mate-choice rules mean that there are no specific kin discrimination mechanisms needed to avoid inbreeding. This is the first empirical study to demonstrate that male dispersal is the result of an adaptive response to female mate-choice.
CONTACT
Oliver Höner (Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany)
Tel: +49 30 5168 516; E-mail: hoener@izw-berlin.de
Tuesday, August 14, 2007
Carotene from Crude Palm Oil
Palm oil is rich in carotene. However current commercial production of edible oil results in the loss of carotenes. Now, researchers have found a way to recover carotenes from crude palm oil.
Carotenes are yellow to orange pigments found in carrots, leafy vegetables, milk fat and egg yolk. The a- and b-carotenes are associated with synthesis of vitamin A in the liver and may offer some protection against cancer as well.
Commercially, carotenes are used in food coloration, vitamin supplements, pharmaceutical and cosmetic products. Although palm oil is rich in carotenes (about 600 parts per million), carotenes are destroyed or discarded by bleaching and stripping operations in the oil refining process. Commercial production of carotenes by chemical conversion of crude palm oil (CPO) results in loss of edible oil.
This recovery method involves adsorption chromatography by synthetic polymer adsorbent. By employing this method, carotenes were concentrated up to 100,000 ppm in a two step chromatography operation.
The basic component is the chromatography column which is packed with a synthetic porous polymer adsorbent. Of several adsorbents tested, one adsorbent was found which could adsorb the carotene from CPO by the chromatographic column, allowing the oil to pass through. The solvents used to elute out both oil and carotene are non-toxic, can be removed by an evaporator and are considered safe for use in producing edible oil.
Using this process, palm carotene was successfully concentrated to about 160 times its original concentration in CPO. More than 90% of the oil was removed without altering the triglyceride profile of the oil. By manipulating the column temperature and CPO loading onto the column, 85% of carotenes were recovered. Only a chromatographic column needs to be inserted in the present palm oil refining process. The addition of an evaporator and a distillation column for solvent removal and solvent regeneration would enable the solvent to be recycled and save cost.
Researcher: Badlishah Sham Baharin
Department of Food Technology
Faculty of Food Science and Technology
Universiti Putra Malaysia
43400 UPM, Serdang, Selangor
Malaysia
Tel: +603 8946 8394, +6012 914 4984
Fax: +603 8942 3552
E-mail: badli@fsb.upm.edu.my
and
Dr. Nayan KANWAL
Email: ndeeps@admin.upm.edu.my
Palm oil is rich in carotene. However current commercial production of edible oil results in the loss of carotenes. Now, researchers have found a way to recover carotenes from crude palm oil.
Carotenes are yellow to orange pigments found in carrots, leafy vegetables, milk fat and egg yolk. The a- and b-carotenes are associated with synthesis of vitamin A in the liver and may offer some protection against cancer as well.
Commercially, carotenes are used in food coloration, vitamin supplements, pharmaceutical and cosmetic products. Although palm oil is rich in carotenes (about 600 parts per million), carotenes are destroyed or discarded by bleaching and stripping operations in the oil refining process. Commercial production of carotenes by chemical conversion of crude palm oil (CPO) results in loss of edible oil.
This recovery method involves adsorption chromatography by synthetic polymer adsorbent. By employing this method, carotenes were concentrated up to 100,000 ppm in a two step chromatography operation.
The basic component is the chromatography column which is packed with a synthetic porous polymer adsorbent. Of several adsorbents tested, one adsorbent was found which could adsorb the carotene from CPO by the chromatographic column, allowing the oil to pass through. The solvents used to elute out both oil and carotene are non-toxic, can be removed by an evaporator and are considered safe for use in producing edible oil.
Using this process, palm carotene was successfully concentrated to about 160 times its original concentration in CPO. More than 90% of the oil was removed without altering the triglyceride profile of the oil. By manipulating the column temperature and CPO loading onto the column, 85% of carotenes were recovered. Only a chromatographic column needs to be inserted in the present palm oil refining process. The addition of an evaporator and a distillation column for solvent removal and solvent regeneration would enable the solvent to be recycled and save cost.
Researcher: Badlishah Sham Baharin
Department of Food Technology
Faculty of Food Science and Technology
Universiti Putra Malaysia
43400 UPM, Serdang, Selangor
Malaysia
Tel: +603 8946 8394, +6012 914 4984
Fax: +603 8942 3552
E-mail: badli@fsb.upm.edu.my
and
Dr. Nayan KANWAL
Email: ndeeps@admin.upm.edu.my
A sponge to soak up regulatory RNAs
Genetically encoded inhibitors that soak up microRNAs in mammalian. MicroRNAs provides valuable insights into their function during normal development and disease.
MicroRNAs, unlike longer messenger RNAs (mRNAs), do not contain information for making a protein, but their short, 21 nucleotide, sequences specifically regulate mRNA expression. MicroRNAs bind to partly complementary sequences on their target mRNAs and as a consequence the mRNA is either marked for decay or protein translation is inhibited. Overexpression of certain microRNAs has been linked to cancer and other diseases and a better understanding of their action is therefore important.
Philip Sharp and colleagues have developed a tool to specifically block microRNAs. The principle of their system is based on soaking up all the microRNAs with a complementary decoy sequence, so the mRNA can express its protein unhindered. In contrast to previously described chemically synthesized microRNA inhibitors, these microRNA sponges are genetically encoded. They are provided to the cell either in form of a plasmid or they are stably integrated into the genome of a cell. This provides a much higher level of control over the amount of microRNA sponges a cell produces and allows microRNA action in a specific cell or tissue type to be studied.
Author contact:
Philip Sharp (Massachusetts Institute of Technology, Cambridge, MA, USA)
Tel: +1 617 253 6421; E-mail: sharppa@mit.edu
Genetically encoded inhibitors that soak up microRNAs in mammalian. MicroRNAs provides valuable insights into their function during normal development and disease.
MicroRNAs, unlike longer messenger RNAs (mRNAs), do not contain information for making a protein, but their short, 21 nucleotide, sequences specifically regulate mRNA expression. MicroRNAs bind to partly complementary sequences on their target mRNAs and as a consequence the mRNA is either marked for decay or protein translation is inhibited. Overexpression of certain microRNAs has been linked to cancer and other diseases and a better understanding of their action is therefore important.
Philip Sharp and colleagues have developed a tool to specifically block microRNAs. The principle of their system is based on soaking up all the microRNAs with a complementary decoy sequence, so the mRNA can express its protein unhindered. In contrast to previously described chemically synthesized microRNA inhibitors, these microRNA sponges are genetically encoded. They are provided to the cell either in form of a plasmid or they are stably integrated into the genome of a cell. This provides a much higher level of control over the amount of microRNA sponges a cell produces and allows microRNA action in a specific cell or tissue type to be studied.
Author contact:
Philip Sharp (Massachusetts Institute of Technology, Cambridge, MA, USA)
Tel: +1 617 253 6421; E-mail: sharppa@mit.edu
Signalling flies to sleep
A particular signalling pathway is shown to be important in regulation and maintenance of sleep. Fruit fly Drosophila may be a good model in which to identify the molecular pathways involved in sleep regulation.
Fruit flies (and other insects) undergo a process that is biologically similar to sleep in mammals, including immobility and additional ‘catch-up’ sleep following sleep deprivation. Ralph Greenspan and colleagues demonstrate that the activation of the epidermal growth factor receptor, which is known to be involved in natural 24 hour rhythms, led to an increase in sleep. Blocking activity in this signalling pathway led to a decrease in sleep and difficulty in catching up on sleep after deprivation. This regulation occurred in a region of the fly brain that is developmentally and functionally similar to the hypothalamus in mammals – the part of our brain that controls sleep.
Using this type of experimental approach may make it easier and faster for scientists to identify additional molecules required for the induction and/or maintenance of sleep. Drug companies might then be able to use this information to design better sleep aids.
Author contact:
Ralph Greenspan (The Neurosciences Institute, San Diego, CA, USA)
Tel: +1 858 626 2075; E-mail: greenspan@nsi.edu
A particular signalling pathway is shown to be important in regulation and maintenance of sleep. Fruit fly Drosophila may be a good model in which to identify the molecular pathways involved in sleep regulation.
Fruit flies (and other insects) undergo a process that is biologically similar to sleep in mammals, including immobility and additional ‘catch-up’ sleep following sleep deprivation. Ralph Greenspan and colleagues demonstrate that the activation of the epidermal growth factor receptor, which is known to be involved in natural 24 hour rhythms, led to an increase in sleep. Blocking activity in this signalling pathway led to a decrease in sleep and difficulty in catching up on sleep after deprivation. This regulation occurred in a region of the fly brain that is developmentally and functionally similar to the hypothalamus in mammals – the part of our brain that controls sleep.
Using this type of experimental approach may make it easier and faster for scientists to identify additional molecules required for the induction and/or maintenance of sleep. Drug companies might then be able to use this information to design better sleep aids.
Author contact:
Ralph Greenspan (The Neurosciences Institute, San Diego, CA, USA)
Tel: +1 858 626 2075; E-mail: greenspan@nsi.edu
Positive selection during human evolution
Sequences in the human genome that have undergone positive selection are found in abundance in regions that regulate the expression of genes involved in neural or nutritional processes. Some of the first large-scale evidence that the evolution of some human-specific traits can be traced to changes in gene regulatory (promoter) regions.
Cognitive, behavioural and dietary differences are among the most obvious differences between humans and the great apes. Although one might expect that genes involved in these processes would show evidence of positive natural selection in humans since the most recent common ancestor of humans and chimpanzees, there is little evidence to support this.
Ralph Haygood and colleagues compared probable promoter regions for more than 6,000 genes in the human, chimpanzee and macaque genomes. They generated statistics to identify those promoters that likely had undergone positive selection in the human genome. At least 250 such promoters were found. Although they represent several functional categories, prominent among them are promoters linked to genes involved in neural development and function, including axon guidance, synapse formation and neurotransmission in the brain. Nutrition-related genes include a large number involved in glucose metabolism.
Author contact:
Ralph Haygood (Duke University, Durham, NC, USA)
Tel: +1 919 668 6249; E-mail: rhaygood@duke.edu
Sequences in the human genome that have undergone positive selection are found in abundance in regions that regulate the expression of genes involved in neural or nutritional processes. Some of the first large-scale evidence that the evolution of some human-specific traits can be traced to changes in gene regulatory (promoter) regions.
Cognitive, behavioural and dietary differences are among the most obvious differences between humans and the great apes. Although one might expect that genes involved in these processes would show evidence of positive natural selection in humans since the most recent common ancestor of humans and chimpanzees, there is little evidence to support this.
Ralph Haygood and colleagues compared probable promoter regions for more than 6,000 genes in the human, chimpanzee and macaque genomes. They generated statistics to identify those promoters that likely had undergone positive selection in the human genome. At least 250 such promoters were found. Although they represent several functional categories, prominent among them are promoters linked to genes involved in neural development and function, including axon guidance, synapse formation and neurotransmission in the brain. Nutrition-related genes include a large number involved in glucose metabolism.
Author contact:
Ralph Haygood (Duke University, Durham, NC, USA)
Tel: +1 919 668 6249; E-mail: rhaygood@duke.edu
Prevention and treatment of craniosynostosis
Two successful strategies for the prevention and treatment of craniosynostosis – premature fusion of the sutures in the skull. At least one of the approaches may be testable in humans in the near term. Craniosynostosis is caused by the sutures of the skull closing too early in infancy, which affects normal brain and skull growth. It occurs in approximately 1 of every 2,500 live births. Apert syndrome, a rare but quite severe form of craniosynostosis, is caused in most cases by a specific mutation in a cell-surface receptor called FGFR2.
Chu-Xia Deng and colleagues created a mouse model of Apert syndrome that bears one of the most common FGFR2 mutations seen in humans. When these mice were crossed with mice expressing a ‘short hairpin’ RNA molecule specifically designed to block expression of the mutant form of FGFR2, the offspring that carry the FGFR2 mutation developed normally. The authors also report the involvement in the disease of an enzyme called ERK, which is regulated by FGFR2. When they injected a drug that inhibits ERK activity into pregnant mice carrying the FGFR2 mutation, the offspring showed no signs of Apert syndrome. Moreover, when the drug was injected at the onset of the disease during the early postnatal period, at least some of the treated mice maintained a normal appearance, although the treatment’s effectiveness was greater in male than in female mice.
Drugs similar to those used in this study are already being tested in clinical trials as anticancer drugs, and may now have additional applications in the prevention and treatment of birth defects such as craniosynostosis.
Author contact:
Chu-Xia Deng (National Institutes of Health, Bethesda, MD, USA)
Tel: +1 301 402 7225; E-mail: chuxiad@bdg10.niddk.nih.gov
Two successful strategies for the prevention and treatment of craniosynostosis – premature fusion of the sutures in the skull. At least one of the approaches may be testable in humans in the near term. Craniosynostosis is caused by the sutures of the skull closing too early in infancy, which affects normal brain and skull growth. It occurs in approximately 1 of every 2,500 live births. Apert syndrome, a rare but quite severe form of craniosynostosis, is caused in most cases by a specific mutation in a cell-surface receptor called FGFR2.
Chu-Xia Deng and colleagues created a mouse model of Apert syndrome that bears one of the most common FGFR2 mutations seen in humans. When these mice were crossed with mice expressing a ‘short hairpin’ RNA molecule specifically designed to block expression of the mutant form of FGFR2, the offspring that carry the FGFR2 mutation developed normally. The authors also report the involvement in the disease of an enzyme called ERK, which is regulated by FGFR2. When they injected a drug that inhibits ERK activity into pregnant mice carrying the FGFR2 mutation, the offspring showed no signs of Apert syndrome. Moreover, when the drug was injected at the onset of the disease during the early postnatal period, at least some of the treated mice maintained a normal appearance, although the treatment’s effectiveness was greater in male than in female mice.
Drugs similar to those used in this study are already being tested in clinical trials as anticancer drugs, and may now have additional applications in the prevention and treatment of birth defects such as craniosynostosis.
Author contact:
Chu-Xia Deng (National Institutes of Health, Bethesda, MD, USA)
Tel: +1 301 402 7225; E-mail: chuxiad@bdg10.niddk.nih.gov
GENETICS : How West Nile virus became dangerous
A single causative mutation has been identified in the virulent strain of West Nile virus that has been responsible for deadly outbreaks of human encephalitis in recent years.
West Nile virus is a mosquito-borne virus that is transmitted between avian hosts and mosquitoes, and until the mid 1990s was associated with only mild infections of humans in Africa and the Middle East. More severe outbreaks of encephalitis were reported in Romania in 1996, and subsequently in Israel, Tunisia, Russia, and North America.
Aaron Brault and colleagues sequenced the genomes of West Nile virus strains that have been sampled globally in recent years, and found that a single mutation in a gene encoding an enzyme called a helicase arose independently on at least three separate occasions in strains associated with outbreaks of disease. When a poorly virulent strain from Kenya was engineered to contain the helicase mutation, it was found to replicate more rapidly and to cause death of inoculated American crows at a much higher rate than that of the original Kenyan virus. The authors also provide evidence that the helicase mutation was positively selected, which they say highlights the potential for viruses like West Nile to adapt rapidly to changing environments, with unpredictable consequences for human health.
Author contact:
Aaron Brault (University of California, Davis, CA, USA)
Tel: +1 530 754 8359; E-mail: acbrault@ucdavis.edu
A single causative mutation has been identified in the virulent strain of West Nile virus that has been responsible for deadly outbreaks of human encephalitis in recent years.
West Nile virus is a mosquito-borne virus that is transmitted between avian hosts and mosquitoes, and until the mid 1990s was associated with only mild infections of humans in Africa and the Middle East. More severe outbreaks of encephalitis were reported in Romania in 1996, and subsequently in Israel, Tunisia, Russia, and North America.
Aaron Brault and colleagues sequenced the genomes of West Nile virus strains that have been sampled globally in recent years, and found that a single mutation in a gene encoding an enzyme called a helicase arose independently on at least three separate occasions in strains associated with outbreaks of disease. When a poorly virulent strain from Kenya was engineered to contain the helicase mutation, it was found to replicate more rapidly and to cause death of inoculated American crows at a much higher rate than that of the original Kenyan virus. The authors also provide evidence that the helicase mutation was positively selected, which they say highlights the potential for viruses like West Nile to adapt rapidly to changing environments, with unpredictable consequences for human health.
Author contact:
Aaron Brault (University of California, Davis, CA, USA)
Tel: +1 530 754 8359; E-mail: acbrault@ucdavis.edu
CHEMICAL BIOLOGY : Natural products in a flask
Despite their complicated chemical structures, some potential drug leads can be created by mixing together enzymes in a flask.Chemicals that occur naturally, such as penicillin, have traditionally been very important sources of drugs. These ‘natural products’ often have very elaborate chemical structures that make them difficult to create by chemical synthesis.
Groups led by Bradley Moore and Christopher Walsh now independently show that two complex natural products, which have potential antibacterial and antitumour activity, can be made by taking the enzymes that normally create these chemicals inside cells and mixing them together outside of a cell. These studies have provided new insight into how these natural products are made and will help further efforts to turn these chemicals into drugs.
Author contacts:
Bradley Moore (University of California, San Diego, CA, USA) Author paper [1]
Tel: +1 858 822 6650; E-mail: bsmoore@ucsd.edu
Christopher Walsh (Harvard Medical School, Boston, MA, USA) Author paper [2]
Tel: +1 617 432 1715; E-mail: christopher_walsh@hms.harvard.edu
Despite their complicated chemical structures, some potential drug leads can be created by mixing together enzymes in a flask.Chemicals that occur naturally, such as penicillin, have traditionally been very important sources of drugs. These ‘natural products’ often have very elaborate chemical structures that make them difficult to create by chemical synthesis.
Groups led by Bradley Moore and Christopher Walsh now independently show that two complex natural products, which have potential antibacterial and antitumour activity, can be made by taking the enzymes that normally create these chemicals inside cells and mixing them together outside of a cell. These studies have provided new insight into how these natural products are made and will help further efforts to turn these chemicals into drugs.
Author contacts:
Bradley Moore (University of California, San Diego, CA, USA) Author paper [1]
Tel: +1 858 822 6650; E-mail: bsmoore@ucsd.edu
Christopher Walsh (Harvard Medical School, Boston, MA, USA) Author paper [2]
Tel: +1 617 432 1715; E-mail: christopher_walsh@hms.harvard.edu
Saturday, August 11, 2007
Halting the inflammation overload
Researchers discover a key molecule involved in regulating our immune response
Our immune system protects us against microbial pathogens that invade our cells and cause illness. When receptors on the cell surface detect microbes, a cascade of signals and activities within the cell is triggered, resulting in inflammation, which is part of our early defense against pathogens.
Immunologists from the RIKEN Research Center for Allergy and Immunology, Yokohama, and the Harvard School of Public Health, US, recently published a study on the regulation of this system1. Without regulation, an unstoppable immune reaction leads to excessive inflammation, which causes conditions such as asthma and arthritis.
The researchers studied a molecule called NF-κB that contains two different subunits known as p65 and p50 and normally resides in the cytoplasm of cells. When this molecule receives the appropriate signal, it enters the cell nucleus and switches on immunoregulatory genes that encode pro-inflammatory molecules. If the process is not stopped, the immune reaction continues. To terminate this reaction promptly, it is important that the p65 molecule that starts this sequence of events is degraded once it has done its job.
RIKEN’s Tsuneyasu Kaisho and his team have identified a pathway that leads to the degradation of p65. Their work shows that the process involves the specific attachment of the protein molecule ubiquitin to p65 followed by transportation of the ‘ubiquitinated’ p65 to distinct sub-nuclear domains, called nuclear bodies, where it is ultimately degraded by the proteins found there (Fig. 1).
Critically, the researchers have described a factor called PDLIM2 that has two highly important roles in the regulation of the immune response. It helps ubiquitin to bind to p65 and then targets this complex to the appropriate nuclear bodies for degradation.
The team showed that PDLIM2-deficient mouse cells had uncontrolled immune responses due to the constant activity of NF-κB and augmented production of molecules that cause inflammation. In vivo studies showed mice lacking PDLIM2 were more sensitive to stimulation of the immune response than mice with normal levels of the molecule.
Developing treatments for inflammatory and autoimmune diseases by modifying the PDLIM2-mediated pathways to terminate NF-κB p65 activation is the future aim of the team. According to team member, Takashi Tanaka, the next step towards this goal is to clarify how PDLIM2 activity itself is regulated. This is very important for developing a way to modify its activity in living cells, he says.
Reference
1. Tanaka, T., Grusby, M.J. & Kaisho, T. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nature Immunology 8, 584–591 (2007).
Researchers discover a key molecule involved in regulating our immune response
Our immune system protects us against microbial pathogens that invade our cells and cause illness. When receptors on the cell surface detect microbes, a cascade of signals and activities within the cell is triggered, resulting in inflammation, which is part of our early defense against pathogens.
Immunologists from the RIKEN Research Center for Allergy and Immunology, Yokohama, and the Harvard School of Public Health, US, recently published a study on the regulation of this system1. Without regulation, an unstoppable immune reaction leads to excessive inflammation, which causes conditions such as asthma and arthritis.
The researchers studied a molecule called NF-κB that contains two different subunits known as p65 and p50 and normally resides in the cytoplasm of cells. When this molecule receives the appropriate signal, it enters the cell nucleus and switches on immunoregulatory genes that encode pro-inflammatory molecules. If the process is not stopped, the immune reaction continues. To terminate this reaction promptly, it is important that the p65 molecule that starts this sequence of events is degraded once it has done its job.
RIKEN’s Tsuneyasu Kaisho and his team have identified a pathway that leads to the degradation of p65. Their work shows that the process involves the specific attachment of the protein molecule ubiquitin to p65 followed by transportation of the ‘ubiquitinated’ p65 to distinct sub-nuclear domains, called nuclear bodies, where it is ultimately degraded by the proteins found there (Fig. 1).
Critically, the researchers have described a factor called PDLIM2 that has two highly important roles in the regulation of the immune response. It helps ubiquitin to bind to p65 and then targets this complex to the appropriate nuclear bodies for degradation.
The team showed that PDLIM2-deficient mouse cells had uncontrolled immune responses due to the constant activity of NF-κB and augmented production of molecules that cause inflammation. In vivo studies showed mice lacking PDLIM2 were more sensitive to stimulation of the immune response than mice with normal levels of the molecule.
Developing treatments for inflammatory and autoimmune diseases by modifying the PDLIM2-mediated pathways to terminate NF-κB p65 activation is the future aim of the team. According to team member, Takashi Tanaka, the next step towards this goal is to clarify how PDLIM2 activity itself is regulated. This is very important for developing a way to modify its activity in living cells, he says.
Reference
1. Tanaka, T., Grusby, M.J. & Kaisho, T. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nature Immunology 8, 584–591 (2007).
A better way to make a muscle?
New revelations about how muscle tissue forms could help scientists develop more effective strategies for therapeutic tissue replacement
Even the mightiest individuals are vulnerable to muscle loss, whether from severe injury, old age, or as a byproduct of disease, and many scientists see the engineering of replacement muscle as a promising solution. Current methods involve the culture of progenitor stem cells, known as myoblasts, for transplantation. These cells in turn fuse and differentiate to form myofibers—mature muscle fibers capable of contraction.
Myoblasts show promise for muscle replacement, but cultured myofibers may be superior for clinical use, and could reduce the risk of tumor formation—a potential hazard with undifferentiated myoblasts. Unfortunately, current strategies for myofiber production have proven inadequate, and myofibers produced from cultured myoblasts tend to be poorly differentiated. “Myoblast transplantation is far ahead of myofiber transplantation,” explains Nobuhiro Morishima, of the RIKEN Discovery Research Institute in Wako. “And one of the reasons for the slow progress of cultured myofiber transplantation is the inefficiency of myofiber formation in culture.”
Previous work by Morishima’s team revealed that differentiation of myoblasts appears to correlate with functional disruption of the endoplasmic reticulum (ER), the cellular organelle responsible for protein folding and processing1. Now the team has used chemicals that directly trigger this condition, known as ‘ER stress’, in cultured myoblasts to better understand the role of this process in muscle development2.
Surprisingly, treated cells responded in different ways; nearly half the treated cells died, via a process known as apoptosis, while the other cells survived and differentiated to form fully functional myofibers. Closer examination revealed that the ‘survivors’ were expressing higher levels of Bcl-xL, a protein known to block apoptosis. Morishima suggests that this process of stress-mediated death may be a means for preventing ‘weak’ cells from forming myofibers, as muscle tissue is routinely exposed to stressful physiological conditions. What remains unclear is how otherwise identical cells end up choosing between two different pathways during differentiation, and Morishima hopes to examine this further in the future.
For now, however, his team is encouraged by the high yield of functioning myofibers that can be generated through this culture method, and they are now attempting to better understand the differentiation process and how to exploit it for biomedical applications. “We would like to answer the question of how the myoblast-differentiating ER stress conditions naturally occur in the body,” he says, “and hopefully we will be able to show the merit of ER stress for myofiber formation in vivo for the advancement of both basic biology and clinical research.”
Reference
1. Nakanishi, K., Sudo, T. & Morishima, N. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. Journal of Cell Biology 169, 555–560 (2005).
2. Nakanishi, K., Dohmae, N. & Morishima, N. Endoplasmic reticulum stress increases myofiber formation in vitro. FASEB Journal, published online, 13 April 2007 (doi: 10.1096/fj06-6408com).
New revelations about how muscle tissue forms could help scientists develop more effective strategies for therapeutic tissue replacement
Even the mightiest individuals are vulnerable to muscle loss, whether from severe injury, old age, or as a byproduct of disease, and many scientists see the engineering of replacement muscle as a promising solution. Current methods involve the culture of progenitor stem cells, known as myoblasts, for transplantation. These cells in turn fuse and differentiate to form myofibers—mature muscle fibers capable of contraction.
Myoblasts show promise for muscle replacement, but cultured myofibers may be superior for clinical use, and could reduce the risk of tumor formation—a potential hazard with undifferentiated myoblasts. Unfortunately, current strategies for myofiber production have proven inadequate, and myofibers produced from cultured myoblasts tend to be poorly differentiated. “Myoblast transplantation is far ahead of myofiber transplantation,” explains Nobuhiro Morishima, of the RIKEN Discovery Research Institute in Wako. “And one of the reasons for the slow progress of cultured myofiber transplantation is the inefficiency of myofiber formation in culture.”
Previous work by Morishima’s team revealed that differentiation of myoblasts appears to correlate with functional disruption of the endoplasmic reticulum (ER), the cellular organelle responsible for protein folding and processing1. Now the team has used chemicals that directly trigger this condition, known as ‘ER stress’, in cultured myoblasts to better understand the role of this process in muscle development2.
Surprisingly, treated cells responded in different ways; nearly half the treated cells died, via a process known as apoptosis, while the other cells survived and differentiated to form fully functional myofibers. Closer examination revealed that the ‘survivors’ were expressing higher levels of Bcl-xL, a protein known to block apoptosis. Morishima suggests that this process of stress-mediated death may be a means for preventing ‘weak’ cells from forming myofibers, as muscle tissue is routinely exposed to stressful physiological conditions. What remains unclear is how otherwise identical cells end up choosing between two different pathways during differentiation, and Morishima hopes to examine this further in the future.
For now, however, his team is encouraged by the high yield of functioning myofibers that can be generated through this culture method, and they are now attempting to better understand the differentiation process and how to exploit it for biomedical applications. “We would like to answer the question of how the myoblast-differentiating ER stress conditions naturally occur in the body,” he says, “and hopefully we will be able to show the merit of ER stress for myofiber formation in vivo for the advancement of both basic biology and clinical research.”
Reference
1. Nakanishi, K., Sudo, T. & Morishima, N. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. Journal of Cell Biology 169, 555–560 (2005).
2. Nakanishi, K., Dohmae, N. & Morishima, N. Endoplasmic reticulum stress increases myofiber formation in vitro. FASEB Journal, published online, 13 April 2007 (doi: 10.1096/fj06-6408com).
Electron theory solves heavy problem
Usual properties of lithium vanadate explained
Today’s high-tech devices would not exist without a good theory to predict how electrons move through semiconductor crystals. But gaps remain in the theory—some insulating materials are erroneously predicted to conduct electricity, for example. Resolving these problems could lead to a more robust theory that enables new breakthroughs in electronics.
As part of this effort, a RIKEN researcher and his colleagues have developed a new theoretical method for predicting how electrons will behave at very low temperatures, called the projective quantum Monte Carlo (PQMC) method, and used it to solve a puzzle about the unusual electrical conductivity, heat capacity and magnetic properties of a material called lithium vanadate (
In a single atom, electrons can only occupy certain energy levels, known as orbitals. But in a crystal made up of trillions of atoms these orbitals smear into bands, each representing a range of energies available to the electrons. In semiconductors, electrons must acquire enough energy to hop into the lowest unoccupied band before they start to flow.
In certain materials, there is a magnetic attraction between the electrons flowing through the conduction band and those which remain trapped on the stationary atoms. This can slow the conduction electrons down, and make the trapped electrons, known as ‘heavy fermions’, behave as if they were much heavier than normal. Lithium vanadate is the first material where electrons residing in a lower orbital, called 3d, are responsible for heavy fermion behavior that appears below about -240 ˚C.
Despite the chilly conditions, there has been hot debate about exactly how this works. Now Ryotaro Arita, of RIKEN’s Discovery Research Institute in Wako, and his colleagues believe they have the answer. The team has combined two established ways of calculating how electrons spread around atoms, and used PQMC to extrapolate the case to very low temperatures.
Their calculations show that the orbitals around the vanadium atoms are subdivided into a lower energy band (a1g) where electrons remain tethered to their parent atoms, while those in an upper level (eg) effectively form a conduction band. The lower band acts as a Mott insulator: such materials do not conduct electricity because the mutual repulsion between neighboring electrons forces them to stick by their parent atoms. This makes the a1g band primarily responsible for the heavy fermion effects seen in LiV2O4.
The team now hopes to refine their theory further to explain other anomalous behavior in metals, insulators and semiconductors, says Arita.
Reference
1. Arita, R., Held, K., Lukoyanov, A. V. & Anisimov V. I. Doped Mott insulator as the origin of heavy-fermion behavior in LiV2O4. Physical Review Letters 98, 166402 (2007).
Usual properties of lithium vanadate explained
Today’s high-tech devices would not exist without a good theory to predict how electrons move through semiconductor crystals. But gaps remain in the theory—some insulating materials are erroneously predicted to conduct electricity, for example. Resolving these problems could lead to a more robust theory that enables new breakthroughs in electronics.
As part of this effort, a RIKEN researcher and his colleagues have developed a new theoretical method for predicting how electrons will behave at very low temperatures, called the projective quantum Monte Carlo (PQMC) method, and used it to solve a puzzle about the unusual electrical conductivity, heat capacity and magnetic properties of a material called lithium vanadate (
In a single atom, electrons can only occupy certain energy levels, known as orbitals. But in a crystal made up of trillions of atoms these orbitals smear into bands, each representing a range of energies available to the electrons. In semiconductors, electrons must acquire enough energy to hop into the lowest unoccupied band before they start to flow.
In certain materials, there is a magnetic attraction between the electrons flowing through the conduction band and those which remain trapped on the stationary atoms. This can slow the conduction electrons down, and make the trapped electrons, known as ‘heavy fermions’, behave as if they were much heavier than normal. Lithium vanadate is the first material where electrons residing in a lower orbital, called 3d, are responsible for heavy fermion behavior that appears below about -240 ˚C.
Despite the chilly conditions, there has been hot debate about exactly how this works. Now Ryotaro Arita, of RIKEN’s Discovery Research Institute in Wako, and his colleagues believe they have the answer. The team has combined two established ways of calculating how electrons spread around atoms, and used PQMC to extrapolate the case to very low temperatures.
Their calculations show that the orbitals around the vanadium atoms are subdivided into a lower energy band (a1g) where electrons remain tethered to their parent atoms, while those in an upper level (eg) effectively form a conduction band. The lower band acts as a Mott insulator: such materials do not conduct electricity because the mutual repulsion between neighboring electrons forces them to stick by their parent atoms. This makes the a1g band primarily responsible for the heavy fermion effects seen in LiV2O4.
The team now hopes to refine their theory further to explain other anomalous behavior in metals, insulators and semiconductors, says Arita.
Reference
1. Arita, R., Held, K., Lukoyanov, A. V. & Anisimov V. I. Doped Mott insulator as the origin of heavy-fermion behavior in LiV2O4. Physical Review Letters 98, 166402 (2007).
Friday, August 10, 2007
New real-time, cross platform intelligent network monitoring system
jEnterprise is a real-time continuous network monitoring tool to prevent potential performance degradation or downtime. It provides intelligent troubleshooting and support for new protocols such as IPv6 to ensure coverage at all times and is the world's only cross platform enterprise level distributed network analysis and troubleshooting tool
Project Title: jEnterprise: An Enterprise Intelligent Network Monitoring and Troubleshooting Tool Based on Autonomous Self Managed Mobile Agent
Researchers:
Assoc. Prof. Dr. Sureswaran Ramadass
Azlan Osman
Ahmad Manasrah
Muhammad Fermi Pasha
Saravaneh A/P Supramaniam
Selvakumar Manickam
Network and system administrators have turned to network monitoring and protection tools to ensure smooth operation of networks within the enterprise. Most organization has about 50 to 1000 computers and the numbers are growing.
Imagine one of the computers is flooding the network; the system administrator would then have to investigate each machine to find out which one is causing the problem by making desk-side visits. Such processes are cumbersome, inaccurate and in some cases, take days (even weeks) to pinpoint and solve the problem.
jEnterprise is a real-time, around-the-clock network monitoring tool that continuously monitor enterprise network to prevent potential performance degradation or downtime. It provides intelligent troubleshooting as well as support for new protocols that supports next generation network protocols such as IPv6 to ensure coverage at all times.
jEnterprise will be able to provide global access to remotely monitor any network on any corner of the world tunneling via the Internet. It offers complete monitoring from Physical Layer to Application Layer. The uniqueness of jEnterprise Suite as compared to other tools is that it not only provides a centralized visualization and analysis engine, called jCMC (Centralized Monitoring Console), it also provides an autonomous and intelligent self managed remote agents, called jRemote, to monitor and protect each remote network segment within the organization and a managed intelligent server, called jServer, to collect network data from jRemote agents and perform intelligent analysis. This interesting and unique distributed architecture creates a complete protected environment for the organizations servers, PC and the network.
j-Enterprise is also the world's only cross platform enterprise level distributed network analysis and troubleshooting tool.
Contact :
Assoc. Prof. Dr. Sureswaran Ramadass
National Advanced IPv6 Centre (NAv6)
Universiti Sains Malaysia
jEnterprise is a real-time continuous network monitoring tool to prevent potential performance degradation or downtime. It provides intelligent troubleshooting and support for new protocols such as IPv6 to ensure coverage at all times and is the world's only cross platform enterprise level distributed network analysis and troubleshooting tool
Project Title: jEnterprise: An Enterprise Intelligent Network Monitoring and Troubleshooting Tool Based on Autonomous Self Managed Mobile Agent
Researchers:
Assoc. Prof. Dr. Sureswaran Ramadass
Azlan Osman
Ahmad Manasrah
Muhammad Fermi Pasha
Saravaneh A/P Supramaniam
Selvakumar Manickam
Network and system administrators have turned to network monitoring and protection tools to ensure smooth operation of networks within the enterprise. Most organization has about 50 to 1000 computers and the numbers are growing.
Imagine one of the computers is flooding the network; the system administrator would then have to investigate each machine to find out which one is causing the problem by making desk-side visits. Such processes are cumbersome, inaccurate and in some cases, take days (even weeks) to pinpoint and solve the problem.
jEnterprise is a real-time, around-the-clock network monitoring tool that continuously monitor enterprise network to prevent potential performance degradation or downtime. It provides intelligent troubleshooting as well as support for new protocols that supports next generation network protocols such as IPv6 to ensure coverage at all times.
jEnterprise will be able to provide global access to remotely monitor any network on any corner of the world tunneling via the Internet. It offers complete monitoring from Physical Layer to Application Layer. The uniqueness of jEnterprise Suite as compared to other tools is that it not only provides a centralized visualization and analysis engine, called jCMC (Centralized Monitoring Console), it also provides an autonomous and intelligent self managed remote agents, called jRemote, to monitor and protect each remote network segment within the organization and a managed intelligent server, called jServer, to collect network data from jRemote agents and perform intelligent analysis. This interesting and unique distributed architecture creates a complete protected environment for the organizations servers, PC and the network.
j-Enterprise is also the world's only cross platform enterprise level distributed network analysis and troubleshooting tool.
Contact :
Assoc. Prof. Dr. Sureswaran Ramadass
National Advanced IPv6 Centre (NAv6)
Universiti Sains Malaysia
Thursday, August 09, 2007
Neuroscience: Understanding antidepressants
A glimpse of the mechanism involved in antidepressant block of neurotransmitter transporters in the brain is revealed in a paper.Eric Gouaux and colleagues wanted to understand the previously elusive action of tricyclic antidepressant (TCA), to aid the design of new inhibitors.
In humans, inhibiting sodium-coupled transporters has an important role in the treatment of a broad range of neurological diseases and conditions. Gouaux and his team provide mechanistic insights into how such transport proteins are blocked by solving the structure of a prokayotic homologue, in complex with various TCAs, at high resolution. They identify an extracellular-facing cavity in the protein as the site of TCA action and thus as a site with therapeutic potential.
Contact:
Eric Gouaux (Oregon Health and Science University/HHMI,Portland, OR, USA)
Tel: +1 503 494 5535; E-mail: gouauxe@ohsu.edu
A glimpse of the mechanism involved in antidepressant block of neurotransmitter transporters in the brain is revealed in a paper.Eric Gouaux and colleagues wanted to understand the previously elusive action of tricyclic antidepressant (TCA), to aid the design of new inhibitors.
In humans, inhibiting sodium-coupled transporters has an important role in the treatment of a broad range of neurological diseases and conditions. Gouaux and his team provide mechanistic insights into how such transport proteins are blocked by solving the structure of a prokayotic homologue, in complex with various TCAs, at high resolution. They identify an extracellular-facing cavity in the protein as the site of TCA action and thus as a site with therapeutic potential.
Contact:
Eric Gouaux (Oregon Health and Science University/HHMI,Portland, OR, USA)
Tel: +1 503 494 5535; E-mail: gouauxe@ohsu.edu
Biodiversity: Insects get tropical
The biodiversity of plant-eating insects across the lowland tropical rainforests of Papua New Guinea may be high, but species tend to be widely distributed. The finding
Vojtech Novotny and colleagues studied around 500 species of butterfly caterpillars, beetles and fruitflies over 75,000 square kilometres of contiguous rainforest. Although species richness was high, as would be expected for the tropics, the species found did not alter much even over hundreds of kilometres, despite a range of different geological terrains.
Host plant specificity of caterpillars, on the other hand, decreases as distance from the equator increases, according to a second paper by Lee A. Dyer and colleagues. So the number of specialist species decreases with increasing latitude. The finding is timely, as biologists have discussed the latitudinal gradient in ecological specialization since the time of Darwin and Wallace, yet quantitative evidence for its existence has been hard to find.
CONTACT
Vojtech Novotny (New Guinea Binatang Research Center, Madang, Papua New Guinea)
Author paper [3]
Tel: +675 853 3258; Email: binatangi@datec.net.pg or novotny@entu.cas.cz
Scott E. Miller (Smithsonian Institution, Washington, DC, USA) Co-author paper [3]
Tel: +1 202 633 5135; E- mail: millers@si.edu
Lee A. Dyer (Tulane University, New Orleans, LA, USA) Author paper [4]
Tel: +1 504 862 8288; E-mail: ldyer@tulane.edu
Nigel E. Stork (University of Melbourne, Australia) N&V author
Tel: +61 3 9250 6806; E-mail: nstork@unimelb.edu.au
The biodiversity of plant-eating insects across the lowland tropical rainforests of Papua New Guinea may be high, but species tend to be widely distributed. The finding
Vojtech Novotny and colleagues studied around 500 species of butterfly caterpillars, beetles and fruitflies over 75,000 square kilometres of contiguous rainforest. Although species richness was high, as would be expected for the tropics, the species found did not alter much even over hundreds of kilometres, despite a range of different geological terrains.
Host plant specificity of caterpillars, on the other hand, decreases as distance from the equator increases, according to a second paper by Lee A. Dyer and colleagues. So the number of specialist species decreases with increasing latitude. The finding is timely, as biologists have discussed the latitudinal gradient in ecological specialization since the time of Darwin and Wallace, yet quantitative evidence for its existence has been hard to find.
CONTACT
Vojtech Novotny (New Guinea Binatang Research Center, Madang, Papua New Guinea)
Author paper [3]
Tel: +675 853 3258; Email: binatangi@datec.net.pg or novotny@entu.cas.cz
Scott E. Miller (Smithsonian Institution, Washington, DC, USA) Co-author paper [3]
Tel: +1 202 633 5135; E- mail: millers@si.edu
Lee A. Dyer (Tulane University, New Orleans, LA, USA) Author paper [4]
Tel: +1 504 862 8288; E-mail: ldyer@tulane.edu
Nigel E. Stork (University of Melbourne, Australia) N&V author
Tel: +61 3 9250 6806; E-mail: nstork@unimelb.edu.au
Neurology: Ubiquitin is ubiquitous in Huntington’s disease
The link between Huntington’s disease and a protein known as ubiquitin may be greater than previously thought
Huntington’s disease is an inherited neurodegenerative disorder, characterized by the accumulation of protein fragments in affected neurons. These so-called inclusion bodies are often abnormally enriched with ubiquitin, suggesting that alterations in the metabolism of this protein might contribute to the disease. Using mass spectrometry, Ron R. Kopito and colleagues systematically analysed the brains of patients with Huntington’s disease as well as two different mouse models of the disease. All of the brain samples contained an abundance of chains of polyubiquitin, establishing changes in the ubiquitin system as a consistent feature of Huntington’s disease pathology.
Protein modification with polyubiquitin chains regulates many essential cellular processes — such as the cell cycle and DNA repair — so altered ubiquitin signalling is likely to have broad consequences for the function and survival of neurons. The authors propose that their technique might be used to achieve a deeper insight into the molecular basis of a variety of neurodegenerative diseases.
CONTACT
Ron R. Kopito (Stanford University, CA, USA)
Tel: +1 650 723 7581; E-mail: kopito@stanford.edu
The link between Huntington’s disease and a protein known as ubiquitin may be greater than previously thought
Huntington’s disease is an inherited neurodegenerative disorder, characterized by the accumulation of protein fragments in affected neurons. These so-called inclusion bodies are often abnormally enriched with ubiquitin, suggesting that alterations in the metabolism of this protein might contribute to the disease. Using mass spectrometry, Ron R. Kopito and colleagues systematically analysed the brains of patients with Huntington’s disease as well as two different mouse models of the disease. All of the brain samples contained an abundance of chains of polyubiquitin, establishing changes in the ubiquitin system as a consistent feature of Huntington’s disease pathology.
Protein modification with polyubiquitin chains regulates many essential cellular processes — such as the cell cycle and DNA repair — so altered ubiquitin signalling is likely to have broad consequences for the function and survival of neurons. The authors propose that their technique might be used to achieve a deeper insight into the molecular basis of a variety of neurodegenerative diseases.
CONTACT
Ron R. Kopito (Stanford University, CA, USA)
Tel: +1 650 723 7581; E-mail: kopito@stanford.edu
Ultrafast X-rays: ‘Dusty mirror’ gets a makeover
Inspired by an old optics experiment carried out by Isaac Newton, researchers have devised a scheme to study microscopic particles with intense ultrafast X-ray pulses. It’s thought this type of X-ray ‘flash’ imaging may be used to explore the three-dimensional dynamics of materials at the timescale of atomic motion.
Newton was puzzled by the circular patterns that appeared when he illuminated a silver-plated mirror. As it turned out, this was caused by interference between two paths of light scattering from dust particles on the front of the mirror — one path of light on its way towards the mirror, and one reflecting from the silvered surface. In this week’s Nature, Henry N. Chapman and colleagues describe a modern, more dynamic version of this ‘dusty mirror’ experiment that uses X-rays.
The team fired their ultrafast light source at a thin membrane containing polystyrene particles placed in front of a mirrored backplate. The incident X-rays cause the polystyrene particles to explode, and they then hit the polystyrene particles a second time as they are reflected back from the mirrored plate. The resulting interference pattern can be used to retrieve information about the polystyrene particles with high time and space resolution.
CONTACT
Henry N. Chapman (Lawrence Livermore National Laboratory, Livermore, CA, USA)
Tel: +1 925 423 1580; E-mail: henry.chapman@llnl.gov
Andrea Cavalleri (University of Oxford, UK) N&V author
Tel: +44 1865 272 365; E-mail: a.cavalleri1@physics.ox.ac.uk
Inspired by an old optics experiment carried out by Isaac Newton, researchers have devised a scheme to study microscopic particles with intense ultrafast X-ray pulses. It’s thought this type of X-ray ‘flash’ imaging may be used to explore the three-dimensional dynamics of materials at the timescale of atomic motion.
Newton was puzzled by the circular patterns that appeared when he illuminated a silver-plated mirror. As it turned out, this was caused by interference between two paths of light scattering from dust particles on the front of the mirror — one path of light on its way towards the mirror, and one reflecting from the silvered surface. In this week’s Nature, Henry N. Chapman and colleagues describe a modern, more dynamic version of this ‘dusty mirror’ experiment that uses X-rays.
The team fired their ultrafast light source at a thin membrane containing polystyrene particles placed in front of a mirrored backplate. The incident X-rays cause the polystyrene particles to explode, and they then hit the polystyrene particles a second time as they are reflected back from the mirrored plate. The resulting interference pattern can be used to retrieve information about the polystyrene particles with high time and space resolution.
CONTACT
Henry N. Chapman (Lawrence Livermore National Laboratory, Livermore, CA, USA)
Tel: +1 925 423 1580; E-mail: henry.chapman@llnl.gov
Andrea Cavalleri (University of Oxford, UK) N&V author
Tel: +44 1865 272 365; E-mail: a.cavalleri1@physics.ox.ac.uk
Human evolution: Same place, same time
Two fossils discovered in Kenya cast doubt on theories of the early evolution of the genus Homo. They show that the species H. habilis and H. erectus — previously thought to have evolved one after the other — actually lived side-by-side in eastern Africa for almost half a million years. The H. erectus fossil is the smallest ever found, suggesting that this species was not as human-like as once thought.
The east-African hominins H. habilis and the generally larger and later H. erectus are often regarded as part of the same pre-human lineage. The new fossils, uncovered east of Lake Turkana in Kenya, now challenge the relationship between these two species. The researchers attribute the first specimen, fragments of an upper jaw bone, to H. habilis. These bones provide the last known occurrence date for this species — 1.44 million years ago — which is significantly younger than previous estimates. The second fossil, a beautifully preserved H. erectus skull from 1.55 million years ago, is remarkable because it is close to the average size of H. habilis. This indicates that the species displayed substantial sexual dimorphism with the male being much larger than the female, like modern day gorillas.
The new dates show that H. habilis and H. erectus did in fact live at the same time in the Turkana basin for nearly half a million years. Their co-existence makes it unlikely that H. erectus evolved from H. habilis — both species must have originated between 2 and 3 million years ago, a time from which few Homo fossils are known. The authors conclude that, because they stayed as separate individual species for such a long time, they probably each had their own ecological niche and avoided direct competition with each other.
CONTACT:
Fred Spoor (University College London, UK)
Please note the author is currently based in Kenya:
Tel: +254 727 497 787 or +254 20 375 2337
Satellite phone: +88 216 5115 6558
E-mail: f.spoor@ucl.ac.uk
Additional author contacts:
Meave Leakey (Koobi Fora Research Project, Kenya)
Satellite phone: +88 216 5115 6558
E-mail: meaveleakey@gmail.com
Louise Leakey (Koobi Fora Research Project, Kenya)
Tel: +254 722 528 586
E-mail: louiseleakey@gmail.com
Two fossils discovered in Kenya cast doubt on theories of the early evolution of the genus Homo. They show that the species H. habilis and H. erectus — previously thought to have evolved one after the other — actually lived side-by-side in eastern Africa for almost half a million years. The H. erectus fossil is the smallest ever found, suggesting that this species was not as human-like as once thought.
The east-African hominins H. habilis and the generally larger and later H. erectus are often regarded as part of the same pre-human lineage. The new fossils, uncovered east of Lake Turkana in Kenya, now challenge the relationship between these two species. The researchers attribute the first specimen, fragments of an upper jaw bone, to H. habilis. These bones provide the last known occurrence date for this species — 1.44 million years ago — which is significantly younger than previous estimates. The second fossil, a beautifully preserved H. erectus skull from 1.55 million years ago, is remarkable because it is close to the average size of H. habilis. This indicates that the species displayed substantial sexual dimorphism with the male being much larger than the female, like modern day gorillas.
The new dates show that H. habilis and H. erectus did in fact live at the same time in the Turkana basin for nearly half a million years. Their co-existence makes it unlikely that H. erectus evolved from H. habilis — both species must have originated between 2 and 3 million years ago, a time from which few Homo fossils are known. The authors conclude that, because they stayed as separate individual species for such a long time, they probably each had their own ecological niche and avoided direct competition with each other.
CONTACT:
Fred Spoor (University College London, UK)
Please note the author is currently based in Kenya:
Tel: +254 727 497 787 or +254 20 375 2337
Satellite phone: +88 216 5115 6558
E-mail: f.spoor@ucl.ac.uk
Additional author contacts:
Meave Leakey (Koobi Fora Research Project, Kenya)
Satellite phone: +88 216 5115 6558
E-mail: meaveleakey@gmail.com
Louise Leakey (Koobi Fora Research Project, Kenya)
Tel: +254 722 528 586
E-mail: louiseleakey@gmail.com
Wednesday, August 08, 2007
Embryos back to front
An important stage in the early development of an embryo is the formation of the dorsal–ventral axis, which distinguishes the front (ventral) side of the animal from the back (dorsal). RIKEN researchers are identifying the genes and proteins that contribute to this process in Xenopus laevis, the African clawed frog.
Several protein interactions help to establish the front and back sides of an embryo
An important stage in the early development of an embryo is the formation of the dorsal–ventral axis, which distinguishes the front (ventral) side of the animal from the back (dorsal). RIKEN researchers at the Center for Developmental Biology in Kobe are identifying the genes and proteins that contribute to this process in Xenopus laevis, the African clawed frog.
Before the dorsal–ventral axis becomes established, the embryo is essentially a symmetrical sphere. The first signs that the symmetry is broken are uneven distributions in a complex network of proteins called the Wnt signaling pathway. However the differences in Wnt activity are too small to induce such a dramatic polarization, implying that other factors may amplify the effect.
The researchers found that XTsh3, a protein produced by the so-called Teashirt (Tsh) gene family, was strongly expressed in dorsal areas of the embryo1. “In Xenopus, it is easy to see gene functions by RNA injection into embryos,” says team leader Yoshiki Sasai. “XTsh3 injection induced dorsalization of the embryos.” Furthermore, when XTsh3 activity was deliberately inhibited, the dorsal axis didn’t form at all.
The activity of XTsh3 was found to be strongly related to levels of a protein called β-catenin, which has a crucial role in Wnt signaling. β-catenin accumulates in the cell nucleus and activates target genes that contribute further to the dorsal development.
“XTsh3 is an essential amplifier of Wnt signaling, which is activated on the dorsal side soon after insemination,” says Sasai. However the formation of the dorsal axis doesn’t occur until several hours later. In future Sasai would like to investigate the specific timings of each event. “One of our favorite hypotheses is that XTsh3 may be involved in the persisting memory of Wnt activation on the dorsal side.”
XTsh3 may have even more functions that the team has not yet discovered, because the molecule has the potential to bind with DNA. For example, the high levels of XTsh3 in the nervous system may contribute to development of the spinal cord once the dorsal–ventral axis is established.
Abnormal Wnt activation is also known to cause certain types of colon cancer in mammals. Four Tsh family genes are known in humans, but the roles of the genes are still to be investigated. It is also not known how far Tsh’s functions are conserved across species. Studies on the Drosophila fruit fly have shown a possible role of Tsh in Wnt signaling, but so far no link between Tsh activity and axis formation.
Reference
1. Onai, T., Matsuo-Takasaki, M., Inomata, H., Aramaki, T., Matsumura, M., Yakura, R., Sasai, N. & Sasai, Y. XTsh3 is an essential enhancing factor of canonical Wnt signaling in Xenopus axial determination. The EMBO Journal 26, 2350–2360 (2007).
An important stage in the early development of an embryo is the formation of the dorsal–ventral axis, which distinguishes the front (ventral) side of the animal from the back (dorsal). RIKEN researchers are identifying the genes and proteins that contribute to this process in Xenopus laevis, the African clawed frog.
Several protein interactions help to establish the front and back sides of an embryo
An important stage in the early development of an embryo is the formation of the dorsal–ventral axis, which distinguishes the front (ventral) side of the animal from the back (dorsal). RIKEN researchers at the Center for Developmental Biology in Kobe are identifying the genes and proteins that contribute to this process in Xenopus laevis, the African clawed frog.
Before the dorsal–ventral axis becomes established, the embryo is essentially a symmetrical sphere. The first signs that the symmetry is broken are uneven distributions in a complex network of proteins called the Wnt signaling pathway. However the differences in Wnt activity are too small to induce such a dramatic polarization, implying that other factors may amplify the effect.
The researchers found that XTsh3, a protein produced by the so-called Teashirt (Tsh) gene family, was strongly expressed in dorsal areas of the embryo1. “In Xenopus, it is easy to see gene functions by RNA injection into embryos,” says team leader Yoshiki Sasai. “XTsh3 injection induced dorsalization of the embryos.” Furthermore, when XTsh3 activity was deliberately inhibited, the dorsal axis didn’t form at all.
The activity of XTsh3 was found to be strongly related to levels of a protein called β-catenin, which has a crucial role in Wnt signaling. β-catenin accumulates in the cell nucleus and activates target genes that contribute further to the dorsal development.
“XTsh3 is an essential amplifier of Wnt signaling, which is activated on the dorsal side soon after insemination,” says Sasai. However the formation of the dorsal axis doesn’t occur until several hours later. In future Sasai would like to investigate the specific timings of each event. “One of our favorite hypotheses is that XTsh3 may be involved in the persisting memory of Wnt activation on the dorsal side.”
XTsh3 may have even more functions that the team has not yet discovered, because the molecule has the potential to bind with DNA. For example, the high levels of XTsh3 in the nervous system may contribute to development of the spinal cord once the dorsal–ventral axis is established.
Abnormal Wnt activation is also known to cause certain types of colon cancer in mammals. Four Tsh family genes are known in humans, but the roles of the genes are still to be investigated. It is also not known how far Tsh’s functions are conserved across species. Studies on the Drosophila fruit fly have shown a possible role of Tsh in Wnt signaling, but so far no link between Tsh activity and axis formation.
Reference
1. Onai, T., Matsuo-Takasaki, M., Inomata, H., Aramaki, T., Matsumura, M., Yakura, R., Sasai, N. & Sasai, Y. XTsh3 is an essential enhancing factor of canonical Wnt signaling in Xenopus axial determination. The EMBO Journal 26, 2350–2360 (2007).
Neuroscience : Stimulating retinal repair
Repairing damaged retinas is now a possibility. Japanese researchers from RIKEN and Kyoto University have demonstrated retinal regeneration in a mammalian model. It is a discovery that may ultimately lead to new therapies for retinal diseases including the degenerative disease called retinitis pigmentosa.
Japanese researchers from RIKEN and Kyoto University have demonstrated retinal regeneration in a
mammalian model of retinal degeneration after stimulation of the Wnt signaling pathway, which functions
as a regulator of some adult stem cell populations—in addition to its better known roles in embryogenesis and development.
It is a discovery that may ultimately lead to new therapies for retinal diseases including the degenerative disease called retinitis pigmentosa.
Previous research by the team led by Masayo Takahashi at the RIKEN Center for Developmental Biology, Kobe, demonstrated that retinal support cells called Müller glia could de-differentiate to assume a neuronal fate, but the level of regeneration via this mechanism was very low, occurring in just a few cells.
But the new study, published recently in the Journal of Neuroscience (1), indicates that retinal cell regeneration in an in vitro model of retinal damage can be increased by as much as twenty-fold in the presence of the protein Wnt3a.
The researchers initially performed experiments in cultured retinas isolated from rats. When they administered Wnt3a, they found a significant increase in proliferation of neuronal progenitors from the de-differentiated cells.
“Newly generated cells constituted almost a layer of cells in the outer nuclear layer in the retinal degeneration model mice,” says Takahashi. “We only observed several cells per field without Wnt treatment. Furthermore, the retinal neurons were regenerated all over the retina.”
The regenerated cells migrated to the outer nuclear layer of the retina, where, in the presence of retinoic acid (a form of vitamin A) or valproic acid, the team observed differentiation into rod photoreceptor cells.
The phenomenon appears to involve the canonical Wnt signaling pathway, in which Wnt activation protects the β-catenin protein from degradation, allowing it to accumulate in the nucleus where it regulates gene transcription. The process could also be stimulated with small molecule inhibitors of glycogen synthase kinase-3β, which normally blocks activation of the pathway.
Treatment of retinas isolated from a murine model of retinitis pigmentosa with Wnt3a similarly resulted in the regeneration of retinal cells, suggesting that the Wnt/β-catenin signaling pathway contributes to central nervous system regeneration. Takahashi believes Wnt signaling may be a part of the natural
restoration mechanism in the retina.
Reference
1. Osakada, F., Ooto, S., Akagi, T., Mandai, M., Akaike, A. & Takahashi, M. Wnt signaling promotes regeneration in the retina of adult mammals. Journal of Neuroscience 27, 4210–4219 (2007).
Repairing damaged retinas is now a possibility. Japanese researchers from RIKEN and Kyoto University have demonstrated retinal regeneration in a mammalian model. It is a discovery that may ultimately lead to new therapies for retinal diseases including the degenerative disease called retinitis pigmentosa.
Japanese researchers from RIKEN and Kyoto University have demonstrated retinal regeneration in a
mammalian model of retinal degeneration after stimulation of the Wnt signaling pathway, which functions
as a regulator of some adult stem cell populations—in addition to its better known roles in embryogenesis and development.
It is a discovery that may ultimately lead to new therapies for retinal diseases including the degenerative disease called retinitis pigmentosa.
Previous research by the team led by Masayo Takahashi at the RIKEN Center for Developmental Biology, Kobe, demonstrated that retinal support cells called Müller glia could de-differentiate to assume a neuronal fate, but the level of regeneration via this mechanism was very low, occurring in just a few cells.
But the new study, published recently in the Journal of Neuroscience (1), indicates that retinal cell regeneration in an in vitro model of retinal damage can be increased by as much as twenty-fold in the presence of the protein Wnt3a.
The researchers initially performed experiments in cultured retinas isolated from rats. When they administered Wnt3a, they found a significant increase in proliferation of neuronal progenitors from the de-differentiated cells.
“Newly generated cells constituted almost a layer of cells in the outer nuclear layer in the retinal degeneration model mice,” says Takahashi. “We only observed several cells per field without Wnt treatment. Furthermore, the retinal neurons were regenerated all over the retina.”
The regenerated cells migrated to the outer nuclear layer of the retina, where, in the presence of retinoic acid (a form of vitamin A) or valproic acid, the team observed differentiation into rod photoreceptor cells.
The phenomenon appears to involve the canonical Wnt signaling pathway, in which Wnt activation protects the β-catenin protein from degradation, allowing it to accumulate in the nucleus where it regulates gene transcription. The process could also be stimulated with small molecule inhibitors of glycogen synthase kinase-3β, which normally blocks activation of the pathway.
Treatment of retinas isolated from a murine model of retinitis pigmentosa with Wnt3a similarly resulted in the regeneration of retinal cells, suggesting that the Wnt/β-catenin signaling pathway contributes to central nervous system regeneration. Takahashi believes Wnt signaling may be a part of the natural
restoration mechanism in the retina.
Reference
1. Osakada, F., Ooto, S., Akagi, T., Mandai, M., Akaike, A. & Takahashi, M. Wnt signaling promotes regeneration in the retina of adult mammals. Journal of Neuroscience 27, 4210–4219 (2007).
Vegetable matters
Japanese researchers identify genes controlling health-giving compounds in common food crops. Vegetables like cabbage, broccoli and cauliflower are anti-carcinogenic with antioxidant properties and offer a natural defense against crop pests, potentially reducing the need for synthetic pesticides.
Japanese scientists have identified genes controlling the production of important compounds, known as glucosinolates, produced in food crops. Vegetable plants from the family Brassicaceae, such as cabbage, broccoli and cauliflower, produce glucosinolates, which are useful in human health and to the environment. They are anti-carcinogenic with antioxidant properties and offer a natural defense against
crop pests, potentially reducing the need for synthetic pesticides.
The biosynthesis of glucosinolates was poorly understood until the research team, led by Masami Yokota Hirai and Kazuki Saito from RIKEN’s Plant Science Center in Yokohama, used an ‘omics-based approach’, combining transcriptome and metabolome data to describe this process1. The transcriptome includes all transcribed genes in certain conditions, and the metabolome comprises all the end products of gene
expression. Integrating these sets of information gives a more complete picture of the biosynthetic pathway under study.
According to Hirai and Saito, the omics-based approach can be used to comprehensively identify a set of genes involved in a particular metabolic pathway—it can be a powerful tool used to distinguish the most important gene of many that may encode a particular transcription factor. A transcription factor is a
protein that controls when and where those genes are expressed.
The researchers revealed that long-chain, or aliphatic, glucosinolate biosynthesis is associated with two uncharacterized transcription factor genes, Myb28 and Myb29, by comparing the condition-independent transcriptome data with condition-specific information—a procedure called transcriptome coexpression analysis. Myb28 is a master transcription factor controlling many genes and Myb29 is an accessory. In
the model plant Arabidopsis, the team then overexpressed Myb28 and found a huge increase in the production of glucosinolates; and in a mutant lacking Myb28, they found a decrease in production. The team later renamed these genes Production of Methionine-Derived Glucosinolate (PMG) 1 and 2.
This is the first report of genes regulating the aliphatic glucosinolate biosynthetic pathway. It shows that transcriptome coexpression analysis is highly versatile and suitable for comprehensively identifying genes involved in plant metabolism. A greater understanding of metabolic systems will lead to
subsequent biotechnological applications.
“We eat Brassicaceae vegetables daily,” says Hirai. “By over-expressing PMG1 or controlling the expression of its orthologs in these vegetables, we can develop physiologically functional vegetables with higher amount of glucosinolates.” This could be useful in human nutrition. These genes are promising targets for the genetic engineering of glucosinolate production, possibly on an industrial scale.
Reference
1. Hirai, M.Y., Sugiyama, K., Sawada, Y., Tohge, T., Obayashi, T., Suzuki, A., Araki, R., Sakurai, N., Suzuki, H., Aoki, K. et al.
Omics-based identification of Arabidopsis Myb transcription factors regulating aliphatic glucosinolate
biosynthesis. Proceedings of the National Academy of Sciences USA 104, 6478–6483 (2007).
Japanese researchers identify genes controlling health-giving compounds in common food crops. Vegetables like cabbage, broccoli and cauliflower are anti-carcinogenic with antioxidant properties and offer a natural defense against crop pests, potentially reducing the need for synthetic pesticides.
Japanese scientists have identified genes controlling the production of important compounds, known as glucosinolates, produced in food crops. Vegetable plants from the family Brassicaceae, such as cabbage, broccoli and cauliflower, produce glucosinolates, which are useful in human health and to the environment. They are anti-carcinogenic with antioxidant properties and offer a natural defense against
crop pests, potentially reducing the need for synthetic pesticides.
The biosynthesis of glucosinolates was poorly understood until the research team, led by Masami Yokota Hirai and Kazuki Saito from RIKEN’s Plant Science Center in Yokohama, used an ‘omics-based approach’, combining transcriptome and metabolome data to describe this process1. The transcriptome includes all transcribed genes in certain conditions, and the metabolome comprises all the end products of gene
expression. Integrating these sets of information gives a more complete picture of the biosynthetic pathway under study.
According to Hirai and Saito, the omics-based approach can be used to comprehensively identify a set of genes involved in a particular metabolic pathway—it can be a powerful tool used to distinguish the most important gene of many that may encode a particular transcription factor. A transcription factor is a
protein that controls when and where those genes are expressed.
The researchers revealed that long-chain, or aliphatic, glucosinolate biosynthesis is associated with two uncharacterized transcription factor genes, Myb28 and Myb29, by comparing the condition-independent transcriptome data with condition-specific information—a procedure called transcriptome coexpression analysis. Myb28 is a master transcription factor controlling many genes and Myb29 is an accessory. In
the model plant Arabidopsis, the team then overexpressed Myb28 and found a huge increase in the production of glucosinolates; and in a mutant lacking Myb28, they found a decrease in production. The team later renamed these genes Production of Methionine-Derived Glucosinolate (PMG) 1 and 2.
This is the first report of genes regulating the aliphatic glucosinolate biosynthetic pathway. It shows that transcriptome coexpression analysis is highly versatile and suitable for comprehensively identifying genes involved in plant metabolism. A greater understanding of metabolic systems will lead to
subsequent biotechnological applications.
“We eat Brassicaceae vegetables daily,” says Hirai. “By over-expressing PMG1 or controlling the expression of its orthologs in these vegetables, we can develop physiologically functional vegetables with higher amount of glucosinolates.” This could be useful in human nutrition. These genes are promising targets for the genetic engineering of glucosinolate production, possibly on an industrial scale.
Reference
1. Hirai, M.Y., Sugiyama, K., Sawada, Y., Tohge, T., Obayashi, T., Suzuki, A., Araki, R., Sakurai, N., Suzuki, H., Aoki, K. et al.
Omics-based identification of Arabidopsis Myb transcription factors regulating aliphatic glucosinolate
biosynthesis. Proceedings of the National Academy of Sciences USA 104, 6478–6483 (2007).
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