Black Carbon Pollution Emerges as Major Player in Global Warming
Black carbon, a form of particulate air pollution most often produced from biomass burning, cooking with solid fuels and diesel exhaust, has a warming effect in the atmosphere three to four times greater than prevailing estimates, according to scientists in an upcoming review article in the journal Nature Geoscience.
Scripps Institution of Oceanography at UC San Diego atmospheric scientist V. Ramanathan and University of Iowa chemical engineer Greg Carmichael, said that soot and other forms of black carbon could have as much as 60 percent of the current global warming effect of carbon dioxide, more than that of any greenhouse gas besides CO2. The researchers also noted, however, that mitigation would have immediate societal benefits in addition to the long term effect of reducing greenhouse gas emissions.
The article, “Global and regional climate changes due to black carbon,” will be posted in the online version of Nature Geoscience on Sunday, March 23.
“Observationally based studies such as ours are converging on the same large magnitude of black carbon heating as modeling studies from Stanford, Caltech and NASA,” said Ramanathan. “We now have to examine if black carbon is also having a large role in the retreat of arctic sea ice and Himalayan glaciers as suggested by recent studies.”
In the paper, Ramanathan and Carmichael integrated observed data from satellites, aircraft and surface instruments about the warming effect of black carbon and found that its forcing, or warming effect in the atmosphere, is about 0.9 watts per meter squared. That compares to estimates of between 0.2 watts per meter squared and 0.4 watts per meter squared that were agreed upon as a consensus estimate in a report released last year by the Intergovernmental Panel on Climate Change (IPCC), a U.N.-sponsored agency that periodically synthesizes the body of climate change research.
Ramanathan and Carmichael said the conservative estimates are based on widely used computer model simulations that do not take into account the amplification of black carbon’s warming effect when mixed with other aerosols such as sulfates. The models also do not adequately represent the full range of altitudes at which the warming effect occurs. The most recent observations, in contrast, have found significant black carbon warming effects at altitudes in the range of 2 kilometers (6,500 feet), levels at which black carbon particles absorb not only sunlight but also solar energy reflected by clouds at lower altitudes.
Between 25 and 35 percent of black carbon in the global atmosphere comes from China and India, emitted from the burning of wood and cow dung in household cooking and through the use of coal to heat homes. Countries in Europe and elsewhere that rely heavily on diesel fuel for transportation also contribute large amounts.
“Per capita emissions of black carbon from the United States and some European countries are still comparable to those from south Asia and east Asia,” Ramanathan said.
In south Asia, pollution often forms a prevalent brownish haze that has been termed the “atmospheric brown cloud.” Ramanathan’s previous research has indicated that the warming effects of this smog appear to be accelerating the melt of Himalayan glaciers that provide billions of people throughout Asia with drinking water. In addition, the inhalation of smoke during indoor cooking has been linked to the deaths of an estimated 400,000 women and children in south and east Asia.
Elimination of black carbon, a contributor to global warming and a public health hazard, offers a nearly instant return on investment, the researchers said. Black carbon particles only remain airborne for weeks at most compared to carbon dioxide, which remains in the atmosphere for more than a century. In addition, technology that could substantially reduce black carbon emissions already exists in the form of commercially available products.
Ramanathan said that an observation program for which he is currently seeking corporate sponsorship could dramatically illustrate the benefits. Known as Project Surya, the proposed venture would provide some 20,000 rural Indian households with smoke-free cookers and equipped to transmit data. At the same time, a team of researchers led by Ramanathan would observe air pollution levels in the region to measure the effect of the cookers.
Carmichael said he hopes that the paper’s presentation of the immediacy of the benefits will make it easier to generate political and regulatory momentum toward reduction of black carbon emissions.
“It offers a chance to get better traction for implementing strategies for reducing black carbon,” he said. (Newswise)
Monday, March 24, 2008
Tuesday, March 04, 2008
Seeking schizophrenia genes
Researchers map genetic alterations associated with human schizophrenia
Japanese scientists have linked atypical expression patterns of the gene FABP7, which encodes the brain fatty acid binding protein 7, with human schizophrenia. Although initially attributed to environmental abnormalities, this debilitating disease is now accepted as being influenced by a strong, yet likely multifactorial, genetic component.
The phenotypic, or behavioral, outcomes of schizophrenia are perhaps just as complicated as the genotypic alterations underlying the disease. Fortunately, suppression of a particular startle response—known as prepulse inhibition (PPI)—provides an easily measurable biological readout of the sensory motor gating mechanisms that are often impaired in schizophrenia.
In an effort to identify genes associated with schizophrenia, a team led by Takeo Yoshikawa at the RIKEN Brain Science Institute in Wako, mapped genetic alterations associated with PPI in mice1.
After tracking the PPI responses of a panel of distinct inbred mouse strains for over one year, the researchers intercrossed the strains having the lowest and highest PPI scores. Next, the team scanned the genomes of the progeny for sets of microsatellite markers, or genetic ‘tags’, and compared the presence of these tags with the PPI scores.
Using progressively rigorous sets of tags, the researchers linked impaired PPI to a region of chromosome 10 containing approximately 30 genes. The team honed in on Fabp7 (Fig. 1), one gene within this region, because of its influence over the metabolism of the polyunsaturated fatty acid DHA (docosahexaenoic acid), a process often impaired in schizophrenia.
Encouragingly, although stronger in males than in females, human schizophrenia patients exhibit abnormally high expression of FABP7 similar to mice exhibiting defective PPI responses. Notably, mice rendered genetically deficient in Fabp7 also score low in PPI measurements and display stronger behavioral responses to chronic NMDA receptor antagonist treatment, another feature of schizophrenia.
Although the team detected defects in the maintenance of neural progenitor cells in Fabp7-deficient mice, future work is needed to elucidate the precise molecular mechanism through which alterations in Fabp7 expression promote schizophrenia-like behavior in mice and humans.
Similarly, why males seem to be more strongly affected by Fabp7 over-expression remains unclear. However, sex hormone-responsive elements in the DNA regions controlling Fabp7 expression might play a role.
“It is well known that malnutrition in utero increases the probability of future schizophrenia. Our results raise the importance of cohort studies to examine whether replenishment of DHA in pregnant mothers can be beneficial in reducing the chance of schizophrenia development in offspring,” says Yoshikawa.
Reference
1. Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Nakaya, A., Maekawa, M., Ohnishi, T., et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 5, 2469–2483 (2007).
Researchers map genetic alterations associated with human schizophrenia
Japanese scientists have linked atypical expression patterns of the gene FABP7, which encodes the brain fatty acid binding protein 7, with human schizophrenia. Although initially attributed to environmental abnormalities, this debilitating disease is now accepted as being influenced by a strong, yet likely multifactorial, genetic component.
The phenotypic, or behavioral, outcomes of schizophrenia are perhaps just as complicated as the genotypic alterations underlying the disease. Fortunately, suppression of a particular startle response—known as prepulse inhibition (PPI)—provides an easily measurable biological readout of the sensory motor gating mechanisms that are often impaired in schizophrenia.
In an effort to identify genes associated with schizophrenia, a team led by Takeo Yoshikawa at the RIKEN Brain Science Institute in Wako, mapped genetic alterations associated with PPI in mice1.
After tracking the PPI responses of a panel of distinct inbred mouse strains for over one year, the researchers intercrossed the strains having the lowest and highest PPI scores. Next, the team scanned the genomes of the progeny for sets of microsatellite markers, or genetic ‘tags’, and compared the presence of these tags with the PPI scores.
Using progressively rigorous sets of tags, the researchers linked impaired PPI to a region of chromosome 10 containing approximately 30 genes. The team honed in on Fabp7 (Fig. 1), one gene within this region, because of its influence over the metabolism of the polyunsaturated fatty acid DHA (docosahexaenoic acid), a process often impaired in schizophrenia.
Encouragingly, although stronger in males than in females, human schizophrenia patients exhibit abnormally high expression of FABP7 similar to mice exhibiting defective PPI responses. Notably, mice rendered genetically deficient in Fabp7 also score low in PPI measurements and display stronger behavioral responses to chronic NMDA receptor antagonist treatment, another feature of schizophrenia.
Although the team detected defects in the maintenance of neural progenitor cells in Fabp7-deficient mice, future work is needed to elucidate the precise molecular mechanism through which alterations in Fabp7 expression promote schizophrenia-like behavior in mice and humans.
Similarly, why males seem to be more strongly affected by Fabp7 over-expression remains unclear. However, sex hormone-responsive elements in the DNA regions controlling Fabp7 expression might play a role.
“It is well known that malnutrition in utero increases the probability of future schizophrenia. Our results raise the importance of cohort studies to examine whether replenishment of DHA in pregnant mothers can be beneficial in reducing the chance of schizophrenia development in offspring,” says Yoshikawa.
Reference
1. Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Nakaya, A., Maekawa, M., Ohnishi, T., et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 5, 2469–2483 (2007).
Quantum corkscrews from twisting electron waves
RIKEN researchers have shown that electron beams, like light, can be twisted into vortices that have useful functions
Recently scientists discovered that light can be twisted like a corkscrew around its direction of travel. This unusual quantum feature allows photons to whirl around in a vortex, even when no external force is applied to the beam. Now researchers from the RIKEN Frontier Research System in Wako have shown that the same kind of vortices can be produced in beams of electrons1, promising novel applications.
“When a light or electron beam is twisted, waves at the central axis cancel each other out forming a dark core, like at the eye of a storm (Fig. 1),” says RIKEN scientist Franco Nori, also with the University of Michigan in the USA. His RIKEN collaborator Sergey Savel’ev, also at Loughborough University in the UK, adds: “As the photons or electrons spin around the axis, they carry orbital angular momentum that can rotate an electric dipole.”
To explain these properties, the researchers solved the Schrödinger equation of quantum mechanics for a twisting beam of electrons. This produced new dynamical equations that are highly analogous to those found for light. The similarities arise because the twisting angular momentum of the electrons interacts with their forward motion in the same way that intrinsic angular momentum (spin) interacts with the motion of photons, which is known as spin-orbit coupling.
The theory implies that vortices in electron beams have all the features of optical vortices. This reinforces the famous concept of wave-particle duality, which states that all particles have a wave associated with them. More importantly, it means that the useful applications of optical vortices could be replicated at much shorter wavelengths.
In practice, optical vortices can be made by passing a laser beam through a fork-shaped computer generated hologram. Electron-beam vortices could be produced in a similar fashion, using a thin crystal plate with a dislocation. Such vortices could power tiny nanomotors and nano-engines, or could be used in telecommunications by storing information in the optical vorticity, or the intensity of twisting. The vorticity is robust against perturbations, so this potential future technology could reduce the loss of information during optical communications.
Furthermore, electron vortices are predicted to cause a shift of the electron beam at right angles to an electric field. “The unique electron microscope developed by Akira Tonomura's group, also at RIKEN, could observe this unusual effect,” says Nori. “Such work would considerably expand the textbook analogy between matter and waves which Tonomura helped to establish in pioneering experiments.”
1. Bliokh, K. Y., Bliokh, Y. P., Savel’ev, S. & Nori, F. Semiclassical dynamics of electron wave packet states with phase vortices. Physical Review Letters 99, 190404 (2007).
RIKEN researchers have shown that electron beams, like light, can be twisted into vortices that have useful functions
Recently scientists discovered that light can be twisted like a corkscrew around its direction of travel. This unusual quantum feature allows photons to whirl around in a vortex, even when no external force is applied to the beam. Now researchers from the RIKEN Frontier Research System in Wako have shown that the same kind of vortices can be produced in beams of electrons1, promising novel applications.
“When a light or electron beam is twisted, waves at the central axis cancel each other out forming a dark core, like at the eye of a storm (Fig. 1),” says RIKEN scientist Franco Nori, also with the University of Michigan in the USA. His RIKEN collaborator Sergey Savel’ev, also at Loughborough University in the UK, adds: “As the photons or electrons spin around the axis, they carry orbital angular momentum that can rotate an electric dipole.”
To explain these properties, the researchers solved the Schrödinger equation of quantum mechanics for a twisting beam of electrons. This produced new dynamical equations that are highly analogous to those found for light. The similarities arise because the twisting angular momentum of the electrons interacts with their forward motion in the same way that intrinsic angular momentum (spin) interacts with the motion of photons, which is known as spin-orbit coupling.
The theory implies that vortices in electron beams have all the features of optical vortices. This reinforces the famous concept of wave-particle duality, which states that all particles have a wave associated with them. More importantly, it means that the useful applications of optical vortices could be replicated at much shorter wavelengths.
In practice, optical vortices can be made by passing a laser beam through a fork-shaped computer generated hologram. Electron-beam vortices could be produced in a similar fashion, using a thin crystal plate with a dislocation. Such vortices could power tiny nanomotors and nano-engines, or could be used in telecommunications by storing information in the optical vorticity, or the intensity of twisting. The vorticity is robust against perturbations, so this potential future technology could reduce the loss of information during optical communications.
Furthermore, electron vortices are predicted to cause a shift of the electron beam at right angles to an electric field. “The unique electron microscope developed by Akira Tonomura's group, also at RIKEN, could observe this unusual effect,” says Nori. “Such work would considerably expand the textbook analogy between matter and waves which Tonomura helped to establish in pioneering experiments.”
1. Bliokh, K. Y., Bliokh, Y. P., Savel’ev, S. & Nori, F. Semiclassical dynamics of electron wave packet states with phase vortices. Physical Review Letters 99, 190404 (2007).
Magnetic flux quanta get a dance lesson
Alternating electric current can be used to precisely control tiny vortices of magnetism
Swirling cyclones of magnetism at the sub-micron scale that can trouble superconducting devices have been tamed by RIKEN scientists. Their technique could help to minimize magnetic noise in sensitive superconducting detectors, and could even help to build a new generation of devices for supercomputers.
When cooled below a critical temperature, superconductors carry electricity with no resistance. But magnetic fields can disrupt this behavior by introducing magnetic flux quanta into the material. These quanta, also known as vortices, are the basic units of magnetism, just as the charge of an electron is the fundamental unit of electricity.
Scientists can control how these vortices move by introducing tiny traps, or nano-holes, into the structure of the superconducting material. But since the pattern of these tiny traps is fixed once the device is made, it’s a relatively inflexible approach that restricts the way the vortices can be moved around.
Now, a team including Franco Nori and Sergey Savel’ev of RIKEN’s Frontier Research System in Wako, have shown how to precisely control the movement of magnetic flux quanta with an alternating electric current (AC)1.
The scientists tested the method on a high-temperature superconductor made from bismuth, strontium, calcium and copper (Bi2Sr2CaCu2O8 + δ). When the electrical current oscillates back and forth, the vortices obediently follow their rhythm.
Nori, also based at University of Michigan, US, says that the technique is like leading the magnetic flux quanta through a series of dance steps (Fig. 1). “The applied current acts as the leading dance partner and the vortices follow the steps imposed by the current,” he says.
More complicated rhythms are created by adding more overlapping alternating currents, allowing the scientists to steer their magnetic flux quanta through the material. “The two ‘control knobs’ we use are the ratio of the AC frequencies, and the relative phase difference between them,” explains Nori.
Savel’ev, also at Loughborough University, UK, adds: “By slowly varying either one of these two control knobs, vortices are pushed either in one direction or the opposite.”
Nori says that the technique could also be used to manipulate trapped ions, moving electrons around in certain types of crystal, or even separating different types of very tiny particles.
In the longer term, the scientists hope that the technique could contribute to the burgeoning field of ‘fluxtronics’—moving magnetic quanta around to manipulate computer data. This would potentially be much faster that conventional methods relying on shuttling electrons between transistors.
1. Ooi, S., Savel'ev, S., Gaifullin, M. B., Mochiku, T., Hirata, K. & Nori, F. Nonlinear nanodevices using magnetic flux quanta. Physical Review Letters 99, 207003 (2007).
Alternating electric current can be used to precisely control tiny vortices of magnetism
Swirling cyclones of magnetism at the sub-micron scale that can trouble superconducting devices have been tamed by RIKEN scientists. Their technique could help to minimize magnetic noise in sensitive superconducting detectors, and could even help to build a new generation of devices for supercomputers.
When cooled below a critical temperature, superconductors carry electricity with no resistance. But magnetic fields can disrupt this behavior by introducing magnetic flux quanta into the material. These quanta, also known as vortices, are the basic units of magnetism, just as the charge of an electron is the fundamental unit of electricity.
Scientists can control how these vortices move by introducing tiny traps, or nano-holes, into the structure of the superconducting material. But since the pattern of these tiny traps is fixed once the device is made, it’s a relatively inflexible approach that restricts the way the vortices can be moved around.
Now, a team including Franco Nori and Sergey Savel’ev of RIKEN’s Frontier Research System in Wako, have shown how to precisely control the movement of magnetic flux quanta with an alternating electric current (AC)1.
The scientists tested the method on a high-temperature superconductor made from bismuth, strontium, calcium and copper (Bi2Sr2CaCu2O8 + δ). When the electrical current oscillates back and forth, the vortices obediently follow their rhythm.
Nori, also based at University of Michigan, US, says that the technique is like leading the magnetic flux quanta through a series of dance steps (Fig. 1). “The applied current acts as the leading dance partner and the vortices follow the steps imposed by the current,” he says.
More complicated rhythms are created by adding more overlapping alternating currents, allowing the scientists to steer their magnetic flux quanta through the material. “The two ‘control knobs’ we use are the ratio of the AC frequencies, and the relative phase difference between them,” explains Nori.
Savel’ev, also at Loughborough University, UK, adds: “By slowly varying either one of these two control knobs, vortices are pushed either in one direction or the opposite.”
Nori says that the technique could also be used to manipulate trapped ions, moving electrons around in certain types of crystal, or even separating different types of very tiny particles.
In the longer term, the scientists hope that the technique could contribute to the burgeoning field of ‘fluxtronics’—moving magnetic quanta around to manipulate computer data. This would potentially be much faster that conventional methods relying on shuttling electrons between transistors.
1. Ooi, S., Savel'ev, S., Gaifullin, M. B., Mochiku, T., Hirata, K. & Nori, F. Nonlinear nanodevices using magnetic flux quanta. Physical Review Letters 99, 207003 (2007).
Two-protein Complex Protects Nerve Cells
Since its discovery as a protein that gets specifically released in response to brain injury, ciliary neurotrophic factor (CNTF) has prompted much interest as a potential therapeutic agent. However, numerous experiments have met with limited success, until now; a research team shows that co-administrating CNTF with its receptor promotes the growth and survival of neurons.
While the receptor for CNTF is normally tied to the surface of neurons, this tether is frequently chopped off during trauma, which led Mark Ozog, Christian Naus and colleagues to suspect that CNTF and the free-floating receptor might act in a complex. Their study appears in JBC online February 29.
They treated mouse neurons with CNTF, its receptor (CNTFR), or both and then exposed the cells to massive amounts of the neurotransmitter glutamate, enough to kill the neurons by over-stimulating them. CNTF or CNTFR alone did not protect the neurons, but the two complexed together could. In addition, the complex could foster increased growth of nerve cells.
Ozog, Naus and colleagues next ran a microarray analysis of the CNTF complex and found that it altered the expression of 47 genes associated with nerve growth and survival, suggesting it protects neurons through multiple direct and indirect mechanisms and thus making it a strong therapeutic candidate.
Since its discovery as a protein that gets specifically released in response to brain injury, ciliary neurotrophic factor (CNTF) has prompted much interest as a potential therapeutic agent. However, numerous experiments have met with limited success, until now; a research team shows that co-administrating CNTF with its receptor promotes the growth and survival of neurons.
While the receptor for CNTF is normally tied to the surface of neurons, this tether is frequently chopped off during trauma, which led Mark Ozog, Christian Naus and colleagues to suspect that CNTF and the free-floating receptor might act in a complex. Their study appears in JBC online February 29.
They treated mouse neurons with CNTF, its receptor (CNTFR), or both and then exposed the cells to massive amounts of the neurotransmitter glutamate, enough to kill the neurons by over-stimulating them. CNTF or CNTFR alone did not protect the neurons, but the two complexed together could. In addition, the complex could foster increased growth of nerve cells.
Ozog, Naus and colleagues next ran a microarray analysis of the CNTF complex and found that it altered the expression of 47 genes associated with nerve growth and survival, suggesting it protects neurons through multiple direct and indirect mechanisms and thus making it a strong therapeutic candidate.
Researchers Find Key Step in Programmed Cell Death
Investigators at St. Jude Children’s Research Hospital have discovered a dance of proteins that protects certain cells from undergoing apoptosis, also known as programmed cell death. Understanding the fine points of apoptosis is important to researchers seeking ways to control this process.
In a series of experiments, St. Jude researchers found that if any one of three molecules is missing, certain cells lose the ability to protect themselves from apoptosis. A report on this work appears in the advance online publication of Nature.
“This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis,” said James Ihle, Ph.D., the paper’s senior author and chair of the St. Jude Department of Biochemistry. “It provides incredible insights into how three proteins work and how they can control apoptosis.”
The molecular interactions that St. Jude researchers describe in Nature play out in nerve cells and blood cells that develop from hematopoietic (blood-forming) stem cells.
A research team elsewhere recently reported that Kostmann’s syndrome, a potentially fatal inherited deficiency of granulocytes in children, caused by excessive apoptosis of granulocytes, results from a deficiency in one of the three proteins, called Hax1.
“This suggests that the protein is playing basically the same role in humans as we described in mice,” Ihle said.
Apoptosis rids the body of faulty or unneeded cells. However, molecular malfunctions that trigger apoptosis may cause some diseases, including Parkinson’s disease. Understanding the biochemical interactions that control the extent of programmed cell death could lead to new treatments.
St. Jude biochemists have long studied how cytokines—small proteins used by neurons and blood-borne cells to communicate messages—contribute to keeping cells alive. For example, they demonstrated earlier that most cytokines controlling hematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.
In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.
“That was intriguing because several studies suggested that Hax1 was controlled by cytokine signaling,” Ihle said. “Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis.”
To pursue this lead, the researchers genetically engineered mice that lacked the gene for Hax1. The results showed that apoptosis in the animals’ brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks.
Second, apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.
“That additional window of survival is extremely important because in the body, cytokines are limiting.” Ihle said. “The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl.”
Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria—tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell’s cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.
In lymphocytes, members of the Bcl-2 family of proteins both protect and initiate apoptosis. For this reason, Ihle and the researchers explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. This led them to discover that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur. This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.
Other authors of this study include Jyh-Rong Chao, Kelli Boyd, Evan Parganas, Cheol Yi Hong and Joseph T. Opferman (all St. Jude).
This work was supported in part by grants from the National Institutes of Health and ALSAC.
Investigators at St. Jude Children’s Research Hospital have discovered a dance of proteins that protects certain cells from undergoing apoptosis, also known as programmed cell death. Understanding the fine points of apoptosis is important to researchers seeking ways to control this process.
In a series of experiments, St. Jude researchers found that if any one of three molecules is missing, certain cells lose the ability to protect themselves from apoptosis. A report on this work appears in the advance online publication of Nature.
“This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis,” said James Ihle, Ph.D., the paper’s senior author and chair of the St. Jude Department of Biochemistry. “It provides incredible insights into how three proteins work and how they can control apoptosis.”
The molecular interactions that St. Jude researchers describe in Nature play out in nerve cells and blood cells that develop from hematopoietic (blood-forming) stem cells.
A research team elsewhere recently reported that Kostmann’s syndrome, a potentially fatal inherited deficiency of granulocytes in children, caused by excessive apoptosis of granulocytes, results from a deficiency in one of the three proteins, called Hax1.
“This suggests that the protein is playing basically the same role in humans as we described in mice,” Ihle said.
Apoptosis rids the body of faulty or unneeded cells. However, molecular malfunctions that trigger apoptosis may cause some diseases, including Parkinson’s disease. Understanding the biochemical interactions that control the extent of programmed cell death could lead to new treatments.
St. Jude biochemists have long studied how cytokines—small proteins used by neurons and blood-borne cells to communicate messages—contribute to keeping cells alive. For example, they demonstrated earlier that most cytokines controlling hematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.
In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.
“That was intriguing because several studies suggested that Hax1 was controlled by cytokine signaling,” Ihle said. “Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis.”
To pursue this lead, the researchers genetically engineered mice that lacked the gene for Hax1. The results showed that apoptosis in the animals’ brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks.
Second, apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.
“That additional window of survival is extremely important because in the body, cytokines are limiting.” Ihle said. “The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl.”
Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria—tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell’s cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.
In lymphocytes, members of the Bcl-2 family of proteins both protect and initiate apoptosis. For this reason, Ihle and the researchers explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. This led them to discover that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur. This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.
Other authors of this study include Jyh-Rong Chao, Kelli Boyd, Evan Parganas, Cheol Yi Hong and Joseph T. Opferman (all St. Jude).
This work was supported in part by grants from the National Institutes of Health and ALSAC.
Researchers Discover Novel Way to Develop Tumor Vaccines
Researchers at the University of Southern California (USC) have uncovered a new way to develop more effective tumor vaccines by turning off the suppression function of regulatory T cells. The results of the study, titled “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression,” will be published in Nature Medicine on March 2, 2008.
“Under normal circumstances, regulatory T cells inhibit the immune system to attack its own cells and tissues to prevent autoimmune diseases. Cancer cells take advantage of regulatory T cells' suppressor ability, recruiting them to keep the immune system at bay or disabling the immune system’s attack provoked by tumor vaccines.” says Si-Yi Chen, M.D., Ph.D., professor of immunology and molecular microbiology at the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of USC. “Our study provides a new vaccination strategy to overcome the regulatory T cells’ immune suppression while avoiding non-specific overactivation of autoreactive T cells and pathological autoimmune toxicities.”
The study identified a new molecular player called A20, an enzyme that restricts inflammatory signal transduction in dendritic cells. When it is inhibited, the dendritic cells overproduce an array of cytokines and co-stimulatory molecules that triggers unusually strong immune responses that cannot be suppressed by regulatory T cells. The resulting hyperactivated immune responses triggered by A20-deficient dendritic cells are capable of destroying various types of tumors that are resistant to current tumor vaccines in mice.
“Through a series of immunological studies, we have identified A20 as an essential antigen presentation attenuator that prevents the overactivation and excessive inflammation of the dendritic cells, which, in turn, restricts the potency of tumor vaccines,” says Chen.
The immune system’s dendritic cells are the guardian cells of the immune systems and play an important role in activating immune responses to recognize and destroy tumor cells. Tumor vaccines have been designed and developed to incite the immune response to cancer cells so that the immune system can attack and destroy cancer cells. However, discovering A20’s role in restricting immune responses has led to a method for blocking tumors from using regulatory T cells for protection.
“Despite intensive efforts, tumor vaccines have been largely ineffective in causing tumor regression in the clinic,” says Chen. “The vaccination approach we developed inhibits the key inhibitor in tumor antigen-loaded dendritic cells to selectively hyperactivate immune responses and to tip the balance from immune suppression in tumor-bearing hosts or cancer patients to effective antitumor immunity.”
This approach is capable of overcoming the regulatory T cells’ suppression mechanism and will allow for a new generation of tumor vaccines to be developed. The next step is to translate these findings into a human clinical trial, says Chen.
The National Institutes of Health and the Leukemia and Lymphoma Society funded the study.
Xiao-Tong Song, Kevin E. Kabler, Lei Shen, Lisa Rollins, Xue F. Huang, Si-Yi Chen. “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.” Nature Medicine, Mar. 2, 2008. Digital object identifier number 10.1038/nm1721.
(NewsWise)
Researchers at the University of Southern California (USC) have uncovered a new way to develop more effective tumor vaccines by turning off the suppression function of regulatory T cells. The results of the study, titled “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression,” will be published in Nature Medicine on March 2, 2008.
“Under normal circumstances, regulatory T cells inhibit the immune system to attack its own cells and tissues to prevent autoimmune diseases. Cancer cells take advantage of regulatory T cells' suppressor ability, recruiting them to keep the immune system at bay or disabling the immune system’s attack provoked by tumor vaccines.” says Si-Yi Chen, M.D., Ph.D., professor of immunology and molecular microbiology at the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of USC. “Our study provides a new vaccination strategy to overcome the regulatory T cells’ immune suppression while avoiding non-specific overactivation of autoreactive T cells and pathological autoimmune toxicities.”
The study identified a new molecular player called A20, an enzyme that restricts inflammatory signal transduction in dendritic cells. When it is inhibited, the dendritic cells overproduce an array of cytokines and co-stimulatory molecules that triggers unusually strong immune responses that cannot be suppressed by regulatory T cells. The resulting hyperactivated immune responses triggered by A20-deficient dendritic cells are capable of destroying various types of tumors that are resistant to current tumor vaccines in mice.
“Through a series of immunological studies, we have identified A20 as an essential antigen presentation attenuator that prevents the overactivation and excessive inflammation of the dendritic cells, which, in turn, restricts the potency of tumor vaccines,” says Chen.
The immune system’s dendritic cells are the guardian cells of the immune systems and play an important role in activating immune responses to recognize and destroy tumor cells. Tumor vaccines have been designed and developed to incite the immune response to cancer cells so that the immune system can attack and destroy cancer cells. However, discovering A20’s role in restricting immune responses has led to a method for blocking tumors from using regulatory T cells for protection.
“Despite intensive efforts, tumor vaccines have been largely ineffective in causing tumor regression in the clinic,” says Chen. “The vaccination approach we developed inhibits the key inhibitor in tumor antigen-loaded dendritic cells to selectively hyperactivate immune responses and to tip the balance from immune suppression in tumor-bearing hosts or cancer patients to effective antitumor immunity.”
This approach is capable of overcoming the regulatory T cells’ suppression mechanism and will allow for a new generation of tumor vaccines to be developed. The next step is to translate these findings into a human clinical trial, says Chen.
The National Institutes of Health and the Leukemia and Lymphoma Society funded the study.
Xiao-Tong Song, Kevin E. Kabler, Lei Shen, Lisa Rollins, Xue F. Huang, Si-Yi Chen. “A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.” Nature Medicine, Mar. 2, 2008. Digital object identifier number 10.1038/nm1721.
(NewsWise)
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