In addition to known antiviral agents such as antibodies and interferons, people also seem to have a similar immune system to that previously identified in plants. This is the result of research carried out by Esther Schnettler at Wageningen University. Together with the group of Professor Ben Berkhout of the Academic Medical Centre (AMC) in Amsterdam, Schnettler discovered that a protein used by plant viruses to bypass plant resistance can also impair the defence against HIV viruses in people. Schnettler's findings may open up new opportunities for improving health.
Plants defend themselves against viruses by attacking, deactivating and breaking down genetic material in a process called RNA silencing. Viruses try to bypass this defence by producing proteins that block it. Schnettler researched the functioning of these silencing suppressor proteins in plants, recognising that the improvement of plant defences would enable more sustainable cultivation by reducing the need for chemical pesticides to combat insects and pathogens.
Schnettler also studied whether the silencing suppressor proteins that allow plant viruses to bypass plant defences could also have an influence on our immunity systems. We know that antibodies can detect the protein shells of viruses, which allow them to be broken down. Our bodies also protect themselves against viruses by releasing interferons that give a sign to cells to die, preventing the viruses within those cells from multiplying or spreading.
In cooperation with a group of scientists from the AMC, Schnettler found that HIV mutants which are unable to produce a specific protein (making it almost impossible for them to multiply) can start multiplying up to wild type virus titer levels when a silencing suppressor protein from a plant virus is added. This seems to suggest that people also have the defence against viruses used by plants against intruders and which detects and deactivates the genetic material of the HIV virus.
"The research has helped us to understand that the process of RNA silencing seems to be a widely occurring antiviral defence," says Schnettler. "Our findings could offer new opportunities for developing antiviral medication. This is not yet certain, however, as the RNA silencing process in the human body has (additional) other functions that must not be impaired by medicines."
Sources: Wageningen University and Research Centre, AlphaGalileo Foundation.
пятница, 12 августа 2011 г.
вторник, 9 августа 2011 г.
Gene Associated With Reduced Mortality From Acute Lung Injury
Researchers at National Jewish Health and the University of Colorado Denver have discovered a gene that is associated with improved survival among patients with acute lung injury. Acute lung injury (ALI) is often caused by a respiratory infection and results in low oxygen levels in the blood, and fluid in the lungs. It is one of the most vexing problems for intensive care units, afflicting almost 200,000 people in the United States each year, and killing 40 percent of them.
"This discovery could benefit patients in two ways," said James Crapo. MD, senior author and Professor of Medicine at National Jewish Health. "By learning how this specific gene can alter the course of acute lung injury, we can gain insight into the biology of the disease, which could lead to better therapies. It also could become a tool in personalized medicine; by screening for this protective genotype and ones that make a person more susceptible to ALI, we can potentially tailor our treatment individual patients with respiratory infections and ALI to minimize the potential harm."
The researchers looked at the gene for extracellular superoxide dismutase (EC-SOD), a powerful antioxidant that has been associated with reduced lung injury in animal models, and better patient outcomes in chronic obstructive pulmonary disease. After sequencing the EC-SOD gene in 52 randomly selected people, they discovered 28 different places within the gene and its promoter that showed variations. Many of the variations, known as single nucleotide polymorphisms (SNPs) occurred together.
The researchers then looked at the various forms of the EC-SOD gene in two groups of patients with infection-associated ALI. They found that patients with a specific combination of four SNPs, had an 75 percent reduced risk of being on a ventilator as all other ALI patients, and an 85 percent reduced risk of dying.
"This specific set of SNPs, which we call the GCCT haplotype, appears to reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with ALI," said John J. Arcaroli, PhD, first author and a post-doctoral fellow at the University of Colorado at Denver. "Although We are not yet sure how these particular SNPs alter the action of the EC-SOD, these findings gives us a good starting point to learn more about possible protective mechanisms in ALI and other lung diseases."
The researchers reported their findings in the January 15, 2009, issue of the American Journal of Respiratory and Critical Care Medicine.
Source: William Allstetter
National Jewish Medical and Research Center
"This discovery could benefit patients in two ways," said James Crapo. MD, senior author and Professor of Medicine at National Jewish Health. "By learning how this specific gene can alter the course of acute lung injury, we can gain insight into the biology of the disease, which could lead to better therapies. It also could become a tool in personalized medicine; by screening for this protective genotype and ones that make a person more susceptible to ALI, we can potentially tailor our treatment individual patients with respiratory infections and ALI to minimize the potential harm."
The researchers looked at the gene for extracellular superoxide dismutase (EC-SOD), a powerful antioxidant that has been associated with reduced lung injury in animal models, and better patient outcomes in chronic obstructive pulmonary disease. After sequencing the EC-SOD gene in 52 randomly selected people, they discovered 28 different places within the gene and its promoter that showed variations. Many of the variations, known as single nucleotide polymorphisms (SNPs) occurred together.
The researchers then looked at the various forms of the EC-SOD gene in two groups of patients with infection-associated ALI. They found that patients with a specific combination of four SNPs, had an 75 percent reduced risk of being on a ventilator as all other ALI patients, and an 85 percent reduced risk of dying.
"This specific set of SNPs, which we call the GCCT haplotype, appears to reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with ALI," said John J. Arcaroli, PhD, first author and a post-doctoral fellow at the University of Colorado at Denver. "Although We are not yet sure how these particular SNPs alter the action of the EC-SOD, these findings gives us a good starting point to learn more about possible protective mechanisms in ALI and other lung diseases."
The researchers reported their findings in the January 15, 2009, issue of the American Journal of Respiratory and Critical Care Medicine.
Source: William Allstetter
National Jewish Medical and Research Center
суббота, 6 августа 2011 г.
Detecting Cold, Feeling Pain: Study Reveals Why Menthol Feels Fresh
Scientists have identified the receptor in cells of the peripheral nervous system that is most responsible for the body's ability to sense cold.
The finding, reported on-line in the journal "Nature", reveals one of the key mechanisms by which the body detects temperature sensation. But in so doing it also illuminates a mechanism that mediates how the body experiences intense stimuli - temperature, in this case - that can cause pain.
As such, the receptor - known as menthol receptor TRPM8 - provides a target for studying acute and chronic pain, as can result from inflammatory or nerve injury, the researchers say, and a potential new target for treating pain.
"By understanding how sensory receptors work, how thresholds for temperature are determined, we gain insight into how these thresholds change in the setting of injury, such as inflammatory and nerve injury, and how these changes may contribute to chronic pain," says senior author David Julius, PhD, chairman and professor of physiology at UCSF.
The methanol receptor, and other temperature receptors discovered in recent years by the Julius lab, offer potential targets for developing analgesic drugs that act in the peripheral, nervous system, rather than centrally, where opiate receptors act, he says.
The finding is a milestone in an investigation the team began several years ago. In 2002, the researchers discovered that the receptor was activated by chemical cooling agents such as menthol, a natural product of mint, and cool air. They reported their discovery, or "cloning," of the receptor in "Nature" (March 7, 2002), hypothesizing that the receptor would play a key role in sensing cold. However, some subsequent papers questioned this theory.
In the current study, the team confirmed their hypothesis by "knocking out" the gene that synthesizes the receptor, both in sensory neurons in cell culture and in mice. The cells in culture were unresponsive to cooling agents, including menthol. The genetically engineered mice did not discriminate between warm and cold surfaces until the temperature dropped to extremes.
"It's been known for years that menthol and related cooling agents evoke the psychophysical sensation of cold - somehow by interacting with the aspect of the sensory nervous system that's related to cold detection," says Julius.
The current study, he says -- led by Diana M. Bautista, PhD, and Jan Siemens, PhD, of the Julius lab and Joshua M. Glazer, PhD, of the lab of co-senior author Cheryl Stucky, PhD, of the Medical College of Wisconsin - puts that question to rest.
As the mice lacking the gene were not completely insensitive to cold -- they avoided contact with surfaces below 10 degrees C, though with reduced efficiency -- the next step, says Julius, will be to illuminate this residual aspect of cold sensation.
The finding is the latest of a series of discoveries led by the Julius lab on the molecular mechanisms of temperature sensation and pain. In 1997, the lab cloned the gene for the capsaicin receptor, the main pungent ingredient in some chili peppers (Nature, Oct. 23, 1997), and in 2000 reported that, in mice, the receptor triggers the nerves to fire pain signals when they are exposed to high ambient heat or the fiery properties of peppery food. (Science, April 14, 2000). The study demonstrated that capsaicin and noxious heat elicit the sensation of burning pain through activation of the same receptor on sensory neurons.
Most recently, they identified the receptor of isothiocyanate compounds, which constitute the pungent ingredients in such plants as wasabi and yellow mustard. In response to high temperatures, the receptor produces pain and irritation.
"All of these studies use natural products to understand pain mechanisms in the periphery of the body, where they are first sensed," says Julius.
Ultimately, pain signals are transmitted from the peripheral nervous system into the body's central nervous system - moving through nerves in the spinal cord and brain stem up to the brain, which prompts a response, or "feeling." Co-author of the current study Allan Basbaum, PhD, also of UCSF, is a pioneer of research into the mechanism of chronic pain within the central nervous system.
The Julius team's complementary work is focused at the level of the sensory nerve fiber, where the signals are first initiated. "We want to know," Julius says, "how do you detect these stimuli to begin with" How do your sensory nerve endings do this to begin with" And what are the biochemical and biophysical mechanisms that account for this""
All three receptors the Julius lab has discovered are members of the TRP family of ion channels expressed on sensory neurons. The latest finding adds to the evidence, says Julius, that TRP channels are the principal transducers of thermal stimuli in the mammalian periphery nervous system.
Other co-authors of the study were Pamela R. Tsuruda, PhD, of UCSF, and Sven-Eric Jordt, PhD, of Yale University School of Medicine.
The study was funded by the National Institutes of Health, the Burroughs Welcome Fund and the Human Frontiers Science Program Organization.
UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.
Related links: ucsf/djlab/
Contact: Jennifer O'Brien
University of California - San Francisco
The finding, reported on-line in the journal "Nature", reveals one of the key mechanisms by which the body detects temperature sensation. But in so doing it also illuminates a mechanism that mediates how the body experiences intense stimuli - temperature, in this case - that can cause pain.
As such, the receptor - known as menthol receptor TRPM8 - provides a target for studying acute and chronic pain, as can result from inflammatory or nerve injury, the researchers say, and a potential new target for treating pain.
"By understanding how sensory receptors work, how thresholds for temperature are determined, we gain insight into how these thresholds change in the setting of injury, such as inflammatory and nerve injury, and how these changes may contribute to chronic pain," says senior author David Julius, PhD, chairman and professor of physiology at UCSF.
The methanol receptor, and other temperature receptors discovered in recent years by the Julius lab, offer potential targets for developing analgesic drugs that act in the peripheral, nervous system, rather than centrally, where opiate receptors act, he says.
The finding is a milestone in an investigation the team began several years ago. In 2002, the researchers discovered that the receptor was activated by chemical cooling agents such as menthol, a natural product of mint, and cool air. They reported their discovery, or "cloning," of the receptor in "Nature" (March 7, 2002), hypothesizing that the receptor would play a key role in sensing cold. However, some subsequent papers questioned this theory.
In the current study, the team confirmed their hypothesis by "knocking out" the gene that synthesizes the receptor, both in sensory neurons in cell culture and in mice. The cells in culture were unresponsive to cooling agents, including menthol. The genetically engineered mice did not discriminate between warm and cold surfaces until the temperature dropped to extremes.
"It's been known for years that menthol and related cooling agents evoke the psychophysical sensation of cold - somehow by interacting with the aspect of the sensory nervous system that's related to cold detection," says Julius.
The current study, he says -- led by Diana M. Bautista, PhD, and Jan Siemens, PhD, of the Julius lab and Joshua M. Glazer, PhD, of the lab of co-senior author Cheryl Stucky, PhD, of the Medical College of Wisconsin - puts that question to rest.
As the mice lacking the gene were not completely insensitive to cold -- they avoided contact with surfaces below 10 degrees C, though with reduced efficiency -- the next step, says Julius, will be to illuminate this residual aspect of cold sensation.
The finding is the latest of a series of discoveries led by the Julius lab on the molecular mechanisms of temperature sensation and pain. In 1997, the lab cloned the gene for the capsaicin receptor, the main pungent ingredient in some chili peppers (Nature, Oct. 23, 1997), and in 2000 reported that, in mice, the receptor triggers the nerves to fire pain signals when they are exposed to high ambient heat or the fiery properties of peppery food. (Science, April 14, 2000). The study demonstrated that capsaicin and noxious heat elicit the sensation of burning pain through activation of the same receptor on sensory neurons.
Most recently, they identified the receptor of isothiocyanate compounds, which constitute the pungent ingredients in such plants as wasabi and yellow mustard. In response to high temperatures, the receptor produces pain and irritation.
"All of these studies use natural products to understand pain mechanisms in the periphery of the body, where they are first sensed," says Julius.
Ultimately, pain signals are transmitted from the peripheral nervous system into the body's central nervous system - moving through nerves in the spinal cord and brain stem up to the brain, which prompts a response, or "feeling." Co-author of the current study Allan Basbaum, PhD, also of UCSF, is a pioneer of research into the mechanism of chronic pain within the central nervous system.
The Julius team's complementary work is focused at the level of the sensory nerve fiber, where the signals are first initiated. "We want to know," Julius says, "how do you detect these stimuli to begin with" How do your sensory nerve endings do this to begin with" And what are the biochemical and biophysical mechanisms that account for this""
All three receptors the Julius lab has discovered are members of the TRP family of ion channels expressed on sensory neurons. The latest finding adds to the evidence, says Julius, that TRP channels are the principal transducers of thermal stimuli in the mammalian periphery nervous system.
Other co-authors of the study were Pamela R. Tsuruda, PhD, of UCSF, and Sven-Eric Jordt, PhD, of Yale University School of Medicine.
The study was funded by the National Institutes of Health, the Burroughs Welcome Fund and the Human Frontiers Science Program Organization.
UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.
Related links: ucsf/djlab/
Contact: Jennifer O'Brien
University of California - San Francisco
среда, 3 августа 2011 г.
Heat Shock Protein Drives Yeast Evolution
Whitehead Institute researchers have determined that heat shock protein 90 (Hsp90) can create heritable traits in brewer's yeast (Saccharomyces cerevisiae) by affecting a large portion of the yeast genome. The finding has led to the conclusion that Hsp90 has played a key role in genome evolution.
"This has been viewed as a very exciting, even revolutionary way of looking at how it is organisms could rapidly evolve new traits," says Whitehead Member Susan Lindquist. "We've come about as close to proving such a broad evolutionary process as it's likely that we can at this present date."
The results are reported in the December 24, 2010 issue of the journal Science.
Proteins perform numerous functions in cells, including promoting chemical reactions, translating DNA, and maintaining the cell's structure. To perform its job, a protein must fold from a long chain of amino acids into a precise form. Moreover, many vital proteins adopt unstable conformations. If the protein loses its normal shape due to, for example, excessive heat, toxins or other stressors, it can no longer perform its job and may even become toxic to the cell. To provide tolerance against such stresses , cells employ a repertoire of heat-shock proteins (Hsps) that guide other proteins into their proper shape. This ancient class of proteins is present in virtually all organisms, ranging from bacteria to humans.
One of these proteins, Hsp90, is particularly abundant, comprising 1-2% of all proteins in a cell. Yet, under normal conditions, a cell uses only about 10% of its Hsp90, leaving a large reservoir of its function available should conditions suddenly turn more stressful.
Over the past several years, Lindquist has built the case that this Hsp reservoir is responsible for substantial evolutionary changes in relatively short periods of time. Her lab has shown that the pathogenic Candida albicans and Aspergillus fungi rely on Hsp90 to evolve drug-resistance. Cancer cells often exploit the Hsps' function to support carcinogenic proteins. Earlier research has also shown that selective breeding can enrich variation responsible for these phenotypes, allowing an Hsp90-reliant trait to be inherited even in the absence of stress.
The Hsp90 buffer appears to function in two ways with mutant proteins: either to mask or reveal the phenotypic consequences of mutations. In the first case, Hsp90 braces mutant proteins into "normal" shapes, thereby hiding the mutant proteins' traits. As conditions become increasingly stressful, the Hsp90 buffer must act on more and more proteins. At a certain point, the Hsp90 buffer becomes overwhelmed, and the mutant proteins' traits are exhibited.
In the second scenario, proteins that are not functional on their own are shaped into working forms. These mutant proteins cannot perform their jobs without the aid of Hsp90, so when the Hsp90 buffer is overwhelmed, the cells lose the mutant proteins' traits.
In both of these scenarios, consumption of the Hsp90 reservoir by environmental stress allows numerous traits to be exhibited or lost immediately and simultaneously. If the new phenotype is beneficial for this stressful environment, the organism will survive. Because the new phenotypes are based on genetic variation they can be passed on to the next generation and evolution progresses. If the traits are detrimental, the organism will not survive and its traits will die with it.
This method of suddenly unveiling a new phenotype consisting of multiple traits could also explain the evolution of interdependent traits that are detrimental on their own. Such a seeming leap forward in evolution has puzzled biologists since Darwin.
Although earlier evidence indicated that Hsp90 activity could affect evolution, a Lindquist postdoctoral researcher, Daniel Jarosz, wanted to understand mechanistically Hsp90's effects on one species and provide solid evidence for Hsp90's impact on evolution.
In the Science paper, first author Jarosz analyzed the effects of Hsp90 on 102 genetically diverse strains of brewer's yeast by placing them under various stressful conditions and inhibiting Hsp90. All of the strains had substantial growth changes in specific conditions.
Jarosz then learned more about the Hsp90-affected traits by crossing two strains and looking at the progeny. He determined that about half of the traits affected by Hsp90 were positive and half were negative. Also, reducing Hsp90 in several of the crossed strains' progeny revealed multiple interdependent traits.
To see how much Hsp90 affects the phenotypes of yeast strains, Jarosz looked at the genetic sequences of 48 strains and compared the genotypes to the phenotypes that he saw in those strains. When Hsp90 functioned normally, the genotype and phenotype weakly resembled each other. But when the Hsp90 reservoir was depleted, the correlation between genotype and phenotype became much stronger.
"We've only looked at a few cases, but in all of them, there was a clear link between Hsp90 activity and phenotype," says Jarosz. "What we show here is that Hsp90's effects are very broad, and it operates on about 20% of all genetic variation in this organism."
For Lindquist, the way Hsp90 is able to affect phenotypes may explain a longstanding mystery of evolution: how an organism could change multiple, interdependent traits in response to environmental changes.
"Taking what had been theory and very isolated incidents that had tremendous potential, we can help explain how organisms can rapidly acquire new traits," says Lindquist, who is also a Howard Hughes Medical Institute investigator and professor of biology at MIT. "We can show that the stress of environmental change and selective pressures can actually influence how evolutionary processes occur. And now we have a much more solid framework to hang that on."
Lindquist says she would like to learn more about the fixation process, which makes an Hsp90-reliant trait heritable, even in the absence of stress. By looking at genome sequences, her lab will try to determine whether Hsp90 affects the mechanisms of genome stability or if it perhaps influences the way that organisms accumulate new genetic variation.
This research was supported by a SPARC grant from the Broad Institute and the G. Harold and Leila Y. Mathers Foundation. Daniel Jarosz is an HHMI fellow of the Damon Runyon Cancer Research Foundation.
Written by Nicole Giese
Susan Lindquist's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
Full Citations:
"Hsp90 and environmental stress transform the adaptive value of natural genetic variation"
Science, December 24, 2010.
Daniel F. Jarosz (1) and Susan Lindquist (1,2)
1. Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, 9 Cambridge Center, Cambridge, MA 02142
2. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
Source:
Nicole Giese
Whitehead Institute for Biomedical Research
"This has been viewed as a very exciting, even revolutionary way of looking at how it is organisms could rapidly evolve new traits," says Whitehead Member Susan Lindquist. "We've come about as close to proving such a broad evolutionary process as it's likely that we can at this present date."
The results are reported in the December 24, 2010 issue of the journal Science.
Proteins perform numerous functions in cells, including promoting chemical reactions, translating DNA, and maintaining the cell's structure. To perform its job, a protein must fold from a long chain of amino acids into a precise form. Moreover, many vital proteins adopt unstable conformations. If the protein loses its normal shape due to, for example, excessive heat, toxins or other stressors, it can no longer perform its job and may even become toxic to the cell. To provide tolerance against such stresses , cells employ a repertoire of heat-shock proteins (Hsps) that guide other proteins into their proper shape. This ancient class of proteins is present in virtually all organisms, ranging from bacteria to humans.
One of these proteins, Hsp90, is particularly abundant, comprising 1-2% of all proteins in a cell. Yet, under normal conditions, a cell uses only about 10% of its Hsp90, leaving a large reservoir of its function available should conditions suddenly turn more stressful.
Over the past several years, Lindquist has built the case that this Hsp reservoir is responsible for substantial evolutionary changes in relatively short periods of time. Her lab has shown that the pathogenic Candida albicans and Aspergillus fungi rely on Hsp90 to evolve drug-resistance. Cancer cells often exploit the Hsps' function to support carcinogenic proteins. Earlier research has also shown that selective breeding can enrich variation responsible for these phenotypes, allowing an Hsp90-reliant trait to be inherited even in the absence of stress.
The Hsp90 buffer appears to function in two ways with mutant proteins: either to mask or reveal the phenotypic consequences of mutations. In the first case, Hsp90 braces mutant proteins into "normal" shapes, thereby hiding the mutant proteins' traits. As conditions become increasingly stressful, the Hsp90 buffer must act on more and more proteins. At a certain point, the Hsp90 buffer becomes overwhelmed, and the mutant proteins' traits are exhibited.
In the second scenario, proteins that are not functional on their own are shaped into working forms. These mutant proteins cannot perform their jobs without the aid of Hsp90, so when the Hsp90 buffer is overwhelmed, the cells lose the mutant proteins' traits.
In both of these scenarios, consumption of the Hsp90 reservoir by environmental stress allows numerous traits to be exhibited or lost immediately and simultaneously. If the new phenotype is beneficial for this stressful environment, the organism will survive. Because the new phenotypes are based on genetic variation they can be passed on to the next generation and evolution progresses. If the traits are detrimental, the organism will not survive and its traits will die with it.
This method of suddenly unveiling a new phenotype consisting of multiple traits could also explain the evolution of interdependent traits that are detrimental on their own. Such a seeming leap forward in evolution has puzzled biologists since Darwin.
Although earlier evidence indicated that Hsp90 activity could affect evolution, a Lindquist postdoctoral researcher, Daniel Jarosz, wanted to understand mechanistically Hsp90's effects on one species and provide solid evidence for Hsp90's impact on evolution.
In the Science paper, first author Jarosz analyzed the effects of Hsp90 on 102 genetically diverse strains of brewer's yeast by placing them under various stressful conditions and inhibiting Hsp90. All of the strains had substantial growth changes in specific conditions.
Jarosz then learned more about the Hsp90-affected traits by crossing two strains and looking at the progeny. He determined that about half of the traits affected by Hsp90 were positive and half were negative. Also, reducing Hsp90 in several of the crossed strains' progeny revealed multiple interdependent traits.
To see how much Hsp90 affects the phenotypes of yeast strains, Jarosz looked at the genetic sequences of 48 strains and compared the genotypes to the phenotypes that he saw in those strains. When Hsp90 functioned normally, the genotype and phenotype weakly resembled each other. But when the Hsp90 reservoir was depleted, the correlation between genotype and phenotype became much stronger.
"We've only looked at a few cases, but in all of them, there was a clear link between Hsp90 activity and phenotype," says Jarosz. "What we show here is that Hsp90's effects are very broad, and it operates on about 20% of all genetic variation in this organism."
For Lindquist, the way Hsp90 is able to affect phenotypes may explain a longstanding mystery of evolution: how an organism could change multiple, interdependent traits in response to environmental changes.
"Taking what had been theory and very isolated incidents that had tremendous potential, we can help explain how organisms can rapidly acquire new traits," says Lindquist, who is also a Howard Hughes Medical Institute investigator and professor of biology at MIT. "We can show that the stress of environmental change and selective pressures can actually influence how evolutionary processes occur. And now we have a much more solid framework to hang that on."
Lindquist says she would like to learn more about the fixation process, which makes an Hsp90-reliant trait heritable, even in the absence of stress. By looking at genome sequences, her lab will try to determine whether Hsp90 affects the mechanisms of genome stability or if it perhaps influences the way that organisms accumulate new genetic variation.
This research was supported by a SPARC grant from the Broad Institute and the G. Harold and Leila Y. Mathers Foundation. Daniel Jarosz is an HHMI fellow of the Damon Runyon Cancer Research Foundation.
Written by Nicole Giese
Susan Lindquist's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
Full Citations:
"Hsp90 and environmental stress transform the adaptive value of natural genetic variation"
Science, December 24, 2010.
Daniel F. Jarosz (1) and Susan Lindquist (1,2)
1. Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, 9 Cambridge Center, Cambridge, MA 02142
2. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
Source:
Nicole Giese
Whitehead Institute for Biomedical Research
воскресенье, 31 июля 2011 г.
First Signal On The Cryogenic Maldi-FTMS Achieved By Researchers
Researchers at Boston University School of Medicine (BUSM) recently achieved first signal on the Cryogenic Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Mass Spectrometry (MALDI-FTMS) being developed at the school's Cardiovascular Proteomics Center (CPC). The Fourier transform mass spectrometer is the highest performance instrumentation currently available to those interested in structural characterization of proteins and other biomolecules.
"When working to its full capacity, the Cryogenic MALDI-FTMS will greatly enhance how we study and understand disease," says Peter B. O'Connor, PhD, research associate professor in the Department of Biochemistry at BUSM and assistant director of the BUSM Mass Spectrometry Resource. "This technology will give us an unbiased view of a disease by identifying proteins by comparing their peptides to those predicted from a DNA database, which helps identify biomarkers for disease." O'Connor goes on to add that this new technology will also allow researchers to identify which proteins are where during certain stages of disease progression, enabling them to more positively identify disease and decide upon treatment options.
The Cryogenic MALDI-FTMS is a major advance in Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometry design. It enables MALDI-FTMS at extremely low temperatures and involves close construction and integration of an FTICR instrument with a modern cryogenic superconducting magnet design.
This configuration provides three major advantages. First, the magnet bore and FTICR cell chamber become very cold, which cryopumps the chamber and decreases the base pressure. Second, because of the cryopumping, the bore tube diameter can be much smaller, allowing high homogeneity and high magnetic fields to be generated at greatly reduced cost. Third, the cold surfaces can be used to cool a preamplifier for improved signal-to-noise ratio.
The BUSM prototype instrument is designed with a 14 Tesla magnet at ~10 ppm homogeneity over the 2x2 cylindrical ICR cell. When fully tuned, this instrument will provide performance several orders of magnitude better than existing instruments, using parts that cost about half as much and a magnet costing about four times less.
This instrument is funded by the National Institutes of Health, National Heart Lung and Blood Institute and the National Center for Research Resources.
Contact: Gina DiGravio
Boston University
"When working to its full capacity, the Cryogenic MALDI-FTMS will greatly enhance how we study and understand disease," says Peter B. O'Connor, PhD, research associate professor in the Department of Biochemistry at BUSM and assistant director of the BUSM Mass Spectrometry Resource. "This technology will give us an unbiased view of a disease by identifying proteins by comparing their peptides to those predicted from a DNA database, which helps identify biomarkers for disease." O'Connor goes on to add that this new technology will also allow researchers to identify which proteins are where during certain stages of disease progression, enabling them to more positively identify disease and decide upon treatment options.
The Cryogenic MALDI-FTMS is a major advance in Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometry design. It enables MALDI-FTMS at extremely low temperatures and involves close construction and integration of an FTICR instrument with a modern cryogenic superconducting magnet design.
This configuration provides three major advantages. First, the magnet bore and FTICR cell chamber become very cold, which cryopumps the chamber and decreases the base pressure. Second, because of the cryopumping, the bore tube diameter can be much smaller, allowing high homogeneity and high magnetic fields to be generated at greatly reduced cost. Third, the cold surfaces can be used to cool a preamplifier for improved signal-to-noise ratio.
The BUSM prototype instrument is designed with a 14 Tesla magnet at ~10 ppm homogeneity over the 2x2 cylindrical ICR cell. When fully tuned, this instrument will provide performance several orders of magnitude better than existing instruments, using parts that cost about half as much and a magnet costing about four times less.
This instrument is funded by the National Institutes of Health, National Heart Lung and Blood Institute and the National Center for Research Resources.
Contact: Gina DiGravio
Boston University
четверг, 28 июля 2011 г.
Estrogen Therapy Gives Aging Brain Cells A Boost
Cyclical, long-term estrogen injections protected brain cells from age-related deterioration, according to a new study conducted at Mount Sinai School of Medicine. The study suggests that age is a factor in estrogen treatment and sheds light on the intricate relationship between mind, age, and hormones. The study is published in the online edition of Proceedings of the National Academy of Sciences.
In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, Assistant Professor of Neuroscience, and senior co-author John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biological Sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, Interim Chair of the Department of Neuroscience and Associate Professor of Neuroscience, and Geriatrics and Adult Development, led the behavioral phase of the study. Partrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.
Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.
Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause - before the onset of full menopause - and began treatment within months of ovariectomy.
Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex - a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys - the older estrogen-treated animals showed a greater density of synaptic spines - tentacle-like structures that link brain cells to one another and aid in brain cell communication - while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.
The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. "There's been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful."
Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.
"We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline," Dr. Morrison explains. "Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything."
"The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity," says Dr. Morrison. "Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories."
The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, "but what's happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit."
Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit.
"'It's possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all," Dr. Morrison explains, "so this window of opportunity may be fairly narrow - we just don't know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it's too late, we may possibly prevent memory loss." What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.
Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center. Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.
Contact: Mount Sinai Press Office
The Mount Sinai Hospital / Mount Sinai School of Medicine
View drug information on Estradiol Transdermal System.
In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, Assistant Professor of Neuroscience, and senior co-author John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biological Sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, Interim Chair of the Department of Neuroscience and Associate Professor of Neuroscience, and Geriatrics and Adult Development, led the behavioral phase of the study. Partrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.
Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.
Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause - before the onset of full menopause - and began treatment within months of ovariectomy.
Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex - a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys - the older estrogen-treated animals showed a greater density of synaptic spines - tentacle-like structures that link brain cells to one another and aid in brain cell communication - while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.
The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. "There's been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful."
Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.
"We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline," Dr. Morrison explains. "Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything."
"The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity," says Dr. Morrison. "Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories."
The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, "but what's happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit."
Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit.
"'It's possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all," Dr. Morrison explains, "so this window of opportunity may be fairly narrow - we just don't know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it's too late, we may possibly prevent memory loss." What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.
Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center. Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.
Contact: Mount Sinai Press Office
The Mount Sinai Hospital / Mount Sinai School of Medicine
View drug information on Estradiol Transdermal System.
понедельник, 25 июля 2011 г.
New Chemistry Approach Promises Less Expensive Drugs
With a newly discovered method of assembling organic molecules, a team of Princeton University chemists may have found a way to sidestep many of the expensive and hazardous barriers that stand in the way of drug development.
The new approach allows scientists to synthesize molecules without employing toxic catalysts, and it also does not generate alternate versions of drug molecules that can damage the body, two perennial issues that plague the manufacturing process. David MacMillan, one of the researchers on the team, said the discovery is important not only for its industrial applications, but also because of the new research possibilities it opens up.
"This is a new type of chemistry that could expand the way people think about making biologically active molecules," said MacMillan, who holds Princeton's A. Barton Hepburn Chair of Chemistry and directs the chemistry department's Merck Center for Catalysis. "We've found more than a new chemical reaction. It's a common mode of molecule activation that allows a whole group of reactions to take place."
Broadly stated, the discovery will open up new possibilities for working with ketones and aldehydes, two chemical groups that are found on a large percentage of the substances in which organic chemists are interested. "They form a big region of the reaction landscape," MacMillan said.
The paper, which MacMillan cowrote with first author Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong and Kate Ashton, all members of his research group, appears in the March 29 issue of the journal Science. John Schwab, a chemist at the National Institutes of Health (NIH), applauded the work for the new possibilities it could provide.
"One sometimes hears that organic chemistry is a mature field, but MacMillan's work shows that there still are rich veins waiting to be mined," said Schwab, also a program director at the NIH's National Institute of General Medical Sciences, which supported the work. "What's particularly exciting to me is the depth and rigor of the analysis that enabled this very creative breakthrough. Equally important, MacMillan has discovered new reactions that will streamline the synthesis of compounds that are relevant to human health."
Most drug molecules that pharmaceutical companies produce can exist in two different forms, which are mirror images of one another. Though both forms of an organic molecule -- known in the chemistry world as "enantiomers" -- have the same chemical formula, their effect on the body can differ dramatically.
"The two enantiomers are like keys with the same number of teeth, but which have different orientation," MacMillan said. "One key fits in with our biology very well, opening the correct doors in our body and helping us to heal. But the other key doesn't fit the same doors because its teeth are in opposing locations."
The two forms are indistinguishable by most modern lab tests, yet our bodies can tell the difference. Where one enantiomer might be the basis for a helpful drug, its mirror image might do nothing for the body, or even damage it.
"This was the problem in the 1960s with the drug phthalidomide," MacMillan said. "One of its enantiomers helped pregnant women overcome morning sickness. Its mirror image, however, caused birth defects."
In the vast majority of cases, the Food and Drug Administration now requires that drug companies create only the beneficial enantiomer during the manufacturing process. While this requirement keeps any of these helpful molecules' "evil twins" from reaching our systems, it also places heavy demands on the drug companies.
Building large quantities of a drug molecule often requires a catalyst, a substance that permits a chemical reaction to take place without itself being affected. Until recently, however most catalysts would create both enantiomers simultaneously, MacMillan said. In cases where the catalyst can create only the helpful enantiomer -- a process called asymmetric catalysis -- they are often expensive, capricious and difficult to work with.
"That is one reason why for several years our lab has been looking for catalysts based on organic molecules rather than metals," MacMillan said. "Organic catalysts are generally inexpensive, robust to water and air and environmentally friendly. Organic catalysts, it turns out, are proving more capable than most people expected."
Since the year 2000, MacMillan's work has enabled the discovery of a new family of organic catalysts, which can be used to produce only beneficial enantiomers. These catalysts have proven desirable because they are based on organic substances, and are therefore not harmful either to patients or to the environment. But his team's latest paper does more than offer chemists a new set of organic catalysts with which to work.
"This discovery does not yield merely more organic catalysts, but makes a whole new type of chemical reactions available to us," MacMillan said. "It's almost like a new airport hub that allows you to extend the range of your air travel. You can reach destinations that were not open to you before."
Gregory Fu of the Massachusetts Institute of Technology said that these destinations would likely prove important to the pharmaceutical industry.
"This work adds an important new dimension to efforts to achieve asymmetric catalysis," said Fu, a professor of chemistry. "It will no doubt have a substantial impact on the discovery of new bioactive compounds for the benefit of society."
MacMillan said he hopes the findings would eventually make drugs both more useful and widely available.
"The big payoff here is that the discovery will allow new chemical reactions to be developed that are powerful yet unprecedented in the field of chemistry," MacMillan said. "They will allow access to single enantiomers, and they will do it using cheap, environmentally friendly small organic molecules as catalysts. It's a double whammy."
Abstract
Enantioselective Organocatalysis using SOMO Activation
Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong, Kate Ashton and David MacMillan
The invention of new modes of catalytic activation is essential for the continued development of the field of asymmetric catalysis. Here, a unique mode of organocatalytic activation is presented wherein a chiral amine catalyst reacts with an aldehyde to transiently generate an enamine that in turn undergoes a single-electron oxidation to yield a Singly Occupied Molecular Orbital (SOMO) radical cation that is subject to enantiofacial discrimination. While the parent enamine reacts only with electrophiles, the radical cation combines with SOMO nucleophiles at the same reaction site, thereby enabling a diverse range of previously unknown asymmetric transformations. As a first example, the direct and enantioselective alpha-allylation of aldehydes is reported.
Contact: Chad Boutin
Princeton University
The new approach allows scientists to synthesize molecules without employing toxic catalysts, and it also does not generate alternate versions of drug molecules that can damage the body, two perennial issues that plague the manufacturing process. David MacMillan, one of the researchers on the team, said the discovery is important not only for its industrial applications, but also because of the new research possibilities it opens up.
"This is a new type of chemistry that could expand the way people think about making biologically active molecules," said MacMillan, who holds Princeton's A. Barton Hepburn Chair of Chemistry and directs the chemistry department's Merck Center for Catalysis. "We've found more than a new chemical reaction. It's a common mode of molecule activation that allows a whole group of reactions to take place."
Broadly stated, the discovery will open up new possibilities for working with ketones and aldehydes, two chemical groups that are found on a large percentage of the substances in which organic chemists are interested. "They form a big region of the reaction landscape," MacMillan said.
The paper, which MacMillan cowrote with first author Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong and Kate Ashton, all members of his research group, appears in the March 29 issue of the journal Science. John Schwab, a chemist at the National Institutes of Health (NIH), applauded the work for the new possibilities it could provide.
"One sometimes hears that organic chemistry is a mature field, but MacMillan's work shows that there still are rich veins waiting to be mined," said Schwab, also a program director at the NIH's National Institute of General Medical Sciences, which supported the work. "What's particularly exciting to me is the depth and rigor of the analysis that enabled this very creative breakthrough. Equally important, MacMillan has discovered new reactions that will streamline the synthesis of compounds that are relevant to human health."
Most drug molecules that pharmaceutical companies produce can exist in two different forms, which are mirror images of one another. Though both forms of an organic molecule -- known in the chemistry world as "enantiomers" -- have the same chemical formula, their effect on the body can differ dramatically.
"The two enantiomers are like keys with the same number of teeth, but which have different orientation," MacMillan said. "One key fits in with our biology very well, opening the correct doors in our body and helping us to heal. But the other key doesn't fit the same doors because its teeth are in opposing locations."
The two forms are indistinguishable by most modern lab tests, yet our bodies can tell the difference. Where one enantiomer might be the basis for a helpful drug, its mirror image might do nothing for the body, or even damage it.
"This was the problem in the 1960s with the drug phthalidomide," MacMillan said. "One of its enantiomers helped pregnant women overcome morning sickness. Its mirror image, however, caused birth defects."
In the vast majority of cases, the Food and Drug Administration now requires that drug companies create only the beneficial enantiomer during the manufacturing process. While this requirement keeps any of these helpful molecules' "evil twins" from reaching our systems, it also places heavy demands on the drug companies.
Building large quantities of a drug molecule often requires a catalyst, a substance that permits a chemical reaction to take place without itself being affected. Until recently, however most catalysts would create both enantiomers simultaneously, MacMillan said. In cases where the catalyst can create only the helpful enantiomer -- a process called asymmetric catalysis -- they are often expensive, capricious and difficult to work with.
"That is one reason why for several years our lab has been looking for catalysts based on organic molecules rather than metals," MacMillan said. "Organic catalysts are generally inexpensive, robust to water and air and environmentally friendly. Organic catalysts, it turns out, are proving more capable than most people expected."
Since the year 2000, MacMillan's work has enabled the discovery of a new family of organic catalysts, which can be used to produce only beneficial enantiomers. These catalysts have proven desirable because they are based on organic substances, and are therefore not harmful either to patients or to the environment. But his team's latest paper does more than offer chemists a new set of organic catalysts with which to work.
"This discovery does not yield merely more organic catalysts, but makes a whole new type of chemical reactions available to us," MacMillan said. "It's almost like a new airport hub that allows you to extend the range of your air travel. You can reach destinations that were not open to you before."
Gregory Fu of the Massachusetts Institute of Technology said that these destinations would likely prove important to the pharmaceutical industry.
"This work adds an important new dimension to efforts to achieve asymmetric catalysis," said Fu, a professor of chemistry. "It will no doubt have a substantial impact on the discovery of new bioactive compounds for the benefit of society."
MacMillan said he hopes the findings would eventually make drugs both more useful and widely available.
"The big payoff here is that the discovery will allow new chemical reactions to be developed that are powerful yet unprecedented in the field of chemistry," MacMillan said. "They will allow access to single enantiomers, and they will do it using cheap, environmentally friendly small organic molecules as catalysts. It's a double whammy."
Abstract
Enantioselective Organocatalysis using SOMO Activation
Teresa Beeson, Anthony Mastracchio, Jun-Bae Hong, Kate Ashton and David MacMillan
The invention of new modes of catalytic activation is essential for the continued development of the field of asymmetric catalysis. Here, a unique mode of organocatalytic activation is presented wherein a chiral amine catalyst reacts with an aldehyde to transiently generate an enamine that in turn undergoes a single-electron oxidation to yield a Singly Occupied Molecular Orbital (SOMO) radical cation that is subject to enantiofacial discrimination. While the parent enamine reacts only with electrophiles, the radical cation combines with SOMO nucleophiles at the same reaction site, thereby enabling a diverse range of previously unknown asymmetric transformations. As a first example, the direct and enantioselective alpha-allylation of aldehydes is reported.
Contact: Chad Boutin
Princeton University
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