Malaria researcher Win Surachetpong, a doctoral candidate at the University of California, Davis, is the 2009 winner of the William C. Reeves New Investigator Award, given to the best scientific paper presented at the annual Mosquito and Vector Control Association of California (MVCAC) meeting.
Surachetpong received $1000 and a plaque at the 77th annual MVCAC meeting, held in Burlingame. His scientific paper focused on regulating the development of malaria parasites.
"Win is a very talented, dedicated student and I have been extremely fortunate to have him in my lab," said his major professor and malaria researcher Shirley Luckhart, an associate professor of medical microbiology and immunology at the UC Davis School of Medicine, and a faculty member of the Graduate Groups of Biochemistry and Molecular Biology; Microbiology; Immunology; and the Graduate Program in Entomology.
"His work," she said, "has been the foundation of the development of a completely new area of work for us that will probably keep us busy for years to come."
The award memorializes a renowned entomologist and professor at UC Berkeley who was widely regarded as the world's foremost authority on the spread and control of mosquito-borne diseases. Reeves (1916-2004) was a frequent visitor to the UC Davis campus.
Surachetpong said that malaria "remains an enormous public health burden, especially in developing countries." Malaria, caused by the parasite Plasmodium and transmitted by infected anopheline mosquitoes, strikes some 350 to 500 million people a year, killing more than a million, according to the Centers for Disease Control and Prevention.
"New strategies including integrated vector management in combination with current conventional malaria control efforts such as drug treatment and bednet usage could synergistically reduce malaria transmission," Surachetpong said.
"However, our current knowledge of vector-host-parasite interactions is limited," he noted. "For example, how mosquito innate immune responses control malaria parasite development and how blood-derived factors modulate mosquito biology remain interesting topics."
"In this study, we reveal the role of MEK-ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling in regulation of malaria parasite development by an ingested blood-derived, mammalian cytokine in the mosquito host."
The results, the researchers said, "provide new insights into the host-parasite-vector relationship that could be utilized as a foundation for new strategies to reduce malaria transmission."
Surachetpong titled his paper "MAPK/ERK Signaling Regulates the TGF-Betal Dependent Mosquito Response to Plasmodium falciparum." TGF-beta is a transforming growth factor beta synthesized by skeletal cells and found in most species.
A native of Thailand, Surachetpong joined the Luckhart lab and the Immunology Graduate Group in 2005. He is seeking his doctorate in immunology, with a designated emphasis in vectorborne diseases. His doctoral thesis is "MAPK Signaling Pathways Regulate Anti-Malarial Response in Anopheles Mosquitoes."
Last year Surachetpong was awarded a prestigious Bill and Melinda Gates Foundation health travel award to present his research at a Keystone Symposia conference in Bangkok, Thailand. The meeting focused on the pathogenesis and control of emerging infections and drug-resistant organisms.
Surachetpong received his doctorate of veterinary science degree at Chulalongkorn University, Bangkok in 2000, ranking first in his class, and his master of science degree in pathobiology in 2005 from the University of Arizona, with high honors.
Source: Kathy Keatley Garvey
University of California - Davis
вторник, 21 июня 2011 г.
понедельник, 20 июня 2011 г.
New Protein Tag Enhances View Within Living Cells
The view into the inner world of living cells just got a little brighter and more colorful. A powerful new research tool, when used with other labeling technologies, allows simultaneous visualization of two or more different proteins as well as the ability to distinguish young and old copies of a protein within one living cell. The research is published by Cell Press in the February issue of Chemistry and Biology.
Scientists have developed innovative technologies that make use of fluorescent molecules to visualize proteins and biochemical processes in living cells. Various technologies exist that allow transfer of fluorescent properties to specific proteins of interest. One such method, developed by Dr. Kai Johnsson and colleagues at Ecole Polytechnique FГ©dГ©rale de Lausanne, is derived from the human DNA repair enzyme alkylguanine-DNA alkyltransferase (AGT). This tool, called SNAP-tag, can be covalently labeled in living cells using benzylguanine (BG) derivatives bearing a chemical probe.
Now, Dr. Johnsson's group has modified SNAP-tag to generate a new AGT-based tag, named CLIP-tag, which reacts specifically with benzylcytosine (BC) derivatives. "Use of SNAP-tag in conjunction with CLIP-tag permits simultaneous labeling of two proteins with different molecular probes for multiparameter imaging of cellular functions in living cells," explains Dr. Johnsson.
The researchers demonstrate that SNAP-tag and CLIP-tag have some significant advantages over existing labeling methods for conducting multi-protein studies within living cells. Both tags can label proteins in any cellular compartment, have very high specificity towards their native substrates, low reactivity to other BC and BG derivatives and have similar properties that will aid in comparison of one fusion protein to another. Further, chemical labeling methods allow for visualization of proteins in organisms that are not suitable for expression of autofluorescent proteins and are well suited for experiments that make use of other biochemical characterizations after imaging.
"The labeling of CLIP-tag fusion proteins is highly specific and mutually independent from other existing labeling approaches, making the method a highly valuable tool for chemical biology," concludes Dr. Johnsson. "Furthermore, we show for the first time simultaneous pulse-chase experiments to visualize different generations of two different proteins in one sample, allowing concurrent investigation of two different dynamic processes."
The researchers include Arnaud Gautier, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Alexandre Juillerat, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Christian Heinis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Ivan Reis Correa, Jr., Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Maik Kindermann, Covalys Biosciences, Witterswil, Switzerland; Florent Beaufils, Covalys Biosciences, Witterswil, Switzerland; and Kai Johnsson, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
Source: Cathleen Genova
Cell Press
Scientists have developed innovative technologies that make use of fluorescent molecules to visualize proteins and biochemical processes in living cells. Various technologies exist that allow transfer of fluorescent properties to specific proteins of interest. One such method, developed by Dr. Kai Johnsson and colleagues at Ecole Polytechnique FГ©dГ©rale de Lausanne, is derived from the human DNA repair enzyme alkylguanine-DNA alkyltransferase (AGT). This tool, called SNAP-tag, can be covalently labeled in living cells using benzylguanine (BG) derivatives bearing a chemical probe.
Now, Dr. Johnsson's group has modified SNAP-tag to generate a new AGT-based tag, named CLIP-tag, which reacts specifically with benzylcytosine (BC) derivatives. "Use of SNAP-tag in conjunction with CLIP-tag permits simultaneous labeling of two proteins with different molecular probes for multiparameter imaging of cellular functions in living cells," explains Dr. Johnsson.
The researchers demonstrate that SNAP-tag and CLIP-tag have some significant advantages over existing labeling methods for conducting multi-protein studies within living cells. Both tags can label proteins in any cellular compartment, have very high specificity towards their native substrates, low reactivity to other BC and BG derivatives and have similar properties that will aid in comparison of one fusion protein to another. Further, chemical labeling methods allow for visualization of proteins in organisms that are not suitable for expression of autofluorescent proteins and are well suited for experiments that make use of other biochemical characterizations after imaging.
"The labeling of CLIP-tag fusion proteins is highly specific and mutually independent from other existing labeling approaches, making the method a highly valuable tool for chemical biology," concludes Dr. Johnsson. "Furthermore, we show for the first time simultaneous pulse-chase experiments to visualize different generations of two different proteins in one sample, allowing concurrent investigation of two different dynamic processes."
The researchers include Arnaud Gautier, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Alexandre Juillerat, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Christian Heinis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Ivan Reis Correa, Jr., Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland; Maik Kindermann, Covalys Biosciences, Witterswil, Switzerland; Florent Beaufils, Covalys Biosciences, Witterswil, Switzerland; and Kai Johnsson, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
Source: Cathleen Genova
Cell Press
воскресенье, 19 июня 2011 г.
Computational Quantum Chemical Methods Promising For Drug Development
Research, led by a Virginia Tech chemist, may someday help natural-products chemists decrease by years the time it takes to develop certain types of medicinal drugs. The research by T. Daniel Crawford, associate professor of chemistry, involves computations of optical rotation angles on chiral non-superimposable molecules
Many chiral molecules are important for medical treatment for illnesses ranging from acid-reflux to cancer. The term "chiral" means that two mirror images of a molecule cannot be superimposed onto each other. In other words, some are "left-handed" and some are "right-handed."
"Most drugs have this handedness property," Crawford said, "and for many of these drugs, even though both hands can cause a reaction, it is a situation where one hand does a good thing and one does a bad thing." He used thalidomide as an example. A mixture of both hands of the drug was used in the late 1950s and early 1960s to treat morning sickness in pregnant women. Later studies revealed that, while one of the two hands acted as the desired sedative, the other hand was found to cause significant birth defects. Thalidomide was never approved by the FDA in the United States and was eventually taken off the market in Europe.
For chemists, therefore, it is often vital to determine which hand of a molecule they are using. In other words, when you have a sample of a chiral molecule, how do you distinguish between the left and right hand?
This is where a technique called polarimetry comes in to play. By shooting plane-polarized light through a sample of one hand, the chiral molecule in question will rotate to a characteristic angle either clockwise or counterclockwise, and the two hands of a chiral molecule produce opposite rotations.
"So if we figure out the direction and rotation of the light or each hand, we have a frame of reference for determining whether we have the left or right hand of a molecule," Crawford said.
The problem with this method is that synthesizing the two hands of chiral molecules is often extremely time consuming. "It can take anywhere from weeks to years," Crawford said.
Crawford's research applies the theory of quantum mechanics to devise computational methods in order to eliminate having to create a synthetic molecule. "The hope is that this will allow us to calculate things like optical rotation very accurately," he said. "So when an organic chemist has a molecule and doesn't know if it is left- or right-handed, we can calculate that directly on the computer."
Crawford said the ultimate goal in his research is to be able to provide organic chemists with computational tools to determine the handedness of a particular molecule they are working with. He said that such tools could speed up the drug development process by years.
The research titled, The Current State of 'Ab Initio' Calculations of Optical Rotation and Electronic Circular Dichcoism Spectra, by Crawford and Mary C. Tam of Virginia Tech and Mica Abrams of the University of Central Arkansas, appeared as the cover article in the November 2007 Journal of Physical Chemistry A. Get the complete article at: pubs.acs/cgi-bin/article.cgi/jpcafh/2007/111/i48/html/jp075046u.html
About the College of Science
The College of Science at Virginia Tech gives students a comprehensive foundation in the scientific method. Outstanding faculty members teach courses and conduct research in biology, chemistry, economics, geosciences, mathematics, physics, psychology, and statistics. The college is dedicated to fostering a research intensive environment and offers programs in many cutting edge areas, including those in nanotechnology, biological sciences, information theory and science, and supports the university's research initiatives through the Institute for Critical Technologies and Applied Sciences, and the Institute for Biomedical and Public Health Sciences. The College of Science also houses programs in intellectual property law and pre-medicine.
Virginia Tech (Virginia Polytechnic Institute and State University)
Room 1, Media Bldg. (0109)
Blacksburg, VA 24061
United States
vt
Many chiral molecules are important for medical treatment for illnesses ranging from acid-reflux to cancer. The term "chiral" means that two mirror images of a molecule cannot be superimposed onto each other. In other words, some are "left-handed" and some are "right-handed."
"Most drugs have this handedness property," Crawford said, "and for many of these drugs, even though both hands can cause a reaction, it is a situation where one hand does a good thing and one does a bad thing." He used thalidomide as an example. A mixture of both hands of the drug was used in the late 1950s and early 1960s to treat morning sickness in pregnant women. Later studies revealed that, while one of the two hands acted as the desired sedative, the other hand was found to cause significant birth defects. Thalidomide was never approved by the FDA in the United States and was eventually taken off the market in Europe.
For chemists, therefore, it is often vital to determine which hand of a molecule they are using. In other words, when you have a sample of a chiral molecule, how do you distinguish between the left and right hand?
This is where a technique called polarimetry comes in to play. By shooting plane-polarized light through a sample of one hand, the chiral molecule in question will rotate to a characteristic angle either clockwise or counterclockwise, and the two hands of a chiral molecule produce opposite rotations.
"So if we figure out the direction and rotation of the light or each hand, we have a frame of reference for determining whether we have the left or right hand of a molecule," Crawford said.
The problem with this method is that synthesizing the two hands of chiral molecules is often extremely time consuming. "It can take anywhere from weeks to years," Crawford said.
Crawford's research applies the theory of quantum mechanics to devise computational methods in order to eliminate having to create a synthetic molecule. "The hope is that this will allow us to calculate things like optical rotation very accurately," he said. "So when an organic chemist has a molecule and doesn't know if it is left- or right-handed, we can calculate that directly on the computer."
Crawford said the ultimate goal in his research is to be able to provide organic chemists with computational tools to determine the handedness of a particular molecule they are working with. He said that such tools could speed up the drug development process by years.
The research titled, The Current State of 'Ab Initio' Calculations of Optical Rotation and Electronic Circular Dichcoism Spectra, by Crawford and Mary C. Tam of Virginia Tech and Mica Abrams of the University of Central Arkansas, appeared as the cover article in the November 2007 Journal of Physical Chemistry A. Get the complete article at: pubs.acs/cgi-bin/article.cgi/jpcafh/2007/111/i48/html/jp075046u.html
About the College of Science
The College of Science at Virginia Tech gives students a comprehensive foundation in the scientific method. Outstanding faculty members teach courses and conduct research in biology, chemistry, economics, geosciences, mathematics, physics, psychology, and statistics. The college is dedicated to fostering a research intensive environment and offers programs in many cutting edge areas, including those in nanotechnology, biological sciences, information theory and science, and supports the university's research initiatives through the Institute for Critical Technologies and Applied Sciences, and the Institute for Biomedical and Public Health Sciences. The College of Science also houses programs in intellectual property law and pre-medicine.
Virginia Tech (Virginia Polytechnic Institute and State University)
Room 1, Media Bldg. (0109)
Blacksburg, VA 24061
United States
vt
суббота, 18 июня 2011 г.
Chemists Concoct New Agents To Easily Study Critical Cell Proteins
They are the portals to the cell, gateways through which critical signals and chemicals are exchanged between living cells and their environments.
But these gateways -- proteins that span the cell membrane and connect the world outside the cell to its vital inner workings - remain, for the most part, black boxes with little known about their structures and how they work. They are of intense interest to scientists as they are the targets on which many drugs act, but are notoriously difficult to study because extracting these proteins intact from cell membranes is tricky.
Now, however, a team of scientists from the University of Wisconsin-Madison and Stanford University has devised a technology to more easily obtain membrane proteins for study. Writing this week (Oct. 31) in the journal Nature Methods, the group reports the development of a class of agents capable of extracting complex membrane proteins without distorting their shape, a key to understanding how they work.
"The proteins are embedded in the membrane to control what gets into the cell and what gets out," explains Samuel Gellman, a UW-Madison professor of chemistry and a senior author of the paper along with Brian Kobilka of Stanford and Bernadette Byrne of Imperial College London. "If we want to understand life at the molecular level, we need to understand the properties and functions of these membrane proteins."
The catch with membrane proteins and unleashing their potential, however, is getting insight into their physical properties, says Gellman.
Like other kinds of proteins, membrane proteins exhibit a complex pattern of folding, and determining the three-dimensional shapes they assume in the membrane provides essential insight into how they do business.
Proteins are workhorse molecules in any organism, and myriad proteins are known. Structures have been solved for many thousands of so-called "soluble" proteins, but only a couple of hundred membrane protein structures are known, Gellman notes. This contrast is important because roughly one-third of the proteins encoded in the human genome appear to be membrane proteins.
To effectively study a protein, scientists must have access to it. A primary obstacle has been simply getting proteins out of the membrane while maintaining their functional shapes. To that end, Gellman's group has developed a family of new chemical agents, known as amphiphiles, that are easily prepared, customizable to specific proteins and cheap.
"These amphiphiles are very simple," says Gellman. "That's one of their charms. The other is that they can be tuned to pull out many different kinds of proteins."
The hope, according to Gellman, is that the new technology will facilitate research at the biomedical frontier.
The development of the amphiphiles was conducted in close collaboration with groups like Kobilka's, which specializes in techniques that help resolve the three-dimensional structures of proteins found in cell membranes.
The lead author of the new study is Pil Seok Chae, a postdoctoral fellow in Gellman's lab. The work was supported primarily by the U.S National Institutes of Health.
Source:
Samuel Gellman
University of Wisconsin-Madison
But these gateways -- proteins that span the cell membrane and connect the world outside the cell to its vital inner workings - remain, for the most part, black boxes with little known about their structures and how they work. They are of intense interest to scientists as they are the targets on which many drugs act, but are notoriously difficult to study because extracting these proteins intact from cell membranes is tricky.
Now, however, a team of scientists from the University of Wisconsin-Madison and Stanford University has devised a technology to more easily obtain membrane proteins for study. Writing this week (Oct. 31) in the journal Nature Methods, the group reports the development of a class of agents capable of extracting complex membrane proteins without distorting their shape, a key to understanding how they work.
"The proteins are embedded in the membrane to control what gets into the cell and what gets out," explains Samuel Gellman, a UW-Madison professor of chemistry and a senior author of the paper along with Brian Kobilka of Stanford and Bernadette Byrne of Imperial College London. "If we want to understand life at the molecular level, we need to understand the properties and functions of these membrane proteins."
The catch with membrane proteins and unleashing their potential, however, is getting insight into their physical properties, says Gellman.
Like other kinds of proteins, membrane proteins exhibit a complex pattern of folding, and determining the three-dimensional shapes they assume in the membrane provides essential insight into how they do business.
Proteins are workhorse molecules in any organism, and myriad proteins are known. Structures have been solved for many thousands of so-called "soluble" proteins, but only a couple of hundred membrane protein structures are known, Gellman notes. This contrast is important because roughly one-third of the proteins encoded in the human genome appear to be membrane proteins.
To effectively study a protein, scientists must have access to it. A primary obstacle has been simply getting proteins out of the membrane while maintaining their functional shapes. To that end, Gellman's group has developed a family of new chemical agents, known as amphiphiles, that are easily prepared, customizable to specific proteins and cheap.
"These amphiphiles are very simple," says Gellman. "That's one of their charms. The other is that they can be tuned to pull out many different kinds of proteins."
The hope, according to Gellman, is that the new technology will facilitate research at the biomedical frontier.
The development of the amphiphiles was conducted in close collaboration with groups like Kobilka's, which specializes in techniques that help resolve the three-dimensional structures of proteins found in cell membranes.
The lead author of the new study is Pil Seok Chae, a postdoctoral fellow in Gellman's lab. The work was supported primarily by the U.S National Institutes of Health.
Source:
Samuel Gellman
University of Wisconsin-Madison
пятница, 17 июня 2011 г.
Researcher Wjho Established A Paradigm Shift In The Regulation Of Neuronal Cell Development Awarded 2008 EMBO Gold Medal
The European Molecular Biology Organization (EMBO) announced that James Briscoe of the Medical Research Council's National Institute for Medical Research will receive the prestigious EMBO Gold Medal for 2008.
Briscoe receives the award in recognition of his discovery that cells integrate time of exposure and concentration of a morphogen to subsequently mount a graded response.
Awarded annually, the EMBO Gold Medal recognises the outstanding contributions of young researchers in the molecular life sciences. Widely regarded as the most prestigious award of its kind in Europe, the Gold Medal highlights the high standards of Europe's best scientists.
"James Briscoe has revolutionized our understanding of the specification of cell identity in a given spatial setting," said Hermann Bujard, EMBO Executive Director. "His work exemplifies how talented scientists are advancing the field of molecular biology."
Four years at Columbia University in New York as a postdoc in Thomas Jessell's lab laid the foundation for Briscoe's career as a developmental biologist. James says he "learned" developmental biology from working alongside Jessell and a "great" postdoc in the lab at the time, Johan Ericson.
While at Columbia University, Briscoe began to unravel the control mechanisms of neuronal cell identity in the ventral neural tube - a research theme sustained in his own lab at NIMR since taking up a group leader position in 2000. Specifically, the Briscoe lab studies the central role of the morphogen Sonic Hedgehog (Shh) to specify the position and subtype identity of neurons in the ventral spinal cord.
"We want to understand how neurons - nerve cells - are arranged in the spinal cord," explains the EMBO Gold Medal winner for audiences other than his peers. "Specifically we are looking at the molecular basis of how different neuronal cells are organized in a developing embryo as a result of signals received from an important molecule called Sonic Hedgehog, or Shh, that is secreted from a particular region in the spinal cord."
Briscoe and his group discovered a novel mechanism that allows cells to integrate the time of exposure and the concentration of the morphogen Shh to subsequently mount a graded response. In other words, different concentrations of the morphogen activate a signal within the receiving cell for different periods of times. Cells in turn respond to different durations of the signal by activating different genes and therefore becoming different types of nerve cells.
"The discovery that concentration is effectively converted into time is a major shift in our understanding of how a graded signal acts to regulate genes," stated David Wilkinson, Head of Genetics and Development at NIMR, in his nomination of Briscoe for the EMBO Gold Medal.
James Briscoe's contribution to the understanding of how cell identity is specified in a given spatial setting has established a new paradigm that may also apply in many other contexts. In addition to Shh, a number of other secreted molecules - members of different protein families - have also been implicated in acting as morphogens to pattern other tissues. "It is possible that other morphogens could use a similar mechanism to control cells, for example early in embryo development during gastrulation," explains the Gold Medal winner.
"James's discoveries have revealed general principles that may apply to many other contexts in which graded signals and downstream transcription factors control cell identity," confirmed David Wilkinson.
Robb Krumlauf, former Head of Division at NIMR who helped to recruit Briscoe to the institute, points out his outstanding qualities at the bench: "At NIMR James rapidly established an independent and creative line of research in his own group. His work is highly rigorous, hits the heart of a problem, and continues to be timely and of wide general interest."
Jim Smith of the Gurdon Institute agrees with Krumlauf that Briscoe's work "has been remarkably creative and imaginative while retaining characteristic levels of careful experimentation and scholarship."
On hearing the news of the EMBO Gold Medal Briscoe referred to the success of his team of researchers: "I have been very fortunate working with very talented and smart people. They taught me a lot, supported me fantastically, and made many significant contributions."
In 2000, James Briscoe was selected to benefit from the highly competitive EMBO Young Investigator Programme, then in its first year and now renowned for its scientific excellence.
James Briscoe will receive the EMBO Gold Medal and an award of 10,000 euro on 6 September 2008 at the EMBO Members Workshop, Frontiers of Molecular Biology, in Tampere, Finland.
Source: Suzanne Beveridge
European Molecular Biology Organization
Briscoe receives the award in recognition of his discovery that cells integrate time of exposure and concentration of a morphogen to subsequently mount a graded response.
Awarded annually, the EMBO Gold Medal recognises the outstanding contributions of young researchers in the molecular life sciences. Widely regarded as the most prestigious award of its kind in Europe, the Gold Medal highlights the high standards of Europe's best scientists.
"James Briscoe has revolutionized our understanding of the specification of cell identity in a given spatial setting," said Hermann Bujard, EMBO Executive Director. "His work exemplifies how talented scientists are advancing the field of molecular biology."
Four years at Columbia University in New York as a postdoc in Thomas Jessell's lab laid the foundation for Briscoe's career as a developmental biologist. James says he "learned" developmental biology from working alongside Jessell and a "great" postdoc in the lab at the time, Johan Ericson.
While at Columbia University, Briscoe began to unravel the control mechanisms of neuronal cell identity in the ventral neural tube - a research theme sustained in his own lab at NIMR since taking up a group leader position in 2000. Specifically, the Briscoe lab studies the central role of the morphogen Sonic Hedgehog (Shh) to specify the position and subtype identity of neurons in the ventral spinal cord.
"We want to understand how neurons - nerve cells - are arranged in the spinal cord," explains the EMBO Gold Medal winner for audiences other than his peers. "Specifically we are looking at the molecular basis of how different neuronal cells are organized in a developing embryo as a result of signals received from an important molecule called Sonic Hedgehog, or Shh, that is secreted from a particular region in the spinal cord."
Briscoe and his group discovered a novel mechanism that allows cells to integrate the time of exposure and the concentration of the morphogen Shh to subsequently mount a graded response. In other words, different concentrations of the morphogen activate a signal within the receiving cell for different periods of times. Cells in turn respond to different durations of the signal by activating different genes and therefore becoming different types of nerve cells.
"The discovery that concentration is effectively converted into time is a major shift in our understanding of how a graded signal acts to regulate genes," stated David Wilkinson, Head of Genetics and Development at NIMR, in his nomination of Briscoe for the EMBO Gold Medal.
James Briscoe's contribution to the understanding of how cell identity is specified in a given spatial setting has established a new paradigm that may also apply in many other contexts. In addition to Shh, a number of other secreted molecules - members of different protein families - have also been implicated in acting as morphogens to pattern other tissues. "It is possible that other morphogens could use a similar mechanism to control cells, for example early in embryo development during gastrulation," explains the Gold Medal winner.
"James's discoveries have revealed general principles that may apply to many other contexts in which graded signals and downstream transcription factors control cell identity," confirmed David Wilkinson.
Robb Krumlauf, former Head of Division at NIMR who helped to recruit Briscoe to the institute, points out his outstanding qualities at the bench: "At NIMR James rapidly established an independent and creative line of research in his own group. His work is highly rigorous, hits the heart of a problem, and continues to be timely and of wide general interest."
Jim Smith of the Gurdon Institute agrees with Krumlauf that Briscoe's work "has been remarkably creative and imaginative while retaining characteristic levels of careful experimentation and scholarship."
On hearing the news of the EMBO Gold Medal Briscoe referred to the success of his team of researchers: "I have been very fortunate working with very talented and smart people. They taught me a lot, supported me fantastically, and made many significant contributions."
In 2000, James Briscoe was selected to benefit from the highly competitive EMBO Young Investigator Programme, then in its first year and now renowned for its scientific excellence.
James Briscoe will receive the EMBO Gold Medal and an award of 10,000 euro on 6 September 2008 at the EMBO Members Workshop, Frontiers of Molecular Biology, in Tampere, Finland.
Source: Suzanne Beveridge
European Molecular Biology Organization
четверг, 16 июня 2011 г.
Scripps Scientists Develop New Tests That Identify Lethal Prion Strains Quickly And Accurately
One of the new in vitro tests, called the Standard Scrapie Cell Assay, measures prion infectivity levels in a highly accurate and extremely rapid way, producing results in less than two weeks. The second test, called the Cell Panel Assay, allows researchers to quickly distinguish between several prion strains in various cells lines. Using the new assays, the scientists were able to show that four different cell lines exhibited widely different responses to four different strains of the infectious protein particles.
The research is being published in an advanced online edition of the Proceedings of the National Academy of Sciences the week of December 3, 2007.
"These new assays vastly accelerate the measurement of prion infectivity and the determination of those cell lines that are able to sustain high infection rates of some prion strains," said Sukhvir P. Mahal, an author of the study who is a senior staff scientist in the laboratory of Charles Weissmann, chair of the Scripps Florida Department of Infectology. "The current test, which takes anywhere from 150 to 250 days and involves large numbers of laboratory mice, is slow, imprecise, and expensive. Our new assays will replace the current mouse brain-bioassays."
The current method of measurement and identification involves injecting a prion-containing sample into the brains of mice and then waiting to see how long it takes for the animals to succumb to disease; the higher the prion level, the less time it takes for them to become lethally infected.
In contrast, the new Standard Scrapie Cell Assay is based on prion-susceptible cell lines. In the test, cells are exposed to prions and then the infected cells are identified and counted using automated imaging equipment.
A Unique Pathogen
Prions (the name stands for proteinaceous infectious particles) are unique infectious pathogens associated with some 15 different diseases, including Bovine Spongiform Encephalopathy ("mad cow") and its rare human form, variant Creutzfeldt-Jacob disease. Infectious prions, which are thought to consist mainly of an abnormally structured or misfolded protein, have the ability to reproduce, despite the fact that they contain no nucleic acid genome as do viruses or bacteria.
Mammalian cells normally produce what is known as cellular prion protein; during infection, the abnormal protein converts production of normal host prion protein to its infectious form. The full details of this process are still not understood.
Prions develop in distinct strains, initially characterized by incubation time and the pattern of brain damage that develops during infection. It is currently thought that strain-specific properties of prions are determined by the three-dimensional structure of the misfolded protein, although the amino acid sequence remains the same. During infection with a single type of prion, several different prion strains can be propagated indefinitely in a single host.
"Some cell lines can be persistently infected by prions and show preference for certain strains," Mahal said. "One intriguing finding of our new study is that a cell line's ability to replicate a particular prion strain is a trait that varies significantly among the members of the cell population-even sibling cell lines may show different relative susceptibilities to various prion strains."
This suggests that the capacity of a cell line to replicate a particular prion strain is controlled epigenetically without any changes to the DNA sequence, she said.
Another fascinating question raised by the study is how cells come to distinguish between prion strains; that is, between the various proteins that differ only in the way they are folded. The exact nature of that recognition process is now the target of a new Scripps Research study using the Cell Panel Assay.
Other authors of the study, Prion Strain Discrimination In Cell Culture: The Cell Panel Assay, include Christopher A. Baker, Cheryl A. Demczyk, Emery W. Smith, and Charles Weissmann of the Department of Infectology, Scripps Florida; and Christian Julius of the Institute of Neuropathology, University Hospital of ZГјrich, ZГјrich, Switzerland.
The study was supported by The Scripps Research Institute and the Alafi Family Foundation.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
Source:
Keith McKeown
Scripps Research Institute
The research is being published in an advanced online edition of the Proceedings of the National Academy of Sciences the week of December 3, 2007.
"These new assays vastly accelerate the measurement of prion infectivity and the determination of those cell lines that are able to sustain high infection rates of some prion strains," said Sukhvir P. Mahal, an author of the study who is a senior staff scientist in the laboratory of Charles Weissmann, chair of the Scripps Florida Department of Infectology. "The current test, which takes anywhere from 150 to 250 days and involves large numbers of laboratory mice, is slow, imprecise, and expensive. Our new assays will replace the current mouse brain-bioassays."
The current method of measurement and identification involves injecting a prion-containing sample into the brains of mice and then waiting to see how long it takes for the animals to succumb to disease; the higher the prion level, the less time it takes for them to become lethally infected.
In contrast, the new Standard Scrapie Cell Assay is based on prion-susceptible cell lines. In the test, cells are exposed to prions and then the infected cells are identified and counted using automated imaging equipment.
A Unique Pathogen
Prions (the name stands for proteinaceous infectious particles) are unique infectious pathogens associated with some 15 different diseases, including Bovine Spongiform Encephalopathy ("mad cow") and its rare human form, variant Creutzfeldt-Jacob disease. Infectious prions, which are thought to consist mainly of an abnormally structured or misfolded protein, have the ability to reproduce, despite the fact that they contain no nucleic acid genome as do viruses or bacteria.
Mammalian cells normally produce what is known as cellular prion protein; during infection, the abnormal protein converts production of normal host prion protein to its infectious form. The full details of this process are still not understood.
Prions develop in distinct strains, initially characterized by incubation time and the pattern of brain damage that develops during infection. It is currently thought that strain-specific properties of prions are determined by the three-dimensional structure of the misfolded protein, although the amino acid sequence remains the same. During infection with a single type of prion, several different prion strains can be propagated indefinitely in a single host.
"Some cell lines can be persistently infected by prions and show preference for certain strains," Mahal said. "One intriguing finding of our new study is that a cell line's ability to replicate a particular prion strain is a trait that varies significantly among the members of the cell population-even sibling cell lines may show different relative susceptibilities to various prion strains."
This suggests that the capacity of a cell line to replicate a particular prion strain is controlled epigenetically without any changes to the DNA sequence, she said.
Another fascinating question raised by the study is how cells come to distinguish between prion strains; that is, between the various proteins that differ only in the way they are folded. The exact nature of that recognition process is now the target of a new Scripps Research study using the Cell Panel Assay.
Other authors of the study, Prion Strain Discrimination In Cell Culture: The Cell Panel Assay, include Christopher A. Baker, Cheryl A. Demczyk, Emery W. Smith, and Charles Weissmann of the Department of Infectology, Scripps Florida; and Christian Julius of the Institute of Neuropathology, University Hospital of ZГјrich, ZГјrich, Switzerland.
The study was supported by The Scripps Research Institute and the Alafi Family Foundation.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
Source:
Keith McKeown
Scripps Research Institute
среда, 15 июня 2011 г.
Nitric Oxide: Key To Cardiovascular And Pulmonary Function And Drug Effectiveness
A naturally occurring molecule in the body appears to control whether certain medications, such as beta adrenergic receptor agonists used in acute heart failure or in inhalers for asthma, lose their effectiveness over time.
Nitric oxide is a molecule produced by the body that controls many functions, including the contraction or dilation of blood vessels.
New experiments conducted by Duke University Medical Center and Howard Hughes Medical Institute researchers have shown that specialized forms of nitric oxide called SNOs may be the key to a problem that has stumped physicians for years -- why specific drugs for such diseases as heart failure or asthma lose their effectiveness over time.
Almost half of all drugs on the market today, as well as many hormone and neurotransmitters, target a specific family of cell surface receptors known as G-protein coupled receptors. The researchers believe that the presence or absence of nitric oxide or SNOs determines whether these receptors continue to function properly. This action is controlled by the ability of nitric oxide to inhibit a key regulatory system which ordinarily shuts the receptors off after they are stimulated
The researchers report their latest findings in the journal Cell.
"This work is significant in that it demonstrates how two of the most pervasive physiological systems -- G-protein coupled receptors and nitric oxide -- come together to influence one another," said Erin Whalen, Ph.D., who spent six years focusing on the link between the two biological systems. Whalen is a postdoctoral fellow in the laboratory of Robert Lefkowitz, M.D., a Howard Hughes Medical Institute investigator at Duke who first cloned these receptors in 1986. The link was cemented through a collaboration with Matt Foster, a post-doctoral fellow in the laboratory of Jonathan Stamler M.D.
G-protein coupled receptors reside on the cell surface where they interact with all manner of stimuli, including circulating factors such as adrenaline, as well such diverse sensory signals as odorants and light. The activation of these receptors leads to the propagation of intracellular signals. Once activated the receptors are quickly turned-off by an enzyme called a G protein-coupled receptor kinase. This process is called desensitization and can limit the effectiveness of many drugs, such as opiates for pain and adrenaline for asthma, and is further associated with numerous diseases including those of the cardiovascular and pulmonary systems. If activated for a long period of time the receptors are carried into the cell and are "turned off."
In animal, cellular and biochemical experiments, the researchers found that a lack of nitric oxide leads to a decrease in beta adrenergic receptor number and function. Also, the researchers found that when SNO compounds were administered to mice they could prevent the receptors from being "turned off" by the drugs.
The researchers said these findings, if confirmed in humans, open up new avenues for the development of non-desensitizing drugs not only for heart failure and asthma but also for other conditions such as pain and high blood pressure.
"We demonstrated that when one of the systems goes awry, so does the other," said Stamler, whose laboratory has made many fundamental discoveries about the role of nitric oxide in human biology, including the discovery of SNOs' ubiquitous role in human health and disease. "When nitric oxide function is impaired by disease, therapeutic agents like beta-agonists in asthma and adrenergic stimulants in heart failure will work less well. The key now is to determine how best to manipulate these ubiquitous receptors, together with nitric oxide for the treatment of human diseases."
"In broad terms, the results of these experiments present a novel role for nitric oxide in regulating the activity of G-protein coupled receptors," Lefkowitz said. "Also, the findings point to the possibility that deficiencies in the activity of nitric oxide, which occurs in common disorders such as high blood pressure, diabetes, atherosclerosis, cystic fibrosis and neurodegenerative conditions, as well as in aging, may interfere with the G-protein coupled receptor signaling."
Other Duke members of the team were Akio Matsumoto, Kentaro Ozama, Jonathan Violin, Loretta Que, Chris Nelson, Moran Benhar and Howard Rockman. Yehia Daaka of the Medical College of Georgia, and Janelle Keys and Walter Koch, both of Jefferson Medical College, in Philadelphia, were also members of the team.
Contact: Richard Merritt
Duke University Medical Center
Nitric oxide is a molecule produced by the body that controls many functions, including the contraction or dilation of blood vessels.
New experiments conducted by Duke University Medical Center and Howard Hughes Medical Institute researchers have shown that specialized forms of nitric oxide called SNOs may be the key to a problem that has stumped physicians for years -- why specific drugs for such diseases as heart failure or asthma lose their effectiveness over time.
Almost half of all drugs on the market today, as well as many hormone and neurotransmitters, target a specific family of cell surface receptors known as G-protein coupled receptors. The researchers believe that the presence or absence of nitric oxide or SNOs determines whether these receptors continue to function properly. This action is controlled by the ability of nitric oxide to inhibit a key regulatory system which ordinarily shuts the receptors off after they are stimulated
The researchers report their latest findings in the journal Cell.
"This work is significant in that it demonstrates how two of the most pervasive physiological systems -- G-protein coupled receptors and nitric oxide -- come together to influence one another," said Erin Whalen, Ph.D., who spent six years focusing on the link between the two biological systems. Whalen is a postdoctoral fellow in the laboratory of Robert Lefkowitz, M.D., a Howard Hughes Medical Institute investigator at Duke who first cloned these receptors in 1986. The link was cemented through a collaboration with Matt Foster, a post-doctoral fellow in the laboratory of Jonathan Stamler M.D.
G-protein coupled receptors reside on the cell surface where they interact with all manner of stimuli, including circulating factors such as adrenaline, as well such diverse sensory signals as odorants and light. The activation of these receptors leads to the propagation of intracellular signals. Once activated the receptors are quickly turned-off by an enzyme called a G protein-coupled receptor kinase. This process is called desensitization and can limit the effectiveness of many drugs, such as opiates for pain and adrenaline for asthma, and is further associated with numerous diseases including those of the cardiovascular and pulmonary systems. If activated for a long period of time the receptors are carried into the cell and are "turned off."
In animal, cellular and biochemical experiments, the researchers found that a lack of nitric oxide leads to a decrease in beta adrenergic receptor number and function. Also, the researchers found that when SNO compounds were administered to mice they could prevent the receptors from being "turned off" by the drugs.
The researchers said these findings, if confirmed in humans, open up new avenues for the development of non-desensitizing drugs not only for heart failure and asthma but also for other conditions such as pain and high blood pressure.
"We demonstrated that when one of the systems goes awry, so does the other," said Stamler, whose laboratory has made many fundamental discoveries about the role of nitric oxide in human biology, including the discovery of SNOs' ubiquitous role in human health and disease. "When nitric oxide function is impaired by disease, therapeutic agents like beta-agonists in asthma and adrenergic stimulants in heart failure will work less well. The key now is to determine how best to manipulate these ubiquitous receptors, together with nitric oxide for the treatment of human diseases."
"In broad terms, the results of these experiments present a novel role for nitric oxide in regulating the activity of G-protein coupled receptors," Lefkowitz said. "Also, the findings point to the possibility that deficiencies in the activity of nitric oxide, which occurs in common disorders such as high blood pressure, diabetes, atherosclerosis, cystic fibrosis and neurodegenerative conditions, as well as in aging, may interfere with the G-protein coupled receptor signaling."
Other Duke members of the team were Akio Matsumoto, Kentaro Ozama, Jonathan Violin, Loretta Que, Chris Nelson, Moran Benhar and Howard Rockman. Yehia Daaka of the Medical College of Georgia, and Janelle Keys and Walter Koch, both of Jefferson Medical College, in Philadelphia, were also members of the team.
Contact: Richard Merritt
Duke University Medical Center
Подписаться на:
Комментарии (Atom)