Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington's disease -- a fatal disorder for which there is currently no cure or even a treatment to slow the disease.
In a paper published in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease. The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington's. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.
While it's too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington's, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn't yet translated to better care for patients.
"There isn't much out there right now for patients who suffer from this utterly devastating disease," said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. "While the promise of stem cells is broadly discussed for many diseases, it's actually conditions like Huntington's -- where a very specific type of brain cell in a particular region of the brain is vulnerable -- that are most likely to benefit from stem-cell-based therapy."
The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.
The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis -- the production of new brain cells -- in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.
The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman's group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells' development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington's project.
"The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington's disease," said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. "Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington's disease."
Huntington's is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient's 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.
Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals -- in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson's and Huntington's diseases, respectively.
To do this work, Goldman's team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington's disease.
The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.
The results in mice, which had a severe form of Huntington's disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren't treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.
The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.
"This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development," said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington's Disease Center of Excellence and is the base for the Huntington Study Group.
In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children's Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.
Source: Tom Rickey
University of Rochester Medical Center
суббота, 30 апреля 2011 г.
пятница, 29 апреля 2011 г.
New Mechanism Discovered For DNA Recombination And Repair
A biochemistry research team led by Dr. Andrew H.-J. Wang and Dr.
Ting-Fang Wang at the Institute of Biological Chemistry, Academia
Sinica (IBCAS), has
discovered that the RecA family recombinases function as a new type of
rotary motor proteins to repair DNA damages.
Dr. Wangs' team has recently published two structural biology articles
related to RecA family recombinases. One paper is to be published in the
online, open-access journal PLoS ONE on September 12, 2007 and the other
has been already published in the Nucleic Acids Research on Feb. 28, 2007.
Homologous recombination (HR) is a mechanism that repairs damaged DNA with
perfect accuracy, it utilizes the homologous sequence from a partner DNA
as
a template. This process involves the bringing together of 2 DNA
molecules, a search for homologous sequences, and exchange of DNA strands.
RecA family proteins are the central recombinases for HR. The family
includes prokaryotic RecA, archaeal RadA, and eukaryotic Rad51 and Dmc1.
They
have important roles in cell proliferation, genome maintenance, and
genetic diversity, particularly in higher eukaryotes. For example,
Rad51-deficient
vertebrate cells accumulate chromosomal breaks before death. Rad51 and its
meiosis-specific homolog, Dmc1, are also indispensable for meiosis, a
specialized cell cycle for production of gametes. Mammalian Rad51 and Dmc1
proteins are known to interact with tumor suppressor proteins such as
BRCA2.
Since scientists discovered RecA family proteins, it has been assumed that
RecA (and other homologs) forms only 61 right-handed filaments (six
protein
monomers per helical turn), and then hydrolyzes ATP to promote HR and
recombinational DNA repair. Whereas a controversial puzzle came out, how
the
energy of ATP facilitating DNA rotation during the strand exchange
reaction.
By X-ray crystallography and atomic force microscopy approaches, Dr. Wangs'
team provided the answer. They reported that archaeal Sulfolobus
solfataricus RadA proteins can also self-polymerize into a 31 right-handed
filament with 3 monomers per helical turn (reported in PLoS ONE) and a 43
right-handed helical filament with 4 monomers per helical turn (reported
in Nucleic Acids Research).
Additional biophysical and biochemical analyses revealed that RecA family
proteins may couple ATP binding and hydrolysis to the DNA strand exchange
reaction in a manner that promotes clockwise axial rotation of
nucleoprotein filaments. Specially, the 61 RadA helical filament undergoes
clockwise
axial rotation in 2 discrete 120° steps to the 31 extended right-handed
filament and then to the 43 left-handed filament. As a result, all the
DNA-binding motifs (denoted L1, L2 and HhH) in the RadA proteins move
concurrently to mediate DNA binding, homology pairing, and strand
exchange,
respectively. Therefore, the energy of ATP is used to rotate not only DNA
substrates but also the RecA family protein filaments.
This new model is in contrast to all current hypotheses, which overlooks
the fact that RecA family proteins are flexible enough to form both
right-handed and left-handed helical filaments. From this perspective,
these researchers in Taiwan have opened a new avenue for understanding the
molecular mechanisms of RecA family proteins.
Article 1. Citation: Chen L-T, Ko T-P, Chang Y-W, Lin K-A, Wang AH-J, et
al (2007) Structural and Functional Analyses of Five Conserved Positively
Charged Residues in the L1 and N-Terminal DNA Binding Motifs of Archaeal
RadA Protein. PLoS ONE 2(9): e858. doi:10.1371/journal.pone.0000858
Please click here
Article 2. "Crystal structure of the left-handed archaeal RadA helical
filament: identification of a functional motif for controlling quaternary
structures and enzymatic functions of RecA family proteins" (Nuclei Acid
Research 2007. 35: 1787-1801).
Nucleic Acid Research (nar.oxfordjournals/)
PLoS ONE is the first journal of primary research from all areas of
science to employ both pre- and post-publication peer review to maximize
the
impact of every report it publishes. PLoS ONE is published by the Public
Library of Science (PLoS), the open access publisher whose goal is to make
the world's scientific and medical literature a public resource.
plosone
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
Ting-Fang Wang at the Institute of Biological Chemistry, Academia
Sinica (IBCAS), has
discovered that the RecA family recombinases function as a new type of
rotary motor proteins to repair DNA damages.
Dr. Wangs' team has recently published two structural biology articles
related to RecA family recombinases. One paper is to be published in the
online, open-access journal PLoS ONE on September 12, 2007 and the other
has been already published in the Nucleic Acids Research on Feb. 28, 2007.
Homologous recombination (HR) is a mechanism that repairs damaged DNA with
perfect accuracy, it utilizes the homologous sequence from a partner DNA
as
a template. This process involves the bringing together of 2 DNA
molecules, a search for homologous sequences, and exchange of DNA strands.
RecA family proteins are the central recombinases for HR. The family
includes prokaryotic RecA, archaeal RadA, and eukaryotic Rad51 and Dmc1.
They
have important roles in cell proliferation, genome maintenance, and
genetic diversity, particularly in higher eukaryotes. For example,
Rad51-deficient
vertebrate cells accumulate chromosomal breaks before death. Rad51 and its
meiosis-specific homolog, Dmc1, are also indispensable for meiosis, a
specialized cell cycle for production of gametes. Mammalian Rad51 and Dmc1
proteins are known to interact with tumor suppressor proteins such as
BRCA2.
Since scientists discovered RecA family proteins, it has been assumed that
RecA (and other homologs) forms only 61 right-handed filaments (six
protein
monomers per helical turn), and then hydrolyzes ATP to promote HR and
recombinational DNA repair. Whereas a controversial puzzle came out, how
the
energy of ATP facilitating DNA rotation during the strand exchange
reaction.
By X-ray crystallography and atomic force microscopy approaches, Dr. Wangs'
team provided the answer. They reported that archaeal Sulfolobus
solfataricus RadA proteins can also self-polymerize into a 31 right-handed
filament with 3 monomers per helical turn (reported in PLoS ONE) and a 43
right-handed helical filament with 4 monomers per helical turn (reported
in Nucleic Acids Research).
Additional biophysical and biochemical analyses revealed that RecA family
proteins may couple ATP binding and hydrolysis to the DNA strand exchange
reaction in a manner that promotes clockwise axial rotation of
nucleoprotein filaments. Specially, the 61 RadA helical filament undergoes
clockwise
axial rotation in 2 discrete 120° steps to the 31 extended right-handed
filament and then to the 43 left-handed filament. As a result, all the
DNA-binding motifs (denoted L1, L2 and HhH) in the RadA proteins move
concurrently to mediate DNA binding, homology pairing, and strand
exchange,
respectively. Therefore, the energy of ATP is used to rotate not only DNA
substrates but also the RecA family protein filaments.
This new model is in contrast to all current hypotheses, which overlooks
the fact that RecA family proteins are flexible enough to form both
right-handed and left-handed helical filaments. From this perspective,
these researchers in Taiwan have opened a new avenue for understanding the
molecular mechanisms of RecA family proteins.
Article 1. Citation: Chen L-T, Ko T-P, Chang Y-W, Lin K-A, Wang AH-J, et
al (2007) Structural and Functional Analyses of Five Conserved Positively
Charged Residues in the L1 and N-Terminal DNA Binding Motifs of Archaeal
RadA Protein. PLoS ONE 2(9): e858. doi:10.1371/journal.pone.0000858
Please click here
Article 2. "Crystal structure of the left-handed archaeal RadA helical
filament: identification of a functional motif for controlling quaternary
structures and enzymatic functions of RecA family proteins" (Nuclei Acid
Research 2007. 35: 1787-1801).
Nucleic Acid Research (nar.oxfordjournals/)
PLoS ONE is the first journal of primary research from all areas of
science to employ both pre- and post-publication peer review to maximize
the
impact of every report it publishes. PLoS ONE is published by the Public
Library of Science (PLoS), the open access publisher whose goal is to make
the world's scientific and medical literature a public resource.
plosone
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
четверг, 28 апреля 2011 г.
Newly Discovered Checkpoint Process Decides Between Death, Division Or Cancer
Each day, a staggering number of cells perform a feat that still amazes researchers with its complexity: they divide to produce perfect replicas of each other. The process is called mitosis, and an inability to control it is one of the hallmarks of cancer.
Little is known about the biochemical processes that control mitosis, but now researchers from Fox Chase Cancer Center and Technion-Israel Institute of Technology in Haifa, Israel, have discovered a novel activity, called the mitotic checkpoint factor 2 (MCF2). This appears to be integral in preventing cells that are unable to equally separate their chromosomes from dividing. The identities of the proteins involved in MCF2 remain to be determined, however, their findings offer insight into a fundamental question of biology, which may also help to increase the efficiency of cancer drugs that disrupt DNA replication, like gemcitabine, or drugs that prevent mitosis, like paclitaxel.
They published their findings online in the Early Edition of the Proceedings of the National Academy of Sciences.
"At any given moment, 250 million cells in your body are undergoing mitosis in order to replenish cells that die as a result of normal turnover," says Tim J. Yen, Ph.D., senior member at Fox Chase. "The mitotic checkpoint is a complex series of quality control systems, just like in a factory assembly line, that ensures that each new cell gets their proper share of DNA." (Click here for illustration)
cell Mitosis
"Cancer cells tend to bypass quality control, such as the mitotic checkpoint, so as to allow them to shuffle their deck of chromosomes to select for traits that promote drug resistance and the ability to divide uncontrollably," says Yen.
Yen, along with visiting researcher Avram Hershko, Ph.D., of Technion, discovered the ability of MCF2 to block mitosis by shutting down an ubiquitin ligase enzyme known as the anaphase-promoting complex/cyclosome (APC/C). Hershko was awarded the 2004 Nobel Prize for Chemistry along with former Fox Chase researcher Irwin Rose, Ph.D., for the discovery of ubiquitin-mediated protein degradation at Fox Chase.
Their findings show that MCF2 joins a previously known group of proteins - the mitotic checkpoint complex - to inhibit the pro-division APC/C protein complex. According to Yen, MCC and MCF2 team up to prevent the activation of APC/C by a signaling molecule called Cdc20. "The mitotic checkpoint is a molecular failsafe system, an intricate clockwork mechanism to ensure that everything is working properly before it allows a cell to divide," Yen says.
When cells divide, one of the first steps is to replicate DNA, which are in the familiar X- and Y-shaped structures called chromosomes. Before the cell can split, the mitotic checkpoint proteins monitor the mechanical connection between microtubule fibers (which act like rope to pull apart replicated pairs of chromosomes) and the chromosomes. If everything is in place, the checkpoint proteins release APC/C and allow division to continue. If not, the cell self-destructs before it can divide.
If the checkpoint proteins themselves are faulty, however, mitosis results in aneuploidy, the loss or gain of chromosomes in the daughter cells. This increases the risk of cancer, and promotes the resistance of cancer cells to chemotherapies.
Certain cancer drugs, such as paclitaxel and gemcitabine, exploit the mechanisms of mitosis to kill cancer cells. Although they act through very different mechanisms, both paclitaxel and gemcitabine sabotage the events monitored by the checkpoint proteins, which then leads to cell death. According to Yen, a deeper understanding of the mechanisms of mitosis will make these drugs, and others like them, more effective and more enduring.
While the researchers characterize the discovery as an important step in understanding mitosis, the existence of MCF2 raises more questions than it does answers. "We still have a lot to understand in how all the components of the mitotic checkpoint fit together and even more to understand in how the chromosomes are aligned and separated so exactingly," Yen says.
Funding for this study was provided through the Fox Chase Cancer Center Research Fund, National Institutes of Health and the Commonwealth of Pennsylvania. Hersko's work is also supported through funds from the Israel Cancer Research Fund, Israel Science Foundation and the Gruss Lipper Foundation.
Fox Chase Cancer Center is one of the leading freestanding cancer research and treatments centers in the United States. Founded in 1904 in Philadelphia as the nation's first cancer hospital, Fox Chase became one of the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, treatment, and community outreach.
Source: Jim Dryden
Washington University School of Medicine
Little is known about the biochemical processes that control mitosis, but now researchers from Fox Chase Cancer Center and Technion-Israel Institute of Technology in Haifa, Israel, have discovered a novel activity, called the mitotic checkpoint factor 2 (MCF2). This appears to be integral in preventing cells that are unable to equally separate their chromosomes from dividing. The identities of the proteins involved in MCF2 remain to be determined, however, their findings offer insight into a fundamental question of biology, which may also help to increase the efficiency of cancer drugs that disrupt DNA replication, like gemcitabine, or drugs that prevent mitosis, like paclitaxel.
They published their findings online in the Early Edition of the Proceedings of the National Academy of Sciences.
"At any given moment, 250 million cells in your body are undergoing mitosis in order to replenish cells that die as a result of normal turnover," says Tim J. Yen, Ph.D., senior member at Fox Chase. "The mitotic checkpoint is a complex series of quality control systems, just like in a factory assembly line, that ensures that each new cell gets their proper share of DNA." (Click here for illustration)
cell Mitosis
"Cancer cells tend to bypass quality control, such as the mitotic checkpoint, so as to allow them to shuffle their deck of chromosomes to select for traits that promote drug resistance and the ability to divide uncontrollably," says Yen.
Yen, along with visiting researcher Avram Hershko, Ph.D., of Technion, discovered the ability of MCF2 to block mitosis by shutting down an ubiquitin ligase enzyme known as the anaphase-promoting complex/cyclosome (APC/C). Hershko was awarded the 2004 Nobel Prize for Chemistry along with former Fox Chase researcher Irwin Rose, Ph.D., for the discovery of ubiquitin-mediated protein degradation at Fox Chase.
Their findings show that MCF2 joins a previously known group of proteins - the mitotic checkpoint complex - to inhibit the pro-division APC/C protein complex. According to Yen, MCC and MCF2 team up to prevent the activation of APC/C by a signaling molecule called Cdc20. "The mitotic checkpoint is a molecular failsafe system, an intricate clockwork mechanism to ensure that everything is working properly before it allows a cell to divide," Yen says.
When cells divide, one of the first steps is to replicate DNA, which are in the familiar X- and Y-shaped structures called chromosomes. Before the cell can split, the mitotic checkpoint proteins monitor the mechanical connection between microtubule fibers (which act like rope to pull apart replicated pairs of chromosomes) and the chromosomes. If everything is in place, the checkpoint proteins release APC/C and allow division to continue. If not, the cell self-destructs before it can divide.
If the checkpoint proteins themselves are faulty, however, mitosis results in aneuploidy, the loss or gain of chromosomes in the daughter cells. This increases the risk of cancer, and promotes the resistance of cancer cells to chemotherapies.
Certain cancer drugs, such as paclitaxel and gemcitabine, exploit the mechanisms of mitosis to kill cancer cells. Although they act through very different mechanisms, both paclitaxel and gemcitabine sabotage the events monitored by the checkpoint proteins, which then leads to cell death. According to Yen, a deeper understanding of the mechanisms of mitosis will make these drugs, and others like them, more effective and more enduring.
While the researchers characterize the discovery as an important step in understanding mitosis, the existence of MCF2 raises more questions than it does answers. "We still have a lot to understand in how all the components of the mitotic checkpoint fit together and even more to understand in how the chromosomes are aligned and separated so exactingly," Yen says.
Funding for this study was provided through the Fox Chase Cancer Center Research Fund, National Institutes of Health and the Commonwealth of Pennsylvania. Hersko's work is also supported through funds from the Israel Cancer Research Fund, Israel Science Foundation and the Gruss Lipper Foundation.
Fox Chase Cancer Center is one of the leading freestanding cancer research and treatments centers in the United States. Founded in 1904 in Philadelphia as the nation's first cancer hospital, Fox Chase became one of the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, treatment, and community outreach.
Source: Jim Dryden
Washington University School of Medicine
среда, 27 апреля 2011 г.
Defeating Salmonella Requires An Understanding Of Guerrilla Warfare, UK
New research from scientists at the University of Cambridge has the potential to radically change our understanding of how infection spreads around the body and improve the methods used to control it.
If you are suffering from Salmonella food poisoning or, worse, typhoid fever, you feel like every cell in your body is under attack from an army of invading bacteria. However, rather than the bacteria mounting a mass assault scientists using state-of-the-art microscopy have found that Salmonella bacteria use a guerrilla warfare-like approach to attacking your body's cells. Researchers at the University of Cambridge have found that the majority of cells infected with bacteria in the body contain just one or two bacteria rather than being overrun as might be expected. Working in collaboration with mathematicians they are now proposing a new model to explain infection. The new explanation shows that a single Salmonella bacterium invades a cell, grows and replicates before its progeny is released when the cell bursts. The released bacteria then fan out each independently infiltrating another cell. This forces the host immune system to fight low numbers of bacteria simultaneously at numerous sites of infection rather than having to deal with a small number of well confined "battlefields" each containing large numbers of Salmonella.
Research leader Dr Pietro Mastroeni explains: "When bacteria infiltrate cells one at a time they gain a head start over your body's immune system. When a bacterium infects a cell it triggers an immune response and the inside of the cell becomes an increasingly hostile environment for the invader. By replicating quickly and escaping the bacteria can individually disseminate in the body and attack many more cells where the immune response has to start again from scratch."
By using mathematical models the researchers have been able to show that as an infection develops most bacteria remain isolated in individual infected cells, even as the number of cells infected grows.
Dr Mastroeni commented: "Understanding the hit-and-run tactics used by infectious bacteria has important healthcare implications. It will help us to identify how different drugs might work most effectively in different combinations and to develop new vaccines. In both cases developments would include a dual approach to slow the replication inside the cell and to attack bacteria on the run outside the cell."
The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust, not only has public health implications but also demonstrates the importance of animals in research.
Professor Julia Goodfellow, BBSRC Chief Executive, explained: "Salmonella bacteria cause hundreds of thousands of deaths worldwide every year. Without using infected mouse cells we would not understand the behaviour of the bacteria. The combined use of biological data and mathematical models has enabled the researchers to test several and sometimes competing theories about infection, greatly reducing the need for many more animal experiments."
The Biotechnology and Biological Sciences Research Council (BBSRC) is the leading funding agency for academic research and training in the biosciences at universities and institutes throughout the UK.
Biotechnology and Biological Sciences Research Council (BBSRC)
bbsrc.ac.uk
If you are suffering from Salmonella food poisoning or, worse, typhoid fever, you feel like every cell in your body is under attack from an army of invading bacteria. However, rather than the bacteria mounting a mass assault scientists using state-of-the-art microscopy have found that Salmonella bacteria use a guerrilla warfare-like approach to attacking your body's cells. Researchers at the University of Cambridge have found that the majority of cells infected with bacteria in the body contain just one or two bacteria rather than being overrun as might be expected. Working in collaboration with mathematicians they are now proposing a new model to explain infection. The new explanation shows that a single Salmonella bacterium invades a cell, grows and replicates before its progeny is released when the cell bursts. The released bacteria then fan out each independently infiltrating another cell. This forces the host immune system to fight low numbers of bacteria simultaneously at numerous sites of infection rather than having to deal with a small number of well confined "battlefields" each containing large numbers of Salmonella.
Research leader Dr Pietro Mastroeni explains: "When bacteria infiltrate cells one at a time they gain a head start over your body's immune system. When a bacterium infects a cell it triggers an immune response and the inside of the cell becomes an increasingly hostile environment for the invader. By replicating quickly and escaping the bacteria can individually disseminate in the body and attack many more cells where the immune response has to start again from scratch."
By using mathematical models the researchers have been able to show that as an infection develops most bacteria remain isolated in individual infected cells, even as the number of cells infected grows.
Dr Mastroeni commented: "Understanding the hit-and-run tactics used by infectious bacteria has important healthcare implications. It will help us to identify how different drugs might work most effectively in different combinations and to develop new vaccines. In both cases developments would include a dual approach to slow the replication inside the cell and to attack bacteria on the run outside the cell."
The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust, not only has public health implications but also demonstrates the importance of animals in research.
Professor Julia Goodfellow, BBSRC Chief Executive, explained: "Salmonella bacteria cause hundreds of thousands of deaths worldwide every year. Without using infected mouse cells we would not understand the behaviour of the bacteria. The combined use of biological data and mathematical models has enabled the researchers to test several and sometimes competing theories about infection, greatly reducing the need for many more animal experiments."
The Biotechnology and Biological Sciences Research Council (BBSRC) is the leading funding agency for academic research and training in the biosciences at universities and institutes throughout the UK.
Biotechnology and Biological Sciences Research Council (BBSRC)
bbsrc.ac.uk
вторник, 26 апреля 2011 г.
X-Ray Laser's Power And Potential
Two studies published in the February 3 issue of Nature demonstrate how the unique capabilities of the world's first hard X-ray free-electron laser - the Linac Coherent Light Source, located at the Department of Energy's SLAC National Accelerator Laboratory - could revolutionize the study of life.
In one study, an international research team used the LCLS to demonstrate a shortcut for determining the 3-D structures of proteins. The laser's brilliant pulses of X-ray light pulled structural data from tiny protein nanocrystals, avoiding the need to use large protein crystals that can be difficult or impossible to prepare. This could lop years off the structural analysis of some proteins and allow scientists to decipher tens of thousands of others that are out of reach today, including many involved in infectious disease.
In a separate paper, the same team reported making the first single-shot images of intact viruses, paving the way for snapshots and movies of molecules, viruses and live microbes in action.
Led by Henry Chapman of the Center for Free-Electron Laser Science at the German national laboratory DESY and Janos Hajdu of Sweden's Uppsala University, the team of more than 80 researchers from 21 institutions performed these experiments in December 2009, just two months after the LCLS opened for research. Their studies are the first to demonstrate the power and potential of the LCLS for biology.
"The LCLS beam is a billion times brighter than previous X-ray sources, and so intense it can cut through steel," Chapman said. "Yet these incredible X-ray bursts are used with surgical, microscopic precision and exquisite control, and this is opening whole new realms of scientific possibilities," including the ability to observe atoms moving and chemical bonds forming and breaking in real time.
Outrunning a laser blast
In the experiments, scientists sprayed viruses or nanocrystals into the path of the X-ray beam and zapped them with bursts of laser light. Each strobe-like laser pulse is so brief - a few millionths of a billionth of a second long - that it gathers all the information needed to make an image before the sample explodes.
Hajdu had proposed this method nearly a decade earlier. Researchers at Arizona State University, Lawrence Livermore National Laboratory, SLAC and Uppsala spent years developing specialized equipment for injecting samples into the beam, and Germany's Max Planck Advanced Study Group brought in a 10-ton, $7 million instrument called CAMP to record every single photon of data with a fast, ultra-sensitive X-ray camera for later analysis.
Tests at DESY and Lawrence Berkeley National Laboratory showed that the concept worked at lower X-ray energies. "But as you go to higher energies, can you still outrun the damage?" said team member Michael Bogan, a SLAC staff scientist and principal investigator at the PULSE Institute for Ultrafast Energy Science, jointly located at SLAC and Stanford University. The answer, he said, was yes: "The physics still holds."
A big payoff from tiny crystals
The protein structure experiments were led by Chapman and Arizona State's John Spence and Petra Fromme. They chose as their target Photosystem I, a biological factory in plant cells that converts sunlight to energy during photosynthesis. It's one of an important class of proteins known as membrane proteins that biologists and drug developers are eager to understand better.
Embedded in cell membranes, these proteins control traffic in and out of the cell and serve as docking points for infectious agents and disease-fighting drugs; in fact, they are the targets of more than 60 percent of the drugs on the market. Yet scientists know the structures of only six of the estimated 30,000 membrane proteins in the human body, given the difficulty of turning them into big crystals for conventional X-ray analysis.
To get around this bottleneck, the researchers squirted millions of nanocrystals containing copies of Photosystem I across the X-ray beam. Laser pulses hit the crystals at various angles and scattered into the detector, forming the patterns needed to reconstitute images. Each crystal immediately vaporized, but by the time the next pulse arrived another crystal had moved into the bull's eye.
The team combined 10,000 of the three million snapshots they took to come up with a good match for the known molecular structure of Photosystem I.
"I attended several meetings this summer where this work was presented and I was extraordinarily excited by it," Michael Wiener of the University of Virginia, who was not involved in the research, said of the results. He leads one of nine institutes set up by the National Institutes of Health to decipher the structures of membrane proteins. "Preparation of these nanocrystals is likely to be very, very much easier than the larger crystals used to date," Wiener said, leaving scientists more time and money to find out how these important biomolecules work.
The team is scheduled to return to the LCLS this month to repeat the experiments with X-ray laser pulses that are much faster and deliver four times as much energy as they did in the initial round. If the physics still hold, future images should capture the extraordinarily complex structure of Photosystem I in atom-by-atom detail.
Portraits of a virus
For the second experiment, the team went a step beyond nanocrystals to no crystals at all. Led by Hajdu, they made single-shot portraits of individual virus particles. These snapshots are a step toward eventually producing stop-action movies of chemical changes taking place in molecules and within living cells.
Biologists have long dreamed of making images of viruses, whole microbes and living cells without freezing, slicing or otherwise disturbing them. This is one of the goals of the LCLS, and the researchers tested its capabilities on Mimivirus, the world's largest known virus, which infects amoebas.
Of the hundreds of Mimiviruses hit by the LCLS beam, two produced enough data to allow scientists to reconstitute their images. The images show the 20-sided structure of the Mimi's outer coat and an area of denser material inside, which may represent its genetic material. Shorter, brighter pulses focused to a smaller area should greatly improve the resolution of these images to reveal details as small as one nanometer, the team wrote in their Feb. 3 Nature report.
Getting a detailed picture of the internal structure of an individual virus "would be a great achievement," said team member Jean-Michel Claverie, director of the Structural & Genomic Information Lab in Marseille and one of the scientists who discovered Mimi's viral nature.
"This is a brand-new way to look at a biological object," he said. "This will allow us to address not only the questions related to the internal structure of the virus, but its intrinsic variability from one individual virus particle to the next - a microscopic variability that might play a fundamental role in evolution."
The team returned to the LCLS in January to look at the Mimivirus at X-ray wavelengths that should maximize the amount of contrast and detail in the images. They will be analyzing the results in the months to come.
SLAC Director Persis Drell, who sat in a control room packed with scientists as raw data from the two experiments came in, said the experience was thrilling - and so is the potential for biology and medicine.
"This first data and these first papers are really just the first view of a new research frontier," she said. "They represent a turning point for the LCLS, demonstrating new technologies that will be great steps forward."
Source:
Melinda Lee
DOE/SLAC National Accelerator Laboratory
In one study, an international research team used the LCLS to demonstrate a shortcut for determining the 3-D structures of proteins. The laser's brilliant pulses of X-ray light pulled structural data from tiny protein nanocrystals, avoiding the need to use large protein crystals that can be difficult or impossible to prepare. This could lop years off the structural analysis of some proteins and allow scientists to decipher tens of thousands of others that are out of reach today, including many involved in infectious disease.
In a separate paper, the same team reported making the first single-shot images of intact viruses, paving the way for snapshots and movies of molecules, viruses and live microbes in action.
Led by Henry Chapman of the Center for Free-Electron Laser Science at the German national laboratory DESY and Janos Hajdu of Sweden's Uppsala University, the team of more than 80 researchers from 21 institutions performed these experiments in December 2009, just two months after the LCLS opened for research. Their studies are the first to demonstrate the power and potential of the LCLS for biology.
"The LCLS beam is a billion times brighter than previous X-ray sources, and so intense it can cut through steel," Chapman said. "Yet these incredible X-ray bursts are used with surgical, microscopic precision and exquisite control, and this is opening whole new realms of scientific possibilities," including the ability to observe atoms moving and chemical bonds forming and breaking in real time.
Outrunning a laser blast
In the experiments, scientists sprayed viruses or nanocrystals into the path of the X-ray beam and zapped them with bursts of laser light. Each strobe-like laser pulse is so brief - a few millionths of a billionth of a second long - that it gathers all the information needed to make an image before the sample explodes.
Hajdu had proposed this method nearly a decade earlier. Researchers at Arizona State University, Lawrence Livermore National Laboratory, SLAC and Uppsala spent years developing specialized equipment for injecting samples into the beam, and Germany's Max Planck Advanced Study Group brought in a 10-ton, $7 million instrument called CAMP to record every single photon of data with a fast, ultra-sensitive X-ray camera for later analysis.
Tests at DESY and Lawrence Berkeley National Laboratory showed that the concept worked at lower X-ray energies. "But as you go to higher energies, can you still outrun the damage?" said team member Michael Bogan, a SLAC staff scientist and principal investigator at the PULSE Institute for Ultrafast Energy Science, jointly located at SLAC and Stanford University. The answer, he said, was yes: "The physics still holds."
A big payoff from tiny crystals
The protein structure experiments were led by Chapman and Arizona State's John Spence and Petra Fromme. They chose as their target Photosystem I, a biological factory in plant cells that converts sunlight to energy during photosynthesis. It's one of an important class of proteins known as membrane proteins that biologists and drug developers are eager to understand better.
Embedded in cell membranes, these proteins control traffic in and out of the cell and serve as docking points for infectious agents and disease-fighting drugs; in fact, they are the targets of more than 60 percent of the drugs on the market. Yet scientists know the structures of only six of the estimated 30,000 membrane proteins in the human body, given the difficulty of turning them into big crystals for conventional X-ray analysis.
To get around this bottleneck, the researchers squirted millions of nanocrystals containing copies of Photosystem I across the X-ray beam. Laser pulses hit the crystals at various angles and scattered into the detector, forming the patterns needed to reconstitute images. Each crystal immediately vaporized, but by the time the next pulse arrived another crystal had moved into the bull's eye.
The team combined 10,000 of the three million snapshots they took to come up with a good match for the known molecular structure of Photosystem I.
"I attended several meetings this summer where this work was presented and I was extraordinarily excited by it," Michael Wiener of the University of Virginia, who was not involved in the research, said of the results. He leads one of nine institutes set up by the National Institutes of Health to decipher the structures of membrane proteins. "Preparation of these nanocrystals is likely to be very, very much easier than the larger crystals used to date," Wiener said, leaving scientists more time and money to find out how these important biomolecules work.
The team is scheduled to return to the LCLS this month to repeat the experiments with X-ray laser pulses that are much faster and deliver four times as much energy as they did in the initial round. If the physics still hold, future images should capture the extraordinarily complex structure of Photosystem I in atom-by-atom detail.
Portraits of a virus
For the second experiment, the team went a step beyond nanocrystals to no crystals at all. Led by Hajdu, they made single-shot portraits of individual virus particles. These snapshots are a step toward eventually producing stop-action movies of chemical changes taking place in molecules and within living cells.
Biologists have long dreamed of making images of viruses, whole microbes and living cells without freezing, slicing or otherwise disturbing them. This is one of the goals of the LCLS, and the researchers tested its capabilities on Mimivirus, the world's largest known virus, which infects amoebas.
Of the hundreds of Mimiviruses hit by the LCLS beam, two produced enough data to allow scientists to reconstitute their images. The images show the 20-sided structure of the Mimi's outer coat and an area of denser material inside, which may represent its genetic material. Shorter, brighter pulses focused to a smaller area should greatly improve the resolution of these images to reveal details as small as one nanometer, the team wrote in their Feb. 3 Nature report.
Getting a detailed picture of the internal structure of an individual virus "would be a great achievement," said team member Jean-Michel Claverie, director of the Structural & Genomic Information Lab in Marseille and one of the scientists who discovered Mimi's viral nature.
"This is a brand-new way to look at a biological object," he said. "This will allow us to address not only the questions related to the internal structure of the virus, but its intrinsic variability from one individual virus particle to the next - a microscopic variability that might play a fundamental role in evolution."
The team returned to the LCLS in January to look at the Mimivirus at X-ray wavelengths that should maximize the amount of contrast and detail in the images. They will be analyzing the results in the months to come.
SLAC Director Persis Drell, who sat in a control room packed with scientists as raw data from the two experiments came in, said the experience was thrilling - and so is the potential for biology and medicine.
"This first data and these first papers are really just the first view of a new research frontier," she said. "They represent a turning point for the LCLS, demonstrating new technologies that will be great steps forward."
Source:
Melinda Lee
DOE/SLAC National Accelerator Laboratory
The Brain's Development Affected By Partnership Of Genes
The human brain consists of approximately one hundred billion nerve cells. Each of these cells needs to connect to specific other cells during the brain's development in order to form a fully functional organism. Yet how does a nerve cell know where it should grow and which cells to contact? Scientists of the Max Planck Institute of Neurobiology in Martinsried have now shown that growing nerve cells realise when they've reached their target area in the fly brain thanks to the interaction of two genes. Similar mechanisms are also likely to play a role during the development of the vertebrate brain and could thus be important for a better understanding of certain developmental disorders.
The nervous system is incredibly complex. Millions and even many billion nerve cells are created during development. Each of these cells sets up connections to their neighbouring cells and then sends out a long connecting cable, the axon, to a different brain region. Once the axon has reached its target area it connects itself with the local nerve cells. In this way a processing chain is established which allows us, for example, to see a cup, recognize it as such, reach out and take hold of it. Had there been a misconnection between the nerve cells somewhere along the way between the eyes and the hand, it would be impossible to reach the coffee in the cup.
It is thus essential for nerve cells to connect to the correct partner cells. Based on this fact, scientists of the Max Planck Institute of Neurobiology in Martinsried and colleagues from Kyoto investigated how an axon knows where it should stop growing and start setting up connections with surrounding cells. For their investigation, the neurobiologists analyzed the function of genes that play a role in the development of the visual system of the fruit fly.
The scientists now report in the scientific journal Nature Neuroscience that the visual system of the fruit fly is only able to develop correctly, when two genes work together - the genes, that are in charge of producing the proteins "Golden Goal" and "Flamingo". These two proteins are located at the tip of a growing axon, where they are believed to gather information about their environment from the surrounding tissue. The actions of these two proteins enable nerve cells in a number of ways to find their way in the brain and recognize their target area. The study showed that chaos results if only one of the genes is active, or if there is a mismatch in the genes' activity: the axons cease to grow somewhere along the way and never reach their target area.
"We assume that very similar mechanisms play a role also in other organisms - including humans", explains Takashi Suzuki, lead author of the study. "We are now a good way into understanding how to manipulate the cells in such a way that they are certain to reach their target area." This knowledge would be an important foundation for eventual therapies of developmental disorders based upon a misguided growth of nerve cells. The knowledge may also help in the guidance of regenerating nerve cells back to their old connection sites.
Notes:
Original publication:
Hakeda-Suzuki S*, Berger-Mueller S*, Tomasi T, Usui T, Horiuchi S, Uemura T, Suzuki T (*equal contribution)
Golden Goal Collaborates with Flamingo in Conferring Synaptic-Layer Specificity in the Visual System
Nature Neuroscience,February 14 2011
Source:
Stefanie Merker
Max-Planck-Gesellschaft
The nervous system is incredibly complex. Millions and even many billion nerve cells are created during development. Each of these cells sets up connections to their neighbouring cells and then sends out a long connecting cable, the axon, to a different brain region. Once the axon has reached its target area it connects itself with the local nerve cells. In this way a processing chain is established which allows us, for example, to see a cup, recognize it as such, reach out and take hold of it. Had there been a misconnection between the nerve cells somewhere along the way between the eyes and the hand, it would be impossible to reach the coffee in the cup.
It is thus essential for nerve cells to connect to the correct partner cells. Based on this fact, scientists of the Max Planck Institute of Neurobiology in Martinsried and colleagues from Kyoto investigated how an axon knows where it should stop growing and start setting up connections with surrounding cells. For their investigation, the neurobiologists analyzed the function of genes that play a role in the development of the visual system of the fruit fly.
The scientists now report in the scientific journal Nature Neuroscience that the visual system of the fruit fly is only able to develop correctly, when two genes work together - the genes, that are in charge of producing the proteins "Golden Goal" and "Flamingo". These two proteins are located at the tip of a growing axon, where they are believed to gather information about their environment from the surrounding tissue. The actions of these two proteins enable nerve cells in a number of ways to find their way in the brain and recognize their target area. The study showed that chaos results if only one of the genes is active, or if there is a mismatch in the genes' activity: the axons cease to grow somewhere along the way and never reach their target area.
"We assume that very similar mechanisms play a role also in other organisms - including humans", explains Takashi Suzuki, lead author of the study. "We are now a good way into understanding how to manipulate the cells in such a way that they are certain to reach their target area." This knowledge would be an important foundation for eventual therapies of developmental disorders based upon a misguided growth of nerve cells. The knowledge may also help in the guidance of regenerating nerve cells back to their old connection sites.
Notes:
Original publication:
Hakeda-Suzuki S*, Berger-Mueller S*, Tomasi T, Usui T, Horiuchi S, Uemura T, Suzuki T (*equal contribution)
Golden Goal Collaborates with Flamingo in Conferring Synaptic-Layer Specificity in the Visual System
Nature Neuroscience,February 14 2011
Source:
Stefanie Merker
Max-Planck-Gesellschaft
New Broad-Spectrum Vaccine To Prevent Cervical Cancer Induces Strong Responses In Animals
Mice and rabbits immunized with a multimeric-L2 protein vaccine had robust antibody responses and were protected from infection when exposed to human papillomavirus (HPV) type 16 four months after vaccination, according to a new study published in the May 26 online issue of the Journal of the National Cancer Institute.
Current HPV L1-based vaccines are almost 100% protective against infection by the two HPV types that are responsible for 70% of all cervical cancer cases world wide. However, the existing vaccines provide limited protection against the other HPV types that cause cancer. With that limitation in mind, Richard Roden, Ph.D., of the Johns Hopkins University in Baltimore, and colleagues have been working on an alternate vaccine that is based on the HPV minor capsid protein L2, which is highly conserved between HPV types. Previous experiments showed that the L2 protein induced only a weak antibody response in animals.
In the current study, Roden and colleagues linked together a short segment of the L2 protein from several HPV types to generate a single multimeric L2 fusion protein. They tested the ability of this multimeric-L2 protein to induce antibody responses in animals and its ability to protect them from subsequent infection with HPV type 16.
Mice immunized with the multimeric L2 vaccine developed robust antibody responses against all of the HPV types tested, although the antibody titer was still lower than the type-restricted responses following vaccination with an existing HPV L1-based vaccine. When a multimeric L2 vaccine was delivered with a potent adjuvant to stimulate the immune response, such as alum, the vaccinated animals were able to resist infection by HPV16.
"Clinical studies are warranted to assess the safety and immunogenicity of multitype L2 vaccines in alum and other adjuvant formulations," the authors write. "If an L2 vaccine were proven effective in people, its simpler manufacturing process could make the local production of such a vaccine highly feasible, which might achieve the goal of producing it at sustainable prices in emerging countries and lead to its widespread implementation in the developing world."
In an accompanying editorial, F. Xavier Bosch, M.D., Ph.D., of the Catalan Institute of Oncology, in Barcelona, Spain, reviews the strengths of the current HPV vaccines but notes that they are too expensive to be used in much of the world and do not protect against enough HPV types. A broad-spectrum vaccine, such as the one being developed by Roden and colleagues, could solve those problems. The new data represent a meaningful step forward, Bosch says.
"The results open the door to a novel family of second generation HPV vaccines with significant potential value in the public health horizon," the editorialist writes. "As soon as appropriate, Phase 1 trials in humans should be initiated."
The clinical evaluation of new products, however, will likely take years. During this time, the currently available vaccines should be used as widely as possible, according to the editorialists.
Citations:
Article: Jagu et al. Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines. J Natl Cancer Inst 2009, 101: 782-792.
Editorial: Bosch, F.X. Broad-Spectrum Human Papillomavirus Vaccines: New Horizons but One Step at a Time. J Natl Cancer Inst 2009, 101: 771-773
Source:
Steve Graff
Journal of the National Cancer Institute
Current HPV L1-based vaccines are almost 100% protective against infection by the two HPV types that are responsible for 70% of all cervical cancer cases world wide. However, the existing vaccines provide limited protection against the other HPV types that cause cancer. With that limitation in mind, Richard Roden, Ph.D., of the Johns Hopkins University in Baltimore, and colleagues have been working on an alternate vaccine that is based on the HPV minor capsid protein L2, which is highly conserved between HPV types. Previous experiments showed that the L2 protein induced only a weak antibody response in animals.
In the current study, Roden and colleagues linked together a short segment of the L2 protein from several HPV types to generate a single multimeric L2 fusion protein. They tested the ability of this multimeric-L2 protein to induce antibody responses in animals and its ability to protect them from subsequent infection with HPV type 16.
Mice immunized with the multimeric L2 vaccine developed robust antibody responses against all of the HPV types tested, although the antibody titer was still lower than the type-restricted responses following vaccination with an existing HPV L1-based vaccine. When a multimeric L2 vaccine was delivered with a potent adjuvant to stimulate the immune response, such as alum, the vaccinated animals were able to resist infection by HPV16.
"Clinical studies are warranted to assess the safety and immunogenicity of multitype L2 vaccines in alum and other adjuvant formulations," the authors write. "If an L2 vaccine were proven effective in people, its simpler manufacturing process could make the local production of such a vaccine highly feasible, which might achieve the goal of producing it at sustainable prices in emerging countries and lead to its widespread implementation in the developing world."
In an accompanying editorial, F. Xavier Bosch, M.D., Ph.D., of the Catalan Institute of Oncology, in Barcelona, Spain, reviews the strengths of the current HPV vaccines but notes that they are too expensive to be used in much of the world and do not protect against enough HPV types. A broad-spectrum vaccine, such as the one being developed by Roden and colleagues, could solve those problems. The new data represent a meaningful step forward, Bosch says.
"The results open the door to a novel family of second generation HPV vaccines with significant potential value in the public health horizon," the editorialist writes. "As soon as appropriate, Phase 1 trials in humans should be initiated."
The clinical evaluation of new products, however, will likely take years. During this time, the currently available vaccines should be used as widely as possible, according to the editorialists.
Citations:
Article: Jagu et al. Concatenated Multitype L2 Fusion Proteins as Candidate Prophylactic Pan-Human Papillomavirus Vaccines. J Natl Cancer Inst 2009, 101: 782-792.
Editorial: Bosch, F.X. Broad-Spectrum Human Papillomavirus Vaccines: New Horizons but One Step at a Time. J Natl Cancer Inst 2009, 101: 771-773
Source:
Steve Graff
Journal of the National Cancer Institute
Surprising Infection Inducing Mechanism Found In Bacteria
A research appearing in Nature, with the participation of doctors Susana Campoy and Jordi BarbГ© from the Department of Genetics and Microbiology at Universitat AutГІnoma de Barcelona, demonstrates that bacteria have a surprising mechanism to transfer virulent genes causing infections. The research describes an unprecedented evolutionary adaptation and could contribute to finding new ways of treating and preventing bacterial infections.
Pathogenic genes are responsible for making bacteria capable of causing diseases. These genes cause bacteria to produce specific types of toxins and determine whether or not a disease will later develop in an individual. These virulent genes can be passed from one bacteria to another if the genome segments containing them, known as pathogenicity islands, are transferred from one to another.
A team of researchers from Universitat AutГІnoma de Barcelona, together with members of the CSIC Institute for Agrobiotechnology, Public University of Navarre, Virginia Commonwealth University, and New York University Medical Center, coordinated by the Valencian Institute for Agronomic Research (IVIA) and CEU-Cardenal Herrera University, have studied the mechanisms producing virulence in staphylococcus bacteria and causing the Toxic Shock Syndrome, a rare but potentially fatal illness in 50% of the cases.
Researchers observed how pathogenicity islands underwent an unprecedented evolutionary adaptation to be able to transfer pathogens to other innocuous bacteria and thus transform them into virulent bacteria.
Under normal conditions, pathogenicity islands produce the protein Stl, which binds to the DNA segment containing virulent genes and represses the transfer of the island. However, sometimes bacteria become infected with a virus which packages and transfers these virulent genes to other bacteria.
Scientists have discovered that these islands can detect the presences of a virus, eliminate the repression produced by Stl, and thus commence a replication and packaging cycle. The island is then capable of transference and of making other harmless bacteria turn virulent.
The new mechanism discovered by scientists is of great importance for the development of new treatments for diseases caused by bacterial toxins. The pathogenicity island studied is a prototype of a new family of virulent DNA recently discovered which also can be transferred to other species of bacteria such as Listeria monocytogenes, responsible for a large number of intoxications.
Less than a year ago, the research group led by Dr Jordi BarbГ© from the Department of Genetics and Microbiology at UAB published an article in Science on the antibiotic resistance mechanism in bacteria ["The SOS Response Controls Integron Recombination". Science. Vol. 324 (2009)]. "With the two articles in Nature and Science we have basic knowledge of the mechanisms used by bacteria to cause infections. This "doublet" in science not only demonstrates the quality of research being carried out at universities in our country, but also the possibility of creating applications for the treatment and prevention of bacterial infections", says Dr Jordi BarbГ©.
The research was led by professor JosГ© R. PenadГ©s of the CEU-Cardenal Herrera University and members of the Valencian Institute for Agronomic Research (CITA-IVIA). In addition to doctors Susana Campoy and Jordi BarbГ© of the Department of Genetics and Microbiology at UAB, participating in the study were researchers Maria Angeles Tormo MГЎs and Ignacio Mir Sanchis from CITA-IVIA and scientists from CSIC Institute for Agrobiotechnology, Public University of Navarre, Virginia Commonwealth University and New York University Medical Center.
Source: Universitat AutГІnoma de Barcelona
Pathogenic genes are responsible for making bacteria capable of causing diseases. These genes cause bacteria to produce specific types of toxins and determine whether or not a disease will later develop in an individual. These virulent genes can be passed from one bacteria to another if the genome segments containing them, known as pathogenicity islands, are transferred from one to another.
A team of researchers from Universitat AutГІnoma de Barcelona, together with members of the CSIC Institute for Agrobiotechnology, Public University of Navarre, Virginia Commonwealth University, and New York University Medical Center, coordinated by the Valencian Institute for Agronomic Research (IVIA) and CEU-Cardenal Herrera University, have studied the mechanisms producing virulence in staphylococcus bacteria and causing the Toxic Shock Syndrome, a rare but potentially fatal illness in 50% of the cases.
Researchers observed how pathogenicity islands underwent an unprecedented evolutionary adaptation to be able to transfer pathogens to other innocuous bacteria and thus transform them into virulent bacteria.
Under normal conditions, pathogenicity islands produce the protein Stl, which binds to the DNA segment containing virulent genes and represses the transfer of the island. However, sometimes bacteria become infected with a virus which packages and transfers these virulent genes to other bacteria.
Scientists have discovered that these islands can detect the presences of a virus, eliminate the repression produced by Stl, and thus commence a replication and packaging cycle. The island is then capable of transference and of making other harmless bacteria turn virulent.
The new mechanism discovered by scientists is of great importance for the development of new treatments for diseases caused by bacterial toxins. The pathogenicity island studied is a prototype of a new family of virulent DNA recently discovered which also can be transferred to other species of bacteria such as Listeria monocytogenes, responsible for a large number of intoxications.
Less than a year ago, the research group led by Dr Jordi BarbГ© from the Department of Genetics and Microbiology at UAB published an article in Science on the antibiotic resistance mechanism in bacteria ["The SOS Response Controls Integron Recombination". Science. Vol. 324 (2009)]. "With the two articles in Nature and Science we have basic knowledge of the mechanisms used by bacteria to cause infections. This "doublet" in science not only demonstrates the quality of research being carried out at universities in our country, but also the possibility of creating applications for the treatment and prevention of bacterial infections", says Dr Jordi BarbГ©.
The research was led by professor JosГ© R. PenadГ©s of the CEU-Cardenal Herrera University and members of the Valencian Institute for Agronomic Research (CITA-IVIA). In addition to doctors Susana Campoy and Jordi BarbГ© of the Department of Genetics and Microbiology at UAB, participating in the study were researchers Maria Angeles Tormo MГЎs and Ignacio Mir Sanchis from CITA-IVIA and scientists from CSIC Institute for Agrobiotechnology, Public University of Navarre, Virginia Commonwealth University and New York University Medical Center.
Source: Universitat AutГІnoma de Barcelona
New View On Biology Of Flavonoids
Flavonoids, a group of compounds found in fruits and vegetables that had been thought to be nutritionally important for their antioxidant activity, actually have little or no value in that role, according to an analysis by scientists in the Linus Pauling Institute at Oregon State University.
However, these same compounds may indeed benefit human health, but for reasons that are quite different - the body sees them as foreign compounds, researchers say, and through different mechanisms, they could play a role in preventing cancer or heart disease.
Based on this new view of how flavonoids work, a relatively modest intake of them - the amount you might find in a healthy diet with five to nine servings of fruits and vegetables - is sufficient. Large doses taken via dietary supplements might do no additional good; an apple a day may still be the best bet.
A research survey, and updated analysis of how flavonoids work and function in the human body, were recently published in Free Radical Biology and Medicine, a professional journal.
"What we now know is that flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant," said Balz Frei, professor and director of the Linus Pauling Institute. "The body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile."
Flavonoids are polyphenolic compounds with some common characteristics that are widely found in fruits and vegetables and often give them their color - they make lemons yellow and certain apples red. They are also found in some other foods, such as coffee, tea, wine, beer and chocolate, and studies in recent years had indicated that they had strong antioxidant activity - and because of that, they might be important to biological function and health.
"If you measure the activity of flavonoids in a test tube, they are indeed strong antioxidants," Frei said. "Based on laboratory tests of their ability to scavenge free radicals, it appears they have 3-5 times more antioxidant capacity than vitamins C or E. But with flavonoids in particular, what goes on in a test tube is not what's happening in the human body."
Research has now proven that flavonoids are poorly absorbed by the body, usually less than five percent, and most of what does get absorbed into the blood stream is rapidly metabolized in the intestines and liver and excreted from the body. By contrast, vitamin C is absorbed 100 percent by the body up to a certain level. And vitamin C accumulates in cells where it is 1,000 to 3,000 times more active as an antioxidant than flavonoids.
The large increase in total antioxidant capacity of blood observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, Frei said, but most likely is the result of increased uric acid levels.
But just because flavonoids have been found to be ineffectual as antioxidants in the human body does not mean they are without value, Frei said. They appear to strongly influence cell signaling pathways and gene expression, with relevance to both cancer and heart disease.
"We can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them," Frei said. "But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention.
"Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion," Frei added.
It also appears that flavonoids increase the activation of existing nitric oxide synthase, which has the effect of keeping blood vessels healthy and relaxed, preventing inflammation, and lowering blood pressure - all key goals in prevention of heart disease.
Both of these protective mechanisms could be long-lasting compared to antioxidants, which are more readily used up during their free radical scavenging activity and require constant replenishment through diet, scientists say.
However, Frei said, it's also true that such mechanisms require only relatively small amounts of flavonoids to trigger them - conceptually, it's a little like a vaccine in which only a very small amount of an offending substance is required to trigger a much larger metabolic response. Because of this, there would be no benefit - and possibly some risk - to taking dietary supplements that might inject large amounts of substances the body essentially sees as undesirable foreign compounds.
Numerous studies in the United States and Europe have documented a relationship between adequate dietary intake of flavonoid-rich foods, mostly fruits and vegetables, and protection against heart disease, cancer and neurodegenerative disease, Frei said.
Studies Force New View on Biology, Nutritional Action of Flavonoids
By David Stauth
The Linus Pauling Institute is a national leader in the study of such phytochemicals, or plant chemicals that may affect human health.
This research was supported by the American Heart Association and the National Center for Complementary and Alternative Medicine, which is part of the National Institutes of Health.
Contact: Balz Frei
Oregon State University
However, these same compounds may indeed benefit human health, but for reasons that are quite different - the body sees them as foreign compounds, researchers say, and through different mechanisms, they could play a role in preventing cancer or heart disease.
Based on this new view of how flavonoids work, a relatively modest intake of them - the amount you might find in a healthy diet with five to nine servings of fruits and vegetables - is sufficient. Large doses taken via dietary supplements might do no additional good; an apple a day may still be the best bet.
A research survey, and updated analysis of how flavonoids work and function in the human body, were recently published in Free Radical Biology and Medicine, a professional journal.
"What we now know is that flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant," said Balz Frei, professor and director of the Linus Pauling Institute. "The body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile."
Flavonoids are polyphenolic compounds with some common characteristics that are widely found in fruits and vegetables and often give them their color - they make lemons yellow and certain apples red. They are also found in some other foods, such as coffee, tea, wine, beer and chocolate, and studies in recent years had indicated that they had strong antioxidant activity - and because of that, they might be important to biological function and health.
"If you measure the activity of flavonoids in a test tube, they are indeed strong antioxidants," Frei said. "Based on laboratory tests of their ability to scavenge free radicals, it appears they have 3-5 times more antioxidant capacity than vitamins C or E. But with flavonoids in particular, what goes on in a test tube is not what's happening in the human body."
Research has now proven that flavonoids are poorly absorbed by the body, usually less than five percent, and most of what does get absorbed into the blood stream is rapidly metabolized in the intestines and liver and excreted from the body. By contrast, vitamin C is absorbed 100 percent by the body up to a certain level. And vitamin C accumulates in cells where it is 1,000 to 3,000 times more active as an antioxidant than flavonoids.
The large increase in total antioxidant capacity of blood observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, Frei said, but most likely is the result of increased uric acid levels.
But just because flavonoids have been found to be ineffectual as antioxidants in the human body does not mean they are without value, Frei said. They appear to strongly influence cell signaling pathways and gene expression, with relevance to both cancer and heart disease.
"We can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them," Frei said. "But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention.
"Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion," Frei added.
It also appears that flavonoids increase the activation of existing nitric oxide synthase, which has the effect of keeping blood vessels healthy and relaxed, preventing inflammation, and lowering blood pressure - all key goals in prevention of heart disease.
Both of these protective mechanisms could be long-lasting compared to antioxidants, which are more readily used up during their free radical scavenging activity and require constant replenishment through diet, scientists say.
However, Frei said, it's also true that such mechanisms require only relatively small amounts of flavonoids to trigger them - conceptually, it's a little like a vaccine in which only a very small amount of an offending substance is required to trigger a much larger metabolic response. Because of this, there would be no benefit - and possibly some risk - to taking dietary supplements that might inject large amounts of substances the body essentially sees as undesirable foreign compounds.
Numerous studies in the United States and Europe have documented a relationship between adequate dietary intake of flavonoid-rich foods, mostly fruits and vegetables, and protection against heart disease, cancer and neurodegenerative disease, Frei said.
Studies Force New View on Biology, Nutritional Action of Flavonoids
By David Stauth
The Linus Pauling Institute is a national leader in the study of such phytochemicals, or plant chemicals that may affect human health.
This research was supported by the American Heart Association and the National Center for Complementary and Alternative Medicine, which is part of the National Institutes of Health.
Contact: Balz Frei
Oregon State University
Spread Of New And Deadly Viruses Passed Through Sweet Food And Domestic Animals
Nipah virus is a new and deadly brain and lung disease that emerged from Singapore and Malaysia ten years ago. It is now spreading into rural India and Bangladesh killing up to three-quarters of the people who become infected in some outbreaks, scientists heard today (Thursday 3 April 2008) at the Society for General Microbiology's 162nd meeting being held this week at the Edinburgh International Conference Centre.
"People are catching this disease by drinking date palm juice or probably by eating fruit contaminated by the virus, or through contact with infected animals. We have seen nine outbreaks in Bangladesh since 2001, which killed 40-100% of the people who were infected", says Dr Jahangir Hossain, a scientist working in the Dhaka Hospital at the International Centre for Diarrheal Disease Research in Bangladesh (ICDDR,B).
Fruit bats are a natural reservoir of Nipah virus, and the first outbreaks in Singapore and Malaysia started when pigs on farms ate fruit which had been bitten by infected bats and dropped near their pens. The pigs developed coughs and breathing difficulties, and an epidemic spread across the Asian peninsula due to the pig trade. Pig farmers and abattoir workers became infected from sick pigs.
"Three outbreaks in Bangladesh were caused when people ate fresh date palm sap, a local sweet delicacy, which had been contaminated by bats." says Dr Jahangir Hossain. "Because both people and animals in Bangladesh often eat fresh date palm sap and fruits which have been bitten by bats, contaminated food and domestic animals form an important transmission pathway for Nipah virus to infect people".
The researchers have been trying to discover the way Nipah virus outbreaks start and to identify the factors which could help prevent virus transmission in the future. The large outbreak in pigs in Malaysia and Singapore caused the biggest outbreak in humans so far. In one outbreak in Bangladesh, people became infected after contact with sick cows, and close contact with pig herds was associated with virus transmission in another outbreak.
"We are working with local date palm sap collectors to learn about traditional practices that prevent bats from getting at and contaminating the sap", says Dr Jahangir Hossain. "If we can identify the factors that allow the virus to be passed from bats to humans so frequently, we might be able to help intervene and interfere with the transmission pathways. Current efforts should focus on restricting the consumption of fruit bitten by bats, restricting human contact with sick animals, and protecting date palm sap from contamination by bat secretions".
Source: Lucy Goodchild
Society for General Microbiology
"People are catching this disease by drinking date palm juice or probably by eating fruit contaminated by the virus, or through contact with infected animals. We have seen nine outbreaks in Bangladesh since 2001, which killed 40-100% of the people who were infected", says Dr Jahangir Hossain, a scientist working in the Dhaka Hospital at the International Centre for Diarrheal Disease Research in Bangladesh (ICDDR,B).
Fruit bats are a natural reservoir of Nipah virus, and the first outbreaks in Singapore and Malaysia started when pigs on farms ate fruit which had been bitten by infected bats and dropped near their pens. The pigs developed coughs and breathing difficulties, and an epidemic spread across the Asian peninsula due to the pig trade. Pig farmers and abattoir workers became infected from sick pigs.
"Three outbreaks in Bangladesh were caused when people ate fresh date palm sap, a local sweet delicacy, which had been contaminated by bats." says Dr Jahangir Hossain. "Because both people and animals in Bangladesh often eat fresh date palm sap and fruits which have been bitten by bats, contaminated food and domestic animals form an important transmission pathway for Nipah virus to infect people".
The researchers have been trying to discover the way Nipah virus outbreaks start and to identify the factors which could help prevent virus transmission in the future. The large outbreak in pigs in Malaysia and Singapore caused the biggest outbreak in humans so far. In one outbreak in Bangladesh, people became infected after contact with sick cows, and close contact with pig herds was associated with virus transmission in another outbreak.
"We are working with local date palm sap collectors to learn about traditional practices that prevent bats from getting at and contaminating the sap", says Dr Jahangir Hossain. "If we can identify the factors that allow the virus to be passed from bats to humans so frequently, we might be able to help intervene and interfere with the transmission pathways. Current efforts should focus on restricting the consumption of fruit bitten by bats, restricting human contact with sick animals, and protecting date palm sap from contamination by bat secretions".
Source: Lucy Goodchild
Society for General Microbiology
In Mouse Model Scientists Find Obesity Alone Does Not Cause Arthritis
The link between obesity and osteoarthritis may be more than just the wear and tear on the skeleton caused by added weight.
A Duke University study has found that the absence of the appetite hormone leptin can determine whether obese mice experience arthritis, no matter how heavy they are.
"We were completely surprised to find that mice that became extremely obese had no arthritis if their bodies didn't have leptin," said Farshid Guilak, Ph.D., director of orthopaedic research in the Duke Department of Surgery. "Although there was some earlier evidence that leptin might be involved in the arthritis disease process, we didn't think that there would be no arthritis at all."
In fact, the joints from the obese mice in the study appearing in the journal Arthritis & Rheumatism looked better than those of the normal control mice, Guilak said. "However, in another study, we found that mice that gained half as much weight on a high-fat diet but processed leptin normally showed significant knee osteoarthritis."
Leptin influences many of the factors involved in osteoarthritis--body weight, inflammation, sex hormone levels, and bone metabolism, said lead author Tim Griffin, Ph.D., who was at Duke Orthopaedic Department and now is an assistant member of the Free Radical Biology and Aging Program at the Oklahoma Medical Research Foundation. "That also makes leptin challenging to study, however, because it's difficult to isolate which pathway is being altered to prevent the development of osteoarthritis."
Leptin is a well-known regulator of appetite, but this is the first time scientists have reported a role for leptin as a metabolic link between obesity and altered cartilage metabolism in joints.
The role of obesity as a risk factor for arthritis is well characterized, but it was thought to be merely a case of overloading joints with extra weight. "It hadn't been studied beyond that," Guilak said. "We knew from other studies that obese people got arthritis in their hands, too, which don't bear weight. This indicated that something besides just body-weight level affected their joints."
The Duke team set out to learn whether the increased body fat of obesity causes an inflammatory response in joints - an imbalance of the immune system signaling proteins called cytokines and other chemicals in osteoarthritis.
They studied mice that were leptin-deficient or deficient in leptin receptors - mice that didn't have any effective leptin in their bodies. Both types of mice overate and gained weight. Then they compared the study mice with normal mice to document knee osteoarthritis. The measurements included pro- and anti-inflammatory cytokines present in arthritis, and several tests to assess bone changes in the knees of the mice.
The knee bones of the leptin-free, obese mice did change, but without forming osteoarthritis. The levels of inflammatory cytokines, which correlate with arthritis, were largely unchanged in these mice. The results suggested that leptin may have a dual role in the development of osteoarthritis by regulating both the skeletal and immune systems.
What does this mean for people? "Obesity is still the number one preventable risk factor of osteoarthritis, but now it seems body fat by itself is not what is causing it," Guilak said. "If you are obese, there are benefits to losing weight in terms of arthritis. For example, if you are obese and lose just 10 pounds, pain decreases significantly. Pain modulation is another clue it might be a chemical or systemic metabolic effect, rather than just a mechanical effect of less weight on the joints."
As with many studies that yield unanticipated findings, "we have a lot of additional questions and experiments that need to be done to further understand how leptin mediates the development of osteoarthritis," Griffin said.
"With obesity and osteoarthritis, there are good similarities between humans and mice," Guilak said. "If we can find a pathway that links a high-fat diet with arthritis, then we can try to identify and block the inflammatory mediators that are linked with the dietary fat."
The study was sponsored by the National Institute for Arthritis, Musculoskeletal and Skin Diseases and the Arthritis Foundation. Lead author Timothy M. Griffin, formerly of the Duke Department of Surgery, is now with the Oklahoma Medical Research Foundation. Co-authors Janet L. Huebner and Virginia B. Kraus are with the Duke Department of Medicine.
Source:
Mary Jane Gore
Duke University Medical Center
A Duke University study has found that the absence of the appetite hormone leptin can determine whether obese mice experience arthritis, no matter how heavy they are.
"We were completely surprised to find that mice that became extremely obese had no arthritis if their bodies didn't have leptin," said Farshid Guilak, Ph.D., director of orthopaedic research in the Duke Department of Surgery. "Although there was some earlier evidence that leptin might be involved in the arthritis disease process, we didn't think that there would be no arthritis at all."
In fact, the joints from the obese mice in the study appearing in the journal Arthritis & Rheumatism looked better than those of the normal control mice, Guilak said. "However, in another study, we found that mice that gained half as much weight on a high-fat diet but processed leptin normally showed significant knee osteoarthritis."
Leptin influences many of the factors involved in osteoarthritis--body weight, inflammation, sex hormone levels, and bone metabolism, said lead author Tim Griffin, Ph.D., who was at Duke Orthopaedic Department and now is an assistant member of the Free Radical Biology and Aging Program at the Oklahoma Medical Research Foundation. "That also makes leptin challenging to study, however, because it's difficult to isolate which pathway is being altered to prevent the development of osteoarthritis."
Leptin is a well-known regulator of appetite, but this is the first time scientists have reported a role for leptin as a metabolic link between obesity and altered cartilage metabolism in joints.
The role of obesity as a risk factor for arthritis is well characterized, but it was thought to be merely a case of overloading joints with extra weight. "It hadn't been studied beyond that," Guilak said. "We knew from other studies that obese people got arthritis in their hands, too, which don't bear weight. This indicated that something besides just body-weight level affected their joints."
The Duke team set out to learn whether the increased body fat of obesity causes an inflammatory response in joints - an imbalance of the immune system signaling proteins called cytokines and other chemicals in osteoarthritis.
They studied mice that were leptin-deficient or deficient in leptin receptors - mice that didn't have any effective leptin in their bodies. Both types of mice overate and gained weight. Then they compared the study mice with normal mice to document knee osteoarthritis. The measurements included pro- and anti-inflammatory cytokines present in arthritis, and several tests to assess bone changes in the knees of the mice.
The knee bones of the leptin-free, obese mice did change, but without forming osteoarthritis. The levels of inflammatory cytokines, which correlate with arthritis, were largely unchanged in these mice. The results suggested that leptin may have a dual role in the development of osteoarthritis by regulating both the skeletal and immune systems.
What does this mean for people? "Obesity is still the number one preventable risk factor of osteoarthritis, but now it seems body fat by itself is not what is causing it," Guilak said. "If you are obese, there are benefits to losing weight in terms of arthritis. For example, if you are obese and lose just 10 pounds, pain decreases significantly. Pain modulation is another clue it might be a chemical or systemic metabolic effect, rather than just a mechanical effect of less weight on the joints."
As with many studies that yield unanticipated findings, "we have a lot of additional questions and experiments that need to be done to further understand how leptin mediates the development of osteoarthritis," Griffin said.
"With obesity and osteoarthritis, there are good similarities between humans and mice," Guilak said. "If we can find a pathway that links a high-fat diet with arthritis, then we can try to identify and block the inflammatory mediators that are linked with the dietary fat."
The study was sponsored by the National Institute for Arthritis, Musculoskeletal and Skin Diseases and the Arthritis Foundation. Lead author Timothy M. Griffin, formerly of the Duke Department of Surgery, is now with the Oklahoma Medical Research Foundation. Co-authors Janet L. Huebner and Virginia B. Kraus are with the Duke Department of Medicine.
Source:
Mary Jane Gore
Duke University Medical Center
How Digits Grow Described By Wisconsin Researchers
Researchers at the University of Wisconsin School of Medicine and Public Health (SMPH) are wagging a finger at currently held notions about the way digits are formed.
Studying the embryonic chick foot, the developmental biologists have come up with a model that explains how digits grow and why each digit is different from the others.
As reported in the Proceedings of the National Academy of Sciences Online Early Edition the week of March 10-14, 2008, the scientists found that the development and fate of each digit depends on a surprisingly dynamic process in unanticipated locations and involving unexpected players.
The UW-Madison team showed that growth begins in a portion of the developing digit they have named the phalanx-forming region (PFR). They illustrated that phalanges, structures that later become finger or toe bones, arise not from cartilage cells but from mesenchymal cells. And they discovered that a complex array of signals from a variety of genes at different times combine to form each phalanx.
Though the research was done on chick digits, it may have implications for humans born with a genetic condition known as bradydactyly, or stubby fingers and toes. The work was undertaken in the laboratory of John Fallon, the Harland Winfield Mossman Professor of Anatomy at the SMPH, who for years has sought to understand how cell fate is determined and patterning-of digits, teeth and feathers-is achieved during embryonic development.
In birds and mammals, digits arise in the mitten-shaped autopod, or developing foot, which consists of two alternating regions. The digital rays, made up of cartilage and mesenchyme, become the phalanges in the adult chicken's toes. These alternate with the interdigits, also consisting of mesenchymal tissue, which fill the space between the digit rays and eventually regress.
Scientists know that the gene Sonic Hedgehog (SHH) plays an important role in determining the form and number of digits, and many believe that other secondary signaling centers downstream of SHH also are involved in establishing a particular digit's identity.
In a 2000 paper published in Science, Fallon and graduate student Randall Dahn showed that the interdigit tissue was more important than previously thought. It was not just a spacer between developing digits; experimental manipulations showed that it controlled how the neighboring digit would develop. The team proposed that different signal levels in each interdigit resulted in specific digit identities.
"We thought that bone morphogenic protein (BMP) signals from interdigit cells were sent to the digit primordium, a rod of cartilage, in the neighboring digit ray, breaking up the cartilage into phalanges," Fallon says.
Sean Hasso, Fallon's current graduate student, wanted to know precisely which cells in the digital ray give rise to phalanges and which molecular events determine the number, size and shape of each phalanx. Performing microsurgery and cell marking studies on the embryonic chick autopod, Hasso showed that the cells that eventually form phalanges arise from the growth of mesenchyme at the tip of the digital ray.
"This finding is absolutely contrary to what we and other scientists had been thinking-which was that growth and phalanx formation occurred in the cartilaginous rods in the digit primordia," says Fallon. "These observations were the foundation for further studies."
In the next set of experiments, Takayuki Suzuki, a post-doctoral fellow in the Fallon lab, conducted an in-depth examination of several aspects of genetic expression in the PFR. He observed that the up-regulation of a gene called Sox9 indicated that the cells of the PFR commit to becoming cartilage.
The scientists were most interested to see that these cells also up-regulated a BMP receptor. Suzuki devised an assay to quantitate BMP receptor signaling in the PFR cells. The assay showed that the signaling activity through the BMP receptor correlated with the digit that forms either normally or after experimental manipulation of the interdigit.
"Our studies showed that a specific region of mesenchymal cells in the digital ray receive the interdigital signal, and that BMP receptor signaling in this region plays a central role in the process," notes Fallon. "Changes in the levels of signaling lead to different developmental outcomes."
The research explains how improper signaling through specific BMP receptors may lead to malformations of phalanges, such as those seen in certain types of bradydactyly in humans.
"The molecular mechanisms controlling the formation of chicken and mammalian limbs, including those of humans, are similar," says Fallon. "We can learn a great deal about the causes of human malformations from studying these mechanisms in the developing chick."
Source: Dian Land
University of Wisconsin-Madison
Studying the embryonic chick foot, the developmental biologists have come up with a model that explains how digits grow and why each digit is different from the others.
As reported in the Proceedings of the National Academy of Sciences Online Early Edition the week of March 10-14, 2008, the scientists found that the development and fate of each digit depends on a surprisingly dynamic process in unanticipated locations and involving unexpected players.
The UW-Madison team showed that growth begins in a portion of the developing digit they have named the phalanx-forming region (PFR). They illustrated that phalanges, structures that later become finger or toe bones, arise not from cartilage cells but from mesenchymal cells. And they discovered that a complex array of signals from a variety of genes at different times combine to form each phalanx.
Though the research was done on chick digits, it may have implications for humans born with a genetic condition known as bradydactyly, or stubby fingers and toes. The work was undertaken in the laboratory of John Fallon, the Harland Winfield Mossman Professor of Anatomy at the SMPH, who for years has sought to understand how cell fate is determined and patterning-of digits, teeth and feathers-is achieved during embryonic development.
In birds and mammals, digits arise in the mitten-shaped autopod, or developing foot, which consists of two alternating regions. The digital rays, made up of cartilage and mesenchyme, become the phalanges in the adult chicken's toes. These alternate with the interdigits, also consisting of mesenchymal tissue, which fill the space between the digit rays and eventually regress.
Scientists know that the gene Sonic Hedgehog (SHH) plays an important role in determining the form and number of digits, and many believe that other secondary signaling centers downstream of SHH also are involved in establishing a particular digit's identity.
In a 2000 paper published in Science, Fallon and graduate student Randall Dahn showed that the interdigit tissue was more important than previously thought. It was not just a spacer between developing digits; experimental manipulations showed that it controlled how the neighboring digit would develop. The team proposed that different signal levels in each interdigit resulted in specific digit identities.
"We thought that bone morphogenic protein (BMP) signals from interdigit cells were sent to the digit primordium, a rod of cartilage, in the neighboring digit ray, breaking up the cartilage into phalanges," Fallon says.
Sean Hasso, Fallon's current graduate student, wanted to know precisely which cells in the digital ray give rise to phalanges and which molecular events determine the number, size and shape of each phalanx. Performing microsurgery and cell marking studies on the embryonic chick autopod, Hasso showed that the cells that eventually form phalanges arise from the growth of mesenchyme at the tip of the digital ray.
"This finding is absolutely contrary to what we and other scientists had been thinking-which was that growth and phalanx formation occurred in the cartilaginous rods in the digit primordia," says Fallon. "These observations were the foundation for further studies."
In the next set of experiments, Takayuki Suzuki, a post-doctoral fellow in the Fallon lab, conducted an in-depth examination of several aspects of genetic expression in the PFR. He observed that the up-regulation of a gene called Sox9 indicated that the cells of the PFR commit to becoming cartilage.
The scientists were most interested to see that these cells also up-regulated a BMP receptor. Suzuki devised an assay to quantitate BMP receptor signaling in the PFR cells. The assay showed that the signaling activity through the BMP receptor correlated with the digit that forms either normally or after experimental manipulation of the interdigit.
"Our studies showed that a specific region of mesenchymal cells in the digital ray receive the interdigital signal, and that BMP receptor signaling in this region plays a central role in the process," notes Fallon. "Changes in the levels of signaling lead to different developmental outcomes."
The research explains how improper signaling through specific BMP receptors may lead to malformations of phalanges, such as those seen in certain types of bradydactyly in humans.
"The molecular mechanisms controlling the formation of chicken and mammalian limbs, including those of humans, are similar," says Fallon. "We can learn a great deal about the causes of human malformations from studying these mechanisms in the developing chick."
Source: Dian Land
University of Wisconsin-Madison
Structural Biology Study Reveals Shape Of Epigenetic Enzyme Complex
To understand the emerging science of epigenetics - a field that describes how genes may be regulated without altering the underlying DNA itself - scientists are deciphering the many ways in which enzymes act on the proteins surrounding DNA within cells.
One type of these enzymes, proteins known as histone acetyltransferases (HATs), act on DNA by modifying DNA-bound proteins called histones. This act of modification, called acetlyation, can dictate how histones interact with DNA and other proteins affecting processes such as DNA replication, transcription (reading the gene), and repair. In the February 9 issue of the journal Structure, available online, researchers at The Wistar Institute are the first to describe the complete atomic structure formed by a yeast HAT, known as Rtt109, and one of its associated proteins. Their findings demonstrate how a particular histone acetylation event works, a crucial step to understanding epigenetics and the related processes that underlie both health and disease.
According to the study's senior author, Ronen Marmorstein, Ph.D., professor and program leader of Wistar's Gene Expression and Regulation Program, two copies of Rtt109 bind to two copies of a "chaperone" protein to form a ring.
"The ring fits atop a histone much like a halo, and we find that the type of chaperone dictates exactly how the enzyme affects the histone by determining the exact position of acetylation," said Marmorstein. "The structure represents a nice model system for the regulation of protein acetylation, and teaches us something new about the biology of this enzyme, Rtt109."
The act of acetylation adds an "acetyl group," a small chemical structure, to a lysine - one of the amino acids that make up a given protein. Altering one lysine could change the shape of a protein, such as a histone, in a subtle way, perhaps redirecting how it functions. Rtt109, the researchers say, acetylates any of three specific lysines on histones, and exactly which of the histone lysines are modified is determined by which chaperone escorts Rtt109 into place. Since histones are such crucial DNA-associated proteins, altering a single lysine in a single part of the structure can have profound effects on the "behavior" of that histone, such as exposing a particular set of genes to be read, for example.
In the paper, Marmorstein and his colleagues show how Rtt109 associates with a particular chaperone called Vps75. Rtt109 also associates with another chaperone, Asf1, which has been shown to enable the Rtt109 to modify lysines in a different spot on a given histone, creating a different effect in how that histone interacts with DNA and in turn changing the cell's biological properties.
Their study is the first to show that two Rtt109 enzymes pair up with two Vps75 chaperones to form a ring. The laboratory created crystals of the protein complex and used a technique called X-ray crystallography to "see" the structure of the complex by analyzing the patterns formed when X-rays bounce off the crystals. They used the powerful X-ray source at the Argonne National Laboratory's Advanced Photon Source, which enabled the team to determine the structure of the protein complex at the atomic scale - at a resolution of 2.8 angstroms (2.8 billionths of a meter), which is smaller than the distance between individual rungs on the DNA ladder.
Since the Marmorstein laboratory began its work on HATs over a decade ago, several large-scale studies have shown that acetylation occurs to over 2000 proteins, not just histones. According to Marmorstein, it appears there is an entire web of communication going on within cells directly attributable to protein acetylation, another level of complexity in an already-complex field.
"We have seen many different proteins over several different pathways become affected by acetylation, which can alter the processes of RNA metabolism, cell cycle control, cancer, and a number of different aspects of life. It looks like protein acetylation has much broader biological implications than initially appreciated," said Marmorstein.
"In many ways, it seems a lot like what we have seen in recent years with protein kinases and cell signaling," said Marmorstein. "What we're learning is that these HATs, and possibly other protein acetyltransferases, are regulated in much the same way. They have these profound effects within cells, but it is still very new to science. How it works is a big black box that we intend to decipher."
Notes:
This work from the Marmorstein laboratory was supported by a grant from the National Institute of General Medical Sciences.
The lead author of the study is Yong Tang, Ph.D., a staff scientist in the Marmorstein laboratory. Wistar co-authors also include Katrina Meeth, a research associate and Hua Yuan, Ph.D., a postdoctoral fellow in the Marmorstein laboratory. Collaborators include Philip A. Cole, Ph.D., and his laboratory at the Johns Hopkins University School of Medicine, including Marc A. Holbert, Ph.D.; and the laboratories of Alain Verreault, Ph.D., and Pierre Thibault, Ph.D., at the Institute for Research in Immunology and Cancer at the UniversitГ© de MontrГ©al; and their colleagues, including research associates, Neda Delgoshaie, Paul Drogaris, Chantal Durette, and Eun-Hye Lee, and postdoctoral fellows Hugo Wurtele, Ph.D., and Benoit Guillemette, Ph.D.
Source:
Greg Lester
The Wistar Institute
One type of these enzymes, proteins known as histone acetyltransferases (HATs), act on DNA by modifying DNA-bound proteins called histones. This act of modification, called acetlyation, can dictate how histones interact with DNA and other proteins affecting processes such as DNA replication, transcription (reading the gene), and repair. In the February 9 issue of the journal Structure, available online, researchers at The Wistar Institute are the first to describe the complete atomic structure formed by a yeast HAT, known as Rtt109, and one of its associated proteins. Their findings demonstrate how a particular histone acetylation event works, a crucial step to understanding epigenetics and the related processes that underlie both health and disease.
According to the study's senior author, Ronen Marmorstein, Ph.D., professor and program leader of Wistar's Gene Expression and Regulation Program, two copies of Rtt109 bind to two copies of a "chaperone" protein to form a ring.
"The ring fits atop a histone much like a halo, and we find that the type of chaperone dictates exactly how the enzyme affects the histone by determining the exact position of acetylation," said Marmorstein. "The structure represents a nice model system for the regulation of protein acetylation, and teaches us something new about the biology of this enzyme, Rtt109."
The act of acetylation adds an "acetyl group," a small chemical structure, to a lysine - one of the amino acids that make up a given protein. Altering one lysine could change the shape of a protein, such as a histone, in a subtle way, perhaps redirecting how it functions. Rtt109, the researchers say, acetylates any of three specific lysines on histones, and exactly which of the histone lysines are modified is determined by which chaperone escorts Rtt109 into place. Since histones are such crucial DNA-associated proteins, altering a single lysine in a single part of the structure can have profound effects on the "behavior" of that histone, such as exposing a particular set of genes to be read, for example.
In the paper, Marmorstein and his colleagues show how Rtt109 associates with a particular chaperone called Vps75. Rtt109 also associates with another chaperone, Asf1, which has been shown to enable the Rtt109 to modify lysines in a different spot on a given histone, creating a different effect in how that histone interacts with DNA and in turn changing the cell's biological properties.
Their study is the first to show that two Rtt109 enzymes pair up with two Vps75 chaperones to form a ring. The laboratory created crystals of the protein complex and used a technique called X-ray crystallography to "see" the structure of the complex by analyzing the patterns formed when X-rays bounce off the crystals. They used the powerful X-ray source at the Argonne National Laboratory's Advanced Photon Source, which enabled the team to determine the structure of the protein complex at the atomic scale - at a resolution of 2.8 angstroms (2.8 billionths of a meter), which is smaller than the distance between individual rungs on the DNA ladder.
Since the Marmorstein laboratory began its work on HATs over a decade ago, several large-scale studies have shown that acetylation occurs to over 2000 proteins, not just histones. According to Marmorstein, it appears there is an entire web of communication going on within cells directly attributable to protein acetylation, another level of complexity in an already-complex field.
"We have seen many different proteins over several different pathways become affected by acetylation, which can alter the processes of RNA metabolism, cell cycle control, cancer, and a number of different aspects of life. It looks like protein acetylation has much broader biological implications than initially appreciated," said Marmorstein.
"In many ways, it seems a lot like what we have seen in recent years with protein kinases and cell signaling," said Marmorstein. "What we're learning is that these HATs, and possibly other protein acetyltransferases, are regulated in much the same way. They have these profound effects within cells, but it is still very new to science. How it works is a big black box that we intend to decipher."
Notes:
This work from the Marmorstein laboratory was supported by a grant from the National Institute of General Medical Sciences.
The lead author of the study is Yong Tang, Ph.D., a staff scientist in the Marmorstein laboratory. Wistar co-authors also include Katrina Meeth, a research associate and Hua Yuan, Ph.D., a postdoctoral fellow in the Marmorstein laboratory. Collaborators include Philip A. Cole, Ph.D., and his laboratory at the Johns Hopkins University School of Medicine, including Marc A. Holbert, Ph.D.; and the laboratories of Alain Verreault, Ph.D., and Pierre Thibault, Ph.D., at the Institute for Research in Immunology and Cancer at the UniversitГ© de MontrГ©al; and their colleagues, including research associates, Neda Delgoshaie, Paul Drogaris, Chantal Durette, and Eun-Hye Lee, and postdoctoral fellows Hugo Wurtele, Ph.D., and Benoit Guillemette, Ph.D.
Source:
Greg Lester
The Wistar Institute
Updated Standards To Reduce Metal Contaminants In Prescription Drugs
Prescription medicines in the United States could soon have lower levels of potentially harmful metals, as the organization that sets drug standards develops new limits for impurities like mercury, arsenic, and lead, according to an article scheduled for the December 8 issue of Chemical & Engineering News, ACS' weekly news magazine.
In the article, C&EN Associate Editor Jyllian Kemsley notes that researchers have known for years that potentially toxic metals can wind up in pharmaceutical ingredients through raw materials, catalysts, equipment, and other sources. But the testing method currently prescribed by the U.S. Pharmacopeia (USP), the nonprofit organization that sets standards for the pharmaceutical industry, has not kept pace with that new knowledge. That method involves a 100-year-old test that is time-consuming, difficult to interpret, and generally not quantitative, according to the article.
USP now is developing new standards and testing methods that will be finished in 2010 and implemented over a span of years. USP will require drug makers to use improved methods and instruments to detect metal contaminants.
"Detecting metals in drugs"
pubs.acs/cen/science/86/8649sci1.html
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
American Chemical Society
In the article, C&EN Associate Editor Jyllian Kemsley notes that researchers have known for years that potentially toxic metals can wind up in pharmaceutical ingredients through raw materials, catalysts, equipment, and other sources. But the testing method currently prescribed by the U.S. Pharmacopeia (USP), the nonprofit organization that sets standards for the pharmaceutical industry, has not kept pace with that new knowledge. That method involves a 100-year-old test that is time-consuming, difficult to interpret, and generally not quantitative, according to the article.
USP now is developing new standards and testing methods that will be finished in 2010 and implemented over a span of years. USP will require drug makers to use improved methods and instruments to detect metal contaminants.
"Detecting metals in drugs"
pubs.acs/cen/science/86/8649sci1.html
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
American Chemical Society
Dispersal Of Sibling Coalitions Promotes Helping Among Immigrants In A Cooperatively Breeding Bird
Kinship is a key factor in social evolution, although the extent of its impact is often debated.
Dispersal is a ubiquitous process that potentially inhibits sociality by diluting relatedness.
We studied dispersal in a social bird, the long-tailed tit, in which failed breeders often help others to raise young. Helpers usually aid kin, but helping among immigrants is poorly understood because the origins of these individuals are unknown.
Here, we use genetic methods alongside observational data to show that immigrants disperse in sibling groups and helping occurs between these siblings. This result challenges the widespread assumption that dispersal precludes sociality.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
publishing.royalsociety/proceedingsb
Dispersal is a ubiquitous process that potentially inhibits sociality by diluting relatedness.
We studied dispersal in a social bird, the long-tailed tit, in which failed breeders often help others to raise young. Helpers usually aid kin, but helping among immigrants is poorly understood because the origins of these individuals are unknown.
Here, we use genetic methods alongside observational data to show that immigrants disperse in sibling groups and helping occurs between these siblings. This result challenges the widespread assumption that dispersal precludes sociality.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
publishing.royalsociety/proceedingsb
Olfactory Bulb Glial Cell Transplant Preserves Muscles In Paraplegic Rats
Researchers from the "Centro de BiologГa Molecular Severo Ochoa" (CSIC-UAM), CГіrdoba University and the "Instituto de Biomedicina de Valencia" (CSIC) have analysed the degree of preservation in the skeletal muscles of paraplegic rats treated with a transplant of Olfactory bulb glial cells (OBG).
Spinal chord injuries represent a serious and irreversible handicap that is sadly frequent in our society. Because of the permanent break in the nervous connections between the brain and the organs and muscles, such injuries impair their movement inducing atrophy and deterioration while they disturb organic functions.
The pioneering studies carried out by Santiago RamГіn y Cajal established that while nerve cells from the peripheral nervous system (PNS) have the capacity to repair themselves, the same does not apply to adult brain cells and spinal cord cells from the central nervous system (CNS). The difference is not in the nerve cells themselves but in the cellular enviroment that gives them support - the glial cells. These cells are involved in the transmision of nerve impulses and produce myelin. Schwann cells (a variety of glial cell) in the peripheral nervous system (PNS) provide factors that contribute to the regeneration of the axons whereas the glia of the CNS do not have such a nurturing role. For this reason, one of the strategic experimental approaches for the regeneration of spinal chord neurons consists in altering their cellular enviroment by introducing cells that create a supportive environment for axon regeneration in the damaged area. The glial cells that surround the axons in the olfactory bulb (OBG) are a promising example because they promote axon regeneration in the CNS.
In an experiment using paraplegic rats, it was found that 8 months after a transplant treatment in a transected spinal chord using OBS, axon regeneration was taking place and sensorial and motor recovery was perceived in behavioural tests. The investigation recently published in the Journal of Physiology (London) [J Physiol 586.10 (2008) pp 2593 2610], with the collaboration of scientists from the "Centro de BiologГa Molecular Severo Ochoa" (CSIC-UAM), CГіrdoba University, and the "Instituto de Biomedicina de Valencia" (CSIC), has analysed for the first time the muscular characteristics of paraplegic animals treated with an OBG transplant and compared them with those of untreated paraplegic animals and healthy control animals. The study exhibits a high correlation between the functional capability shown by the animals in behavioural tests and some biochemical parameters. The parameters measured differentiate the muscular characteristics of paraplegic and healthy animals and they established that animals treated with the transplant had more similar characteristics to the healthy animals than the untreated paraplegic animals. In spite of the global effect of OBG transplants, only 3 of the 9 treated animals (and none of the untreated) showed near normal muscle characteristics. This could imply that maintaining the muscular phenotype might rely on the interaction between the transplanted cells and other factors. One the possible factors that affect the result could be the physical exercise to which the animals were subjected. This could be significant since it is well known that rehabilitation treatment aids regenerative therapies. Both voluntary and assisted exercise stimulates synaptic plasticity and the regenerative capabilities of neurons of the CNS as well as re-establishes adequate trophic factors. The role of the OBG in establishing a nurturing cellular environment for axon regeneration could induce adaptation in the local spinal circuits that favours the conservation of muscular properties and automatic contractions even while the damaged neural pathways are not fully recovered.
MADRIMASD
C/ AlcalГЎ 30-32, 3ВЄplanta
Madrid
madrimasd
Spinal chord injuries represent a serious and irreversible handicap that is sadly frequent in our society. Because of the permanent break in the nervous connections between the brain and the organs and muscles, such injuries impair their movement inducing atrophy and deterioration while they disturb organic functions.
The pioneering studies carried out by Santiago RamГіn y Cajal established that while nerve cells from the peripheral nervous system (PNS) have the capacity to repair themselves, the same does not apply to adult brain cells and spinal cord cells from the central nervous system (CNS). The difference is not in the nerve cells themselves but in the cellular enviroment that gives them support - the glial cells. These cells are involved in the transmision of nerve impulses and produce myelin. Schwann cells (a variety of glial cell) in the peripheral nervous system (PNS) provide factors that contribute to the regeneration of the axons whereas the glia of the CNS do not have such a nurturing role. For this reason, one of the strategic experimental approaches for the regeneration of spinal chord neurons consists in altering their cellular enviroment by introducing cells that create a supportive environment for axon regeneration in the damaged area. The glial cells that surround the axons in the olfactory bulb (OBG) are a promising example because they promote axon regeneration in the CNS.
In an experiment using paraplegic rats, it was found that 8 months after a transplant treatment in a transected spinal chord using OBS, axon regeneration was taking place and sensorial and motor recovery was perceived in behavioural tests. The investigation recently published in the Journal of Physiology (London) [J Physiol 586.10 (2008) pp 2593 2610], with the collaboration of scientists from the "Centro de BiologГa Molecular Severo Ochoa" (CSIC-UAM), CГіrdoba University, and the "Instituto de Biomedicina de Valencia" (CSIC), has analysed for the first time the muscular characteristics of paraplegic animals treated with an OBG transplant and compared them with those of untreated paraplegic animals and healthy control animals. The study exhibits a high correlation between the functional capability shown by the animals in behavioural tests and some biochemical parameters. The parameters measured differentiate the muscular characteristics of paraplegic and healthy animals and they established that animals treated with the transplant had more similar characteristics to the healthy animals than the untreated paraplegic animals. In spite of the global effect of OBG transplants, only 3 of the 9 treated animals (and none of the untreated) showed near normal muscle characteristics. This could imply that maintaining the muscular phenotype might rely on the interaction between the transplanted cells and other factors. One the possible factors that affect the result could be the physical exercise to which the animals were subjected. This could be significant since it is well known that rehabilitation treatment aids regenerative therapies. Both voluntary and assisted exercise stimulates synaptic plasticity and the regenerative capabilities of neurons of the CNS as well as re-establishes adequate trophic factors. The role of the OBG in establishing a nurturing cellular environment for axon regeneration could induce adaptation in the local spinal circuits that favours the conservation of muscular properties and automatic contractions even while the damaged neural pathways are not fully recovered.
MADRIMASD
C/ AlcalГЎ 30-32, 3ВЄplanta
Madrid
madrimasd
On The Threshold Of A New Chapter In Biological Imaging
The Springer journal Analytical and Bioanalytical Chemistry (ABC) has chosen the chemist Wei Sun (26) as the recipient of its Best Paper Award 2008. Sun is the lead author of a paper in ABC on developing advanced tools for in vivo biological imaging. The award, including the 1,000 euro prize, was created by Springer to help exceptional young scientists establish their research careers.
Sun's paper demonstrates the excellent resolving power of differential interference contrast (DIC) in providing depth-resolved information in a living system in real time. DIC microscopy, a wide-field optical technique based on light interference, can provide excellent resolution and detectability for nonintrusive observation of biological processes. Although DIC microscopes are commercially available, their unique capabilities for biological imaging have rarely been exploited. Sun and his team recorded a complete endocytosis process of a single mesoporous silica nanoparticle (MSN) by a living human lung cancer cell. For the first time, valuable three-dimensional information on particle diffusion and vesicle formation and transport were extracted as a function of time. This approach can be employed to study real-time drug release events in living cells when MSNs or other nanoparticles are used as drug delivery vectors.
Wei Sun is a Ph.D. candidate in analytical chemistry at Iowa State University, USA. He received his B.S. in polymer science and engineering in 2004 from the University of Science and Technology of China in Hefei, Anhui Province. His research projects include the application of differential interference contrast microscopy in analytical chemistry as well as scanning-angle evanescent field microscopy.
Dr. Sylvia Daunert, Editor of Analytical and Bioanalytical Chemistry, said, "The work of Wei Sun under the guidance of Professors Ed Yeung and Ning Fang represents an important contribution to the field of real-time in vivo imaging microscopy that, undoubtedly, will help shed light into molecular events. The keen competition and the quality of the manuscripts considered for this year's award are a homage to the excellent research performed by Wei Sun."
Analytical and Bioanalytical Chemistry is an international journal dealing with all aspects of analytical and bioanalytical sciences. The journal covers all fields of pure and applied analytical chemistry and bioanalysis, including topics at their interfaces with life and health sciences, engineering and materials sciences, environmental science, earth sciences and others. With a rating of 2.867, ABC has seen the highest growth of the Impact Factor over the last five years among related journals of analytical chemistry.
Springer is the second-largest publisher of journals in the science, technology, and medicine (STM) sector and the largest publisher of STM books. Springer is part of Springer Science+Business Media, one of the world's leading suppliers of scientific and specialist literature. The group publishes over 1,700 journals and more than 5,500 new books a year, as well as the largest STM eBook Collection worldwide. Springer has operations in over 20 countries in Europe, the USA, and Asia, and some 5,000 employees.
The article is freely available online on SpringerLink at
springerlink/content/?k=10.1007%2fs00216-008-2162-1.
Source: Joan Robinson
Springer
Sun's paper demonstrates the excellent resolving power of differential interference contrast (DIC) in providing depth-resolved information in a living system in real time. DIC microscopy, a wide-field optical technique based on light interference, can provide excellent resolution and detectability for nonintrusive observation of biological processes. Although DIC microscopes are commercially available, their unique capabilities for biological imaging have rarely been exploited. Sun and his team recorded a complete endocytosis process of a single mesoporous silica nanoparticle (MSN) by a living human lung cancer cell. For the first time, valuable three-dimensional information on particle diffusion and vesicle formation and transport were extracted as a function of time. This approach can be employed to study real-time drug release events in living cells when MSNs or other nanoparticles are used as drug delivery vectors.
Wei Sun is a Ph.D. candidate in analytical chemistry at Iowa State University, USA. He received his B.S. in polymer science and engineering in 2004 from the University of Science and Technology of China in Hefei, Anhui Province. His research projects include the application of differential interference contrast microscopy in analytical chemistry as well as scanning-angle evanescent field microscopy.
Dr. Sylvia Daunert, Editor of Analytical and Bioanalytical Chemistry, said, "The work of Wei Sun under the guidance of Professors Ed Yeung and Ning Fang represents an important contribution to the field of real-time in vivo imaging microscopy that, undoubtedly, will help shed light into molecular events. The keen competition and the quality of the manuscripts considered for this year's award are a homage to the excellent research performed by Wei Sun."
Analytical and Bioanalytical Chemistry is an international journal dealing with all aspects of analytical and bioanalytical sciences. The journal covers all fields of pure and applied analytical chemistry and bioanalysis, including topics at their interfaces with life and health sciences, engineering and materials sciences, environmental science, earth sciences and others. With a rating of 2.867, ABC has seen the highest growth of the Impact Factor over the last five years among related journals of analytical chemistry.
Springer is the second-largest publisher of journals in the science, technology, and medicine (STM) sector and the largest publisher of STM books. Springer is part of Springer Science+Business Media, one of the world's leading suppliers of scientific and specialist literature. The group publishes over 1,700 journals and more than 5,500 new books a year, as well as the largest STM eBook Collection worldwide. Springer has operations in over 20 countries in Europe, the USA, and Asia, and some 5,000 employees.
The article is freely available online on SpringerLink at
springerlink/content/?k=10.1007%2fs00216-008-2162-1.
Source: Joan Robinson
Springer
Schizophrenia Mouse Model With Genetic On-Off Switch
Scientists at Johns Hopkins have developed a mouse model for schizophrenia in which a mutated gene linked to schizophrenia can be turned on or off at will.
The researchers developed the transgenic mouse by inserting the gene for mutant Disrupted-In-Schizophrenia-1 (DISC-1) into a normal mouse, along with a promoter that enables the gene to be switched on or off. Mutant DISC-1 was previously identified in a Scottish family with a strong history of schizophrenia and related mental disorders.
The study was performed in the laboratory of Mikhail Pletnikov, M.D., Ph.D., in the Department of Psychiatry and Behavioral Sciences.
Last month, another Hopkins researcher in the Department of Psychiatry and Behavioral Sciences, Akira Sawa, M.D., Ph.D., and his team, developed a comparable mutant DISC-1 mouse model for schizophrenia. Pletnikov's is the first model in which researchers can control the expression of this mutated gene, and the model illuminates additional aspects of the biology of the disorder.
Researchers turn off the mutant DISC-1 gene by feeding the mice a nontoxic chemical that controls a genetically engineered switch mechanism to turn on production of the DISC-1 protein.
The study, which appears in the September issue of Molecular Psychiatry, showed that male mice with the mutant DISC-1 gene were significantly more active than control mice without the mutated gene. The investigators also observed that the male mutant DISC-1 mice had altered social interactions with other mice and were more aggressive. Females with the mutated gene had a more difficult time remembering how to navigate a maze.
"Schizophrenia is a human disorder, so we cannot say the symptoms displayed by the mouse model are schizophrenic. But they are in line with the kinds of behavioral changes we see in humans with schizophrenia," says Pletnikov.
The research showed other strong similarities between the mouse model and humans with schizophrenia.
Examination of the brains of the mutated mice using MRI scans showed significant enlargement of the lateral ventricles (fluid-filled areas in the front of the brain), very similar to MRI findings in humans with schizophrenia.
Tissue culture studies showed that there was an abnormality in the development of brain cells in the part of the brain generally associated with schizophrenia. Also, the transgenic mice had abnormal levels of the proteins 25 kDa synaptosome-associated protein (SNAP-25) and lissencephaly-1 (LIS-1).
It's known from previous research that SNAP 25 and LIS-1 are key players in brain cell development and maturation, and several prior studies of brain tissue from humans with schizophrenia showed abnormal levels of SNAP-25.
"This model supports the idea that schizophrenia is a disease associated with abnormal brain development," says senior co-author of the study Christopher Ross, M.D., Ph.D., of the Department of Psychiatry and Behavioral Sciences. "And being able to regulate the timing of expression of the mutant protein provides an opportunity to study the timing and mechanism of specific abnormalities -- a tool that could eventually lead to the discovery of drugs that could potentially control or even prevent the disease."
Additional authors of the study from Johns Hopkins include Yavuz Ayhan, M.D., Olga Nikolskaia, M.D., Yanqun Xu, M.S., and Timothy H. Moran, Ph.D., of the Department of Psychiatry and Behavioral Sciences; and Hao Huang, Ph.D., and Susumu Mori, Ph.D., of the Department of Radiology-Magnetic Resonance Research.
This study was supported by the Stanley Medical Research Institute, a NARSAD Distinguished Investigator Award, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
Source: Christen Brownlee
Johns Hopkins Medical Institutions
The researchers developed the transgenic mouse by inserting the gene for mutant Disrupted-In-Schizophrenia-1 (DISC-1) into a normal mouse, along with a promoter that enables the gene to be switched on or off. Mutant DISC-1 was previously identified in a Scottish family with a strong history of schizophrenia and related mental disorders.
The study was performed in the laboratory of Mikhail Pletnikov, M.D., Ph.D., in the Department of Psychiatry and Behavioral Sciences.
Last month, another Hopkins researcher in the Department of Psychiatry and Behavioral Sciences, Akira Sawa, M.D., Ph.D., and his team, developed a comparable mutant DISC-1 mouse model for schizophrenia. Pletnikov's is the first model in which researchers can control the expression of this mutated gene, and the model illuminates additional aspects of the biology of the disorder.
Researchers turn off the mutant DISC-1 gene by feeding the mice a nontoxic chemical that controls a genetically engineered switch mechanism to turn on production of the DISC-1 protein.
The study, which appears in the September issue of Molecular Psychiatry, showed that male mice with the mutant DISC-1 gene were significantly more active than control mice without the mutated gene. The investigators also observed that the male mutant DISC-1 mice had altered social interactions with other mice and were more aggressive. Females with the mutated gene had a more difficult time remembering how to navigate a maze.
"Schizophrenia is a human disorder, so we cannot say the symptoms displayed by the mouse model are schizophrenic. But they are in line with the kinds of behavioral changes we see in humans with schizophrenia," says Pletnikov.
The research showed other strong similarities between the mouse model and humans with schizophrenia.
Examination of the brains of the mutated mice using MRI scans showed significant enlargement of the lateral ventricles (fluid-filled areas in the front of the brain), very similar to MRI findings in humans with schizophrenia.
Tissue culture studies showed that there was an abnormality in the development of brain cells in the part of the brain generally associated with schizophrenia. Also, the transgenic mice had abnormal levels of the proteins 25 kDa synaptosome-associated protein (SNAP-25) and lissencephaly-1 (LIS-1).
It's known from previous research that SNAP 25 and LIS-1 are key players in brain cell development and maturation, and several prior studies of brain tissue from humans with schizophrenia showed abnormal levels of SNAP-25.
"This model supports the idea that schizophrenia is a disease associated with abnormal brain development," says senior co-author of the study Christopher Ross, M.D., Ph.D., of the Department of Psychiatry and Behavioral Sciences. "And being able to regulate the timing of expression of the mutant protein provides an opportunity to study the timing and mechanism of specific abnormalities -- a tool that could eventually lead to the discovery of drugs that could potentially control or even prevent the disease."
Additional authors of the study from Johns Hopkins include Yavuz Ayhan, M.D., Olga Nikolskaia, M.D., Yanqun Xu, M.S., and Timothy H. Moran, Ph.D., of the Department of Psychiatry and Behavioral Sciences; and Hao Huang, Ph.D., and Susumu Mori, Ph.D., of the Department of Radiology-Magnetic Resonance Research.
This study was supported by the Stanley Medical Research Institute, a NARSAD Distinguished Investigator Award, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
Source: Christen Brownlee
Johns Hopkins Medical Institutions
How Drug That Blocks Cholesterol Absorption From The Diet Works
A new study in the June issue of Cell Metabolism, a Cell Press publication, sheds light on the action of the drug ezetimibe (trade name Zetia), which is used to treat high cholesterol. Ezetimibe is unique among cholesterol-lowering drugs in that it works by cutting the amount of cholesterol taken in from the diet rather than by blocking cholesterol's manufacture in the body.
Earlier studies had suggested that ezetimibe acts on an intestinal and liver protein recently found to play a critical role in cholesterol absorption. Now, the researchers reveal how that protein known as Niemann-Pick C1-like 1 (NPC1L1) carries cholesterol into the cell. They also show that ezetimibe bars NPC1L1's entry into the cell, thereby keeping cholesterol at bay.
"This is a breakthrough in terms of understanding how cholesterol is absorbed," said Bao-Liang Song of Shanghai Institutes for Biological Sciences. "Now we see how NPC1L1 is recycled between the cell surface and vesicles [inside the cell] and how it takes in cholesterol."
The findings might also have important implications for the search for new cholesterol absorption inhibitors, he added. "If we can uncover the players, we can try to identify new small molecules to interfere with the process."
Despite its bad reputation as a major risk factor for coronary heart disease, cholesterol is an essential component of most biological membranes and is the precursor for synthesis of steroid hormones and bile acids produced by the liver to break down fat. Almost every kind of mammalian cell can synthesize cholesterol, but the process is an energy-intensive one. Therefore, mammals including humans obtain significant amounts of cholesterol from their diets.
Four years ago, scientists identified NPC1L1 as a critical player in cholesterol's absorption. Researchers also found that mice lacking NPC1L1 stop responding to ezetimibe. While there were clues that the drug interacts directly with the cholesterol absorption protein, the details remained unclear.
Song's group now finds that cholesterol specifically encourages cells to engulf and internalize NPC1L1 in a process known as endocytosis. In that process, part of the cell membrane pinches off to form a vesicle containing the protein.
By preventing NPC1L1's entry into the cell, the researchers showed they could dramatically reduce the amount of cholesterol taken up by cells. Ezetimibe accomplishes that by preventing NPC1L1 from incorporating into vesicles.
Although ezetimibe can dramatically decrease blood cholesterol concentrations in some people, it is barely effective in others, the researchers said.
" Therefore," Song said, "there is an urgent need for more cholesterol uptake inhibitory drugs. Our work provides the molecular basis for developing additional cholesterol absorption inhibitors. Moreover, the cell-based assay that we have established can potentially be used to screen for novel inhibitors of NPC1L1 endocytosis, which will block cholesterol uptake eventually."
The researchers include Liang Ge, Jing Wang, Wei Qi, Hong-Hua Miao, Jian Cao, Yu-Xiu Qu, Bo-Liang Li, and Bao-Liang Song, of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Shanghai Science and Technology Committee.
Ge et al.: "The Cholesterol Absorption Inhibitor Ezetimibe Acts by Blocking the Sterol-Induced Internalization of NPC1L1." Publishing in Cell Metabolism 7, 508-519, June 2008. DOI 10.1016/j.cmet.2008.04.001 cellmetabolism
Author Contact: Song, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences in Shanghai, China
Source: Cathleen Genova
Cell Press
Earlier studies had suggested that ezetimibe acts on an intestinal and liver protein recently found to play a critical role in cholesterol absorption. Now, the researchers reveal how that protein known as Niemann-Pick C1-like 1 (NPC1L1) carries cholesterol into the cell. They also show that ezetimibe bars NPC1L1's entry into the cell, thereby keeping cholesterol at bay.
"This is a breakthrough in terms of understanding how cholesterol is absorbed," said Bao-Liang Song of Shanghai Institutes for Biological Sciences. "Now we see how NPC1L1 is recycled between the cell surface and vesicles [inside the cell] and how it takes in cholesterol."
The findings might also have important implications for the search for new cholesterol absorption inhibitors, he added. "If we can uncover the players, we can try to identify new small molecules to interfere with the process."
Despite its bad reputation as a major risk factor for coronary heart disease, cholesterol is an essential component of most biological membranes and is the precursor for synthesis of steroid hormones and bile acids produced by the liver to break down fat. Almost every kind of mammalian cell can synthesize cholesterol, but the process is an energy-intensive one. Therefore, mammals including humans obtain significant amounts of cholesterol from their diets.
Four years ago, scientists identified NPC1L1 as a critical player in cholesterol's absorption. Researchers also found that mice lacking NPC1L1 stop responding to ezetimibe. While there were clues that the drug interacts directly with the cholesterol absorption protein, the details remained unclear.
Song's group now finds that cholesterol specifically encourages cells to engulf and internalize NPC1L1 in a process known as endocytosis. In that process, part of the cell membrane pinches off to form a vesicle containing the protein.
By preventing NPC1L1's entry into the cell, the researchers showed they could dramatically reduce the amount of cholesterol taken up by cells. Ezetimibe accomplishes that by preventing NPC1L1 from incorporating into vesicles.
Although ezetimibe can dramatically decrease blood cholesterol concentrations in some people, it is barely effective in others, the researchers said.
" Therefore," Song said, "there is an urgent need for more cholesterol uptake inhibitory drugs. Our work provides the molecular basis for developing additional cholesterol absorption inhibitors. Moreover, the cell-based assay that we have established can potentially be used to screen for novel inhibitors of NPC1L1 endocytosis, which will block cholesterol uptake eventually."
The researchers include Liang Ge, Jing Wang, Wei Qi, Hong-Hua Miao, Jian Cao, Yu-Xiu Qu, Bo-Liang Li, and Bao-Liang Song, of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Shanghai Science and Technology Committee.
Ge et al.: "The Cholesterol Absorption Inhibitor Ezetimibe Acts by Blocking the Sterol-Induced Internalization of NPC1L1." Publishing in Cell Metabolism 7, 508-519, June 2008. DOI 10.1016/j.cmet.2008.04.001 cellmetabolism
Author Contact: Song, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences in Shanghai, China
Source: Cathleen Genova
Cell Press
Develolpment Of Micrometer-Sized Capsules To Safely Deliver Drugs Inside Living Cells Could Mean An End To Regular Dosing
Scientists working at Queen Mary, University of London, have developed micrometer-sized capsules to safely deliver drugs inside living cells.
In the future, this technique could allow full courses of prescription drugs to be effectively 'shrink-wrapped' and buried under the skin or inside the body.
These "micro shuttles" can be loaded with a specific dose of medication and be opened remotely, releasing their contents.
Using this new technique, drugs - like insulin for managing diabetes - could be implanted inside the body for use when they are needed. Their release could then be prompted by a biological trigger like a drop in blood sugar levels, or activated manually with a pulse of light.
PhD student Matthieu BГ©dard and Prof Gleb Sukhorukov of Queen Mary's School of Engineering and Materials Science have proved this new technique to work in living tissue by delivering fluorescent test-molecules in light-activated capsules.
The work is in partnership with Dr Sebastian Springer at Jacobs University in Bremen and colleagues from the Max Plank Institute of Colloids. The findings are reported in the October issue of Small (DOI: 10.1002/smll.200900809).
Matthieu BГ©dard said: "The main advantage of using such microcapsules is that they can be designed to be very stable inside the body, protecting their contents. This is particularly important for the many medications that are rapidly degraded or altered by the body. These capsules can be used to 'store' drugs in the body for later use."
The capsules, which have a diameter of two micrometers (about the size of a bacterium), are built by wrapping strands of a metabolism-resistant material around spherical particles, which are then dissolved in acid, leaving behind an empty container.
To fill the capsules, the scientists heat them in a solution that contains the desired drug compound. This makes them shrink and traps some of the solution and compound inside.
The loaded capsules are introduced into live cells by a technique known as electroporation - a tiny electric shock - which makes the cell walls permeable for micrometer-sized particles. The cells are unharmed by this treatment and retain the capsules.
In this experiment, the capsules were exposed to an infra-red laser beam that does not affect the cell but is picked up by nano-gold particles in the capsule walls, changing their structure and releasing the micro shuttle contents.
Prof Gleb Sukhorukov said: "This new technique could have many biological applications, including delivering DNA into cells for gene therapy. The capsules could also be filled in with magnetic particles that collect and extract miniscule samples from inside cells. Other applications could see patients needing internal medication after surgery being administered drugs without the need for further invasive procedures or hospital visits.
"However, there are still questions about how to direct the capsules to the right cells as well as finding a way to make capsules that are safe for human use. It is possible that we will see useful applications for this technology being tested in the next five years."
Source:
Simon Levey
Queen Mary, University of London
In the future, this technique could allow full courses of prescription drugs to be effectively 'shrink-wrapped' and buried under the skin or inside the body.
These "micro shuttles" can be loaded with a specific dose of medication and be opened remotely, releasing their contents.
Using this new technique, drugs - like insulin for managing diabetes - could be implanted inside the body for use when they are needed. Their release could then be prompted by a biological trigger like a drop in blood sugar levels, or activated manually with a pulse of light.
PhD student Matthieu BГ©dard and Prof Gleb Sukhorukov of Queen Mary's School of Engineering and Materials Science have proved this new technique to work in living tissue by delivering fluorescent test-molecules in light-activated capsules.
The work is in partnership with Dr Sebastian Springer at Jacobs University in Bremen and colleagues from the Max Plank Institute of Colloids. The findings are reported in the October issue of Small (DOI: 10.1002/smll.200900809).
Matthieu BГ©dard said: "The main advantage of using such microcapsules is that they can be designed to be very stable inside the body, protecting their contents. This is particularly important for the many medications that are rapidly degraded or altered by the body. These capsules can be used to 'store' drugs in the body for later use."
The capsules, which have a diameter of two micrometers (about the size of a bacterium), are built by wrapping strands of a metabolism-resistant material around spherical particles, which are then dissolved in acid, leaving behind an empty container.
To fill the capsules, the scientists heat them in a solution that contains the desired drug compound. This makes them shrink and traps some of the solution and compound inside.
The loaded capsules are introduced into live cells by a technique known as electroporation - a tiny electric shock - which makes the cell walls permeable for micrometer-sized particles. The cells are unharmed by this treatment and retain the capsules.
In this experiment, the capsules were exposed to an infra-red laser beam that does not affect the cell but is picked up by nano-gold particles in the capsule walls, changing their structure and releasing the micro shuttle contents.
Prof Gleb Sukhorukov said: "This new technique could have many biological applications, including delivering DNA into cells for gene therapy. The capsules could also be filled in with magnetic particles that collect and extract miniscule samples from inside cells. Other applications could see patients needing internal medication after surgery being administered drugs without the need for further invasive procedures or hospital visits.
"However, there are still questions about how to direct the capsules to the right cells as well as finding a way to make capsules that are safe for human use. It is possible that we will see useful applications for this technology being tested in the next five years."
Source:
Simon Levey
Queen Mary, University of London
First cloned pet delivered by a US company
The first cloned-to-order pet has been delivered by a US company, reigniting debate over the ethics of commercial
cloning.
The 9-week-old kitten, named Little Nicky, was cloned for a woman in Texas, to replace a 17-year-old pet cat called Nicky,
which died in 2003. She paid for $50,000 for her new pet.
But experts warn that cloning will never produce a perfect replica of any animal is also associated with health problems in
later life. US Animal welfare groups have also criticised pet cloning, noting that that thousands of unwanted cats and dogs
have to be euthanised every year.
Little Nicky was cloned by Genetic Savings and Clone, based in Sausalito, California, US, which produced the first ever clone
of a domestic cat in December 2001. The company hopes to have produced a cloned-to-order dog by May 2005.
Scientists have cloned many different animals in the laboratory, including sheep, rabbits, goats, pigs and horses. Prized
cattle can also be cloned-to-order for around $20,000 each. But Little Nicky is the first clone to be sold as a pet and could
mark the start of a lucrative business………..
CONTINUES……….newscientist
cloning.
The 9-week-old kitten, named Little Nicky, was cloned for a woman in Texas, to replace a 17-year-old pet cat called Nicky,
which died in 2003. She paid for $50,000 for her new pet.
But experts warn that cloning will never produce a perfect replica of any animal is also associated with health problems in
later life. US Animal welfare groups have also criticised pet cloning, noting that that thousands of unwanted cats and dogs
have to be euthanised every year.
Little Nicky was cloned by Genetic Savings and Clone, based in Sausalito, California, US, which produced the first ever clone
of a domestic cat in December 2001. The company hopes to have produced a cloned-to-order dog by May 2005.
Scientists have cloned many different animals in the laboratory, including sheep, rabbits, goats, pigs and horses. Prized
cattle can also be cloned-to-order for around $20,000 each. But Little Nicky is the first clone to be sold as a pet and could
mark the start of a lucrative business………..
CONTINUES……….newscientist
Dr. Alexander Varshavsky And Dr. Harmit Malik Awarded Vilcek Prizes In Biomedical Science
The Vilcek Foundation is pleased to announce the granting of the 2010 Vilcek Prize for Biomedical Science to Dr. Alexander Varshavsky, the Howard & Gwen Laurie Smits Professor of Cell Biology at California Institute of Technology, for elucidating the process and biological significance of regulated protein degradation in living cells. Another Vilcek Prize, for Creative Promise, is awarded annually to a scientist aged 38 years or younger. It will be given to Dr. Harmit Malik, Associate Member of the Fred Hutchinson Cancer Research Center, for his research on the co-evolution of humans and diseases. The Vilcek Prize is a cash award of $50,000 and an individually designed trophy; the Vilcek Prize for Creative Promise is a cash award of $25,000. Created by Stefan Sagmeister, the trophy is a 12-inch spire, reflecting the upward journey of the immigrant experience in the United States. Both prizes are awarded only to foreign-born American citizens to reflect the guiding philosophy, values, and mission of the Vilcek Foundation and its founders - Dr. Jan and Marica Vilcek - who immigrated to this country from Czechoslovakia in the 1960's.
The Vilcek Prize in Biomedical Science has been awarded annually since 2006 to an established biomedical scientist whose work has profoundly advanced science over the course of his or her career. Dr. Varshavsky's research on the ubiquitin system led to the discovery of its fundamentally important biological functions in living cells, demonstrating that the regulated protein degradation underlies major physiological processes. Today, the study of ubiquitin has major implications for research into the causes of birth defects, neuro-degenerative syndromes, cancer, and immune disorders. As a pioneer and leader in the field of ubiquitin research who has ushered it into the age of molecular genetics, Dr. Varshavsky has also helped establish this field as one of the most important and "ubiquitous" in biomedical science, a point of convergence for disparate disciplines.
Since 2009, the Vilcek Foundation also awards a Vilcek Prize for Creative Promise to a research scientist who has demonstrated significant creativity and originality in the early stages of his/her career. Dr. Harmit Malik studies genetic conflict, battles raging within a cell's nucleus as genes compete for evolutionary dominance. He uses biochemistry and genomics to study the causes and consequences of these genetic conflicts in yeast, fruit flies and other model organisms. This original and imaginative approach to genetic conflict has led to new ways of examining why humans are susceptible to cancer and other diseases, as well as to the development of a new field called paleovirology - the study of ancient viruses.
"Both Dr. Varshavsky and Dr. Malik have impacted biomedical science through their innovative, breakthrough research," said Dr. Jan Vilcek, President of the Vilcek Foundation and renowned microbiologist at NYU Langone Medical Center. "My wife Marica and I are pleased to honor them - not only for their extraordinary achievements in the field of biomedical science, but also as American immigrants who have made important contributions to society."
Nobel Laureate Dr. David Baltimore will present Dr. Varshavsky and Dr. Malik with these awards at the April 7 invitation-only dinner at the Mandarin Oriental Hotel in the company of 250 guests from the worlds of science, the arts, business, and society.
Source:
Beth Amorosi
Vilcek Foundation
The Vilcek Prize in Biomedical Science has been awarded annually since 2006 to an established biomedical scientist whose work has profoundly advanced science over the course of his or her career. Dr. Varshavsky's research on the ubiquitin system led to the discovery of its fundamentally important biological functions in living cells, demonstrating that the regulated protein degradation underlies major physiological processes. Today, the study of ubiquitin has major implications for research into the causes of birth defects, neuro-degenerative syndromes, cancer, and immune disorders. As a pioneer and leader in the field of ubiquitin research who has ushered it into the age of molecular genetics, Dr. Varshavsky has also helped establish this field as one of the most important and "ubiquitous" in biomedical science, a point of convergence for disparate disciplines.
Since 2009, the Vilcek Foundation also awards a Vilcek Prize for Creative Promise to a research scientist who has demonstrated significant creativity and originality in the early stages of his/her career. Dr. Harmit Malik studies genetic conflict, battles raging within a cell's nucleus as genes compete for evolutionary dominance. He uses biochemistry and genomics to study the causes and consequences of these genetic conflicts in yeast, fruit flies and other model organisms. This original and imaginative approach to genetic conflict has led to new ways of examining why humans are susceptible to cancer and other diseases, as well as to the development of a new field called paleovirology - the study of ancient viruses.
"Both Dr. Varshavsky and Dr. Malik have impacted biomedical science through their innovative, breakthrough research," said Dr. Jan Vilcek, President of the Vilcek Foundation and renowned microbiologist at NYU Langone Medical Center. "My wife Marica and I are pleased to honor them - not only for their extraordinary achievements in the field of biomedical science, but also as American immigrants who have made important contributions to society."
Nobel Laureate Dr. David Baltimore will present Dr. Varshavsky and Dr. Malik with these awards at the April 7 invitation-only dinner at the Mandarin Oriental Hotel in the company of 250 guests from the worlds of science, the arts, business, and society.
Source:
Beth Amorosi
Vilcek Foundation
New Insight Into Diabetes From Sea-Creatures' Sex Protein
A genetic accident in the sea more than 500 million years ago has provided new insight into diabetes, according to research from Queen Mary, University of London.
Professor Maurice Elphick, from Queen Mary's School of Biological and Chemical Sciences, says his findings could help to explain a rare form of the disease that causes sufferers to urinate more than three litres every day.
As reported in the journal Gene, Professor Elphick has discovered that some marine animals produce 'NG peptides' - proteins that help the creatures release their eggs and sperm at the same time. Critically, it emerges that NG peptides are made by a gene very similar to the mutant gene that causes diabetes insipidus.
He says: "Genetic tests on patients with diabetes insipidus show their symptoms are caused by an inability to produce the hormone vasopressin, which tells the body how much urine to make.
"I have discovered that marine animals, like sea urchins and acorn worms, produce NG peptides in much the same way to how our brain cells produce vasopressin. This similarity can be traced back to a one-off genetic accident in one of our ancient sea-dwelling ancestors, when a gene for vasopressin-like molecules mutated and became associated with a gene for NG peptides."
Asked about the medical relevance of his discovery, Professor Elphick said: "By researching further into how animals like sea urchins produce NG peptides, we will understand better why the faulty human vasopressin gene can cause this form of diabetes in around 10,000 people in the UK."
Source:
Simon Levey
Queen Mary, University of London
Professor Maurice Elphick, from Queen Mary's School of Biological and Chemical Sciences, says his findings could help to explain a rare form of the disease that causes sufferers to urinate more than three litres every day.
As reported in the journal Gene, Professor Elphick has discovered that some marine animals produce 'NG peptides' - proteins that help the creatures release their eggs and sperm at the same time. Critically, it emerges that NG peptides are made by a gene very similar to the mutant gene that causes diabetes insipidus.
He says: "Genetic tests on patients with diabetes insipidus show their symptoms are caused by an inability to produce the hormone vasopressin, which tells the body how much urine to make.
"I have discovered that marine animals, like sea urchins and acorn worms, produce NG peptides in much the same way to how our brain cells produce vasopressin. This similarity can be traced back to a one-off genetic accident in one of our ancient sea-dwelling ancestors, when a gene for vasopressin-like molecules mutated and became associated with a gene for NG peptides."
Asked about the medical relevance of his discovery, Professor Elphick said: "By researching further into how animals like sea urchins produce NG peptides, we will understand better why the faulty human vasopressin gene can cause this form of diabetes in around 10,000 people in the UK."
Source:
Simon Levey
Queen Mary, University of London
New Electron Microscopy Images Reveal The Assembly Of HIV
Scientists at the European Molecular Biology Laboratory (EMBL) and the University Clinic Heidelberg, Germany, have produced a three-dimensional reconstruction of HIV (Human Immunodeficiency Virus), which shows the structure of the immature form of the virus at unprecedented detail. Immature HIV is a precursor of the infectious virus, which can cause AIDS. The study, published in the 22-26 June online edition of PNAS, describes how the protein coat that packages the virus' genetic material assembles in human cells. Drugs that block this assembly process and prevent the virus from maturing into its infectious form are considered a promising therapeutic approach.
HIV consists of an RNA molecule that carries the genetic information of the virus and is surrounded by protective protein and membrane layers. During infection the virus deposits its genetic material into a human cell where it reprogrammes the host cell machinery to generate many copies of the viral genome and initiates the production of a viral protein called Gag. In the immature virus, many copies of Gag interact to form a roughly spherical lattice that encloses the virus' genetic material. The virus then leaves the cell with the help of proteins of the host and infects new cells.
Using a method called cryoelectron tomography researchers in the groups of John Briggs at EMBL and Hans-Georg Kräusslich at the University Clinic Heidelberg generated the as yet highest resolution 3D computer reconstruction images of the immature Gag lattice. The results suggest a simple model of HIV formation in human cells: multiple Gag proteins interact to form a hexameric lattice that grows with an inherent curvature and that incorporates new proteins stochastically. Several further steps in which Gag is cleaved by an enzyme are necessary to transform this immature lattice into its mature, infectious form.
Briggs and his team are now working on producing an even higher resolution structure of the protein lattice to gain a more detailed understanding of the virus' assembly and maturation processes, which may eventually help to find weak points that could be targeted by drugs.
Cryoelectron tomography is a technique with which a sample is instantly frozen in its natural state and then examined with an electron microscope. Images are taken from different directions and assembled into an accurate 3D reconstruction by a computer.
Source: European Molecular Biology Laboratory (EMBL)
HIV consists of an RNA molecule that carries the genetic information of the virus and is surrounded by protective protein and membrane layers. During infection the virus deposits its genetic material into a human cell where it reprogrammes the host cell machinery to generate many copies of the viral genome and initiates the production of a viral protein called Gag. In the immature virus, many copies of Gag interact to form a roughly spherical lattice that encloses the virus' genetic material. The virus then leaves the cell with the help of proteins of the host and infects new cells.
Using a method called cryoelectron tomography researchers in the groups of John Briggs at EMBL and Hans-Georg Kräusslich at the University Clinic Heidelberg generated the as yet highest resolution 3D computer reconstruction images of the immature Gag lattice. The results suggest a simple model of HIV formation in human cells: multiple Gag proteins interact to form a hexameric lattice that grows with an inherent curvature and that incorporates new proteins stochastically. Several further steps in which Gag is cleaved by an enzyme are necessary to transform this immature lattice into its mature, infectious form.
Briggs and his team are now working on producing an even higher resolution structure of the protein lattice to gain a more detailed understanding of the virus' assembly and maturation processes, which may eventually help to find weak points that could be targeted by drugs.
Cryoelectron tomography is a technique with which a sample is instantly frozen in its natural state and then examined with an electron microscope. Images are taken from different directions and assembled into an accurate 3D reconstruction by a computer.
Source: European Molecular Biology Laboratory (EMBL)
Male Blue Monkeys Alarm Call In Response To Danger Experienced By Others
Primate vocal behaviour is often said to be biologically hard-wired. According to this idea, individuals produce calls from a limited repertoire, and mostly to evolutionarily important events, such as discovery of food or a predator.
In doing so, they are thought to have little or no awareness of their audience and how listeners might be affected by their calls. In this paper, we show that male blue monkeys of Budongo Forest, Uganda, adjust their own alarm call rates depending on the predator threat that other group members experience.
In playback experiments, males gave signficantly more alarm calls when their fellow group members were dangerously close to a suspected crowned eagle, compared to when they were further away.
Since this effect was independent of the calling male's own distance to the danger, the study provides some evidence that non-human primates are able to take others into account when producing vocalisations.
Royal Society journal Biology Letters
Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.
publishing.royalsociety/biologyletters
In doing so, they are thought to have little or no awareness of their audience and how listeners might be affected by their calls. In this paper, we show that male blue monkeys of Budongo Forest, Uganda, adjust their own alarm call rates depending on the predator threat that other group members experience.
In playback experiments, males gave signficantly more alarm calls when their fellow group members were dangerously close to a suspected crowned eagle, compared to when they were further away.
Since this effect was independent of the calling male's own distance to the danger, the study provides some evidence that non-human primates are able to take others into account when producing vocalisations.
Royal Society journal Biology Letters
Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.
publishing.royalsociety/biologyletters
Septic Shock Patients Offered New Hope
To help progress and financially back the drug's development, the Florey and Starfish Ventures, a leading Australian venture capital firm, have formed a start-up company, 'Nephrodynamics Pty Ltd'.
Septic shock can occur if a patient contracts a bacterial infection after surgery. It is the main cause of mortality in Intensive Care Units (ICUs) and has up to a 40% mortality rate.
Patients who experience acute kidney failure during septic shock can require dialysis for up to two weeks, which costs the national health budget $50 million annually.
Nephrodynamics's research has focused on treating kidney failure during and after septic shock, but the drug it is developing could eventually treat other causes of kidney failure.
Dr Clive May from the Howard Florey Institute said the mechanisms causing the blood flow changes in kidney failure were unknown.
"It is currently thought that blood flow to the kidneys is due to constriction of the blood vessels in the kidney but we have proven this theory incorrect.
"This discovery has helped us develop a drug that could be a kidney-saving therapy for septic shock patients," Dr May said.
Head of Research at the Austin Hospital's Intensive Care Unit, Prof Rinaldo Bellomo, said this drug could not only prevent kidney failure in patients with infection, but also in those with other causes of acute kidney injury.
"Kidney failure from septic shock has a high mortality rate and the current treatments are inadequate, so we urgently need a therapy to save the kidneys and lives of those who develop septic shock," Prof Bellomo said.
"The first stage of clinical trials soon to be conducted will give us an indication of the potential benefits of our new kidney protective septic shock treatment," he said.
The Howard Florey Institute is committed to translating its taxpayer-funded research into tangible public health outcomes to benefit all Australians.
Bringing together research and business to create companies such as Nephrodynamics accelerates drug development and supports Victoria's emerging biotechnology industry.
About the Howard Florey Institute
The Howard Florey Institute is Australia's leading brain research centre. Its scientists undertake clinical and applied research that can be developed into treatments to combat brain disorders, and new medical practices. Their discoveries will improve the lives of those directly, and indirectly, affected by brain and mind disorders in Australia, and around the world. The Florey's research areas cover a variety of brain and mind disorders including Parkinson's disease, stroke, motor neuron disease, addiction, epilepsy, multiple sclerosis, autism and dementia.
About Starfish Ventures
Established in 2001, Starfish Ventures is an Australian owned venture capital fund manager seeking superior returns through active investment in innovative technology companies. Starfish Ventures has over $150 million in funds under management and has made investments in over 20 companies to date. Starfish seeks investments in emerging Australian businesses across all technology sectors including, information and communications technology, biotechnology and life sciences, information and communications technology, industrial technology and material sciences. The team's track record includes Australian technology success stories ResMed, Moldflow, Preston Aviation Solution Engana and Sirtex Medical. Further information about Starfish Ventures can be found at starfishventures.au
Contact: Merrin Rafferty
Research Australia
Septic shock can occur if a patient contracts a bacterial infection after surgery. It is the main cause of mortality in Intensive Care Units (ICUs) and has up to a 40% mortality rate.
Patients who experience acute kidney failure during septic shock can require dialysis for up to two weeks, which costs the national health budget $50 million annually.
Nephrodynamics's research has focused on treating kidney failure during and after septic shock, but the drug it is developing could eventually treat other causes of kidney failure.
Dr Clive May from the Howard Florey Institute said the mechanisms causing the blood flow changes in kidney failure were unknown.
"It is currently thought that blood flow to the kidneys is due to constriction of the blood vessels in the kidney but we have proven this theory incorrect.
"This discovery has helped us develop a drug that could be a kidney-saving therapy for septic shock patients," Dr May said.
Head of Research at the Austin Hospital's Intensive Care Unit, Prof Rinaldo Bellomo, said this drug could not only prevent kidney failure in patients with infection, but also in those with other causes of acute kidney injury.
"Kidney failure from septic shock has a high mortality rate and the current treatments are inadequate, so we urgently need a therapy to save the kidneys and lives of those who develop septic shock," Prof Bellomo said.
"The first stage of clinical trials soon to be conducted will give us an indication of the potential benefits of our new kidney protective septic shock treatment," he said.
The Howard Florey Institute is committed to translating its taxpayer-funded research into tangible public health outcomes to benefit all Australians.
Bringing together research and business to create companies such as Nephrodynamics accelerates drug development and supports Victoria's emerging biotechnology industry.
About the Howard Florey Institute
The Howard Florey Institute is Australia's leading brain research centre. Its scientists undertake clinical and applied research that can be developed into treatments to combat brain disorders, and new medical practices. Their discoveries will improve the lives of those directly, and indirectly, affected by brain and mind disorders in Australia, and around the world. The Florey's research areas cover a variety of brain and mind disorders including Parkinson's disease, stroke, motor neuron disease, addiction, epilepsy, multiple sclerosis, autism and dementia.
About Starfish Ventures
Established in 2001, Starfish Ventures is an Australian owned venture capital fund manager seeking superior returns through active investment in innovative technology companies. Starfish Ventures has over $150 million in funds under management and has made investments in over 20 companies to date. Starfish seeks investments in emerging Australian businesses across all technology sectors including, information and communications technology, biotechnology and life sciences, information and communications technology, industrial technology and material sciences. The team's track record includes Australian technology success stories ResMed, Moldflow, Preston Aviation Solution Engana and Sirtex Medical. Further information about Starfish Ventures can be found at starfishventures.au
Contact: Merrin Rafferty
Research Australia
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