Researchers at the University of Pennsylvania School of Medicine have identified proteins in the rod and cones of the eye that could lead to the discovery of the genetic causes of a host of inherited eye diseases. The investigators hope to gain a clearer understanding of what goes wrong at the most basic level in these diseases that cause blindness and other disorders.
Specifically, they have identified and measured the types and amounts of proteins in the light-sensing parts of the eye's retina. These light-sensitive structures, called photoreceptor sensory cilia, enable the rod and cone cells of the retina to detect light. While the proteins of cilia in single-celled organisms have been studied, this is the first time that a comprehensive description of the proteins of a mammalian cilium used for movement and sensing has been determined.
"We want to understand how cilia work normally and how their function is disrupted in disease, because their dysfunction is such an important cause of disease," says senior author Eric A. Pierce, MD, PhD, Associate Professor of Ophthalmology at the F.M. Kirby Center for Molecular Ophthalmology at Penn. "One of the first steps to achieve this is to put together a complete parts list. Now that we have that, we can figure out how all 2000 proteins we've identified fit together correctly."
The study will appear in the August print issue of Molecular & Cellular Proteomics and has been pre-published online.
Cilia, specialized structures that extend from cells, have recently taken the spotlight in studying genetic diseases. They are commonly used by cells for movement or sensory purposes, and, in many cases with mammals, have been thought to be remnants of evolution without much purpose. But new research has shown that mutations in genes that encode the proteins of cilia are common causes of a host of genetic diseases, including inherited retinal diseases and polycystic kidney disease.
Cilia diseases can also affect multiple organ systems in such disorders as Bardet-Biedl Syndrome, which causes kidney disease, obesity, polydactyly, diabetes, and retinal degeneration; Senior-Loken Syndrome, which causes kidney disease and retinal degeneration; Joubert Syndrome, which causes neurological disease, kidney disease, and retinal degeneration; Usher Syndrome, which causes deafness and blindness; and Meckel Syndrome, which causes kidney disease and neural tube defects.
Lead author Qin Liu, MD, PhD, Research Assistant Professor and Pierce collaborated with a team at the Wistar Institute led by David Speicher to perform the analyses for this study. The researchers used mass spectrometry to identify and measure the amounts of proteins in mouse photoreceptor sensory cilia. They found many proteins in the cilia that had not been identified in photoreceptors before. This includes proteins involved in intraflagellar transport, which is a process that moves materials from the cell body into the cilia. Mutations in proteins associated with this transport system lead to a number of cilia-related diseases.
The investigators also found 60 proteins encoded by genes on chromosomes implicated in 23 inherited cilia-related disorders. Armed with this knowledge, researchers hope to be able to more quickly find the exact genetic mutations that cause these 23 cilia diseases, which include eye and kidney diseases, among others.
Pierce is a pediatric ophthalmologist who specializes in caring for children with inherited retinal degenerations. He says that about half of his patients with degenerative eye diseases have a type of disease that can be identified according to its genetic mutation. He believes that this research will help identify the genetic causes behind the other half of his patients' conditions.
"We're narrowing the field," says Pierce. "This research in and of itself can't find a cure, but it's a great start because it tells you what proteins to study."
Co-authors also include Edward N. Pugh Jr. from Penn; Glenn Tan, Natasha Levenkova, and John J. Rux of the Wistar Institute; and Tiansen Li of Harvard Medical School. The National Eye Institute, the F.M. Kirby Foundation, Foundation Fighting Blindness, Research to Prevent Blindness, the Rosanne H. Silbermann Foundation, the Mackall Foundation Trust, and the Commonwealth University Research Enhancement Program provided funding for this research.
PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
University of Pennsylvania School of Medicine
3600 Market St., Ste 240
Philadelphia, PA 19104
United States
med.upenn
суббота, 30 апреля 2011 г.
пятница, 29 апреля 2011 г.
Controlling Schistosomiasis: Buffalo Or Snails?
A parasitic infection common in China and Southeast Asia could be effectively reduced by controlling snail populations, according to research
published in PLoS Medicine.
Infection with schistosomes of various species affects some 200 million people worldwide, and can cause serious chronic illnesses, including liver
failure. Steven Riley of the University of Hong Kong and collaborators analyzed infection patterns of the parasitic worm Schistosoma japonicum in
fifty villages in Samar Province, the Philippines. Rates of infection among humans and animals have been found to differ among villages, and the
researchers developed a mathematical model incorporating fecal parasite test results from thousands of people and animals (including, cats, pigs,
dogs, water buffalo, and rats) to explain these differences.
Schistosomes are passed from mammals to fresh-water snails via feces, and then cycle back to infect mammals that contact water inhabited by infected
snails. Using the mathematical model, the team found that transmission from snails to mammals was a more important factor in explaining the
differences among villages than transmission from mammals to snails.
As with all scientific models, the findings of this one depend on the assumptions made to build the model. Nevertheless, the findings suggest that
interventions to reduce the size of the snail population and the exposure of mammals to parasite-containing water might reduce human infection levels
more effectively than interventions that interrupt other parts of the parasite's life cycle.
The results also indicate that the contribution of water buffaloes to human S. japonicum infection in the Philippines is not particularly important.
This finding contrasts with a recent study that identified water buffalo as the major mammalian reservoir for S. japonicum in China.
(who.int/bulletin/volumes/85/7/06-034033/en/index.html) , and suggests that further studies of the transmission of S. japonicum by water
buffalo are warranted before efforts are dedicated to treat or vaccinate water buffalo as a control measure against human S. japonicum infection.
In a related perspective article, Song Liang and Robert Spear, who were not involved in the study, discuss the findings and conclude that the
"modeling approach can be a useful tool in exploring schistosomiasis transmission in other settings, and may even apply to other macroparasites."
Click here to view article online.
About PLoS Medicine
PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of
human health and disease, together with commentary and analysis of important global health issues.
PLoS Medicine
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.
Public Library of Science
published in PLoS Medicine.
Infection with schistosomes of various species affects some 200 million people worldwide, and can cause serious chronic illnesses, including liver
failure. Steven Riley of the University of Hong Kong and collaborators analyzed infection patterns of the parasitic worm Schistosoma japonicum in
fifty villages in Samar Province, the Philippines. Rates of infection among humans and animals have been found to differ among villages, and the
researchers developed a mathematical model incorporating fecal parasite test results from thousands of people and animals (including, cats, pigs,
dogs, water buffalo, and rats) to explain these differences.
Schistosomes are passed from mammals to fresh-water snails via feces, and then cycle back to infect mammals that contact water inhabited by infected
snails. Using the mathematical model, the team found that transmission from snails to mammals was a more important factor in explaining the
differences among villages than transmission from mammals to snails.
As with all scientific models, the findings of this one depend on the assumptions made to build the model. Nevertheless, the findings suggest that
interventions to reduce the size of the snail population and the exposure of mammals to parasite-containing water might reduce human infection levels
more effectively than interventions that interrupt other parts of the parasite's life cycle.
The results also indicate that the contribution of water buffaloes to human S. japonicum infection in the Philippines is not particularly important.
This finding contrasts with a recent study that identified water buffalo as the major mammalian reservoir for S. japonicum in China.
(who.int/bulletin/volumes/85/7/06-034033/en/index.html) , and suggests that further studies of the transmission of S. japonicum by water
buffalo are warranted before efforts are dedicated to treat or vaccinate water buffalo as a control measure against human S. japonicum infection.
In a related perspective article, Song Liang and Robert Spear, who were not involved in the study, discuss the findings and conclude that the
"modeling approach can be a useful tool in exploring schistosomiasis transmission in other settings, and may even apply to other macroparasites."
Click here to view article online.
About PLoS Medicine
PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of
human health and disease, together with commentary and analysis of important global health issues.
PLoS Medicine
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical
literature a freely available public resource.
Public Library of Science
четверг, 28 апреля 2011 г.
Evolutionary Link To Modern-Day Obesity, Other Problems
That irresistible craving for a cheeseburger has its roots in the dramatic growth of the human brain and body that resulted from environmental changes some 2 million years ago.
Higher quality, nutritionally dense diets became necessary to fuel the high-energy demands of humans' exceptionally large brains and for developing the first rudimentary hunting and gathering economy.
But the transition from a subsistence to a modern, sedentary lifestyle has created energy imbalances that have increased rapidly -- evolutionarily speaking -- in recent years and now play a major role in obesity.
Activity patterns must get every bit as much attention as consumption of unhealthy foods in any attempt to reverse the modern-day permeations of an evolutionary trend that now contributes to obesity worldwide, according to William Leonard.
Leonard, chair and professor of anthropology at Northwestern University, discussed his work during the 2009 American Association for the Advancement of Science (AAAS) meeting in Chicago at a press briefing on Feb. 12 and during a symposium from 8:30 to 11:30 a.m. Feb. 13.
Two million years ago shifts in foraging behavior and dietary quality helped to provide the energy and nutrition to support the rapid evolutionary increases in both the brain and body sizes of our ancestors.
Today modern humans use nearly a quarter of their resting energy needs to feed our brains, considerably more than other primates (about 8 to 10 percent) or other mammals (3 to 5 percent). To support the high-energy costs of our large brains, humans consume diets that are much richer in calories and nutrients than those of other primates.
"While our large-bodied ape relatives -- chimps, gorillas and orangutans -- can subsist on leaves and fruit, we needed to consume meat and other energy-rich foods to support our metabolic demands," Leonard said.
Staple foods for all human societies are much more nutritionally dense than those of other large-bodied primates. "To obtain these higher-quality diets, our foraging ancestors would have had to have moved over larger areas than our ape relatives, requiring large activity budgets," he said.
But substantial reductions of intense physical activities for adults living a modern lifestyle in the industrialized world have dramatically lowered the metabolic costs of survival.
The differences between energy in and energy out widen as we increase the nutritional density of our diets while reducing the time and energy associated with obtaining food. "Think about our ancestors," Leonard said. "Human hunter-gatherers typically move 8 miles per day in the search for food. In contrast, we can simply pick up the phone to get a meal delivered to our door."
That decline in daily energy expenditures contributes not only to obesity, but also to other chronic diseases of the modern world, such as diabetes and cardiovascular disease. "In a sense, those modern diseases represent where we started early in our evolutionary history," Leonard said.
The data clearly suggest the obesity epidemic cannot be understood solely by looking at consumption, he stressed. "Throughout most of our evolutionary history, the acquisition of our high-quality diets required substantial expenditure of energy and movement over much larger areas than for other primates."
The imbalance between energy intake and energy expenditure today, Leonard concludes, is the root cause of obesity in the industrialized world.
American Association for the Advancement of Science (AAAS), Hyatt Regency Chicago, 151 E. Wacker Drive, Acapulco Room
(Leonard's AAAS talks will highlight the work that he and his colleagues -- Marcia L. Robertson, Josh Snodgrass, Mark V. Sorensen and Northwestern's Christopher Kuzawa --have been doing on the evolution of human nutritional requirements over the last 15 years. The work has been featured in prominent publications such as Scientific American and the Annual Review of Nutrition, and in books, recent and forthcoming, on the evolutionary perspectives on health and nutrition.)
Source: Pat Vaughan Tremmel
Northwestern University
Higher quality, nutritionally dense diets became necessary to fuel the high-energy demands of humans' exceptionally large brains and for developing the first rudimentary hunting and gathering economy.
But the transition from a subsistence to a modern, sedentary lifestyle has created energy imbalances that have increased rapidly -- evolutionarily speaking -- in recent years and now play a major role in obesity.
Activity patterns must get every bit as much attention as consumption of unhealthy foods in any attempt to reverse the modern-day permeations of an evolutionary trend that now contributes to obesity worldwide, according to William Leonard.
Leonard, chair and professor of anthropology at Northwestern University, discussed his work during the 2009 American Association for the Advancement of Science (AAAS) meeting in Chicago at a press briefing on Feb. 12 and during a symposium from 8:30 to 11:30 a.m. Feb. 13.
Two million years ago shifts in foraging behavior and dietary quality helped to provide the energy and nutrition to support the rapid evolutionary increases in both the brain and body sizes of our ancestors.
Today modern humans use nearly a quarter of their resting energy needs to feed our brains, considerably more than other primates (about 8 to 10 percent) or other mammals (3 to 5 percent). To support the high-energy costs of our large brains, humans consume diets that are much richer in calories and nutrients than those of other primates.
"While our large-bodied ape relatives -- chimps, gorillas and orangutans -- can subsist on leaves and fruit, we needed to consume meat and other energy-rich foods to support our metabolic demands," Leonard said.
Staple foods for all human societies are much more nutritionally dense than those of other large-bodied primates. "To obtain these higher-quality diets, our foraging ancestors would have had to have moved over larger areas than our ape relatives, requiring large activity budgets," he said.
But substantial reductions of intense physical activities for adults living a modern lifestyle in the industrialized world have dramatically lowered the metabolic costs of survival.
The differences between energy in and energy out widen as we increase the nutritional density of our diets while reducing the time and energy associated with obtaining food. "Think about our ancestors," Leonard said. "Human hunter-gatherers typically move 8 miles per day in the search for food. In contrast, we can simply pick up the phone to get a meal delivered to our door."
That decline in daily energy expenditures contributes not only to obesity, but also to other chronic diseases of the modern world, such as diabetes and cardiovascular disease. "In a sense, those modern diseases represent where we started early in our evolutionary history," Leonard said.
The data clearly suggest the obesity epidemic cannot be understood solely by looking at consumption, he stressed. "Throughout most of our evolutionary history, the acquisition of our high-quality diets required substantial expenditure of energy and movement over much larger areas than for other primates."
The imbalance between energy intake and energy expenditure today, Leonard concludes, is the root cause of obesity in the industrialized world.
American Association for the Advancement of Science (AAAS), Hyatt Regency Chicago, 151 E. Wacker Drive, Acapulco Room
(Leonard's AAAS talks will highlight the work that he and his colleagues -- Marcia L. Robertson, Josh Snodgrass, Mark V. Sorensen and Northwestern's Christopher Kuzawa --have been doing on the evolution of human nutritional requirements over the last 15 years. The work has been featured in prominent publications such as Scientific American and the Annual Review of Nutrition, and in books, recent and forthcoming, on the evolutionary perspectives on health and nutrition.)
Source: Pat Vaughan Tremmel
Northwestern University
среда, 27 апреля 2011 г.
Skin Color Studies On Tadpoles Lead To Cancer Advance
The humble tadpole could provide the key to developing effective anti-skin cancer drugs, thanks to a groundbreaking discovery by researchers at the University of East Anglia (UEA).
The scientists have identified a compound which, when introduced into Xenopus Laevis tadpoles, blocks the movement of the pigment cells that give the tadpoles their distinctive markings and which develop into the familiar greenish-brown of the adult frog.
It is the uncontrolled movement and growth of pigment cells (melanophore) in both tadpoles and humans that causes a particularly dangerous form of skin cancer. By blocking the migration of these cells, the development and spread of cancerous tumours can potentially be prevented.
Published in the Cell Press journal Chemistry & Biology, the findings are the culmination of several years' work by the UEA team. This unconventional study, which was initiated with funding from the UK Medical Research Council, identifies for the first time an effective new man-made MMP (metalloproteinase) inhibitor, known as 'NSC 84093'.
The work was led by the University of East Anglia, in partnership with the John Innes Centre (JIC) and Pfizer.
"This is an exciting advance with implications in the fight against cancer," said lead author Dr Grant Wheeler of UEA's School of Biological Sciences.
"The next step is to test the compound in other species and, in the longer term, embark on the development of new drugs to fight skin cancer in humans."
The species Xenopus Laevis (South African clawed frog) is more closely related to humans than one might expect. It only diverged from man 360 million years ago and has the same organs, molecules and physiology. This means that the same mechanisms are involved in causing cancer in both Xenopus tadpoles and humans.
Until the 1960s, Xenopus Laevis frogs were used as the main human pregnancy test. A woman's urine sample was injected into a live frog. If the urine contained the hCG (human chrionic gonadotropin) hormone, the frog would lay eggs within 24 hours, indicating that the woman was pregnant.
'A chemical genomic approach identifies matrix metallaoproteinases as playing an essential and specific role in Xenopus melanophore migration' by Grant Wheeler (UEA), Matthew Tomlinson (UEA), Carla Garcia-Morales (UEA), Robert Field (JIC), Pingping Guan ( JIC), Richard Morris (JIC), Martin Rejzek (JIC) and Mark Fidock (Pfizer) is published online on January 29 and in print on January 30.
Source: Simon Dunford, Press Officer
University of East Anglia
The scientists have identified a compound which, when introduced into Xenopus Laevis tadpoles, blocks the movement of the pigment cells that give the tadpoles their distinctive markings and which develop into the familiar greenish-brown of the adult frog.
It is the uncontrolled movement and growth of pigment cells (melanophore) in both tadpoles and humans that causes a particularly dangerous form of skin cancer. By blocking the migration of these cells, the development and spread of cancerous tumours can potentially be prevented.
Published in the Cell Press journal Chemistry & Biology, the findings are the culmination of several years' work by the UEA team. This unconventional study, which was initiated with funding from the UK Medical Research Council, identifies for the first time an effective new man-made MMP (metalloproteinase) inhibitor, known as 'NSC 84093'.
The work was led by the University of East Anglia, in partnership with the John Innes Centre (JIC) and Pfizer.
"This is an exciting advance with implications in the fight against cancer," said lead author Dr Grant Wheeler of UEA's School of Biological Sciences.
"The next step is to test the compound in other species and, in the longer term, embark on the development of new drugs to fight skin cancer in humans."
The species Xenopus Laevis (South African clawed frog) is more closely related to humans than one might expect. It only diverged from man 360 million years ago and has the same organs, molecules and physiology. This means that the same mechanisms are involved in causing cancer in both Xenopus tadpoles and humans.
Until the 1960s, Xenopus Laevis frogs were used as the main human pregnancy test. A woman's urine sample was injected into a live frog. If the urine contained the hCG (human chrionic gonadotropin) hormone, the frog would lay eggs within 24 hours, indicating that the woman was pregnant.
'A chemical genomic approach identifies matrix metallaoproteinases as playing an essential and specific role in Xenopus melanophore migration' by Grant Wheeler (UEA), Matthew Tomlinson (UEA), Carla Garcia-Morales (UEA), Robert Field (JIC), Pingping Guan ( JIC), Richard Morris (JIC), Martin Rejzek (JIC) and Mark Fidock (Pfizer) is published online on January 29 and in print on January 30.
Source: Simon Dunford, Press Officer
University of East Anglia
вторник, 26 апреля 2011 г.
Cell Movements Totally Modular, Stanford Study Shows
A study describing how cells within blood vessel walls move en masse overturns an assumption common in the age of genomics - that the proteins driving cell behavior are doing so much multitasking that it would be near impossible to group them according to a few discrete functions.
But now researchers at the Stanford University School of Medicine have shown that distinct groups of proteins each control one of four simple activities involved in the cells' collective migration. The findings will be published in the Dec. 1 issue of Genes and Development.
Graduate student Philip Vitorino, the study's first author, began the project in 2004 in the laboratory of senior author Tobias Meyer, PhD, professor of chemical and systems biology. The work is part of the Meyer lab's larger effort to find order in the overwhelming complexity of the inner workings of cells.
First they grew the cells (originally from umbilical cord tissue) into sheets and watched what happened when they scratched some of the cells away: They were looking to see the movements of individual cells and overall sheet movements as cells filled the open space.
"We stained the nuclei and took a movie under a microscope and watched what they did over a 15- to 20-hour period," said Vitorino. "That's when we noticed the cells moving inside the sheet, even in the absence of an open space. Not only were they moving, but they were moving in a flow-like pattern with neighboring cells moving as small collective groups. It looked like these groups were moving on invisible paths."
The cells moved at a rate of 10 microns an hour, pretty sprightly for a cell, Vitorino said. The researchers found they could break down movement into four processes: single cell movements, coordination of neighboring cells, directional sensing and cell division.
Vitorino went on to inactivate the more than 100 genes suspected of playing a role in controlling movement and watched how each change affected the cells' group behavior.
That's when he was able to show that the genes were acting in concert as distinct modules. "One hypothesis was, if you mess up one gene, everything gets messed up. That was a real possibility," said Vitorino. But he found that blocking a gene tended to disturb only one of the four processes - indicating a modular system at work.
"The cells don't need to activate and inactivate thousands of proteins to control sheet movements," Vitorino said. "Instead they simply coordinate the activity of four simple modules to generate efficient movements."
Vitorino also made some curious, though not immediately useful, observations about the impact of silencing genes for individual cells: "Some inactivations made them spiky, some made them long, some made them so they wouldn't stick together, some made them divide really fast, some, really slow," Vitorino said.
"The hardest part was organizing all of the data and making sense out of it," he added. Generating the data took only a year. Analyzing, retesting and making sense of these data took close to two more.
This discovery, at least in the case of blood vessel cell movement, marks a return to an earlier notion of modules in cell biology, prevalent before the 1990s and the advent of genomics, which led scientists to try to chart the individual actions of millions of genes.
Cell biologists have a penchant for comparing the cell's workings to auto mechanics and Vitorino is no exception. "Using the human genome, biochemical studies and proteomic approaches, scientists have generated a comprehensive list of parts and also some information about where the parts sit under the hood," he said.
"What we have done is organized these parts into those that are involved in generating forward movement, those that are important for steering, those that signal to other cars or those that are important for braking.
"Ultimately, this allows us to simplify very complex behaviors and provides a powerful tool for developing new therapeutics," said Vitorino. "With an understanding of the individual parts of the machine, it will be easier to effectively modify the system to change cell behaviors and ultimately treat human disease."
Notes:
This study was funded by the National Institutes of Health and the National Science Foundation Pre-Doctoral Fellowship Program.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital.
Source:
Rosanne Spector
Stanford University Medical Center
But now researchers at the Stanford University School of Medicine have shown that distinct groups of proteins each control one of four simple activities involved in the cells' collective migration. The findings will be published in the Dec. 1 issue of Genes and Development.
Graduate student Philip Vitorino, the study's first author, began the project in 2004 in the laboratory of senior author Tobias Meyer, PhD, professor of chemical and systems biology. The work is part of the Meyer lab's larger effort to find order in the overwhelming complexity of the inner workings of cells.
First they grew the cells (originally from umbilical cord tissue) into sheets and watched what happened when they scratched some of the cells away: They were looking to see the movements of individual cells and overall sheet movements as cells filled the open space.
"We stained the nuclei and took a movie under a microscope and watched what they did over a 15- to 20-hour period," said Vitorino. "That's when we noticed the cells moving inside the sheet, even in the absence of an open space. Not only were they moving, but they were moving in a flow-like pattern with neighboring cells moving as small collective groups. It looked like these groups were moving on invisible paths."
The cells moved at a rate of 10 microns an hour, pretty sprightly for a cell, Vitorino said. The researchers found they could break down movement into four processes: single cell movements, coordination of neighboring cells, directional sensing and cell division.
Vitorino went on to inactivate the more than 100 genes suspected of playing a role in controlling movement and watched how each change affected the cells' group behavior.
That's when he was able to show that the genes were acting in concert as distinct modules. "One hypothesis was, if you mess up one gene, everything gets messed up. That was a real possibility," said Vitorino. But he found that blocking a gene tended to disturb only one of the four processes - indicating a modular system at work.
"The cells don't need to activate and inactivate thousands of proteins to control sheet movements," Vitorino said. "Instead they simply coordinate the activity of four simple modules to generate efficient movements."
Vitorino also made some curious, though not immediately useful, observations about the impact of silencing genes for individual cells: "Some inactivations made them spiky, some made them long, some made them so they wouldn't stick together, some made them divide really fast, some, really slow," Vitorino said.
"The hardest part was organizing all of the data and making sense out of it," he added. Generating the data took only a year. Analyzing, retesting and making sense of these data took close to two more.
This discovery, at least in the case of blood vessel cell movement, marks a return to an earlier notion of modules in cell biology, prevalent before the 1990s and the advent of genomics, which led scientists to try to chart the individual actions of millions of genes.
Cell biologists have a penchant for comparing the cell's workings to auto mechanics and Vitorino is no exception. "Using the human genome, biochemical studies and proteomic approaches, scientists have generated a comprehensive list of parts and also some information about where the parts sit under the hood," he said.
"What we have done is organized these parts into those that are involved in generating forward movement, those that are important for steering, those that signal to other cars or those that are important for braking.
"Ultimately, this allows us to simplify very complex behaviors and provides a powerful tool for developing new therapeutics," said Vitorino. "With an understanding of the individual parts of the machine, it will be easier to effectively modify the system to change cell behaviors and ultimately treat human disease."
Notes:
This study was funded by the National Institutes of Health and the National Science Foundation Pre-Doctoral Fellowship Program.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital.
Source:
Rosanne Spector
Stanford University Medical Center
понедельник, 25 апреля 2011 г.
Rosalind Franklin University Cell Biology & Anatomy Professor's Results On Neural Plasticity
The Chicago
Medical School (CMS) of the Rosalind Franklin University of Medicine and
Science (RFUMS) today announced that Assistant Professor of Cell Biology &
Anatomy, Athanasios Tzounopoulos, has uncovered novel forms of synaptic
plasticity that occur at the very first step in the processing of sound in
the central nervous system. His findings are being released today in
Neuron, one of two leading journals in Neuroscience.
"The ability to observe synaptic plasticity and uncover its cellular
mechanisms at such an early, relatively unprocessed stage allows us to
study the role of these mechanisms in sensory processing," said Professor
Tzounopoulos. "Our findings also show that the brain is able to change
itself as a result of previous experience at places where processing is
much simpler and better understood. This new capability could have a
significant impact on our understanding and cures for disorders caused by
neural plasticity-like mechanisms," he added.
These findings may be relevant for understanding the mechanisms of
human tinnitus. Tinnitus is the perception of ringing, buzzing, roaring, or
other noises in the ears or head - when there is no external source of the
noise. It is estimated that more than 50 million Americans experience
tinnitus to some degree. Of these, about 12 million have tinnitus severe
enough to seek medical attention. Many learn to ignore the sounds and
experience no major effects. However, about two million patients are so
seriously debilitated that they cannot function normally, finding it
difficult to hear, work or sleep. Though research is providing more
evidence for the causes and treatments of tinnitus, there is no real
understanding of the biological bases of tinnitus, nor are there any
treatments that help most sufferers. Recent studies point to the central
nervous system as the site for the maintenance of tinnitus. Moreover,
animal models of tinnitus indicate a role for the dorsal cochlear nucleus
(DCN, an auditory brainstem nucleus), the brain area where Professor
Tzounopoulos performed his studies.
"It is quite possible that transient exposure to intense sound might
induce long-term changes in the balance of excitation and inhibition in the
DCN, through the mechanisms described in our recent findings. Our studies,
by providing a detailed understanding on how this plasticity is induced,
expressed, and modulated at the cellular level may ultimately lead to
treatments for tinnitus," said Professor Tzounopoulos.
According to these recent findings, newly formed hypotheses suggest
that concerted operation of different forms of synaptic plasticity gate
sensory activation of the DCN and can lead to activity-dependent modulation
of timing precision. Timing is an important feature in the brain and
especially in the auditory system. Many neurons in the auditory system are
known for their ability to fire action potentials that occur in a precise
temporal relationship to the stimulus (phase locking). Activity-dependent
modulation of spike timing precision through these mechanisms is a new
concept that may allow sensory systems to adapt to different patterns of
sensory activity and to properly integrate and encode varying sensory
stimuli.
Recent studies have shown that more robust and faithful brainstem
timing encoding is observed in trained individuals (musicians) compared to
untrained individuals (non-musicians). While these types of learning
phenomena have been attributed to cortical plasticity until now, our
studies suggest that the brainstem itself has the mechanisms and the
capability to support such learning. Similar studies have established that
brainstem timing precision serves as a reliable marker of individuals with
learning disabilities. Faulty mechanisms of neural timing at the brainstem
may be the biological basis of malfunction in children with learning
disabilities. "Therefore, elucidation of mechanisms underlying synaptic
plasticity and timing precision in the brainstem may provide the cellular
basis for these learning disabilities," said Professor Tzounopoulos.
Rosalind Franklin University of Medicine and Science educates medical
doctors, health professionals, and biomedical scientists in a personalized
atmosphere. The University is located at 3333 Green Bay Road, North
Chicago, IL 60064, and encompasses Chicago Medical School, College of
Health Professions, Dr. William M. Scholl College of Podiatric Medicine,
and School of Graduate and Postdoctoral Studies. Visit us at
rosalindfranklin and lifeindiscovery.
Rosalind Franklin University of Medicine and Science
rosalindfranklin
Medical School (CMS) of the Rosalind Franklin University of Medicine and
Science (RFUMS) today announced that Assistant Professor of Cell Biology &
Anatomy, Athanasios Tzounopoulos, has uncovered novel forms of synaptic
plasticity that occur at the very first step in the processing of sound in
the central nervous system. His findings are being released today in
Neuron, one of two leading journals in Neuroscience.
"The ability to observe synaptic plasticity and uncover its cellular
mechanisms at such an early, relatively unprocessed stage allows us to
study the role of these mechanisms in sensory processing," said Professor
Tzounopoulos. "Our findings also show that the brain is able to change
itself as a result of previous experience at places where processing is
much simpler and better understood. This new capability could have a
significant impact on our understanding and cures for disorders caused by
neural plasticity-like mechanisms," he added.
These findings may be relevant for understanding the mechanisms of
human tinnitus. Tinnitus is the perception of ringing, buzzing, roaring, or
other noises in the ears or head - when there is no external source of the
noise. It is estimated that more than 50 million Americans experience
tinnitus to some degree. Of these, about 12 million have tinnitus severe
enough to seek medical attention. Many learn to ignore the sounds and
experience no major effects. However, about two million patients are so
seriously debilitated that they cannot function normally, finding it
difficult to hear, work or sleep. Though research is providing more
evidence for the causes and treatments of tinnitus, there is no real
understanding of the biological bases of tinnitus, nor are there any
treatments that help most sufferers. Recent studies point to the central
nervous system as the site for the maintenance of tinnitus. Moreover,
animal models of tinnitus indicate a role for the dorsal cochlear nucleus
(DCN, an auditory brainstem nucleus), the brain area where Professor
Tzounopoulos performed his studies.
"It is quite possible that transient exposure to intense sound might
induce long-term changes in the balance of excitation and inhibition in the
DCN, through the mechanisms described in our recent findings. Our studies,
by providing a detailed understanding on how this plasticity is induced,
expressed, and modulated at the cellular level may ultimately lead to
treatments for tinnitus," said Professor Tzounopoulos.
According to these recent findings, newly formed hypotheses suggest
that concerted operation of different forms of synaptic plasticity gate
sensory activation of the DCN and can lead to activity-dependent modulation
of timing precision. Timing is an important feature in the brain and
especially in the auditory system. Many neurons in the auditory system are
known for their ability to fire action potentials that occur in a precise
temporal relationship to the stimulus (phase locking). Activity-dependent
modulation of spike timing precision through these mechanisms is a new
concept that may allow sensory systems to adapt to different patterns of
sensory activity and to properly integrate and encode varying sensory
stimuli.
Recent studies have shown that more robust and faithful brainstem
timing encoding is observed in trained individuals (musicians) compared to
untrained individuals (non-musicians). While these types of learning
phenomena have been attributed to cortical plasticity until now, our
studies suggest that the brainstem itself has the mechanisms and the
capability to support such learning. Similar studies have established that
brainstem timing precision serves as a reliable marker of individuals with
learning disabilities. Faulty mechanisms of neural timing at the brainstem
may be the biological basis of malfunction in children with learning
disabilities. "Therefore, elucidation of mechanisms underlying synaptic
plasticity and timing precision in the brainstem may provide the cellular
basis for these learning disabilities," said Professor Tzounopoulos.
Rosalind Franklin University of Medicine and Science educates medical
doctors, health professionals, and biomedical scientists in a personalized
atmosphere. The University is located at 3333 Green Bay Road, North
Chicago, IL 60064, and encompasses Chicago Medical School, College of
Health Professions, Dr. William M. Scholl College of Podiatric Medicine,
and School of Graduate and Postdoctoral Studies. Visit us at
rosalindfranklin and lifeindiscovery.
Rosalind Franklin University of Medicine and Science
rosalindfranklin
воскресенье, 24 апреля 2011 г.
Emerging Pathogens Revealed: Ticks, Flukes, And Genomics
Ehrlichiosis is no star of science. This emerging disease has an awkward name, vague flu-like symptoms, and a nasty habit of being caused by bacteria that live inside ticks and flatworms. But in the current issue of the journal Public Library of Science Genetics (PLoS Genetics), scientists put ehrlichiosis under the genomic spotlight--and discover some brilliant biology.
Led by scientists at The Institute for Genomic Research (TIGR) and The Ohio State University (OSU), a team of researchers report the complete genomes of three emerging pathogens that cause ehrlichiosis--Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia sennetsu--and compare the genomes with those of 16 other bacteria with similar lifestyles. The study reports new genes that allow the bacteria to evade a host's immune system, adapt to new niches, and more. Finally, the report reconstructs the metabolic potential of five representative genomes from these bacteria.
"By comparing so many different pathogens, some closely related and others diverse, we're able to identify genes linked to different diseases and organisms," explains molecular biologist Julie Dunning Hotopp of TIGR, first author of the PLoS Genetics paper. Because the pathogens causing ehrlichiosis are obligate intracellular bacteria--able to thrive only inside host cells--they are hard to isolate and study in the lab, Hotopp adds. "How are these diseases different? How are they the same? Can we correlate certain genes with certain characteristics? For the first time, our comparative genomics database offers a resource for tackling these questions."
Recognized since at least the 1930s, ehrlichiosis sickens not only humans, but also dogs, cattle, sheep, and other animals. In Japan, human ehrlichiosis is commonly called sennetsu fever. In the U.S., most human cases have been linked to ticks.
In the new study, scientists uncovered a clue to how ehrlichiosis-causing bacteria infect such diverse animals. One of the three primary bacteria sequenced, A. phagocytophilum, contains roughly 1,400 genes--including more than 100 variations of a single gene that codes for a protein allowing the bacteria to evade the immune system of the organism it has infected. This protein sits on the bacteria's outer membrane surface. When the bacteria, through tick bites, transfers to a human, say, or horse, the bacteria chooses the protein variation needed to stay hidden from that particular host.
"These genome sequences have revolutionized the types of experiments [scientists] can perform to understand these diseases," says microbiologist Yasuko Rikihisa of OSU's College of Veterinary Medicine. "Already, at least four labs are performing, or planning to perform, whole genome DNA microarray analysis and proteomic analysis of these bacteria."
In addition to comparing genomes, the current study used those genomes to reconstruct the metabolic potential (the ability to use and produce energy and compounds) of five bacteria, representing the numerous organisms compared. With this final analysis, they gleaned new insight into the broader tactics used by different bacteria. Ehrlichiosis pathogens, for instance, appear capable of making vitamins that a host tick lacks in its regular diet.
"This study is a beautiful example of how in-depth comparative genomics can lead to the identification of molecular features that underlie the lifestyle of pathogens," says TIGR molecular biologist Hervщ Tettelin, senior author of the PLoS Genetics article. "We could not have reached these conclusions by independently studying the genome sequence of each individual pathogen," he adds. "Now we know how some of the pathogens studied infect or provide benefits to their hosts."
The scientists hope to build on this work, with potential studies to determine which bacterial genes are turned on during ehrlichiosis infection and to track the evolutionary differences between ehrlichiosis-causing organisms in different parts of the world. Other scientists can build on the new work as well, by accessing the comparative database now online at tigr/sybil/rcd/. This genome sequencing project work was funded by the National Institutes of Health.
The Institute for Genomic Research is a not-for-profit center dedicated to deciphering and analyzing genomes. Since 1992, TIGR, based in Rockville, Md., has been a genomics leader, conducting research critical to medicine, agriculture, energy, the environment and biodefense.
Led by scientists at The Institute for Genomic Research (TIGR) and The Ohio State University (OSU), a team of researchers report the complete genomes of three emerging pathogens that cause ehrlichiosis--Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia sennetsu--and compare the genomes with those of 16 other bacteria with similar lifestyles. The study reports new genes that allow the bacteria to evade a host's immune system, adapt to new niches, and more. Finally, the report reconstructs the metabolic potential of five representative genomes from these bacteria.
"By comparing so many different pathogens, some closely related and others diverse, we're able to identify genes linked to different diseases and organisms," explains molecular biologist Julie Dunning Hotopp of TIGR, first author of the PLoS Genetics paper. Because the pathogens causing ehrlichiosis are obligate intracellular bacteria--able to thrive only inside host cells--they are hard to isolate and study in the lab, Hotopp adds. "How are these diseases different? How are they the same? Can we correlate certain genes with certain characteristics? For the first time, our comparative genomics database offers a resource for tackling these questions."
Recognized since at least the 1930s, ehrlichiosis sickens not only humans, but also dogs, cattle, sheep, and other animals. In Japan, human ehrlichiosis is commonly called sennetsu fever. In the U.S., most human cases have been linked to ticks.
In the new study, scientists uncovered a clue to how ehrlichiosis-causing bacteria infect such diverse animals. One of the three primary bacteria sequenced, A. phagocytophilum, contains roughly 1,400 genes--including more than 100 variations of a single gene that codes for a protein allowing the bacteria to evade the immune system of the organism it has infected. This protein sits on the bacteria's outer membrane surface. When the bacteria, through tick bites, transfers to a human, say, or horse, the bacteria chooses the protein variation needed to stay hidden from that particular host.
"These genome sequences have revolutionized the types of experiments [scientists] can perform to understand these diseases," says microbiologist Yasuko Rikihisa of OSU's College of Veterinary Medicine. "Already, at least four labs are performing, or planning to perform, whole genome DNA microarray analysis and proteomic analysis of these bacteria."
In addition to comparing genomes, the current study used those genomes to reconstruct the metabolic potential (the ability to use and produce energy and compounds) of five bacteria, representing the numerous organisms compared. With this final analysis, they gleaned new insight into the broader tactics used by different bacteria. Ehrlichiosis pathogens, for instance, appear capable of making vitamins that a host tick lacks in its regular diet.
"This study is a beautiful example of how in-depth comparative genomics can lead to the identification of molecular features that underlie the lifestyle of pathogens," says TIGR molecular biologist Hervщ Tettelin, senior author of the PLoS Genetics article. "We could not have reached these conclusions by independently studying the genome sequence of each individual pathogen," he adds. "Now we know how some of the pathogens studied infect or provide benefits to their hosts."
The scientists hope to build on this work, with potential studies to determine which bacterial genes are turned on during ehrlichiosis infection and to track the evolutionary differences between ehrlichiosis-causing organisms in different parts of the world. Other scientists can build on the new work as well, by accessing the comparative database now online at tigr/sybil/rcd/. This genome sequencing project work was funded by the National Institutes of Health.
The Institute for Genomic Research is a not-for-profit center dedicated to deciphering and analyzing genomes. Since 1992, TIGR, based in Rockville, Md., has been a genomics leader, conducting research critical to medicine, agriculture, energy, the environment and biodefense.
Delivering A Biochemical Payload To One Cell With Pinpoint Precision
Imagine being able to drop a toothpick on the head of one particular person standing among 100,000 people in a stadium. It sounds impossible, yet this degree of precision at the cellular level has been demonstrated by researchers affiliated with the Johns Hopkins University Institute for NanoBioTechnology. Their study was published online recently in Nature Nanotechnology.
The team used precise electrical fields as "tweezers" to guide and place gold nanowires, each about one-two hundredth the size of a cell, on predetermined spots, each on a single cell. Molecules coating the surfaces of the nanowires then triggered a biochemical cascade of actions only in the cell where the wire touched, without affecting other cells nearby. The researchers say this technique could lead to better ways of studying individual cells or even cell parts, and eventually could produce novel methods of delivering medication.
Indeed, the techniques not relying on this new nanowire-based technology either are not very precise, leading to stimulation of multiple cells, or require complex biochemical alterations of the cells.
With the new technique the researchers can, for instance, target cells that have cancer properties (higher cell division rate or abnormal morphology), while sparing their healthy neighbors.
"One of the biggest challenges in cell biology is the ability to manipulate the cell environment in as precise a way as possible," said principal investigator Andre Levchenko, an associate professor of biomedical engineering in Johns Hopkins' Whiting School of Engineering. In previous studies, Levchenko has used lab-on-a-chip or microfluidic devices to manipulate cell behavior. But, he said, lab-on-a-chip methods are not as precise as researchers would like them to be. "In microfluidic chips, if you alter the cell environment, it affects all the cells at the same time," he said.
Such is not the case with the gold nanowires, which are metallic cylinders a few hundred nanometers or smaller in diameter. Just as the unsuspecting sports spectator would feel only a light touch from a toothpick being dropped on the head, the cell reacts only to the molecules released from the nanowire in one very precise place where the wire touches the cell's surface.
With contributions from Chia-Ling Chien, a professor of physics and astronomy in the Krieger School of Arts and Sciences, and Robert Cammarata, a professor of materials science and engineering in the Whiting School, the team developed nanowires coated with a molecule called tumor necrosis factor-alpha (TNF-alpha), a substance released by pathogen-gobbling macrophages, commonly called white blood cells. Under certain cellular conditions, the presence of TNF-alpha triggers cells to switch on genes that help fight infection, but TNF-alpha also is capable of blocking tumor growth and halting viral replication.
Exposure to too much TNF-alpha, however, causes an organism to go into a potentially lethal state called septic shock, Levchenko said.
Fortunately, TNF-alpha stays put once it is released from the wire to the cell surface, and because the effect of TNF-alpha is localized, the tiny bit delivered by the wire is enough to trigger the desired cellular response. Much the same thing happens when TNF-alpha is excreted by a white blood cell.
Additionally, the coating of TNF-alpha gives the nanowire a negative charge, making the wire easier to maneuver via the two perpendicular electrical fields of the "tweezer" device, a technique developed by Donglei Fan as part of her Johns Hopkins doctoral research in materials science and engineering.
"The electric tweezers were initially developed to assemble, transport and rotate nanowires in solution," Cammarata said. "Donglei then showed how to use the tweezers to produce patterned nanowire arrays as well as construct nanomotors and nano-oscillators. This new work with Dr. Levchenko's group demonstrates just how extremely versatile a technique it is."
To test the system, the team cultured cervical cancer cells in a dish. Then, using electrical fields perpendicular to one another, they were able to zap the nanowires into a pre-set spot and plop them down in a precise location. "In this way, we can predetermine the path that the wires will travel and deliver a molecular payload to a single cell among many, and even to a specific part of the cell," Levchenko said.
During the course of this study, the team also established that the desired effect generated by the nanowire-delivered TNF-alpha was similar to that experienced by a cell in a living organism.
The team members envision many possibilities for this method of subcellular molecule delivery.
"For example, there are many other ways to trigger the release of the molecule from the wires: photo release, chemical release, temperature release. Furthermore, one could attach many molecules to the nanowires at the same time," Levchenko said. He added that the nanowires can be made much smaller, but said that for this study the wires were made large enough to see with optical microscopy.
Ultimately, Levchenko sees the nanowires becoming a useful tool for basic research.
"With these wires, we are trying to mimic the way that cells talk to each other," he said. "They could be a wonderful tool that could be used in fundamental or applied research." Drug delivery applications could be much further off. However, Levchenko said, "If the wires retain their negative charge, electrical fields could be used to manipulate and maneuver their position in the living tissue."
The lead author for this Nature Nanotechnology article was Fan, a former postdoctoral fellow in the departments of Materials Science and Engineering and Physics and Astronomy. Additional authors included Zhizhong Yin, a former postdoctoral fellow in the Department of Biomedical Engineering; Raymond Cheong, a doctoral student in the Department of Biomedical Engineering; and Frank Q. Zhu, a former doctoral student in the Department of Physics and Astronomy. The research was funded by the National Science Foundation and the National Institutes of Health.
Source:
Mary Spiro
Johns Hopkins University
The team used precise electrical fields as "tweezers" to guide and place gold nanowires, each about one-two hundredth the size of a cell, on predetermined spots, each on a single cell. Molecules coating the surfaces of the nanowires then triggered a biochemical cascade of actions only in the cell where the wire touched, without affecting other cells nearby. The researchers say this technique could lead to better ways of studying individual cells or even cell parts, and eventually could produce novel methods of delivering medication.
Indeed, the techniques not relying on this new nanowire-based technology either are not very precise, leading to stimulation of multiple cells, or require complex biochemical alterations of the cells.
With the new technique the researchers can, for instance, target cells that have cancer properties (higher cell division rate or abnormal morphology), while sparing their healthy neighbors.
"One of the biggest challenges in cell biology is the ability to manipulate the cell environment in as precise a way as possible," said principal investigator Andre Levchenko, an associate professor of biomedical engineering in Johns Hopkins' Whiting School of Engineering. In previous studies, Levchenko has used lab-on-a-chip or microfluidic devices to manipulate cell behavior. But, he said, lab-on-a-chip methods are not as precise as researchers would like them to be. "In microfluidic chips, if you alter the cell environment, it affects all the cells at the same time," he said.
Such is not the case with the gold nanowires, which are metallic cylinders a few hundred nanometers or smaller in diameter. Just as the unsuspecting sports spectator would feel only a light touch from a toothpick being dropped on the head, the cell reacts only to the molecules released from the nanowire in one very precise place where the wire touches the cell's surface.
With contributions from Chia-Ling Chien, a professor of physics and astronomy in the Krieger School of Arts and Sciences, and Robert Cammarata, a professor of materials science and engineering in the Whiting School, the team developed nanowires coated with a molecule called tumor necrosis factor-alpha (TNF-alpha), a substance released by pathogen-gobbling macrophages, commonly called white blood cells. Under certain cellular conditions, the presence of TNF-alpha triggers cells to switch on genes that help fight infection, but TNF-alpha also is capable of blocking tumor growth and halting viral replication.
Exposure to too much TNF-alpha, however, causes an organism to go into a potentially lethal state called septic shock, Levchenko said.
Fortunately, TNF-alpha stays put once it is released from the wire to the cell surface, and because the effect of TNF-alpha is localized, the tiny bit delivered by the wire is enough to trigger the desired cellular response. Much the same thing happens when TNF-alpha is excreted by a white blood cell.
Additionally, the coating of TNF-alpha gives the nanowire a negative charge, making the wire easier to maneuver via the two perpendicular electrical fields of the "tweezer" device, a technique developed by Donglei Fan as part of her Johns Hopkins doctoral research in materials science and engineering.
"The electric tweezers were initially developed to assemble, transport and rotate nanowires in solution," Cammarata said. "Donglei then showed how to use the tweezers to produce patterned nanowire arrays as well as construct nanomotors and nano-oscillators. This new work with Dr. Levchenko's group demonstrates just how extremely versatile a technique it is."
To test the system, the team cultured cervical cancer cells in a dish. Then, using electrical fields perpendicular to one another, they were able to zap the nanowires into a pre-set spot and plop them down in a precise location. "In this way, we can predetermine the path that the wires will travel and deliver a molecular payload to a single cell among many, and even to a specific part of the cell," Levchenko said.
During the course of this study, the team also established that the desired effect generated by the nanowire-delivered TNF-alpha was similar to that experienced by a cell in a living organism.
The team members envision many possibilities for this method of subcellular molecule delivery.
"For example, there are many other ways to trigger the release of the molecule from the wires: photo release, chemical release, temperature release. Furthermore, one could attach many molecules to the nanowires at the same time," Levchenko said. He added that the nanowires can be made much smaller, but said that for this study the wires were made large enough to see with optical microscopy.
Ultimately, Levchenko sees the nanowires becoming a useful tool for basic research.
"With these wires, we are trying to mimic the way that cells talk to each other," he said. "They could be a wonderful tool that could be used in fundamental or applied research." Drug delivery applications could be much further off. However, Levchenko said, "If the wires retain their negative charge, electrical fields could be used to manipulate and maneuver their position in the living tissue."
The lead author for this Nature Nanotechnology article was Fan, a former postdoctoral fellow in the departments of Materials Science and Engineering and Physics and Astronomy. Additional authors included Zhizhong Yin, a former postdoctoral fellow in the Department of Biomedical Engineering; Raymond Cheong, a doctoral student in the Department of Biomedical Engineering; and Frank Q. Zhu, a former doctoral student in the Department of Physics and Astronomy. The research was funded by the National Science Foundation and the National Institutes of Health.
Source:
Mary Spiro
Johns Hopkins University
суббота, 23 апреля 2011 г.
Scorpion Venom Could Be An Alternative To Morphine, TAU Research Suggests
Scorpion venom is notoriously poisonous - but it might be used as an alternative to dangerous and addictive painkillers like morphine, a Tel Aviv University researcher claims.
Prof. Michael Gurevitz of Tel Aviv University's Department of Plant Sciences is investigating new ways for developing a novel painkiller based on natural compounds found in the venom of scorpions. These compounds have gone through millions of years of evolution and some show high efficacy and specificity for certain components of the body with no side effects, he says.
Peptide toxins found in scorpion venom interact with sodium channels in nervous and muscular systems - and some of these sodium channels communicate pain, says Prof. Gurevitz. "The mammalian body has nine different sodium channels of which only a certain subtype delivers pain to our brain. We are trying to understand how toxins in the venom interact with sodium channels at the molecular level and particularly how some of the toxins differentiate among channel subtypes.
"If we figure this out, we may be able to slightly modify such toxins, making them more potent and specific for certain pain mediating sodium channels," Prof. Gurevitz continues. With this information, engineering of chemical derivatives that mimic the scorpion toxins would provide novel pain killers of high specificity that have no side effects.
An ancient Chinese secret?
In his research, Prof. Gurevitz is concentrating on the Israeli yellow scorpion, one of the most potent scorpions in the world. Its venom contains more than 300 peptides of which only a minor fraction has been explored. The reason for working with this venom, he says, is the large arsenal of active components such as the toxins that have diversified during hundreds of millions of years under selective pressure. During that process, some toxins have evolved with the capability to directly affect mammalian sodium channel subtypes whereas others recognize and affect sodium channels of invertebrates such as insects. This deviation in specificity is for us a lesson of how toxins may be manipulated at will by genetic engineering, he says.
While the use of scorpion venom to treat some body disorders seems counter-intuitive, the Chinese have recognized its effectiveness hundreds of years ago. "The Chinese, major practitioners of what we call 'alternative medicine,' use scorpion venom, believing it to have powerful analgesic properties," Prof. Gurevitz says. Some studies have also shown that scorpion venom can be used to treat epilepsy. "We study how these toxins pursue their effects in the Western sense to see how it could be applied as a potent painkiller."
Using an approach called "rational design" or "biomimicry," Prof. Gurevitz is trying to develop painkillers that mimic the venom's bioactive components. The idea is to use nature as the model, and to modify elements of the venom so that a future painkiller designed according to these toxins could be as effective as possible, while eliminating or reducing side effects.
No more morphine addicts
Finding a new and effective pain medication could solve one of the biggest problems in the medical world today. Pain is an important physiological response to danger, physical injury and poor health, yet doctors need to reduce extreme pain in patients which aspirin could never palliate. To date, opiate-derived painkillers have been quite effective, but the medical community is eager to find other solutions due to the risks associated with their use.
"This new class of drugs could be useful against serious burns and cuts, as well as in the military and in the aftermath of earthquakes and natural disasters. Instead of running the risk of addiction, this venom-derived drug, mimicking the small peptide toxin, would do what it needs to do and then pass from the body with no traces or side-effects," Prof. Gurevitz says.
Prof. Michael Gurevitz of Tel Aviv University's Department of Plant Sciences is investigating new ways for developing a novel painkiller based on natural compounds found in the venom of scorpions. These compounds have gone through millions of years of evolution and some show high efficacy and specificity for certain components of the body with no side effects, he says.
Peptide toxins found in scorpion venom interact with sodium channels in nervous and muscular systems - and some of these sodium channels communicate pain, says Prof. Gurevitz. "The mammalian body has nine different sodium channels of which only a certain subtype delivers pain to our brain. We are trying to understand how toxins in the venom interact with sodium channels at the molecular level and particularly how some of the toxins differentiate among channel subtypes.
"If we figure this out, we may be able to slightly modify such toxins, making them more potent and specific for certain pain mediating sodium channels," Prof. Gurevitz continues. With this information, engineering of chemical derivatives that mimic the scorpion toxins would provide novel pain killers of high specificity that have no side effects.
An ancient Chinese secret?
In his research, Prof. Gurevitz is concentrating on the Israeli yellow scorpion, one of the most potent scorpions in the world. Its venom contains more than 300 peptides of which only a minor fraction has been explored. The reason for working with this venom, he says, is the large arsenal of active components such as the toxins that have diversified during hundreds of millions of years under selective pressure. During that process, some toxins have evolved with the capability to directly affect mammalian sodium channel subtypes whereas others recognize and affect sodium channels of invertebrates such as insects. This deviation in specificity is for us a lesson of how toxins may be manipulated at will by genetic engineering, he says.
While the use of scorpion venom to treat some body disorders seems counter-intuitive, the Chinese have recognized its effectiveness hundreds of years ago. "The Chinese, major practitioners of what we call 'alternative medicine,' use scorpion venom, believing it to have powerful analgesic properties," Prof. Gurevitz says. Some studies have also shown that scorpion venom can be used to treat epilepsy. "We study how these toxins pursue their effects in the Western sense to see how it could be applied as a potent painkiller."
Using an approach called "rational design" or "biomimicry," Prof. Gurevitz is trying to develop painkillers that mimic the venom's bioactive components. The idea is to use nature as the model, and to modify elements of the venom so that a future painkiller designed according to these toxins could be as effective as possible, while eliminating or reducing side effects.
No more morphine addicts
Finding a new and effective pain medication could solve one of the biggest problems in the medical world today. Pain is an important physiological response to danger, physical injury and poor health, yet doctors need to reduce extreme pain in patients which aspirin could never palliate. To date, opiate-derived painkillers have been quite effective, but the medical community is eager to find other solutions due to the risks associated with their use.
"This new class of drugs could be useful against serious burns and cuts, as well as in the military and in the aftermath of earthquakes and natural disasters. Instead of running the risk of addiction, this venom-derived drug, mimicking the small peptide toxin, would do what it needs to do and then pass from the body with no traces or side-effects," Prof. Gurevitz says.
пятница, 22 апреля 2011 г.
Eradicating Insomnia In The Over 55's
If you're over 55 and have spent more than a few sleepless nights, you're not alone -- insomnia affects about half of all people over 55 -- but you may also be at increased risk for physical and mental ailments.
Many older adults don't get enough restorative sleep, leading to serious health concerns, including cardiovascular disease, obesity, diabetes, memory problems and increased rates of depression. Unfortunately, current sleeping pills are associated with memory problems, a risk for falls, dependency, withdrawal symptoms and disturbed sleeping patterns.
Circadin, a new drug developed at Tel Aviv University by Prof. Nava Zisapel, a chemist and neurobiologist from TAU's George S. Wise Faculty of Life Sciences, may help America's aging baby boomers get the much-needed sleep they need. Recent results from Prof. Zisapel's research with Circadin appear in the Journal of Sleep Research and are reviewed in Aging Health.
How the Body Tells Time
Prof. Zisapel's research centers on the hormone melatonin, which affects the way our biological functions differentiate between day and night. "As we age, the melatonin hormone signal weakens," says Prof. Zisapel. "As a result, our bodies and brains feel less difference between day and night."
Exacerbating the effect of low melatonin levels, aging people tend to sleep in a less organized fashion than younger people, Prof. Zisapel explains. "People are sleeping in front of the TV, or nodding off during conversations, and taking long afternoon naps. This leads to less sleep at night. In a way, their sleep habits become more like babies', and less like those of healthy adults who sleep in consolidated periods during the night."
Mimicking the profile of nighttime melatonin found in our bodies, Circadin replenishes the much-needed hormone, which declines steadily with age. Clinical trials in the United States and Europe found that Circadin improves sleep quality and morning alertness, and helps those 55 and over get a better night's sleep.
Her new drug therapy "improves sleep and daytime vigilance, helping to re-organize the circadian system, the body's internal clock," Prof. Zisapel says. Added benefits include more normalized blood pressure and blood sugar levels at night. The formulation also has a profound effect on the blind, whose biological clock is disturbed because they can't see light, a trigger for synchronizing with the external day/night cycle.
Advice for Sound Sleep Hygiene
Until Circadin is available in the United States, there are some simple steps seniors can take to get a good night's sleep, Prof. Zisapel says. Spending a couple of hours outdoors every day can help. Sipping lattes on a cafe patio (away from direct sunlight) can be pleasurable, and increases the exposure to natural light from the blue-green spectrum. Experiencing a full spectrum of light during the day could also be beneficial, as is routine exercise and avoiding daytime naps and sleeping in front of the TV.
Prof. Zisapel is the past director of the Adams Brain Research Center at Tel Aviv University and is the Chief Scientific Officer of Neurim Pharmaceuticals, a company commercializing the technology and licensing it from Ramot, the technology transfer arm of Tel Aviv University. The new drug is currently available in Europe, and is expected to be in the United States by next year.
American Friends of Tel Aviv University (aftau/) supports Israel's largest and most comprehensive center of higher learning. It is ranked among the world's top 100 universities in science, biomedical studies, and social science, and rated one of the world's top 200 universities overall. Internationally recognized for the scope and groundbreaking nature of its research programs, Tel Aviv University consistently produces work with profound implications for the future.
Many older adults don't get enough restorative sleep, leading to serious health concerns, including cardiovascular disease, obesity, diabetes, memory problems and increased rates of depression. Unfortunately, current sleeping pills are associated with memory problems, a risk for falls, dependency, withdrawal symptoms and disturbed sleeping patterns.
Circadin, a new drug developed at Tel Aviv University by Prof. Nava Zisapel, a chemist and neurobiologist from TAU's George S. Wise Faculty of Life Sciences, may help America's aging baby boomers get the much-needed sleep they need. Recent results from Prof. Zisapel's research with Circadin appear in the Journal of Sleep Research and are reviewed in Aging Health.
How the Body Tells Time
Prof. Zisapel's research centers on the hormone melatonin, which affects the way our biological functions differentiate between day and night. "As we age, the melatonin hormone signal weakens," says Prof. Zisapel. "As a result, our bodies and brains feel less difference between day and night."
Exacerbating the effect of low melatonin levels, aging people tend to sleep in a less organized fashion than younger people, Prof. Zisapel explains. "People are sleeping in front of the TV, or nodding off during conversations, and taking long afternoon naps. This leads to less sleep at night. In a way, their sleep habits become more like babies', and less like those of healthy adults who sleep in consolidated periods during the night."
Mimicking the profile of nighttime melatonin found in our bodies, Circadin replenishes the much-needed hormone, which declines steadily with age. Clinical trials in the United States and Europe found that Circadin improves sleep quality and morning alertness, and helps those 55 and over get a better night's sleep.
Her new drug therapy "improves sleep and daytime vigilance, helping to re-organize the circadian system, the body's internal clock," Prof. Zisapel says. Added benefits include more normalized blood pressure and blood sugar levels at night. The formulation also has a profound effect on the blind, whose biological clock is disturbed because they can't see light, a trigger for synchronizing with the external day/night cycle.
Advice for Sound Sleep Hygiene
Until Circadin is available in the United States, there are some simple steps seniors can take to get a good night's sleep, Prof. Zisapel says. Spending a couple of hours outdoors every day can help. Sipping lattes on a cafe patio (away from direct sunlight) can be pleasurable, and increases the exposure to natural light from the blue-green spectrum. Experiencing a full spectrum of light during the day could also be beneficial, as is routine exercise and avoiding daytime naps and sleeping in front of the TV.
Prof. Zisapel is the past director of the Adams Brain Research Center at Tel Aviv University and is the Chief Scientific Officer of Neurim Pharmaceuticals, a company commercializing the technology and licensing it from Ramot, the technology transfer arm of Tel Aviv University. The new drug is currently available in Europe, and is expected to be in the United States by next year.
American Friends of Tel Aviv University (aftau/) supports Israel's largest and most comprehensive center of higher learning. It is ranked among the world's top 100 universities in science, biomedical studies, and social science, and rated one of the world's top 200 universities overall. Internationally recognized for the scope and groundbreaking nature of its research programs, Tel Aviv University consistently produces work with profound implications for the future.
четверг, 21 апреля 2011 г.
Sex Based Prenatal Brain Differences Found
Prenatal sex-based biological differences extend to genetic expression in cerebral cortices. The differences in question are probably associated with later divergences in how our brains develop. This is shown by a new study by Uppsala University researchers Elena Jazin and Bj├╢rn Reinius, which has been published in the latest issue of the journal Molecular Psychiatry.
Professor Elena Jazin and doctoral student Bj├╢rn Reinius at the Department of Physiology and Developmental Biology previously demonstrated that genetic expression in the cerebral cortices of human beings and other primates exhibits certain sex-based differences. It is presumed that these differences are very old and have survived the evolutionary process. The purpose of the new study was to determine whether they appear during the process of brain development or first upon the conclusion of that process. Identifying the initial genetic mechanisms that prompt the brain to develop in a female or male direction is a long-range research objective.
The Uppsala University researchers analysed data, on the basis of sex, from another extensive study of the prenatal human brain.
"The results show that many of the genes situated on the Y chromosome are expressed in various parts of the brain prior to birth and probably provide a developmental basis for the sex-based differences exhibited by adult brains," according to Elena Jazin.
More than a third of Y-chromosomal genes appear to be involved in sex-based human brain differentiation. Some of the genetic activity in question is evident in the adult brain, while other of it only appears at earlier stages of brain development. It is yet unknown whether the differences in genetic expression among female and male brains have any functional significance.
"The findings are consistent with other factors, such as environment, also playing a role in how we develop," emphasizes Elena Jazin.
Knowledge of the development of sex-based brain differences is of potential significance for the treatment of brain disturbances and diseases. A large number of psychiatric illnesses, including depression and autism, affect men and women differentially.
"Taking account of sex-based differences is crucial to the study of normal and abnormal brain activity," according to Elena Jazin.
Professor Elena Jazin and doctoral student Bj├╢rn Reinius at the Department of Physiology and Developmental Biology previously demonstrated that genetic expression in the cerebral cortices of human beings and other primates exhibits certain sex-based differences. It is presumed that these differences are very old and have survived the evolutionary process. The purpose of the new study was to determine whether they appear during the process of brain development or first upon the conclusion of that process. Identifying the initial genetic mechanisms that prompt the brain to develop in a female or male direction is a long-range research objective.
The Uppsala University researchers analysed data, on the basis of sex, from another extensive study of the prenatal human brain.
"The results show that many of the genes situated on the Y chromosome are expressed in various parts of the brain prior to birth and probably provide a developmental basis for the sex-based differences exhibited by adult brains," according to Elena Jazin.
More than a third of Y-chromosomal genes appear to be involved in sex-based human brain differentiation. Some of the genetic activity in question is evident in the adult brain, while other of it only appears at earlier stages of brain development. It is yet unknown whether the differences in genetic expression among female and male brains have any functional significance.
"The findings are consistent with other factors, such as environment, also playing a role in how we develop," emphasizes Elena Jazin.
Knowledge of the development of sex-based brain differences is of potential significance for the treatment of brain disturbances and diseases. A large number of psychiatric illnesses, including depression and autism, affect men and women differentially.
"Taking account of sex-based differences is crucial to the study of normal and abnormal brain activity," according to Elena Jazin.
среда, 20 апреля 2011 г.
Journal Of Neurodevelopmental Disorders Added To Springer's Biomedical Journal Portfolio
Springer is launching the Journal of Neurodevelopmental Disorders to complement its portfolio of biomedical journals. Published quarterly, it will be available in both online and print formats beginning March 2009. Target audiences will include both researchers and clinicians interested in an integrated, interdisciplinary perspective on the pathogenesis and treatment of neurodevelopmental disorders.
The Journal of Neurodevelopmental Disorders is aimed at integrating current, cutting-edge research across a number of disciplines - neurobiology, genetics, cognitive neuroscience and psychology - and disorders. The primary focus will be on pathogenesis: that is, the study of the origin and development of a disease or disorder. Treatment studies which lead to new insights about the pathogenesis of neurodevelopmental disorders will be relevant subjects for this publication. An international editorial board will support Editor-in-Chief Dr. Joseph Piven of the University of North Carolina at Chapel Hill.
Ann Avouris, Editor, Neuroscience, at Springer, said, "I am proud to welcome the journal into our portfolio of groundbreaking publications in translational research. The Journal of Neurodevelopmental Disorders will support and promote interdisciplinary research into such disorders as autism, Fragile X Syndrome and tuberous sclerosis, helping to bridge the gap between basic research and treatment in these critical areas."
Dr. Joseph Piven, Editor-in-Chief, said, "Progress in understanding the pathogenesis of complex neurodevelopmental disorders will require an interdisciplinary perspective that juxtaposes a number of disorders to tease apart common and unique aspects of their phenomenology and underlying mechanisms. The Journal of Neurodevelopmental Disorders will provide a forum for this research."
The Journal of Neurodevelopmental Disorders will be available in print and on Springer's online platform springerlink/. All articles will be published online via Online First™ before they appear in print, thereby ensuring rapid dissemination of papers to the scientific community. The journal will include Cross Reference Linking and ToC Alerts, a feature by which subscribers receive the table of contents by email weeks in advance of the new issue. All authors, via the Springer Open Choice™ program, will have the option of publishing their articles using the open access publishing model.
Springer (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.
Journal of Neurodevelopmental Disorders ISSN: 1866-1947 (print version) ISSN: 186
The Journal of Neurodevelopmental Disorders is aimed at integrating current, cutting-edge research across a number of disciplines - neurobiology, genetics, cognitive neuroscience and psychology - and disorders. The primary focus will be on pathogenesis: that is, the study of the origin and development of a disease or disorder. Treatment studies which lead to new insights about the pathogenesis of neurodevelopmental disorders will be relevant subjects for this publication. An international editorial board will support Editor-in-Chief Dr. Joseph Piven of the University of North Carolina at Chapel Hill.
Ann Avouris, Editor, Neuroscience, at Springer, said, "I am proud to welcome the journal into our portfolio of groundbreaking publications in translational research. The Journal of Neurodevelopmental Disorders will support and promote interdisciplinary research into such disorders as autism, Fragile X Syndrome and tuberous sclerosis, helping to bridge the gap between basic research and treatment in these critical areas."
Dr. Joseph Piven, Editor-in-Chief, said, "Progress in understanding the pathogenesis of complex neurodevelopmental disorders will require an interdisciplinary perspective that juxtaposes a number of disorders to tease apart common and unique aspects of their phenomenology and underlying mechanisms. The Journal of Neurodevelopmental Disorders will provide a forum for this research."
The Journal of Neurodevelopmental Disorders will be available in print and on Springer's online platform springerlink/. All articles will be published online via Online First™ before they appear in print, thereby ensuring rapid dissemination of papers to the scientific community. The journal will include Cross Reference Linking and ToC Alerts, a feature by which subscribers receive the table of contents by email weeks in advance of the new issue. All authors, via the Springer Open Choice™ program, will have the option of publishing their articles using the open access publishing model.
Springer (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.
Journal of Neurodevelopmental Disorders ISSN: 1866-1947 (print version) ISSN: 186
вторник, 19 апреля 2011 г.
Researchers Discover And Manipulate Molecular Interplay That Moves Cancer Cells
Based on research that reveals new insight into mechanisms that allow invasive tumor cells to move, researchers at the Mayo Clinic campus in Florida have a new understanding about how to stop cancer from spreading. A cancer that spreads elsewhere in the body, known as metastasis, is the process that most often leads to death from the disease.
In the March 29 online issue of Nature Cell Biology, researchers say that a molecule known as protein kinase D1 (PKD1) is key to the ability of a tumor cell to "remodel" its structure, enabling it to migrate and invade. The researchers found that if PKD1 is active, tumor cells cannot move, a finding they say explains why PKD1 is silenced in some invasive cancers.
During metastasis, invasive cancer cells respond to biological signals to move away from a primary tumor. Multiple research groups at Mayo Clinic in Florida are especially interested in this process. One team, led by cancer biologist Peter Storz, Ph.D., has been investigating a process known as actin remodeling at the leading edge - the most forward point - of these migrating tumor cells.
"The events that reorganize the actin cytoskeleton at the leading edge are complex a multitude of molecules act in concert," Dr. Storz says. "But it appears that PKD1 must be turned off if cancer cells are to migrate."
Actin filaments help make up the cytoskeleton of cells. For cancer cells to move, the actin-based cell structure has to be continually reorganized, Dr. Storz says, and to do this, new actin filaments need to be generated to shift the cell forward.
Dr. Storz' group discovered that PKD1 was critical to this process. The researchers found that PKD1 inhibits another protein known as slingshot, which regulates the severing of existing actin structures so that new actin filaments can be synthesized, an event that is essential for cell movement.
The researchers used methods to deplete tumor cells of PKD1 and found that their motility increased. They then expressed activated PKD1 in tumor cells and found that movement was blocked. PKD1 is therefore a negative regulator of directed cell migration, and if PKD1 is not expressed in tumor cells, slingshot will become active and will contribute to the reorganization of actin, and a tumor cell will move, according to researchers.
"This makes sense, because other investigators have found that PKD1 is down-regulated, or turned off, in invasive forms of gastric, prostate, and breast cancer," says Dr. Storz.
So far, investigators have identified a number of players along the pathways that regulate cancer cell movement, from the molecule (RhoaA) that activates PKD1, to the well-known protein (cofilin) that disassembles actin filaments and which is regulated by slingshot. When PKD1 is activated, cofilin does not function and so the cell cannot move.
"Now that we have identified PKD1 as key regulator in processes regulating actin-based directed tumor cell movement, we can begin to think about designing treatments to stop invasive cancer cells from metastasizing," says Dr. Storz. "The basic mechanisms we have uncovered are key to developing those strategies."
Co-authors include Tim Eiseler, Ph.D., Heike Döppler, and Irene Yan from the Mayo Clinic Department of Cancer Biology; and Kanae Kitatani, Ph.D., and Kensaku Mizuno, Ph.D., from the Graduate School of Life Sciences at Tohoku University in Japan.
The study was funded by Mayo Foundation and the Mayo Comprehensive Cancer Center, the National Cancer Institute, a 'Friends for an Earlier Breast Cancer Test' Grant, and by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Mayo Clinic
200 First St. SW
Rochester
MN 55902
United States
mayoclinic
In the March 29 online issue of Nature Cell Biology, researchers say that a molecule known as protein kinase D1 (PKD1) is key to the ability of a tumor cell to "remodel" its structure, enabling it to migrate and invade. The researchers found that if PKD1 is active, tumor cells cannot move, a finding they say explains why PKD1 is silenced in some invasive cancers.
During metastasis, invasive cancer cells respond to biological signals to move away from a primary tumor. Multiple research groups at Mayo Clinic in Florida are especially interested in this process. One team, led by cancer biologist Peter Storz, Ph.D., has been investigating a process known as actin remodeling at the leading edge - the most forward point - of these migrating tumor cells.
"The events that reorganize the actin cytoskeleton at the leading edge are complex a multitude of molecules act in concert," Dr. Storz says. "But it appears that PKD1 must be turned off if cancer cells are to migrate."
Actin filaments help make up the cytoskeleton of cells. For cancer cells to move, the actin-based cell structure has to be continually reorganized, Dr. Storz says, and to do this, new actin filaments need to be generated to shift the cell forward.
Dr. Storz' group discovered that PKD1 was critical to this process. The researchers found that PKD1 inhibits another protein known as slingshot, which regulates the severing of existing actin structures so that new actin filaments can be synthesized, an event that is essential for cell movement.
The researchers used methods to deplete tumor cells of PKD1 and found that their motility increased. They then expressed activated PKD1 in tumor cells and found that movement was blocked. PKD1 is therefore a negative regulator of directed cell migration, and if PKD1 is not expressed in tumor cells, slingshot will become active and will contribute to the reorganization of actin, and a tumor cell will move, according to researchers.
"This makes sense, because other investigators have found that PKD1 is down-regulated, or turned off, in invasive forms of gastric, prostate, and breast cancer," says Dr. Storz.
So far, investigators have identified a number of players along the pathways that regulate cancer cell movement, from the molecule (RhoaA) that activates PKD1, to the well-known protein (cofilin) that disassembles actin filaments and which is regulated by slingshot. When PKD1 is activated, cofilin does not function and so the cell cannot move.
"Now that we have identified PKD1 as key regulator in processes regulating actin-based directed tumor cell movement, we can begin to think about designing treatments to stop invasive cancer cells from metastasizing," says Dr. Storz. "The basic mechanisms we have uncovered are key to developing those strategies."
Co-authors include Tim Eiseler, Ph.D., Heike Döppler, and Irene Yan from the Mayo Clinic Department of Cancer Biology; and Kanae Kitatani, Ph.D., and Kensaku Mizuno, Ph.D., from the Graduate School of Life Sciences at Tohoku University in Japan.
The study was funded by Mayo Foundation and the Mayo Comprehensive Cancer Center, the National Cancer Institute, a 'Friends for an Earlier Breast Cancer Test' Grant, and by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Mayo Clinic
200 First St. SW
Rochester
MN 55902
United States
mayoclinic
Cancer Research Taking The Main Stage At Baylor University
Two Baylor University faculty members are working to create and test dozens of new cancer fighting compounds that disrupt solid cancer tumors and target any remaining tumor cells that may grow after the tumor is treated. In another project, two Baylor adjunct faculty members and a Baylor graduate student are developing vaccines against melanoma. These are just two examples of some of the latest cancer research projects faculty and students are involved with at Baylor and at Baylor's Institute of Biomedical Studies.
With more than 30 students and more than 40 faculty and adjunct faculty members, Baylor's Institute of Biomedical Studies is an interdisciplinary program in biomedical-related areas of science leading to the doctoral degree. The program combines graduate students with an extremely diverse faculty who are actively involved in basic and translational research, both at Baylor University in Waco and at the Baylor University Medical Center (BUMC) in Dallas.
Cancer research funding comes from numerous public and private outlets, including one project that is looking into two main kinds of tumor-starving compounds, which has resulted in several patents for several Baylor professors like Dr. Kevin Pinney, professor of chemistry at Baylor. In Pinney's research, he and his team are creating new bioreductive compounds that take advantage of the lack of oxygen in the tumor. These compounds damage the tumor's DNA, so the tumor can not divide effectively. In another project, Baylor researchers are working to create a new type of Vascular Disrupting Agent. VDAs target the flow of blood to solid cancer tumors and other abnormal blood vessels while leaving healthy cells intact.
Baylor University
One Bear Pl. #97024
Waco, TX 76798-7024
United States
baylor
With more than 30 students and more than 40 faculty and adjunct faculty members, Baylor's Institute of Biomedical Studies is an interdisciplinary program in biomedical-related areas of science leading to the doctoral degree. The program combines graduate students with an extremely diverse faculty who are actively involved in basic and translational research, both at Baylor University in Waco and at the Baylor University Medical Center (BUMC) in Dallas.
Cancer research funding comes from numerous public and private outlets, including one project that is looking into two main kinds of tumor-starving compounds, which has resulted in several patents for several Baylor professors like Dr. Kevin Pinney, professor of chemistry at Baylor. In Pinney's research, he and his team are creating new bioreductive compounds that take advantage of the lack of oxygen in the tumor. These compounds damage the tumor's DNA, so the tumor can not divide effectively. In another project, Baylor researchers are working to create a new type of Vascular Disrupting Agent. VDAs target the flow of blood to solid cancer tumors and other abnormal blood vessels while leaving healthy cells intact.
Baylor University
One Bear Pl. #97024
Waco, TX 76798-7024
United States
baylor
New System Gives Improved Gene Technology Analysis
A patent for a system that gives more reliable results in gene technology-based diagnostic tests has been granted to researchers at the Norwegian Institute of Public Health (NIPH).
Gene technology analysis is used increasingly in diagnostic tests for detection of minute amounts of cells, bacteria and viruses in biological samples. However, false positive or negative results may occur.
"To uncover false negative results, an internal control reagent can be included in the tests to verify that the analysis results are valid. The problem with the internal controls used in today's analyses is that they can only be added during, or at the end of the analysis process. This means that quality assurance is incomplete," explains Einar Sverre Berg at the Department for Virology.
Together with colleague Kjell Skaug he invented a protective shell for the internal control, based on cell/virus-mimicking liposomes. The liposome/internal control particles can thus be mixed with the biological test material when the sample is taken and be present during the entire analytical process. Whole process quality assurance is thereby achieved with more reliable results.
Chlamydia test first
Berg and Skaug were among the first in the world to show that restrictive substances in urine samples are an important source of false negative results in gene technology-based chlamydia tests. The scientists recognised the problem with incomplete quality assurance, and invented the solution for the tests.
"A fantastic property of the system is that it isn't limited to just one test. It can be used in any gene technology-based assay detecting biologically substances. The liposome can be tailored and adapted according to the target - be it a virus or bacterium. The potential, in other words, is enormous," says Berg.
Berg and his colleague have applied for a patent on their discovery in all industrialised countries and have established the company IC Particles AS. Patents were first granted in New Zealand and Australia, followed by Norway. Berg is also optimistic about getting a patent in the USA within this year.
"Without the NIPH's goodwill and patience it is likely that the IC Particle's invention would not have been developed," concludes Einar Sverre Berg.
Source: Media contact
Norwegian Institute of Public Health
Gene technology analysis is used increasingly in diagnostic tests for detection of minute amounts of cells, bacteria and viruses in biological samples. However, false positive or negative results may occur.
"To uncover false negative results, an internal control reagent can be included in the tests to verify that the analysis results are valid. The problem with the internal controls used in today's analyses is that they can only be added during, or at the end of the analysis process. This means that quality assurance is incomplete," explains Einar Sverre Berg at the Department for Virology.
Together with colleague Kjell Skaug he invented a protective shell for the internal control, based on cell/virus-mimicking liposomes. The liposome/internal control particles can thus be mixed with the biological test material when the sample is taken and be present during the entire analytical process. Whole process quality assurance is thereby achieved with more reliable results.
Chlamydia test first
Berg and Skaug were among the first in the world to show that restrictive substances in urine samples are an important source of false negative results in gene technology-based chlamydia tests. The scientists recognised the problem with incomplete quality assurance, and invented the solution for the tests.
"A fantastic property of the system is that it isn't limited to just one test. It can be used in any gene technology-based assay detecting biologically substances. The liposome can be tailored and adapted according to the target - be it a virus or bacterium. The potential, in other words, is enormous," says Berg.
Berg and his colleague have applied for a patent on their discovery in all industrialised countries and have established the company IC Particles AS. Patents were first granted in New Zealand and Australia, followed by Norway. Berg is also optimistic about getting a patent in the USA within this year.
"Without the NIPH's goodwill and patience it is likely that the IC Particle's invention would not have been developed," concludes Einar Sverre Berg.
Source: Media contact
Norwegian Institute of Public Health
Duluth Foundation For Advancing Non-Animal Tests Receives $120,000 From PETA
PETA have donated $120,000 to the Duluth-based International QSAR Foundation to Reduce Animal Testing, to further its important work aimed at improving toxicity testing and saving the lives of millions of animals who are routinely maimed and killed in laboratory experiments. PETA presented the check at the McKim Conference yesterday, September 25, at the Inn on Lake Superior in Duluth. The annual McKim Conference provides a stimulating environment for scientists, regulators, and other stakeholders to identify scientific barriers to intelligent testing paradigms and to discuss critical pathways of research to overcome those barriers. The International QSAR Foundation then facilitates special projects to develop the proposed solutions.
Under the direction of founder Dr. Gilman Veith -- a pioneer of a technology known as quantitative structure-activity relationship (QSAR) -- the foundation's work holds promise for greatly reducing the number of animals used in chemical safety testing by developing databases and computer modeling tools that increase the accuracy of QSAR models. QSAR methodology uses mathematical modeling of the structure of chemicals to determine their levels of toxicity. This "virtual testing" will also improve the development of in vitro methods -- producing results that are faster, more accurate, less expensive, and far more humane than animal tests.
The foundation's work is being applied to major testing methods required by the Food and Drug Administration, the Environmental Protection Service, and international regulatory testing agencies and include acute and chronic oral, dermal, and inhalation toxicity, all of which cause extreme pain and suffering to the animals used. This work is fundamental to enacting the vision for a more intelligent and humane toxicity testing strategy that was set forth recently in a landmark report by the National Academy of Sciences.
"Minimizing animal testing is an important national goal, much like putting a man on the moon was in the 1960s," said Veith. "While we committed public money to create the technology for flying to the moon, there has been little public funding for the QSAR technology that eliminates the need for the animal tests used back in the 1960s. The Foundation is grateful to PETA for supporting this science and hopes the chemical industry and our government will do likewise."
In recent years, PETA has donated $760,000 toward the development of alternatives to animal testing. This award is funded by the estate of former Memphis resident Lavelle Shaw Brooks, who made a bequest dedicated to the development of alternatives to animal testing.
"Not only is testing toxic substances on animals cruel, it's also bad science," says PETA Director Jessica Sandler. "We hope that our gift to the International QSAR Foundation will be an incentive for others in the scientific community to move away from outdated, ineffective, and cruel animal testing."
For more information, please visit PETA's Web site StopAnimalTests. To learn more about the International QSAR Foundation, please visit QSARI.
Source: Holly Beal
People for the Ethical Treatment of Animals
Under the direction of founder Dr. Gilman Veith -- a pioneer of a technology known as quantitative structure-activity relationship (QSAR) -- the foundation's work holds promise for greatly reducing the number of animals used in chemical safety testing by developing databases and computer modeling tools that increase the accuracy of QSAR models. QSAR methodology uses mathematical modeling of the structure of chemicals to determine their levels of toxicity. This "virtual testing" will also improve the development of in vitro methods -- producing results that are faster, more accurate, less expensive, and far more humane than animal tests.
The foundation's work is being applied to major testing methods required by the Food and Drug Administration, the Environmental Protection Service, and international regulatory testing agencies and include acute and chronic oral, dermal, and inhalation toxicity, all of which cause extreme pain and suffering to the animals used. This work is fundamental to enacting the vision for a more intelligent and humane toxicity testing strategy that was set forth recently in a landmark report by the National Academy of Sciences.
"Minimizing animal testing is an important national goal, much like putting a man on the moon was in the 1960s," said Veith. "While we committed public money to create the technology for flying to the moon, there has been little public funding for the QSAR technology that eliminates the need for the animal tests used back in the 1960s. The Foundation is grateful to PETA for supporting this science and hopes the chemical industry and our government will do likewise."
In recent years, PETA has donated $760,000 toward the development of alternatives to animal testing. This award is funded by the estate of former Memphis resident Lavelle Shaw Brooks, who made a bequest dedicated to the development of alternatives to animal testing.
"Not only is testing toxic substances on animals cruel, it's also bad science," says PETA Director Jessica Sandler. "We hope that our gift to the International QSAR Foundation will be an incentive for others in the scientific community to move away from outdated, ineffective, and cruel animal testing."
For more information, please visit PETA's Web site StopAnimalTests. To learn more about the International QSAR Foundation, please visit QSARI.
Source: Holly Beal
People for the Ethical Treatment of Animals
Cryptic Preference For MHC-Dissimilar Females In Male Red Junglefowl, Gallus Gallus
The functional significance of partner choice remains puzzling. One hypothesis that is attracting increasing interest proposes that, because individuals that are more genetically diverse are often able to recognise and combat a wider range of pathogens, preference for genetically compatible partners should evolve to promote offspring genetic diversity.
A number of studies have tested this idea in females, but few have investigated or controlled for corresponding preferences in males. In this study, we address this gap by focusing on partner similarity at the Major Histocompatibility Complex (MHC), a key gene complex in vertebrate immune function. We experimentally tested whether male red junglefowl, Gallus gallus, prefer MHC-dissimilar females.
While we found that males were as likely to copulate with MHC-similar as with MHC-dissimilar females, they allocated more sperm to the most MHC-dissimilar of two sequentially presented females.
These results provide the first experimental evidence that males might respond to the MHC similarity of a female through differential ejaculate expenditure. The present study demonstrates the need to experimentally disentangle male and female effects when studying preferences for genetically compatible partners.
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.
Proceedings of the Royal Society B: Biological Sciences
A number of studies have tested this idea in females, but few have investigated or controlled for corresponding preferences in males. In this study, we address this gap by focusing on partner similarity at the Major Histocompatibility Complex (MHC), a key gene complex in vertebrate immune function. We experimentally tested whether male red junglefowl, Gallus gallus, prefer MHC-dissimilar females.
While we found that males were as likely to copulate with MHC-similar as with MHC-dissimilar females, they allocated more sperm to the most MHC-dissimilar of two sequentially presented females.
These results provide the first experimental evidence that males might respond to the MHC similarity of a female through differential ejaculate expenditure. The present study demonstrates the need to experimentally disentangle male and female effects when studying preferences for genetically compatible partners.
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.
Proceedings of the Royal Society B: Biological Sciences
Scientists Closer To Finding Treatment For Life-threatening Hereditary Disease
Scientists at Royal Holloway, University of London have reported encouraging results in a new gene-based therapy for Duchenne Muscular dystrophy (DMD) which at present has no known cure and affects one in 3,000 young boys.
All the muscular dystrophies are caused by faults in genes passed on by parents to their children and they cause progressive muscle weakness because muscle cells break down and are gradually lost. The Duchenne type affects only boys and those affected develop the first signs of difficulty in walking at the age of one to three years.
The research, led by Professor George Dickson from the School of Biological Sciences at Royal Holloway, involved a new genetic therapy called exon skipping, which was tested in an experimental model of the debilitating muscle disease. As a result of the treatment there was a remarkable and long-term improvement in the symptoms of the disease.
Exon skipping is a gene therapy approach that is currently in clinical trial for DMD and involves short strands of synthetic DNA known as an 'antisense oligonucleotide' which can be considered a sort of 'molecular patches'. The treatment can restore production of the protein dystrophin (which is missing in boys with DMD) and works by masking the faulty part of the dystrophin gene, allowing a shortened but functional dystrophin protein to be produced. It is thought that this method could potentially transform the symptoms of the severe Duchenne form of muscular dystrophy to those akin to the much milder so-called 'Becker' muscular dystrophy.
This study provides further evidence of the potential of this technique for treating DMD. There are currently clinical trials in progress in the UK and the Netherlands testing slightly different forms of the molecular patches which are producing promising initial results. Professor Dickson commented, "Duchenne dystrophy is very serious inherited disorder which affects 1 in 3,000 boys from age four onwards. It is a progressive and severe muscle wasting disease which is currently untreatable. These latest exciting and encouraging results suggest that current ongoing clinical trials of exon skipping in muscular dystrophy patients have great promise as a long-term treatment."
The research, published in Molecular Therapy, is part-funded by the Muscular Dystrophy Campaign. Director of Research at the Muscular Dystrophy Campaign, Dr Marita Pohlschmidt said: "Finding the right dose of this new potential drug is key to its success and we are proud that the research we fund continues to shed light on this. Professor Dickson's work has provided us with a good indication of what dose might be effective to improve muscle function in boys with Duchenne muscular dystrophy and we hope that these results are confirmed in clinical trials."
Sources: Royal Holloway University of London, AlphaGalileo Foundation.
All the muscular dystrophies are caused by faults in genes passed on by parents to their children and they cause progressive muscle weakness because muscle cells break down and are gradually lost. The Duchenne type affects only boys and those affected develop the first signs of difficulty in walking at the age of one to three years.
The research, led by Professor George Dickson from the School of Biological Sciences at Royal Holloway, involved a new genetic therapy called exon skipping, which was tested in an experimental model of the debilitating muscle disease. As a result of the treatment there was a remarkable and long-term improvement in the symptoms of the disease.
Exon skipping is a gene therapy approach that is currently in clinical trial for DMD and involves short strands of synthetic DNA known as an 'antisense oligonucleotide' which can be considered a sort of 'molecular patches'. The treatment can restore production of the protein dystrophin (which is missing in boys with DMD) and works by masking the faulty part of the dystrophin gene, allowing a shortened but functional dystrophin protein to be produced. It is thought that this method could potentially transform the symptoms of the severe Duchenne form of muscular dystrophy to those akin to the much milder so-called 'Becker' muscular dystrophy.
This study provides further evidence of the potential of this technique for treating DMD. There are currently clinical trials in progress in the UK and the Netherlands testing slightly different forms of the molecular patches which are producing promising initial results. Professor Dickson commented, "Duchenne dystrophy is very serious inherited disorder which affects 1 in 3,000 boys from age four onwards. It is a progressive and severe muscle wasting disease which is currently untreatable. These latest exciting and encouraging results suggest that current ongoing clinical trials of exon skipping in muscular dystrophy patients have great promise as a long-term treatment."
The research, published in Molecular Therapy, is part-funded by the Muscular Dystrophy Campaign. Director of Research at the Muscular Dystrophy Campaign, Dr Marita Pohlschmidt said: "Finding the right dose of this new potential drug is key to its success and we are proud that the research we fund continues to shed light on this. Professor Dickson's work has provided us with a good indication of what dose might be effective to improve muscle function in boys with Duchenne muscular dystrophy and we hope that these results are confirmed in clinical trials."
Sources: Royal Holloway University of London, AlphaGalileo Foundation.
Back To Basics: Simple Model Cell Is Key To Understanding Cell Complexity
A team of Penn State researchers has developed a simple artificial cell with which to investigate the organization and function of two of the most basic cell components: the cell membrane and the cytoplasm--the gelatinous fluid that surrounds the structures in living cells. The work could lead to the creation of new drugs that take advantage of properties of cell organization to prevent the development of diseases. The team's findings will be published later this month (late May 2008) in the Journal of the American Chemical Society.
"Many scientists are trying to understand cells by turning off genes, one at a time, and are observing the effects on cell function, but we're doing the opposite," said Associate Professor of Chemistry Christine D. Keating, who led the research. "We're starting from scratch, adding in components to find out what is needed to simulate the most basic cell functions. Our goal is to find out how much complexity can be observed in very simple collections of molecules."
Building on previous work that was published in the 16 January 2008 issue of Journal of the American Chemical Society, Keating and her colleagues built a model cell using as the cytoplasm a solution of two different polymers: polyethyleneglycol (PEG) and dextran. The researchers encapsulated this polymer solution inside a cell membrane and, because the two polymers do not mix, one of the phases surrounded the other like the white of an egg around a yolk. The team then exposed the cell to a concentrated solution of sugar. Through a process known as osmosis--in which water diffuses across a cell membrane from a region of higher water concentration to a region of lower water concentration--water traveled from the relatively diluted polymer solution inside the cell to the more concentrated sugar solution outside the cell. As a result, the volume of the polymer solution inside the membrane was reduced.
With a cell membrane that was now too large and also unconstrained by its spherical shape, the cell converted to a budded form. A dextran-rich mixture filled the bud while a PEG-rich mixture remained inside the body of the cell. This new structure exhibited the type of complexity that the team had been looking for; it exhibited polarity. "Polarity is critical to development," said Keating. "It is an important first step in the development of a complex multi-cellular organism, like a human being, in which different cells perform different functions."
In previous work, the team created a membrane that was entirely uniform, but in their most recent paper, they describe an asymmetric membrane containing a mixture of lipid molecules. Some of these lipid molecules contained tiny pieces of PEG, which interacted with the PEG in the cytoplasm, thus generating polarity in the model cell. "Our work demonstrated the interrelationship of the cytoplasm and the cell membrane," said Keating.
The team's next step is to create a cascade in polarity. "By creating a model cytoplasm with different compositions, we demonstrated that we can control the behavior of cell membranes," said Keating. "Now we want to find out what will happen if, for example, we add an enzyme whose activity depends on the compositions of the cytoplasm and cell membrane."
Although Keating and her colleagues plan to continue adding components to their model cell, they don't expect to make a real cell. "We aren't trying to generate life here. Rather, we want to understand the physical principles that govern biological systems," said Keating. "For me the big picture is trying to understand how the staggering complexity observed in biological systems might have arisen from seemingly simple chemical and physical principles."
The research team includes Ann-Sofie Cans, a former postdoctoral researcher in the Department of Chemistry who is now at Chalmers University of Technology in Sweden, and M. Scott Long and Meghan Andes, both graduate students in the Department of Chemistry. The work was supported primarily by a grant from the National Science Foundation and by the Arnold and Mabel Beckman Foundation.
Source: Barbara K. Kennedy
Penn State
"Many scientists are trying to understand cells by turning off genes, one at a time, and are observing the effects on cell function, but we're doing the opposite," said Associate Professor of Chemistry Christine D. Keating, who led the research. "We're starting from scratch, adding in components to find out what is needed to simulate the most basic cell functions. Our goal is to find out how much complexity can be observed in very simple collections of molecules."
Building on previous work that was published in the 16 January 2008 issue of Journal of the American Chemical Society, Keating and her colleagues built a model cell using as the cytoplasm a solution of two different polymers: polyethyleneglycol (PEG) and dextran. The researchers encapsulated this polymer solution inside a cell membrane and, because the two polymers do not mix, one of the phases surrounded the other like the white of an egg around a yolk. The team then exposed the cell to a concentrated solution of sugar. Through a process known as osmosis--in which water diffuses across a cell membrane from a region of higher water concentration to a region of lower water concentration--water traveled from the relatively diluted polymer solution inside the cell to the more concentrated sugar solution outside the cell. As a result, the volume of the polymer solution inside the membrane was reduced.
With a cell membrane that was now too large and also unconstrained by its spherical shape, the cell converted to a budded form. A dextran-rich mixture filled the bud while a PEG-rich mixture remained inside the body of the cell. This new structure exhibited the type of complexity that the team had been looking for; it exhibited polarity. "Polarity is critical to development," said Keating. "It is an important first step in the development of a complex multi-cellular organism, like a human being, in which different cells perform different functions."
In previous work, the team created a membrane that was entirely uniform, but in their most recent paper, they describe an asymmetric membrane containing a mixture of lipid molecules. Some of these lipid molecules contained tiny pieces of PEG, which interacted with the PEG in the cytoplasm, thus generating polarity in the model cell. "Our work demonstrated the interrelationship of the cytoplasm and the cell membrane," said Keating.
The team's next step is to create a cascade in polarity. "By creating a model cytoplasm with different compositions, we demonstrated that we can control the behavior of cell membranes," said Keating. "Now we want to find out what will happen if, for example, we add an enzyme whose activity depends on the compositions of the cytoplasm and cell membrane."
Although Keating and her colleagues plan to continue adding components to their model cell, they don't expect to make a real cell. "We aren't trying to generate life here. Rather, we want to understand the physical principles that govern biological systems," said Keating. "For me the big picture is trying to understand how the staggering complexity observed in biological systems might have arisen from seemingly simple chemical and physical principles."
The research team includes Ann-Sofie Cans, a former postdoctoral researcher in the Department of Chemistry who is now at Chalmers University of Technology in Sweden, and M. Scott Long and Meghan Andes, both graduate students in the Department of Chemistry. The work was supported primarily by a grant from the National Science Foundation and by the Arnold and Mabel Beckman Foundation.
Source: Barbara K. Kennedy
Penn State
The Starting Point Of Sun-Induced Skin Cancer Disovered By U Of Minnesota Researcher
According to a new study from the University of Minnesota, the earliest event in the development of sun-induced skin cancer may have been identified. The researchers found that the point of entry for skin cancer in response to sun exposure is in receptor molecules, molecular "hooks" on the outer surface of cells that also pull cannabinoid compounds found in marijuana out of the bloodstream. The research appears in Cancer Research.
"The question at the core of this research was, 'Why does ultraviolet light induce skin cancer?'" said lead researcher Zigang Dong, a professor of cellular and molecular biology and director of the university's Hormel Institute, which supported the study. "The idea is to find an agent that can prevent skin cancers after exposure to the sun."
The receptor molecules are protein structures that are components of cells's outer membranes. Acting like receiving docks, their function is to catch specific compounds from the blood and enable the cells to engulf or otherwise interact with the compounds. Receptors have been identified for many substances, including hormones and other chemical signals that regulate what cells do.
The researchers found that two receptors for cannabinoids also responded to UV light. They made the discovery during a search for the initial interaction between UV light and human skin cells.
The researchers began their search with plant cells because plants must interact with UV light in order to harness its energy for photosynthesis. They concluded that the UV receptors in plants ought to be similar to any found in humans, and, therefore, the genes for the plant and human receptors must also be similar. When they compared plant genes for UV receptors to human genetic material, they found that the human genes for cannabinoid receptors matched.
If cannabinoid receptors are important in the initiation of skin cancer by UV light, then animals that lack the receptors should be relatively protected from the ravages of the light. Working with mouse embryos, the researchers removed the genes for the cannabinoid receptors. They found that the skin of the resulting adult mice, which lacked the receptors, was resistant to the development of UV-induced inflammation and skin tumors called papillomas.
Also, when they exposed cannabinoid receptors to UV light, the receptors changed from an inactive to an active state, indicating they had absorbed and responded to the light.
Why should evolution have produced receptors that respond to both UV light and cannabinoids"
"That we don't know," said Dong.
The Hormel Institute is a collaborative research unit of the University of Minnesota and Mayo Clinic. The work was supported by the Hormel Foundation and the National Institutes of Health.
Source: Patty Mattern
University of Minnesota
"The question at the core of this research was, 'Why does ultraviolet light induce skin cancer?'" said lead researcher Zigang Dong, a professor of cellular and molecular biology and director of the university's Hormel Institute, which supported the study. "The idea is to find an agent that can prevent skin cancers after exposure to the sun."
The receptor molecules are protein structures that are components of cells's outer membranes. Acting like receiving docks, their function is to catch specific compounds from the blood and enable the cells to engulf or otherwise interact with the compounds. Receptors have been identified for many substances, including hormones and other chemical signals that regulate what cells do.
The researchers found that two receptors for cannabinoids also responded to UV light. They made the discovery during a search for the initial interaction between UV light and human skin cells.
The researchers began their search with plant cells because plants must interact with UV light in order to harness its energy for photosynthesis. They concluded that the UV receptors in plants ought to be similar to any found in humans, and, therefore, the genes for the plant and human receptors must also be similar. When they compared plant genes for UV receptors to human genetic material, they found that the human genes for cannabinoid receptors matched.
If cannabinoid receptors are important in the initiation of skin cancer by UV light, then animals that lack the receptors should be relatively protected from the ravages of the light. Working with mouse embryos, the researchers removed the genes for the cannabinoid receptors. They found that the skin of the resulting adult mice, which lacked the receptors, was resistant to the development of UV-induced inflammation and skin tumors called papillomas.
Also, when they exposed cannabinoid receptors to UV light, the receptors changed from an inactive to an active state, indicating they had absorbed and responded to the light.
Why should evolution have produced receptors that respond to both UV light and cannabinoids"
"That we don't know," said Dong.
The Hormel Institute is a collaborative research unit of the University of Minnesota and Mayo Clinic. The work was supported by the Hormel Foundation and the National Institutes of Health.
Source: Patty Mattern
University of Minnesota
Parkinson's Disease: Novel Drug Discovery Tool Could Identify Promising New Therapies
Researchers funded by the National Institutes of Health have turned simple baker's yeast into a virtual army of medicinal chemists capable of rapidly searching for drugs to treat Parkinson's disease.
In a study published online today Nature Chemical Biology, the researchers showed that they can rescue yeast cells from toxic levels of a protein implicated in Parkinson's disease by stimulating the cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson's disease.
"This biological approach to compound development opens up an entirely new direction for drug discovery, not only for Parkinson's disease, but theoretically for any disease where key aspects of the pathology can be reproduced in yeast," says Margaret Sutherland, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS). "A key step for the future will be to identify the cellular pathways that are affected by these cyclic peptides."
The research emerged from the lab of Susan Lindquist, Ph.D., a professor of biology at the Massachusetts Institute of Technology (MIT), a member of the Whitehead Institute for Biomedical Research, and a Howard Hughes Medical Institute investigator. Dr. Lindquist is also an investigator at the Massachusetts General Hospital (MGH)/MIT Morris K. Udall Center for Excellence in Parkinson's Research, one of 14 such centers funded by NINDS to develop treatment breakthroughs for Parkinson's disease. The study received additional funding from NIH's National Institute of Environmental Health Sciences, and from the Michael J. Fox Foundation and the American Parkinson's Disease Association.
Parkinson's disease attacks cells in a part of the brain responsible for motor control and coordination. As those neurons degenerate, the disease leads to progressive deterioration of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance. The neurons normally produce a chemical called dopamine. A synthetic precursor of dopamine called L-DOPA or drugs that mimic dopamine's action can provide symptomatic relief from Parkinson's disease. Unfortunately, these drugs lose much of their effectiveness in later stages of the disease, and there is currently no means to slow the disease's progressive course.
In most cases, the cause of Parkinson's disease is unknown, but there are recent, tantalizing clues. Investigators have discovered that vulnerable brain cells in patients with Parkinson's disease accumulate a protein called alpha-synuclein. Moreover, genetic abnormalities in alpha-synuclein cause a rare familial form of the disease. Dr. Lindquist and her team previously showed that when yeast cells are engineered to produce large amounts of human alpha-synuclein, they die.
In their new study, Dr. Lindquist and her team tested whether yeast could make cyclic peptides that would save them from alpha-synuclein's toxicity. Cyclic peptides are fragments of protein that connect end-to-end to form a circle. Although cyclic peptides are synthetic, they resemble structures that are found in natural proteins and protein-based drugs, including pain killers, antibiotics and immunosuppressants. Cyclic peptides that suppress alpha-synuclein toxicity could be candidate drugs for Parkinson's disease, or they could help researchers identify new drug targets for the disease.
"Our technique, which capitalizes on a long line of investigation in my lab, will lead to a whole new way to obtain small molecule tools useful for improving our understanding of disease mechanisms and for developing new therapies," says Dr. Lindquist. She notes that her lab and others have modeled many human diseases in yeast and in other kinds of cells.
Joshua Kritzer, Ph.D., a chemist and postdoctoral fellow in Dr. Lindquist's lab, designed and executed the cyclic peptide strategy. His procedure involves exposing yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, he flips the genetic switch that causes the cells to produce toxic levels of alpha-synuclein. If the yeast make cyclic peptides that suppress alpha-synuclein toxicity, they live; if not, they die. This simple assay enables testing millions of cyclic peptides simultaneously in millions of yeast cells. The process is extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs.
"We are making the yeast do a ton of work for us. They make the compounds and then they tell us which ones are functional," Dr. Kritzer says. Out of a library of 50 million cyclic peptides, only two saved the yeast from alpha-synuclein toxicity.
Dr. Lindquist's team collaborated with other researchers to test these two cyclic peptides in C. elegans, a millimeter-long worm with a small number of dopamine-producing neurons that are easy to examine and count. Those neurons are vulnerable to alpha-synuclein toxicity, but they were less vulnerable and more likely to survive in worms that were genetically modified to make either of the two cyclic peptides. Guy Caldwell, Ph.D., and Kim Caldwell, Ph.D., professors of biology at the University of Alabama in Tuscaloosa developed this C. elegans model, and performed the testing.
The researchers have not yet determined why the cyclic peptides are protective. They found that the cyclic peptides do not affect a system of transport inside cells known as vesicle trafficking - which was a surprise, since alpha-synuclein and other proteins that have been implicated in human Parkinson's disease are believed to play a role in vesicle trafficking. However, the researchers observed that the two peptides share a structure that may hold clues to their targets.
"This protein structure has important biological functions," says Dr. Kritzer. It is found in a class of antioxidant proteins known as thioredoxins, in proteins that shuttle metals around a cell, and in proteins that regulate gene activity. The connection to antioxidants and to metals ties into other lines of research. NINDS is currently supporting clinical trials in patients to test whether specific antioxidants slow the progression of Parkinson's disease. High doses of heavy metals such as lead, manganese, iron and mercury are known to be toxic to brain cells.
The researchers are conducting further experiments to explore how cyclic peptides prevent cell death. They are also adapting their system for making cyclic peptides so that it can be used in other cell types (including human cells) and other diseases.
Reference:
Kritzer JA et al. "Rapid Selection of Cyclic Peptides that Reduce alpha-Synuclein Toxicity in Yeast and Animal Models." Nature Chemical Biology, published online July 13, 2009.
Source:
Daniel Stimson
NIH/National Institute of Neurological Disorders and Stroke
In a study published online today Nature Chemical Biology, the researchers showed that they can rescue yeast cells from toxic levels of a protein implicated in Parkinson's disease by stimulating the cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson's disease.
"This biological approach to compound development opens up an entirely new direction for drug discovery, not only for Parkinson's disease, but theoretically for any disease where key aspects of the pathology can be reproduced in yeast," says Margaret Sutherland, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS). "A key step for the future will be to identify the cellular pathways that are affected by these cyclic peptides."
The research emerged from the lab of Susan Lindquist, Ph.D., a professor of biology at the Massachusetts Institute of Technology (MIT), a member of the Whitehead Institute for Biomedical Research, and a Howard Hughes Medical Institute investigator. Dr. Lindquist is also an investigator at the Massachusetts General Hospital (MGH)/MIT Morris K. Udall Center for Excellence in Parkinson's Research, one of 14 such centers funded by NINDS to develop treatment breakthroughs for Parkinson's disease. The study received additional funding from NIH's National Institute of Environmental Health Sciences, and from the Michael J. Fox Foundation and the American Parkinson's Disease Association.
Parkinson's disease attacks cells in a part of the brain responsible for motor control and coordination. As those neurons degenerate, the disease leads to progressive deterioration of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance. The neurons normally produce a chemical called dopamine. A synthetic precursor of dopamine called L-DOPA or drugs that mimic dopamine's action can provide symptomatic relief from Parkinson's disease. Unfortunately, these drugs lose much of their effectiveness in later stages of the disease, and there is currently no means to slow the disease's progressive course.
In most cases, the cause of Parkinson's disease is unknown, but there are recent, tantalizing clues. Investigators have discovered that vulnerable brain cells in patients with Parkinson's disease accumulate a protein called alpha-synuclein. Moreover, genetic abnormalities in alpha-synuclein cause a rare familial form of the disease. Dr. Lindquist and her team previously showed that when yeast cells are engineered to produce large amounts of human alpha-synuclein, they die.
In their new study, Dr. Lindquist and her team tested whether yeast could make cyclic peptides that would save them from alpha-synuclein's toxicity. Cyclic peptides are fragments of protein that connect end-to-end to form a circle. Although cyclic peptides are synthetic, they resemble structures that are found in natural proteins and protein-based drugs, including pain killers, antibiotics and immunosuppressants. Cyclic peptides that suppress alpha-synuclein toxicity could be candidate drugs for Parkinson's disease, or they could help researchers identify new drug targets for the disease.
"Our technique, which capitalizes on a long line of investigation in my lab, will lead to a whole new way to obtain small molecule tools useful for improving our understanding of disease mechanisms and for developing new therapies," says Dr. Lindquist. She notes that her lab and others have modeled many human diseases in yeast and in other kinds of cells.
Joshua Kritzer, Ph.D., a chemist and postdoctoral fellow in Dr. Lindquist's lab, designed and executed the cyclic peptide strategy. His procedure involves exposing yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, he flips the genetic switch that causes the cells to produce toxic levels of alpha-synuclein. If the yeast make cyclic peptides that suppress alpha-synuclein toxicity, they live; if not, they die. This simple assay enables testing millions of cyclic peptides simultaneously in millions of yeast cells. The process is extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs.
"We are making the yeast do a ton of work for us. They make the compounds and then they tell us which ones are functional," Dr. Kritzer says. Out of a library of 50 million cyclic peptides, only two saved the yeast from alpha-synuclein toxicity.
Dr. Lindquist's team collaborated with other researchers to test these two cyclic peptides in C. elegans, a millimeter-long worm with a small number of dopamine-producing neurons that are easy to examine and count. Those neurons are vulnerable to alpha-synuclein toxicity, but they were less vulnerable and more likely to survive in worms that were genetically modified to make either of the two cyclic peptides. Guy Caldwell, Ph.D., and Kim Caldwell, Ph.D., professors of biology at the University of Alabama in Tuscaloosa developed this C. elegans model, and performed the testing.
The researchers have not yet determined why the cyclic peptides are protective. They found that the cyclic peptides do not affect a system of transport inside cells known as vesicle trafficking - which was a surprise, since alpha-synuclein and other proteins that have been implicated in human Parkinson's disease are believed to play a role in vesicle trafficking. However, the researchers observed that the two peptides share a structure that may hold clues to their targets.
"This protein structure has important biological functions," says Dr. Kritzer. It is found in a class of antioxidant proteins known as thioredoxins, in proteins that shuttle metals around a cell, and in proteins that regulate gene activity. The connection to antioxidants and to metals ties into other lines of research. NINDS is currently supporting clinical trials in patients to test whether specific antioxidants slow the progression of Parkinson's disease. High doses of heavy metals such as lead, manganese, iron and mercury are known to be toxic to brain cells.
The researchers are conducting further experiments to explore how cyclic peptides prevent cell death. They are also adapting their system for making cyclic peptides so that it can be used in other cell types (including human cells) and other diseases.
Reference:
Kritzer JA et al. "Rapid Selection of Cyclic Peptides that Reduce alpha-Synuclein Toxicity in Yeast and Animal Models." Nature Chemical Biology, published online July 13, 2009.
Source:
Daniel Stimson
NIH/National Institute of Neurological Disorders and Stroke
9th Mycological Congress, August 1-6, 2010, Edinburgh
The British Mycological Society, in association with Elsevier, the world-leading publisher of scientific, technical and medical information, have announced the final programme for the 9th Mycological Congress IMC9: The Biology of Fungi. This congress takes place every 4 years at a different venue around the world.
Taking place at the Edinburgh International Conference Centre, a comprehensive programme encompasses the latest research in all areas of fungal biology. More than 300 oral presentations are arranged within 45 thematic symposia and supplemented by over 1000 posters, optional special interest group meetings, field trips and an exhibition. A complementary public exhibition, entitled 'From Another Kingdom', will be hosted at the Royal Botanic Gardens in Edinburgh during the Congress and later into Autumn 2010.
Fungal biology has never been as important in our everyday lives as it is today because of the commercial importance for biotechnology, medicine and the food industry. Fungi also provide a model for studying the eukaryotic mode of life. Further, fungi are crucial to the functioning of the ecosystems of our planet because of the role they play in decomposition and nutrient cycling. New areas of research will be reviewed within the following five main themes of the congress: Cell biology, biochemistry and physiology; Environment, ecology and interactions; Evolution, biodiversity and systematics; Fungal pathogenesis and disease control; Genomics, genetics and molecular biology.
Nick Read, Professor of Fungal Cell Biology at the University of Edinburgh and Chair of IMC9, is looking forward to the culmination of years of planning, "The UK has a long tradition of being at the forefront of international mycology and we are exceptionally pleased to welcome more than 1700 delegates from around the world to hear from an eminent line up of plenary speakers and to enjoy a wide ranging programme. Edinburgh has much to offer our delegates and we are looking forward to bringing the mycological community together to sample Edinburgh's fantastic arts festival and hospitality as well as the latest science."
The 9th Mycological Congress takes place at the Edinburgh Convention Centre in Edinburgh, UK, 1-6 August 2010. Full information is available here.
Source:
Nina Cosgrove
Elsevier
Taking place at the Edinburgh International Conference Centre, a comprehensive programme encompasses the latest research in all areas of fungal biology. More than 300 oral presentations are arranged within 45 thematic symposia and supplemented by over 1000 posters, optional special interest group meetings, field trips and an exhibition. A complementary public exhibition, entitled 'From Another Kingdom', will be hosted at the Royal Botanic Gardens in Edinburgh during the Congress and later into Autumn 2010.
Fungal biology has never been as important in our everyday lives as it is today because of the commercial importance for biotechnology, medicine and the food industry. Fungi also provide a model for studying the eukaryotic mode of life. Further, fungi are crucial to the functioning of the ecosystems of our planet because of the role they play in decomposition and nutrient cycling. New areas of research will be reviewed within the following five main themes of the congress: Cell biology, biochemistry and physiology; Environment, ecology and interactions; Evolution, biodiversity and systematics; Fungal pathogenesis and disease control; Genomics, genetics and molecular biology.
Nick Read, Professor of Fungal Cell Biology at the University of Edinburgh and Chair of IMC9, is looking forward to the culmination of years of planning, "The UK has a long tradition of being at the forefront of international mycology and we are exceptionally pleased to welcome more than 1700 delegates from around the world to hear from an eminent line up of plenary speakers and to enjoy a wide ranging programme. Edinburgh has much to offer our delegates and we are looking forward to bringing the mycological community together to sample Edinburgh's fantastic arts festival and hospitality as well as the latest science."
The 9th Mycological Congress takes place at the Edinburgh Convention Centre in Edinburgh, UK, 1-6 August 2010. Full information is available here.
Source:
Nina Cosgrove
Elsevier
Potential Cancer Drugs From Bacteria In Small Sea Life
Researchers led by a University of Utah medicinal chemist have developed a novel method to make drugs for cancer and other diseases from bacteria found in sponges and other small ocean creatures.
In a study published Sunday, Nov. 5, in Nature Chemical Biology online, researchers examined symbiotic bacteria that live only in sea squirts and other marine life. These bacteria are responsible for making a wealth of chemicals, which accumulate in the tissues of sea squirts and may help to defend them against predators. Many of these chemicals have anticancer properties, but harvesting them in quantities for large-scale testing and production has been impractical.
The new method uses genetic pathways in the bacteria to produce the small chemicals and to manipulate them to invent new potential drugs. The ability to make these chemicals in the laboratory opens myriad possibilities for developing drugs to fight cancer, HIV, and other diseases, according to Eric W. Schmidt, Ph.D., assistant professor of medicinal chemistry at the University of Utah College of Pharmacy and senior author on the study.
"This represents a new way of attacking the problem," Schmidt said. "We're hoping we can use this to find a way to make natural molecules of compounds through single mutations in DNA."
To synthesize natural compounds, researchers have traditionally made them in the lab using labor-intensive routes. More recently, researchers have begun to use genes to make small molecules within laboratory strains of bacteria. This genetic synthesis method is complicated because it's still difficult to understand how changing genes can lead to changes in small drug molecules.
"The promise of genes is that you can access the tremendous natural diversity of the world's organisms to find new natural compounds for human health," Schmidt said. "You can also use genetic engineering to modify these compounds and invent new drugs to target human diseases."
Sea squirts live with diverse bacteria that synthesize many small molecules. By examining the natural chemical and genetic diversity found in sea squirts and their symbionts, Schmidt and his colleagues from around the country identified individual mutations responsible for changing from one compound to another. By mimicking this natural process, the researchers synthesized a completely new compound. This paves the way to the genetic creation of large chemical libraries for testing against human diseases.
"This proves the concept works," Schmidt said. "We can extract bacteria from animals, take DNA from the bacteria, and produce compounds."
Now that they've shown compounds can be synthesized from DNA, the researchers want to figure out how to produce greater quantities of compounds for testing and drug development. E. coli is a good producer of compounds, but yields are not yet practical.
Contact Information: Eric W. Schmidt, Ph.D.
For the study, Schmidt obtained sample bacteria from 46 ascidians in the tropical Pacific Ocean near New Guinea.
Collaborators on the study include: Margo G. Haywood, from the Oregon Health Sciences University; Sebastian Sudek, from the Scripps Institution of Oceanography at the University of California, San Diego; M.J. Rosovitz and Jacques Ravel, both of the The Institute for Genomic Research, Rockville, Md.; Mohamed S. Donia and Brian J. Hathaway, both of the Department of Medicinal Chemistry, University of Utah College of Pharmacy.
Contact: Phil Sahm
University of Utah Health Sciences Center
In a study published Sunday, Nov. 5, in Nature Chemical Biology online, researchers examined symbiotic bacteria that live only in sea squirts and other marine life. These bacteria are responsible for making a wealth of chemicals, which accumulate in the tissues of sea squirts and may help to defend them against predators. Many of these chemicals have anticancer properties, but harvesting them in quantities for large-scale testing and production has been impractical.
The new method uses genetic pathways in the bacteria to produce the small chemicals and to manipulate them to invent new potential drugs. The ability to make these chemicals in the laboratory opens myriad possibilities for developing drugs to fight cancer, HIV, and other diseases, according to Eric W. Schmidt, Ph.D., assistant professor of medicinal chemistry at the University of Utah College of Pharmacy and senior author on the study.
"This represents a new way of attacking the problem," Schmidt said. "We're hoping we can use this to find a way to make natural molecules of compounds through single mutations in DNA."
To synthesize natural compounds, researchers have traditionally made them in the lab using labor-intensive routes. More recently, researchers have begun to use genes to make small molecules within laboratory strains of bacteria. This genetic synthesis method is complicated because it's still difficult to understand how changing genes can lead to changes in small drug molecules.
"The promise of genes is that you can access the tremendous natural diversity of the world's organisms to find new natural compounds for human health," Schmidt said. "You can also use genetic engineering to modify these compounds and invent new drugs to target human diseases."
Sea squirts live with diverse bacteria that synthesize many small molecules. By examining the natural chemical and genetic diversity found in sea squirts and their symbionts, Schmidt and his colleagues from around the country identified individual mutations responsible for changing from one compound to another. By mimicking this natural process, the researchers synthesized a completely new compound. This paves the way to the genetic creation of large chemical libraries for testing against human diseases.
"This proves the concept works," Schmidt said. "We can extract bacteria from animals, take DNA from the bacteria, and produce compounds."
Now that they've shown compounds can be synthesized from DNA, the researchers want to figure out how to produce greater quantities of compounds for testing and drug development. E. coli is a good producer of compounds, but yields are not yet practical.
Contact Information: Eric W. Schmidt, Ph.D.
For the study, Schmidt obtained sample bacteria from 46 ascidians in the tropical Pacific Ocean near New Guinea.
Collaborators on the study include: Margo G. Haywood, from the Oregon Health Sciences University; Sebastian Sudek, from the Scripps Institution of Oceanography at the University of California, San Diego; M.J. Rosovitz and Jacques Ravel, both of the The Institute for Genomic Research, Rockville, Md.; Mohamed S. Donia and Brian J. Hathaway, both of the Department of Medicinal Chemistry, University of Utah College of Pharmacy.
Contact: Phil Sahm
University of Utah Health Sciences Center
UK Sugar Study Is Sweetener For Stem Cell Science
Scientists at The University of Manchester are striving to discover how the body's natural sugars can be used to create stem cell treatments for heart disease and nerve damage - thanks to a 370,000 pound funding boost.
All cells that make up the tissues of the body - such as skin, liver, brain and blood - are surrounded by a layer of sugars that coat the cells.
These sugars help the cells to know what type of cell they are and to respond to the other cells which surround them and the chemical messages that pass between cells.
Now Dr Catherine Merry from The School of Materials has been awarded a prestigious New Investigator Research Grant by the Medical Research Council (MRC) to investigate how different cells make different sugar types and to test out theories on how sugars can influence cell behaviour.
Dr Merry, who is leading the research, said: "At present, the way in which cells make these sugars is not well understood. From the little we do know, we believe isolated fragments of these sugars could be used to instruct cells to behave in particular ways.
"We also think we might be able to force cells to make one particular type of sugar and not another, thereby influencing the way in which that cell grows and interacts with other cells.
"This work is important in helping us understand how the sugars made by the cells change during this process.
"We also believe our research might suggest how sugars can be used to help embryonic stem cells grow in the lab - or how they can be instructed to become cell types which could be of use in human therapies to treat problems with nerve, heart muscle or blood cells.
"Although the prospect of creating cells from embryonic stem cells for use in humans is still a considerable time away, research such as ours helps move towards this goal."
Dr Merry's research will take place over three years in newly refurbished high-tech laboratories in the Materials Science Centre at the University.
A recent ВЈ300,000 upgrade to five laboratories has led to a new biomaterials and tissue engineering research facility being established - and has helped transform what was a very small interest in The School of Materials into a major focus of future work.
The upgrade, funded by the Royal Society Wolfson Foundation, is paving the way for cutting-edge research in the fields of molecular biology, stem cell culture and nanofabrication,
A new confocal microscope that produces high-resolution 3D optical images has also been installed thanks to ВЈ250,000 funding from the Biotechnology and Biological Sciences Research Council (BBSRC).
The new labs in the Materials Science Centre form part of the UK Centre for Tissue Regeneration, which was established in 2006 with a ВЈ1.5 million grant from the Northwest Regional Development Agency and involves researchers from across the university
Source: Alex Waddington
University of Manchester
All cells that make up the tissues of the body - such as skin, liver, brain and blood - are surrounded by a layer of sugars that coat the cells.
These sugars help the cells to know what type of cell they are and to respond to the other cells which surround them and the chemical messages that pass between cells.
Now Dr Catherine Merry from The School of Materials has been awarded a prestigious New Investigator Research Grant by the Medical Research Council (MRC) to investigate how different cells make different sugar types and to test out theories on how sugars can influence cell behaviour.
Dr Merry, who is leading the research, said: "At present, the way in which cells make these sugars is not well understood. From the little we do know, we believe isolated fragments of these sugars could be used to instruct cells to behave in particular ways.
"We also think we might be able to force cells to make one particular type of sugar and not another, thereby influencing the way in which that cell grows and interacts with other cells.
"This work is important in helping us understand how the sugars made by the cells change during this process.
"We also believe our research might suggest how sugars can be used to help embryonic stem cells grow in the lab - or how they can be instructed to become cell types which could be of use in human therapies to treat problems with nerve, heart muscle or blood cells.
"Although the prospect of creating cells from embryonic stem cells for use in humans is still a considerable time away, research such as ours helps move towards this goal."
Dr Merry's research will take place over three years in newly refurbished high-tech laboratories in the Materials Science Centre at the University.
A recent ВЈ300,000 upgrade to five laboratories has led to a new biomaterials and tissue engineering research facility being established - and has helped transform what was a very small interest in The School of Materials into a major focus of future work.
The upgrade, funded by the Royal Society Wolfson Foundation, is paving the way for cutting-edge research in the fields of molecular biology, stem cell culture and nanofabrication,
A new confocal microscope that produces high-resolution 3D optical images has also been installed thanks to ВЈ250,000 funding from the Biotechnology and Biological Sciences Research Council (BBSRC).
The new labs in the Materials Science Centre form part of the UK Centre for Tissue Regeneration, which was established in 2006 with a ВЈ1.5 million grant from the Northwest Regional Development Agency and involves researchers from across the university
Source: Alex Waddington
University of Manchester
Gestational Diabetes And Menin Regulation Linked In Study By Stanford Researchers
A protein in the pancreas is giving researchers at the Stanford University School of Medicine their first chance at cracking the code that determines how diabetes develops during pregnancy, a finding that could lead to new treatments for all forms of diabetes.
The study may help explain why roughly 5 percent of women develop diabetes temporarily while pregnant, a condition called gestational diabetes. That condition is a leading cause of birth defects and can predispose the child to develop diabetes later in life.
"The basis of gestational diabetes has been a black box," said Seung Kim, MD, PhD, associate professor of developmental biology and senior author on the study. The results are published in the Nov. 2 issue of the journal Science.
The protein Kim and his colleagues studied, called menin, was already known to have a role in preventing cancer in the pancreas and other organs. When menin is present it blocks the growth of pancreatic cells and, in that way, prevents cancer.
However, cells of the hormone-producing part of the pancreas, called the islets, need to grow in pregnant women or when people gain weight as a way of providing enough insulin for the burgeoning supply of cells. The increase in pancreas islet cells provides the additional insulin needed for the cells of the body to take up sugar from the blood. After a pregnant woman delivers her child, the pancreatic islets return to their original size.
According to Kim's work in mice, the pancreas accomplishes that adaptive growth by producing less menin during pregnancy. With less of the brake present, the pancreatic islet cells can divide, and this growth provides the additional insulin. Within a week after delivery the menin levels in the mice were back up to normal and the pancreatic islets began shrinking to their original size.
When Kim and postdoctoral scholar Satyajit Karnik, PhD, first author of the study, created mice that produce too much menin, the islets couldn't grow sufficiently during pregnancy and the mice ended up with gestational diabetes.
"This suggests that there is an internal code for controlling pancreatic islet growth, a code we intend to crack," Kim said. That code appears to be regulated partly by the level of menin.
Kim's group also showed that a natural way of regulating the amount of menin present in the pancreas is through a hormone called prolactin, which is abundant in pregnant women. Other researchers had previously shown that prolactin during pregnancy stimulates the islet cells to start dividing, but how it accomplished this stimulation was unclear.
Kim and Karnik suspected menin might be the link other researchers had been looking for. To test that idea, they gave prolactin to nonpregnant mice. As predicted, menin levels dropped and the pancreas increased in size, mimicking what is seen during pregnancy.
Kim said that although most of this research relates to menin regulation during pregnancy, similar forces may be at work in obese adults with diabetes. He and Karnik found that obese mice have less menin in the pancreas than mice at a normal weight. That finding suggests that menin may have a central role in obesity-related diabetes as well.
Kim said prolactin may be just one way of regulating menin levels and as a result regulating pancreatic growth. Other hormones may be involved in increasing or decreasing menin in nonpregnant adults.
Understanding the mechanisms of regulating menin should lead to new ways of growing islets for transplantation into people with type-1 diabetes and could lead to new treatments for diabetes in pregnant women or obese adults, Kim said.
Gestational diabetes, which is on the rise nationwide, is becoming more recognized as a significant risk to mothers and their babies. Sen. Hillary Rodham Clinton, D-NY, recently cosponsored a bill aimed at devoting more funding to understanding, preventing and treating the disease.
The work was funded by a Kirschstein Postdoctoral Fellowship, the Stanford Regenerative Medicine Training Program, the Stanford Medical Scientist Training Program, the American Diabetes Association and the National Institutes of Health.
Other Stanford researchers involved in the study include postdoctoral scholars Hainan Chen, PhD, and Michael H. Yen, MD, PhD; research associate Graeme W. McLean; MD/PhD student Jeremy Heit; research assistant Xueying Gu; Andrew Zhang, and assistant professor of pathology Magali Fontaine, MD, PhD.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions -- Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Source: Amy Adams
Stanford University Medical Center
The study may help explain why roughly 5 percent of women develop diabetes temporarily while pregnant, a condition called gestational diabetes. That condition is a leading cause of birth defects and can predispose the child to develop diabetes later in life.
"The basis of gestational diabetes has been a black box," said Seung Kim, MD, PhD, associate professor of developmental biology and senior author on the study. The results are published in the Nov. 2 issue of the journal Science.
The protein Kim and his colleagues studied, called menin, was already known to have a role in preventing cancer in the pancreas and other organs. When menin is present it blocks the growth of pancreatic cells and, in that way, prevents cancer.
However, cells of the hormone-producing part of the pancreas, called the islets, need to grow in pregnant women or when people gain weight as a way of providing enough insulin for the burgeoning supply of cells. The increase in pancreas islet cells provides the additional insulin needed for the cells of the body to take up sugar from the blood. After a pregnant woman delivers her child, the pancreatic islets return to their original size.
According to Kim's work in mice, the pancreas accomplishes that adaptive growth by producing less menin during pregnancy. With less of the brake present, the pancreatic islet cells can divide, and this growth provides the additional insulin. Within a week after delivery the menin levels in the mice were back up to normal and the pancreatic islets began shrinking to their original size.
When Kim and postdoctoral scholar Satyajit Karnik, PhD, first author of the study, created mice that produce too much menin, the islets couldn't grow sufficiently during pregnancy and the mice ended up with gestational diabetes.
"This suggests that there is an internal code for controlling pancreatic islet growth, a code we intend to crack," Kim said. That code appears to be regulated partly by the level of menin.
Kim's group also showed that a natural way of regulating the amount of menin present in the pancreas is through a hormone called prolactin, which is abundant in pregnant women. Other researchers had previously shown that prolactin during pregnancy stimulates the islet cells to start dividing, but how it accomplished this stimulation was unclear.
Kim and Karnik suspected menin might be the link other researchers had been looking for. To test that idea, they gave prolactin to nonpregnant mice. As predicted, menin levels dropped and the pancreas increased in size, mimicking what is seen during pregnancy.
Kim said that although most of this research relates to menin regulation during pregnancy, similar forces may be at work in obese adults with diabetes. He and Karnik found that obese mice have less menin in the pancreas than mice at a normal weight. That finding suggests that menin may have a central role in obesity-related diabetes as well.
Kim said prolactin may be just one way of regulating menin levels and as a result regulating pancreatic growth. Other hormones may be involved in increasing or decreasing menin in nonpregnant adults.
Understanding the mechanisms of regulating menin should lead to new ways of growing islets for transplantation into people with type-1 diabetes and could lead to new treatments for diabetes in pregnant women or obese adults, Kim said.
Gestational diabetes, which is on the rise nationwide, is becoming more recognized as a significant risk to mothers and their babies. Sen. Hillary Rodham Clinton, D-NY, recently cosponsored a bill aimed at devoting more funding to understanding, preventing and treating the disease.
The work was funded by a Kirschstein Postdoctoral Fellowship, the Stanford Regenerative Medicine Training Program, the Stanford Medical Scientist Training Program, the American Diabetes Association and the National Institutes of Health.
Other Stanford researchers involved in the study include postdoctoral scholars Hainan Chen, PhD, and Michael H. Yen, MD, PhD; research associate Graeme W. McLean; MD/PhD student Jeremy Heit; research assistant Xueying Gu; Andrew Zhang, and assistant professor of pathology Magali Fontaine, MD, PhD.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions -- Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Source: Amy Adams
Stanford University Medical Center
Biotech Factories Created From Bacteria
High-throughput sequencing has turned biologists into voracious genome readers, enabling them to scan millions of DNA letters, or bases, per hour. When revising a genome, however, they struggle, suffering from serious writer's block, exacerbated by outdated cell programming technology. Labs get bogged down with particular DNA sentences, tinkering at times with subsections of a single gene ad nauseam before moving along to the next one.
A team has finally overcome this obstacle by developing a new cell programming method called Multiplex Automated Genome Engineering (MAGE). Published online in Nature, the platform promises to give biotechnology, in particular synthetic biology, a powerful boost.
Led by a pair of researchers in the lab of Harvard Medical School Professor of Genetics George Church, the team rapidly refined the design of a bacterium by editing multiple genes in parallel instead of targeting one gene at a time. They transformed self-serving E. coli cells into efficient factories that produce a desired compound, accomplishing in just three days a feat that would take most biotech companies months or years.
"We initiated the project to close the gap between DNA sequencing technology and cell programming technology," explains graduate student Harris Wang, the paper's co-first author.
"The goal was to use information gleaned from genetics and genomics to rapidly engineer new functions and improve existing functions in cells," adds postdoctoral researcher Farren Isaacs, the other first author. "We wanted to develop a new tool and demonstrate how to apply it; we were determined to hand labs a hammer and a nail."
The key was to break free of linear genetic engineering techniques and move beyond the serial manipulation of single genes.
The researchers selected a harmless strain of the intestinal nemesis E. coli and added a few genes to its solitary circular chromosome, coaxing the organism to produce lycopene, a powerful antioxidant that occurs naturally in tomatoes and other vegetables. Now they could focus on tweaking the cells to increase the yield of this compound.
Traditionally, labs would accomplish this type of transformation by using recombinant DNA technology, also known as gene cloning, a complicated technique that involves isolating, breaking up, reassembling, and then reinserting genes.
The Church lab researchers took a different approach, blending an engineer's logic with a biologist's appreciation for complexity. "Genes function in teams, not in isolation," says Wang. "Cloning often encourages us to ignore the interdependence of genes and oversimplify the cellular system. We might forget, for example, that one mutation can strengthen or weaken the effects of another mutation."
"It's nearly impossible to predict which combinations of mutations will confer the desired behavior," explains Isaacs. "Biology is so complex that we don't know the optimal solution."
So the team retooled evolution to generate genetic diversity at an unprecedented rate, increasing the odds of finding cells with desirable properties.
The E. coli bacterium contains approximately 4,500 genes. The team focused on 24 of these - honing a pathway with tremendous potential - to increase production of the antioxidant, optimizing the sequences simultaneously. They took the 24 DNA sequences, divided them up into manageable 90-letter segments, and modified each, generating a suite of genetic variants. Next, armed with specific sequences, the team enlisted a company to manufacture thousands of unique constructs. The team was then able to insert these new genetic constructs back into the cells, allowing the natural cellular machinery to absorb this revised genetic material.
Some bacteria ended up with one construct, some ended up with multiple constructs. The resulting pool contained an assortment of cells, some better at producing lycopene than others. The team extracted the best producers from the pool and repeated the process over and over to further hone the manufacturing machinery. To make things easier, the researchers automated all of these steps.
"We accelerated evolution, generating as many as 15 billion genetic variants in three days and increasing the yield of lycopene by 500 percent," Harris says. "Can you imagine how long it would take to generate 15 billion genetic variants with traditional cloning techniques? It would take years."
The pathway the team refined plays a role in the synthesis of many valuable compounds, ranging from hormones to antibiotics, so the reprogrammed bacteria can be used for a variety of purposes. In addition, the MAGE platform itself unlocks new possibilities.
"We decided to engineer in the context of biology, embracing evolution rather than trying to fit a square peg in a round hole," says Church. "This automated, multiplex technology will allow labs to engineer entire pathways and genomes and take cell programming to a whole new level."
This research is funded by NSF, DOE, DARPA, the Wyss Institute for Biologically Inspired Engineering, NIH and NDSEG.
Source:
Alyssa Kneller
Harvard Medical School
A team has finally overcome this obstacle by developing a new cell programming method called Multiplex Automated Genome Engineering (MAGE). Published online in Nature, the platform promises to give biotechnology, in particular synthetic biology, a powerful boost.
Led by a pair of researchers in the lab of Harvard Medical School Professor of Genetics George Church, the team rapidly refined the design of a bacterium by editing multiple genes in parallel instead of targeting one gene at a time. They transformed self-serving E. coli cells into efficient factories that produce a desired compound, accomplishing in just three days a feat that would take most biotech companies months or years.
"We initiated the project to close the gap between DNA sequencing technology and cell programming technology," explains graduate student Harris Wang, the paper's co-first author.
"The goal was to use information gleaned from genetics and genomics to rapidly engineer new functions and improve existing functions in cells," adds postdoctoral researcher Farren Isaacs, the other first author. "We wanted to develop a new tool and demonstrate how to apply it; we were determined to hand labs a hammer and a nail."
The key was to break free of linear genetic engineering techniques and move beyond the serial manipulation of single genes.
The researchers selected a harmless strain of the intestinal nemesis E. coli and added a few genes to its solitary circular chromosome, coaxing the organism to produce lycopene, a powerful antioxidant that occurs naturally in tomatoes and other vegetables. Now they could focus on tweaking the cells to increase the yield of this compound.
Traditionally, labs would accomplish this type of transformation by using recombinant DNA technology, also known as gene cloning, a complicated technique that involves isolating, breaking up, reassembling, and then reinserting genes.
The Church lab researchers took a different approach, blending an engineer's logic with a biologist's appreciation for complexity. "Genes function in teams, not in isolation," says Wang. "Cloning often encourages us to ignore the interdependence of genes and oversimplify the cellular system. We might forget, for example, that one mutation can strengthen or weaken the effects of another mutation."
"It's nearly impossible to predict which combinations of mutations will confer the desired behavior," explains Isaacs. "Biology is so complex that we don't know the optimal solution."
So the team retooled evolution to generate genetic diversity at an unprecedented rate, increasing the odds of finding cells with desirable properties.
The E. coli bacterium contains approximately 4,500 genes. The team focused on 24 of these - honing a pathway with tremendous potential - to increase production of the antioxidant, optimizing the sequences simultaneously. They took the 24 DNA sequences, divided them up into manageable 90-letter segments, and modified each, generating a suite of genetic variants. Next, armed with specific sequences, the team enlisted a company to manufacture thousands of unique constructs. The team was then able to insert these new genetic constructs back into the cells, allowing the natural cellular machinery to absorb this revised genetic material.
Some bacteria ended up with one construct, some ended up with multiple constructs. The resulting pool contained an assortment of cells, some better at producing lycopene than others. The team extracted the best producers from the pool and repeated the process over and over to further hone the manufacturing machinery. To make things easier, the researchers automated all of these steps.
"We accelerated evolution, generating as many as 15 billion genetic variants in three days and increasing the yield of lycopene by 500 percent," Harris says. "Can you imagine how long it would take to generate 15 billion genetic variants with traditional cloning techniques? It would take years."
The pathway the team refined plays a role in the synthesis of many valuable compounds, ranging from hormones to antibiotics, so the reprogrammed bacteria can be used for a variety of purposes. In addition, the MAGE platform itself unlocks new possibilities.
"We decided to engineer in the context of biology, embracing evolution rather than trying to fit a square peg in a round hole," says Church. "This automated, multiplex technology will allow labs to engineer entire pathways and genomes and take cell programming to a whole new level."
This research is funded by NSF, DOE, DARPA, the Wyss Institute for Biologically Inspired Engineering, NIH and NDSEG.
Source:
Alyssa Kneller
Harvard Medical School
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